TEM ELLS A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES
J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS
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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1
Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Stem Cells: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-84224-8 1. Stem Cells-Popular works. I. Title.
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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.
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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on stem cells. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.
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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.
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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health
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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON STEM CELLS .............................................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Stem Cells ..................................................................................... 5 E-Journals: PubMed Central ....................................................................................................... 61 The National Library of Medicine: PubMed ................................................................................ 69 CHAPTER 2. NUTRITION AND STEM CELLS................................................................................... 115 Overview.................................................................................................................................... 115 Finding Nutrition Studies on Stem Cells .................................................................................. 115 Federal Resources on Nutrition ................................................................................................. 118 Additional Web Resources ......................................................................................................... 119 CHAPTER 3. ALTERNATIVE MEDICINE AND STEM CELLS ............................................................ 121 Overview.................................................................................................................................... 121 National Center for Complementary and Alternative Medicine................................................ 121 Additional Web Resources ......................................................................................................... 131 General References ..................................................................................................................... 132 CHAPTER 4. DISSERTATIONS ON STEM CELLS .............................................................................. 135 Overview.................................................................................................................................... 135 Dissertations on Stem Cells ....................................................................................................... 135 Keeping Current ........................................................................................................................ 137 CHAPTER 5. CLINICAL TRIALS AND STEM CELLS ......................................................................... 139 Overview.................................................................................................................................... 139 Recent Trials on Stem Cells ....................................................................................................... 139 Keeping Current on Clinical Trials ........................................................................................... 163 CHAPTER 6. PATENTS ON STEM CELLS ......................................................................................... 165 Overview.................................................................................................................................... 165 Patents on Stem Cells ................................................................................................................ 165 Patent Applications on Stem Cells............................................................................................. 204 Keeping Current ........................................................................................................................ 244 CHAPTER 7. BOOKS ON STEM CELLS ............................................................................................. 245 Overview.................................................................................................................................... 245 Book Summaries: Federal Agencies............................................................................................ 245 Book Summaries: Online Booksellers......................................................................................... 246 Chapters on Stem Cells .............................................................................................................. 255 CHAPTER 8. PERIODICALS AND NEWS ON STEM CELLS ............................................................... 257 Overview.................................................................................................................................... 257 News Services and Press Releases.............................................................................................. 257 Newsletter Articles .................................................................................................................... 262 Academic Periodicals covering Stem Cells................................................................................. 262 CHAPTER 9. RESEARCHING MEDICATIONS .................................................................................. 265 Overview.................................................................................................................................... 265 U.S. Pharmacopeia..................................................................................................................... 265 Commercial Databases ............................................................................................................... 266 Researching Orphan Drugs ....................................................................................................... 266 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 271 Overview.................................................................................................................................... 271 NIH Guidelines.......................................................................................................................... 271 NIH Databases........................................................................................................................... 273 Other Commercial Databases..................................................................................................... 275 The Genome Project and Stem Cells .......................................................................................... 275
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APPENDIX B. PATIENT RESOURCES ............................................................................................... 279 Overview.................................................................................................................................... 279 Patient Guideline Sources.......................................................................................................... 279 Finding Associations.................................................................................................................. 285 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 287 Overview.................................................................................................................................... 287 Preparation................................................................................................................................. 287 Finding a Local Medical Library................................................................................................ 287 Medical Libraries in the U.S. and Canada ................................................................................. 287 ONLINE GLOSSARIES................................................................................................................ 293 Online Dictionary Directories ................................................................................................... 293 STEM CELLS DICTIONARY ...................................................................................................... 295 INDEX .............................................................................................................................................. 377
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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with stem cells is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about stem cells, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to stem cells, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on stem cells. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to stem cells, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on stem cells. The Editors
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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.
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CHAPTER 1. STUDIES ON STEM CELLS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on stem cells.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and stem cells, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “stem cells” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •
Neuronal Stem Cells: Their Characterization and Utilization Source: Neurobiology of Aging. 15(Supplement 2): S191. 1994. Summary: Many cells of the developing brain can be induced to proliferate and differentiate into neurons in vitro. The fate and longevity of those cells is not well known, nor is there terminology to describe them during various stages of proliferation, migration, and differentiation. Research is progressing to assess in vivo cellular replacement in a therapeutic context. This research relates to Alzheimer's disease by expanding the focus beyond the understanding of cell death to one of cell birth. Brain cell homeostasis is likely a balance between death and birth, and age-related degeneration may be influenced both by preventing cell death and inducing neurogenesis in the adult brain. 10 references.
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State of Stem Cell Research Source: Access. 16(1): 22-29. January 2002. Contact: Available from American Dental Hygienists' Association. 444 North Michigan Avenue, Chicago, IL 60611. Summary: This article familiarizes dental hygienists with stem cell research, focusing on the political decisions made to Federally fund research on only approximately 60 of the already existing stem cell lines. The author discusses the uneasy compromise that presently exists and the perspectives of each of the interested groups, including embryonic stem cell researchers, the biotech industry, patients' rights groups, and members of the pro-life movement. Other topics include the issue of using so called leftover embryos from in vitro fertilization, the location of the stem cell lines presently in existence, and other sources of stem cells (such as placenta and umbilical cords). The author also cautions that even with full support of stem cell research, the chasm between theory and useful application for therapy is still huge. 1 table.
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Hematopoietic Stem Cell Transplantation for Systemic Lupus Erythematosus Source: Rheumatic Disease Clinics of North America. 26(2): 377-387. May 2000. Summary: This journal article provides health professionals with information on the use of hematopoietic stem cell transplantation (HSCT) to treat systemic lupus erythematosus (SLE). Most allogenic HSCTs are from a human leukocyte antigen matched sibling donor. Bone marrow from the donor is infused into the patient following completion of a myeloablative preparative regimen. Autologous HSCT involves removal, cryopreservation, and reinfusion of hematopoietic stem cells following myeloablative therapy. The source of autologous stem cells can be either the bone marrow or peripheral blood progenitors. Many institutions throughout the world are conducting clinical studies using immunoablative therapy followed by HSCT for the treatment of SLE. Interpretation of these studies will be complicated by the differences in patient selection, conditioning regimens, and methods of stem cell collection. A major concern with this approach is that autoreactive effector cells will be reinfused with the autologous graft. The recent demonstration that immunoablative therapy can be safely delivered without the need for stem cell rescue offers a possible way to circumvent this problem. Early results using immunoablative therapy, with or without stem cell rescue, are encouraging; however, longer followup and additional patients are needed to validate this approach. 51 references. (AA-M).
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Tissue Engineering, Stem Cells, and Cloning: Applications in Urology (Part 1) Source: Contemporary Urology. 14(10): 40, 42, 44, 46-47,50-52,55-57. October 2002. Contact: Available from Medical Economics Publishing Inc. Montvale, NJ 07645. (800) 432-4570. Summary: Using the principles of cell transplantation, materials science, and engineering, researchers are replacing damaged urologic structures with biologic substitutes that can restore and maintain normal function. This article reviews applications of tissue engineering, stem cells, and cloning in the field of urology. Tissue engineering is used to develop biologic substitutes that will restore and maintain normal function. Tissue engineering may involve matrices alone (where the body's natural ability to regenerate is used to orient or direct new tissue growth) or the use of matrices with cells. The authors review how tissue engineering has been used to generate tissues for a variety of urologic structures, including the urethra, bladder, penis, and kidney.
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Other topics include fetal tissue engineering, injectable therapies, and testicular hormone replacement. 4 figures. 58 references.
Federally Funded Research on Stem Cells The U.S. Government supports a variety of research studies relating to stem cells. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to stem cells. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore stem cells. The following is typical of the type of information found when searching the CRISP database for stem cells: •
Project Title: A CELL-BASED THERAPY FOR CATARACTS Principal Investigator & Institution: Lang, Richard A.; Associate Professor; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 45229 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2006 Summary: (provided by applicant): Our long term objective is to develop a cell-based therapy for cataracts. In the case of the cataractous lens in adults, this approach offers the advantage, when compared with plastic prosthetic lenses, that the regenerated lens would be entirely natural in function and would accommodate normally. The regenerated organ would also be young in cellular terms and would therefore have extended function even in an environment, such as the diabetic patient, that favored the formation of cataracts. A cell-based therapy would also offer a unique advantage for the treatment of cataracts in newborns where conventional intraocular lens implantation is complicated by the rapid growth of the immature eye (a newborn's eye is 17 mm in length but grows to 22 mm by the end of the second year). The experimental strategy is to develop the techniques for production, identification and isolation of lens progenitor cells from mouse embryonic stem cells, and then to determine whether lens progenitors will form a lens in situ after implantation in the empty lens capsule of an experimental animal. Three Aims are designed to lead us towards this long-term goal. Aim 1 - to derive ES cell lines that give lens progenitor-GFP expression in chimeric mice. To prepare for the derivation on lens progenitor cells in culture, we will generate ES celt lines that give the normal Pax6 ectoderm enhancer expression pattern in chimeric mice. Aim 2 - To determine whether lens progenitor cells can be identified and isolated from embryonic stem cells. We will ask whether mouse embryonic stem cells are a source of lens progenitor cells using a variety of differentiation conditions in culture. Aim 3 - To determine whether lens progenitors will form a lens in situ. We will determine if lens
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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).
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progenitors isolated according to Aim 2 can generate a lens when placed in the empty lens capsule in nude (immune deficient) rats. If we are able to observe lens development from implanted progenitors, we will have established the basis of a cell-based therapy. Once established in animal models, the techniques described would be used with human ES cells and additional steps taken toward a practical therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ACTIVATION & PROLIFERATION OF HEMATOPOIETIC STEM CELLS Principal Investigator & Institution: Lansdorp, Peter M.; Associate Professor; British Columbia Cancer Research Centre 601 W 10Th Ave Vancouver, Timing: Fiscal Year 2002; Project Start 01-AUG-1990; Project End 31-MAY-2007 Summary: (provided by applicant): Hematopoietic stern cells (HSC), unlike e.g. embryonic stem cells, have a finite potential to divide. Limitations in the replication potential of HSC appear to be important in hematological disorders such as aplastic anemia and chronic myeloid leukemia. Such limitations could furthermore hamper the development of novel therapeutic strategies, including ex vivo stem cell expansion and gene therapy. Based on these considerations, studies that may help define and extend the replicative potential of HSC are important and a general interest. Previous studies with purified human "candidate" HSC funded by this grant have shown that the functional properties of HSC change dramatically during ontogeny and that the loss in HSC proliferative potential with age correlates with measurable shortening of telomeres. Here we propose to further examine the role of telomerase and telomeres in hematopoiesis. Specifically, we want to test the hypothesis that the replication history of HSC can be traced by studies of their telomere length. In order to test this hypothesis, we will examine the telomere length in subsets of purified HSC and their cultured progeny relative to defined populations of more mature cells using refined flow cytometry techniques developed in our laboratory. These techniques will also be used to further study the age related decline in telomere length in nucleated blood cells from normal individuals, patients with various hematological disorders and pedigrees of genotyped normal baboons. We will furthermore attempt to manipulate the telomere length in HSC using gene transfer and protein transduction strategies and study the functional properties of cells with extended telomeres in vitro and in vivo. The specific aims are:1) To study the telomere length in purified HSC and nucleated blood cells from normal individuals and patients with various hematological disorders before and after therapy.2) To study the telomere length in nucleated blood cells from baboons in relation to their age and genotype.3) To study the effect of artificial telomere elongation and telomerase inhibition on the proliferation, differentiation and replicative potential of purified "candidate" HSC in vitro and in vivo.Taken together, these studies will provide crucial baseline information on the role of telomeres in the biology of HSC. Such information is relevant for a basic understanding of hematopoiesis as well as applications of stem cells in and outside hematology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ADULT STEM CELL THERAPY IN PARKINSON'S DISEASE Principal Investigator & Institution: Li, Jia-Yi; University of Lund Box 1703 Lund, Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2005 Summary: (provided by applicant): Objective: The aim of this project is to develop a novel source of adult stem cells as an alternative to embryonic-derived stem cells/tissue
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for neural grafting in Parkinson's disease (PD). Bone marrow-derived hematopoietic stem cells and brain-derived adult ependymal stem cells will be investigated with respect to their potential to differentiate into dopaminergic (DA-ergic) neurons in vitro: In a final phase, the cells will be grafted into PD animal models. The work program includes (phase 1) isolation and purification of both cell types by using specific markers and magnetic sorting or FACS. In phase 2, cells will be propagated in vitro and characterized; respective mitogenes screened and protocols optimized. Phase 3 involves the identification of factors promoting neuronal/DA-ergic differentiation for the respective cell types and optimization of differentiation protocols in vitro. Cells will be characterized morphologically by immunocytochemistry and functionally by measuring K+-stimulated DA release in vitro. Subsequently, to verify a possible clinical application of the investigated cell types for neural grafting, undifferentiated as well as differentiated cells will be transplanted intracerebrally in rat/mouse models of PD in phase 4. Grafted cells will be assessed morphologically by immunohistochemistry, their ability to form synaptic contacts with the host brain by staining for synaptic vesicle proteins (such as synaptophysin) in combination with confocal and electron microscopy. Functionality of grafted cells will be tested by rotational behavior pre- and post transplantation. The project is aimed at further understanding of neural stem cell biology and more importantly, to use a highly goal-derived approach to develop a translation protocol for adult-derived stem cells that can be readily applied in future clinical trials in PD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AGE-RELATED RESPONSES OF EPIDERMAL STEM CELLS TO ENVIRON Principal Investigator & Institution: Bickenbach, Jackie R.; Associate Professor; Anatomy and Cell Biology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: Homeostasis of continuously renewing tissues, such as the epidermis, is maintained by somatic stem cells. These are undifferentiated, self-renewing cells, which also produce daughter transient amplifying (TA) cells that make up the majority of the proliferative population. TA cells undergo a finite number of cell divisions before leaving the proliferative compartment and moving toward terminal differentiation, whereas it has been assumed that the stem cells persist throughout the lifetime of the organism. Through a series of labeling experiments with tritiated thymidine, we previously showed that stem cells from adult mouse skin did not divide as often as the other basal cells, but they did divide at a steady rate in vivo. We also showed that they continued to proliferate in vivo throughout life, and that they have a high proliferative potential in vitro. Thus, it may be that epidermal stem cells do not follow the Hayflick theory and possibly "live forever." Last year, we developed a sorting method that yields a viable population of stem cells from the epidermis. We showed that these stem cells have the capacity to regenerate the epidermis and to continuously express a recombinant gene in the regenerated tissue. Thus, they are the stem cells for the epidermis. Very recently, we determined that these epidermal stem cells also have the remarkable ability to participate in the formation of the other tissues, a plasticity similar to that of embryonic stem cells and a few other somatic stem cells. Our preliminary data show that the epidermal stem cells isolated from neonatal mouse skin incorporate into a variety of tissues and alter their phenotype after injection into blastocysts. Thus, the fate determination of these stem cells appears to be in direct response to their environment. We also determined that the cell cycle profile of these cells appears to be
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an intrinsic property of the stem cell and not related to the age of the cell. These data have led us to ask what happens to epidermal stem cells as the organism ages? In this application, we propose to test whether the age of the stem cells has an effect on its response to the environment or extrinsic factors in determining its fate pathway. We propose the following specific aims: 1) to compare old vs. young murine epidermal stem cells by determining their number, altered phenotype and longevity after injection into blastocysts, and to determine whether there is a difference in the life span of mice derived from blastocysts injected with old vs. young stem cells; and 2) to compare old vs. young adult human epidermal stem cells by determining if there is a difference in their in vitro growth potential and if they respond differently to extrinsic environmental signals in vitro and after injection into blastocysts. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BIOACTIVE FACTORS IN SKELETAL REPAIR (STEM CELLS) Principal Investigator & Institution: Caplan, Arnold I.; Professor; Biology; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-APR-1985; Project End 31-MAY-2004 Summary: (Adapted from the Applicant's Abstract): The initially supported studies associated with this grant focused on the isolation and characterization of bioactive molecules which caused ectopic bone and cartilage formation when implanted into in vivo sites. This work emphasized the presence of progenitor mesenchymal cells which responded to these bioactive factors. The focus of the first subsequent renewal application was to characterize a preparation of progenitors (referred to collectively as "Mesenchymal Stem Cells"). It is suggested (by the applicant) that substantial progress has been made on the two Specific Aims of that proposal and this second competitive renewal application now focuses on one of these Aims, in which efforts were previously proposed to optimize cell-mediated repair of large femoral defects in rodents. The investigators now propose a multi-institutional collaboration to study the factors involved in engineering fracture repair. A 2 mm femoral gap in rodents will be analyzed for repair by inserting a uniform plug of cultured-expanded and marked marrowderived "mesenchymal stem cells". It is suggested that this model allows a detailed analysis of this "pseudo repair blastema" and focuses on the cellular and molecular contributions of these cells to the repair tissue. Three Specific Aims are complimented by three separate experimental projects. In the first Aim, the applicants propose to determine the contribution of these stem cells to the repair process and to the repair tissue. In the second Aim, they propose to insert plugs which contain relatively homogenous populations of cells that are at three different stages of osteogenic lineage and to determine their contribution to the fracture repair tissue. The last Aim will focus on the contribution of mechanical load to this repair process and its effects on stem cells and the population of cells from the three distinct stages of osteogenic lineage. The goal of the proposed research is to test several predictions related to the control of engineered fracture repair at one well-defined site. The molecular, cellular and mechanical determinants involved in such an engineered fracture repair have considerable clinical complications and the proposed studies are designed to highlight the key and controlling features of these events. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BIOLOGY OF STEM CELLS FROM THE ADULT BRAIN Principal Investigator & Institution: Leonard, Jack L.; Professor; Nuclear Medicine; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655
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Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: The recent discovery of multipotent progenitor cells in the adult central nervous system (CNS) offers the potential that these cells can be used to re-wire damaged neural circuits. These progenitor cells are propagated by relatively simple culture conditions, and implants of in vitro propagated neural stem cells can reverse and even cure neurological problems in animals. Cell-based strategies to CNS repair using both totipotent embryonic stem (ES) cells, and in vitro amplified spinal cord progenitor cells (SCPC) has restored a significant level of function to spinal cord injured rats, and overcome genetic defects in cerebellar function. In this proposal we will compare the expressed gene profiles of the totipotent ES cell, with those of the in vitro propagated neural progenitor cells isolated from the adult cerebral cortex and the spinal cord, from the cerebrospinal fluid, from fat and from the neonatal cerebellum. We will identify progenitor cell specific genes by DNA microarray analysis and characterize the developmental expression pattern of cerebellar external granule layer (EGL) progenitor cells during their differentiation into granule neurons. The Specific Aims of the proposal will address the following questions: 1) Do the transcript profiles of in vitro amplified progenitor cells isolated from adult cerebral cortex, spinal cord, the cerebrospinal fluid, the neonatal cerebellum and fat differ from the totipotent ES cell? 2) How does the expressed gene profile change when neural progenitor cells differentiate into neurons in vitro? The proposed body of work will provide the basic information required to establish the similarity/differences between the ES cell and the adult progenitor cells at the genomic level. The results of the proposed studies will provide the basic information required to generate sufficient numbers of undifferentiated progenitor cell for therapeutic use and establish the consequences of in vitro amplification on the fate of the progenitor cell. In addition, this work will lead to studies aimed at predetermining program of an important in situ pool of neuronal precursors that can be used to repair the lost circuitry typically found in the aging CNS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BONE MARROW-DERIVED STEM CELL TRANSPLANTATION TO RETINA Principal Investigator & Institution: Mcloon, Steven C.; Professor; Neuroscience; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2006 Summary: (provided by applicant): Degeneration of retinal photoreceptor neurons, such as that seen in age-related macular degeneration (AMD), is the most common cause of blindness in the United States. There are compelling reasons to believe that subretinal cell transplantation could be used to replace missing photoreceptor neurons. No effective and practical source of cells for transplantation is currently available. The goal of this project is to develop cells to be used for transplantation to replace photoreceptor neurons in AMD and related diseases. Bone marrow-derived stem cells offer numerous advantages over other cell types as a possible source of donor cells. These cells can differentiate into neurons. They are readily available, and if used for autologous transplantation to the retina, they would not have the same immunological consequences inherent in the use of other cell types. To our knowledge, no other laboratories are investigating bone marrow-derived stem cells for transplantation to the retina. At this time, there is no evidence that bone marrow-derived stem cells can differentiate into retinal neurons. The specific aim of this preliminary investigation is to determine conditions that would allow these cells to differentiate as photoreceptor neurons or other retinal cell types. The study has three sequential steps. First, treat GFP-
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labeled, bone marrow-derived stem cells in ways likely to induce the photoreceptor phenotype. This includes culturing cells in factors such as FGF-2, EGF, retinoic acid, sonic hedgehog and taurine, and/or transfecting the cells with a gene for the photoreceptor cell specific transcription factor, Crx. Second, co-culture treated bone marrow-derived stem cells with embryonic retina or transplant the cells to the subretinal space in animals depleted of photoreceptor cells. Third, assess histologically the differentiation of bone marrow-derived stem cells in the retinal co-cultures or after transplantation to the retina by determining their laminar distribution in the host retina and by immunohistochemistry with antibodies specific to retinal cell types. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CELL CYCLE RELATED TRANSDIFFERENTIATION INTO LUNG CELLS Principal Investigator & Institution: Quesenberry, Peter J.; Chair, Department of Research; Roger Williams Hospital 825 Chalkstone Ave Providence, Ri 02908 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Recent studies have indicated the phenotype of the hematopoietic stem cell may show dramatic cell cycle related plasticity as relates to long-term engraftment, progenitor numbers, and probably differentiation profile. These data have led to the concept that at the primitive marrow hematopoietic stem cell level, there is a continuum rather than a hierarchy with a continuously shifting phenotype. Other data have shown that marrow cells and purified marrow stem cells when infused into mice under varying conditions may give rise to nonhematopoietic cells in liver, skin, lung, brain, heart, and GI tract. In several instances, both quantitatively and functionally, significant transdifferentiation has been attained and shown to impact on specific disease manifestations, i.e., in the liver and heart. These data form the basis for the current proposal in which we will be exploring whether or not the transdifferentiation of marrow to lung cells is a phenotype which also shifts with phase of cell cycle. We will study whole marrow cells or purified marrow stem cells stimulated to transit cell cycle by IL-3, IL-6, IL-11, and Steel factor and at different points in cell cycle we will evaluated their ability to form lung cells. Host animals will be subjected to different lung injuries including intertracheal bleomycin and irradiation. Marrow cells will be infused at varying times after injuries. We will utilize B6129SF1/J, Rosa26, and C57BL/6 mice for these studies and track donor cells determining lacZ expression. In separate experiments, we will establish Rosa 26 donor marrow chimerism in lethally irradiated mice, allow for a period of stability, and then evaluate the ability of those chimeric cells subjected to varying stem cell mobilizations to produce lung cells in damaged lung. We plan to evaluate clonality as a measure of the heritogeneity of potential marrow to lung cells and an evaluation of the surface phenotype of stem cells at particular lung differentiation hot spots. We will evaluate adhesion proteins, cytokine receptors, and other epitopes of interest. These studies utilize MoFIo high-speed cell sorting, standard engraftment techniques, phage display biopanning, and immunohistochemical staining. We will also evaluate specific lungs from mice with specific injuries for possible homing peptides using phage display. This proposal hopes to define populations of cells either with cytokine stimulation at particular points in cell cycle or selected from whole marrow populations which will have a phenotype of producing lung cells and which might provide an approach to get quantitatively and functionally significant lung cell production, such that a pre-clinical model might be established. This could then lead to therapies of various lung disorders such as acute respiratory distress syndrome.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHARACTERIZATION OF HUMAN LEUKEMIC STEM CELLS Principal Investigator & Institution: Bonnet, Dominique A.; Assistant Professor/Chief; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2004 Summary: Understanding the processes that regulate the developmental program of normal stem cells and how aberrations in this program initiate leukemic proliferation remain a major challenge in biology. Progress to address these major questions in the human hematopoietic system has been hampered, until recently, by the lack of in vivo assays for normal and leukemic stem cells. The only way to conclusively assay stem cells is to follow their repopulating capacity. The recent development of methods to transplant human hematopoietic cells into immune-deficient mice provides an important approach to characterize stem cells and to develop animal models for hematopoietic diseases including leukemia. The development of an in vivo model that replicates many aspects of human AML and allows the identification of a novel leukemic stem cell (termed the SCID-Leukemia Initiating Cell, SL-IC) based on the ability of that cell to initiate AML in NOD/SCID mice provides the foundation of an assay to define the biological and molecular properties of such new leukemic stem cells. The major long-term objectives of my research program are to further characterize human leukemic stem cells. The research project proposed here will focus on three objectives: 1) determine the existence of an heterogeneity at the leukemic stem cell level (both Lin-CD34+ and Lin-CD341o/- subfractions have leukemic stem cell properties); 2) evaluate the biological properties of the leukemic stem cell pool (i.e., self-renewal, proliferation and differentiation capacities, response to cytokines and/or stromal cell environment); 3) to study the gene expression pattern of six regulatory molecules (AML1, PU.1, GATA- 1, Hox A5, Hox B4 and SCL/tal-1), known to be involved in the early stage of hematopoietic development and/or in the physiopathology of leukemia, before and after induction of differentiation of the leukemic stem cell fraction. The information obtained from these studies will gave us a more complete understanding of the nature of the leukemic stem cells, their biological properties, and the early molecular factors involved in the maintenance and/or differentiation of such leukemic stem cells. Furthermore, the knowledge gained about leukemic stem cells will allow us to devise new therapeutic strategies such as cell purging strategy, gene suicide therapy, antisense therapy and others, targeted specifically to the leukemic stem cell pool. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CHARACTERIZATION OF NEURAL STEM CELLS IN THE ADULT BRAIN Principal Investigator & Institution: Alvarez-Buylla, Arturo; Professor; Neurological Surgery; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 01-SEP-1994; Project End 31-JUL-2005 Summary: Adapted from applicant's abstract): New neurons continue to be born in the adult mammalian brain subventricular zone (SVZ) of the lateral ventricles and the subgranular layer (SGL) of the hippocampal dentate gyrus. Neural stem cells, cells that self-renew and generate neurons and glia, have been isolated from the SVZ and SGL with growth factors in vitro. The presence of neurogenic stem cells in the adult brain and the potential to manipulate these cells offers unprecedented opportunities for the
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Stem Cells
replacement of brain cells lost in injury or disease. Recent work has identified the SVZ stem cell as Type B cell. Type B cells have the structure of astrocytes and express glial fibrillary acidic protein (GFAP). To understand the molecular regulation of adult neurogenesis, it is necessary to catalog the cell types and cell-cell interactions in these germinal zones, and describe the gene expression of the specific cell types. We thus propose the following Specific Aims: (1) To identify the cell types and architecture of the developing SVZ. Preliminary data suggests that cells containing a single specialized cilium in the ventricle walls of the juvenile animal are equivalent to the Type B cell in the adult. We present experiments to test this hypothesis. (2) To purify different SVZ cell types and construct representative cDNA libraries for each cell type. The libraries will be used to generate probes for GeneChip arrays to profile the gene expression of the major cell types of the adult SVZ. This experiment will be performed in collaboration with Affymetrix. Gene profiling data will be made available to the scientific community via the Internet. This data will reveal the molecular regulatory signals present in the SVZ cells as well as provide markers differentiating Type B cells from other brain astrocytes. (3) To investigate the cell types and architecture of the hippocampal SGL. The SGL stem cell will be identified using techniques similar to those used to identify the SVZ stem cell. Preliminary results suggest that SGL stem cells have properties in common with SVZ Type B cells. The combined knowledge of stem cell biology in the two major germinal regions of the adult brain will advance the ability to utilize adultderived neural stem cells for brain repair. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHEMOKINES/CYTOKINES AND RECEPTORS IN STEM CELL HOMING Principal Investigator & Institution: Broxmeyer, Hal E.; Professor; Microbiology and Immunology; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 01-SEP-1997; Project End 31-MAR-2006 Summary: (provided by applicant): Little is known regarding homing/engraftment and mobilization of hematopoietic stem and progenitor cells. We hypothesized that the CXC chemokine Stromal cell derived factor-1 (SDF-l/CXCL12) and its receptor CXCR4 are involved in these important and clinically relevant processes. Towards our long-term goals to modulate homing and mobilization for clinical benefit, we propose the following two Specific Aims: 1. Evaluate roles of SDF-1 (CXCL12) and its receptor, CXCR4, in the processes of stem and progenitor cell homing, engraftment and growth factor-induced or spontaneous mobilization in mice by modulating expression and activities of SDF-1 and/or CXCR4 in stem/progenitor cells and/or the microenvironment. To these goals, use the SDF-1 antagonist AMD 3100 as well as RSVSDF-1 and LCK-SDF-1 transgenic mice to evaluate homing and engraftment, and AMO 3100 and G-CSF to evaluate mobilization in mice of differing genetic backgrounds as well as in RSV-SDF-1 and LCK-SDF-1 transgenic mice, and CCR1 -/- mice. 2. Evaluate mechanisms involved in SDF-1/CXCR4 effects on chemotaxis and mobilization of hematopoietic stem and progenitor cells in mice by determining intracellular signaling molecules and pathways involved in these effects in normal primary stem and progenitor cells, and by use of mice with functional deletions in selected intracellular signaling molecule. To the goals of aim 2, evaluate signaling in phenotypically defined populations of primary stem and progenitor cells using multivariate intracellular and cell surface flow cytometry, and use cells from mice functionally deleted in specific intracellular molecules or normal cells transduced with genes expressing dominant
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negative or activated forms of intracellular molecules. Also use intracellular gene deleted mice to assess their response to in viva mobilization with AMD 3100 and/or GCSF. These studies should clarity the relevance of SDF-1 and CXCR4 for homing/engraftment and mobilization of primary stem/progenitor cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONNEXINS: STEM CELLS AND EPIDERMAL DIFFERENTIATION Principal Investigator & Institution: Matic, Maja; Oral Biology and Pathology; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2002; Project Start 18-APR-2000; Project End 31-MAR-2005 Summary: (Taken from the applicant's abstract): The long-term objective is to identify markers whose modulation results in epithelial differentiation. This objective has a direct impact on the application of epithelial grafts as therapy for full thickness skin injury and as a delivery system for specific gene products. Connexin-negative cells are found in the basal cell layers that harbor stem cells. Connexin expression or lack thereof will be correlated with markers thought to be indicative of stem cells. For correlation with label retaining cells, which are putative stem cells, thymidine-labeled mouse skin will be used. For correlation with K19 expressing follicular cells, also purported to be stem cells, human skin will be utilized. To accomplish this aim, FACS analysis and immunohistochemistry combined with fluorescent and confocal microscopy will be employed. The functionality of gap junctions within both mouse skin and human hair follicles will also be evaluated. Cell populations able to carry out dye transfer will be compared to those populations containing label retaining cells in mouse skin, and K19 expressing cells in human hair follicles. These experiments will further indicate whether stem cells lack gap junction-mediated cell-to-cell communication. The connexinnegative cells of the epidermis will be isolated and compared in culture with other cells of the basal layer. For these experiments, antibodies against the extracellular domain of connexin molecule will be used as a negative selection factor in isolating cells by FACS. Individual cell populations will be assayed for culture life-span, and colony forming efficiency at each passage. Finally, retroviral vectors will be used to introduce both Cx43 gene and antisense oligonucleotides into keratinocytes. The effects will be assessed in submerged cultures, organotypic cultures and on organotypic cultures grafted onto athymic mice. The proposed research plan, as well as the activities described in the application, are aimed at achieving the career goals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CONTROL SPERMATOGENESIS
OF
STEM
CELL
FATE
IN
DROSOPHILA
Principal Investigator & Institution: Matunis, Erika L.; Staff Associate; Carnegie Institution of Washington, Dc 1530 P St Nw Washington, Dc 20005 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2004 Summary: (Scanned from the applicant's abstract) Spermatogenesis relies on the establishment and maintenance of a stem cell population within the testis. Although spermatogonial stem cells are essential for reproduction, little is known about their regulation. Environmental cues from nearby cells are thought to be crucial for stem cell maintenance, but identifying them is extremely challenging in mammalian systems. Drosophila spermatogenesis provides an excellent model system for studying stem cell regulation, since spermatogonial stem cells can be identified, and genetics can be used to systematically identify regulatory molecules. In this proposal the role of the highly
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conserved Jak-STAT signal transduction pathway in stem cell maintenance is examined. The Jak kinase homologue Hopscotch (Hop) is required for stem cell maintenance, and overactivation of the Jak-Stat signaling pathway leads to ectopic cells with stem cell character. Also, the ligand activating Jak-STAT is present in a small group of somatic cells, called the hub, to which the stem cells are anchored. This leads to the hypothesis that the hub comprises a stem cell niche, or specialized local environment, that instructs nearby cells to retain a stem cell fate by activating the Jak-STAT pathway within these cells. To test this hypothesis, the precise role of Jak-STAT signaling in the niche will be examined. In Aim 1, marked loss-of-function clones will be generated to determine if stem cells directly require Jak-STAT signaling. In Aim 2, both loss-of-function and ectopic expression of Jak-Stat signaling molecules will test whether Jak-STAT signaling instructs stem cell fate or, alternatively, is required to permit stem cell viability. In Aim 3, the role of Jak-STAT signaling in limiting stem cell numbers in the niche will be studied. Finally, since it is likely that other factors act either in concert with Jak-STAT, or subsequent to it in maintaining the stem cell niche, we employ genetic approaches to systematically identify these factors in Aim 4. Since Drosophila and mammalian spermatogenesis are conserved, the regulatory mechanisms uncovered in this proposal will likely add to the understanding of the regulation of stem cells residing in more complex and less defined environments, such as mammalian spermatogonial stem cells, which are essential for human fertility. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CORNEA BIOENGINEERING
EPITHELIAL
STEM
CELL
ISOLATION
FOR
Principal Investigator & Institution: Li, De-Quan; Assistant Professor; Ophthalmology; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2006 Summary: (provided by applicant): Corneal epithelial stem cell disease or dysfunction, known as limbal stem cell deficiency, is among the most common blinding eye conditions worldwide. There was no effective therapy for these conditions until the potential of limbal transplantation for surface reconstruction of eyes with this condition was realized in the past decade. The success of limbal transplantation has been attributed to the healing potential of the corneal epithelial stem cells that are only a small subpopulation contained within the mixture of cells transplanted in these grafts. The ability to isolate a pure population of corneal epithelial stem cells from small limbal biopsies, expand them in culture and use them for regenerating a corneal surface of normal phenotype and regenerative capacity would represent a major advance in this field. But to date, no specific markers for corneal epithelial stem cells have been identified. Isolation of corneal epithelial stem cells has not been achieved. Our preliminary studies have provided encouraging results in support of our hypothesis that the novel isolation methods and proposed markers for stem cells and basal cells in non-ocular tissues can be utilized to isolate a pure population of corneal epithelial stem cells. Two proposed Specific Aims will realize the long-term objectives. Aim 1 will create novel approaches to isolate corneal epithelial stem cells based on their unique properties and molecular markers for use in corneal tissue engineering. Three isolating strategies in combination will be used: 1) Size sorting based on the correlation between cell differentiation and enlarged size; 2) Enrichment by their rapid adherence to extracellular matrix based on their higher-expression of beta1integrin; 3) Purification of stem cells as a side population by flow cytometry using a vital DNA binding dye, Hoechst 33342. Aim 2 will search for new specific markers for corneal epithelial stem
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cells by characterizing gene expression patterns in the purified populations of stem cells using advanced gene array/microarray techniques. With the proposed Aims accomplished, pure populations of corneal epithelial stem cells will be available for the first time, which will make the corneal epithelial stem cell concept become reality and bring stem cell research and clinical application into a new age. This work will have important scientific significance and high impact on the adult stem cell concept, not only for cornea and ocular surface, but also for other tissues. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DERIVATION OF SMOOTH MUSCLE LINEAGES FROM STEM CELLS Principal Investigator & Institution: Owens, Gary K.; Professor and Associate Dean; Mol Physiol/Biological Physics; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2005 Summary: (provided by applicant): A large number of major human diseases including coronary artery disease, hypertension, and asthma are associated with abnormal function of the smooth muscle cell (SMC). The long term goal of the studies in this proposal is to develop methods for producing SMC or SMC "progenitor" cells from various human multi-potential stem cell populations with the intent of potentially using these cells for a variety of clinical applications including: a) in vitro production of SMC tissues or cells for surgical repair or augmentation; and b) production of SM tissues or cells that are genetically engineered to express a desired therapeutic gene or agent. Of particular relevance to this grant application, we have developed unique experimental methods, employing SMC specific/selective promoter-enhancers initially characterized in our laboratory, that permit high efficiency induction, identification, and purification of SMC and SMC "progenitor" cells from multi-potential murine P19 stem cell populations. The studies outlined in this proposal will: 1) use representative difference analyses (RDA), and gene array analyses of unique P19 derived mouse SMC "progenitor" cell lines previously developed in our lab to identify markers of SMC progenitor cells, and/or genes that control early commitment/determination events in SMC (Aim 1); 2) test the applicability of our unique SM a-actin/SM MHC promoterenhancer based screening methods for identifying and purifying SMC or SMC "progenitor" cells from various murine and human stem cell populations (Aim 2-3); and 3) characterize the properties of stem cell derived SMC and SMC "progenitors" upon surgical re-implantation in vivo (Aim 4). Taken together studies will provide novel insights of mechanisms that control specification of SMC during embryonic development, and lead to development of unique methods for producing SMC from stem cell sources for potential therapeutic applications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DEVELOPMENTAL LYMPHOPOIESIS
STAGE-RELATED
CHANGES
IN
Principal Investigator & Institution: Kincade, Paul W.; Head; Oklahoma Medical Research Foundation Oklahoma City, Ok 73104 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2008 Summary: (provided by applicant): The immune system is initially formed and replenished by differentiation of hematopoietic stem cells into various types of lymphocytes. Recently developed knock-in mice now make it possible to study early
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specification of stem cells into lymphoid fates, correlating changes in gene expression, function and surface markers with activation of the RAG-1 locus. As information accumulates about the sequence of events in adult bone marrow, it has become increasingly clear that it differs substantially from the fetal/neonatal process. Stem cells emerge in at least two sites in embryonic life, but developmental relationships between those populations and their counterparts in adult marrow remain poorly understood. Unique features and limitations to the newborn immune system could result from differentiation mechanisms that are only used for fetal lymphocyte production. We will chart emergence of the earliest lymphoid progenitors in murine embryos, comparing and contrasting their characteristics with ones in adults. Transplantation and culture experiments may attribute many differences to residence in fetal versus adult environments, exposure to unique differentiation cues and/or the recent proliferation of stem cells. Other properties of lymphoid progenitors in embryos may be intrinsic and related to their origin from fetal, rather than adult, stem cells. We will use new transgenic animal models to test the hypothesis that early emerging hematopoietic stem cells are replaced by ones that arise later. The resulting information may suggest new ways to augment neonatal immunity, treat immunodeficiency and restore lymphocytes following transplantation. It will also be useful within a broader context of developmental changes in stem cells, highlighting limitations and opportunities in regenerative medicine. For example, desirable properties of fetal stem cells may be used to advantage or artificially conferred on their adult counterparts. Furthermore, basic investigation of this type could provide explanations for the sensitivity of neonates to lymphocytic leukemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EMBRYONIC STEM CELLS AND SQUAMOUS EPITHELIA Principal Investigator & Institution: Green, Howard; Cell Biology; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): Human embryonic stem (ES) cells are now available for the study of the generation of somatic cell types. For this purpose, human ES cells have important advantages over the murine ES cells available earlier. We propose to study the generation of keratinocytes of stratified squamous epithelium from the human ES cells (WA01). ES cells are known to have the capacity to generate such epithelium outside the developing embryo, since the epithelium develops when the ES cells are injected into scid mice. But our main intention is to find conditions promoting differentiation of the ES cells in culture and then to isolate strains of keratinocytes resulting from that differentiation, using 3T3 support. We will examine the factors that influence the development of keratinocytes, using as criterion a quantitative measure of the number obtained, and in this way arrive at the conditions producing maximal yield of keratinocytes. We will identify, when possible, the specific squamous epithelium to which isolated keratinocytes belong. We will attempt to find somatic stem cell precursors of the mature keratinocytes using stem cell markers for their identification. Depending on the nature of the keratinocytes or keratinocyte precursors isolated, practical applications can be readily envisioned. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ENGINEERING BONE FROM HUMAN ADIPOSE DERIVED STEM CELLS Principal Investigator & Institution: Hedrick, Marc H.; Associate Professor; Dental Research Institute; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2006 Summary: Bone engineering with osteoprogenitor cells has enormous clinical potential for the treatment of aging-related bone loss (osteoporosis) or traumatic bone defects. Osteoprogenitor cells such as mesenchymal stem cells (MSCs) from bone marrow are a source of such cells. When combined with polymeric scaffolds and/or osteogenic growth factors these cells may provide new therapies for bone replacement. Our longrange objective is the development of new treatments for human bone loss through tissue engineering. Our central hypothesis is that human adipose tissue contains stem cells or adipose-derived stem cells (ADSCs) which offer advantages over MSCs and other osteoprogenitor cell types. The specific aims of this application are: (1) to clone and characterize human ADSCs, (2) to investigate their ability to form bone both in vitro and in vivo and (3) to determine their ability to repair non-healing bone defects. An understanding of ADSC function and ultimately their regulation, has important implications. First, tissue engineering strategies will benefit by an autologous stem cell source (adipose tissue) that is easily obtainable in 'liter' quantities through a minor surgical procedure (liposuction) that is well tolerated by patients. Second, a detailed understanding of the regulation of stem cell differentiation in adipose tissue could significantly impact the treatment of diseases that are characterized by dysregulated mesodermal cell growth and differentiation such as osteoporosis, heterotopic calcification and obesity. Finally, fundamental issues of mesodermal cell differentiation, mesodermal phylogeny and ontogeny, may be better understood by study of these cells. At the completion of this grant, our expectation is that human adipose tissue will be shown to be a reservoir of stem cells. We will also begin to have a basic understanding of the phenotypic changes occurring in differentiating ADSCs after commitment to the osteogenic lineage. Finally, we will assess the clinical utility of ADSCs to repair criticalsized bone defects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ENGINEERING INSULIN PRODUCTION BY K-CELLS TO TREAT T1DM Principal Investigator & Institution: Wice, Burton M.; Internal Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2005 Summary: (provided by applicant): Preliminary and published results provide strong evidence that engineering short-lived Gut K-Cells to express the insulin gene is a potential therapy to treat type 1 diabetes mellitus (T1DM). Transgenic technologies are not amenable for human gene therapy, and a mechanism to stably introduce transgenes into small intestinal [epithelial] stem cells of adults is required. All published studies have demonstrated inefficient transduction of this stem cell population in vivo. Organoids containing functional intestinal epithelial stem cells can be isolated from rat small intestine and then grafted back onto denuded colonic muscle. The neomucosa exhibits a small intestinal, rather than colonic, phenotype. Grafts generated within the PI's laboratory contained Gut K-Cells, a cell normally present in the proximal small intestine and absent from colon. Thus, transplanted stem cells are hardwired to express
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Stem Cells
genes from their original position along the duodenal to colonic axis. This suggests that organoids isolated from the proximal small intestine could be genetically modified before grafting back into the host and if so, could be engineered so Gut K-Cells derived from these stem cells could express the human insulin gene. Initial studies to test the feasibility of this strategy will determine whether the intestinal epithelial stem cells within the organoids can be genetically modified ex vivo by retroviral vectors (encoding beta-galactosidase) and then transplanted onto denuded colonic muscle. Grafts will also be assessed to determine whether beta-galactosidase expression is maintained for extended periods of time (9 months). Since retroviral vectors only infect proliferating cells, agents known to enhance crypt cell proliferation and/or inhibit apoptosis will be used in conjunction with viral infection in an attempt to increase the efficiency of stem cell transduction. Organoids can be grafted onto synthetic biodegradable polymers instead of colonic muscle and then anastomosed into the jejunum where the grafts remain intact for >9 months. If grafts containing genetically engineered Gut K-Cells were anastomosed back into the jejunum, they would be positioned to respond to normal metabolic and secretory signals. Thus, engineered Gut K-Cells would secrete insulin at the proper time to treat T1DM. Studies will be conducted to bring this alternative technique to the laboratory. Results from these pilot studies should provide a sound basis for devising a strategy to isolate, genetically modify and then transplant adult human intestinal epithelial stem cells as a potential treatment for T1DM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EPITHELIAL DIFFERENTIATION OF BONE MARROW STEM CELLS Principal Investigator & Institution: Krause, Diane S.; Associate Professor; Laboratory Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2005 Summary: (provided by applicant): My laboratory has recently demonstrated engraftment from bone marrow cells of fully differentiated pneumocytes in mice and hepatocytes in mice and humans. This remarkable discovery and those of others showing a previously unexpected level of differential plasticity of stem cell, open up many new avenues of research. In order to efficiently address the critical questions in this new broad field of stem cell plasticity, I have brought together a group of experienced researchers, each of whom has clinical or scientific expertise in a different organ system. The focus for this proposal is to determine the cellular and biological mechanisms that induce the bone marrow cells to differentiate into epithelial cell, and to use stem cell plasticity as a therapeutic moiety by autologous transplantation of gene modified cells. In order to dissect the mechanisms of this phenomenon in vivo, I will first determine whether epithelial engraftment as liver, lung, and skin cells can be directed in vivo in mice and in humans by induction of tissue repair mechanisms in response to injury or disease. Identification of the cellular and biological mechanisms by which bone marrow cells differentiate into hepatocytes will require the development of in vitro systems in which bone marrow derived cells become liver cells. I will use three dimensional collagen system and organ culture to achieve this differentiation in vitro. Finally, using viral vectors to infect bone marrow stem cells, I will use an autologous/syngeneic transplantation model to obtain liver specific gene expression in vivo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: EXPANSION OF STEM CELLS BY FIBROBLAST GROWTH FACTOR1 Principal Investigator & Institution: De Haan, Gerald; State University at Groningen 5 Broerstraat Groningen, Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Hematopoietic stem cell transplantations are increasingly employed to restore normal blood cell production after high-dose cytotoxic therapy in cancer patients. In addition, recent studies suggest that bone marrow-derived stem cells may have the potential to contribute to non-hematopoietic tissue regeneration after transplant, which potentially increases the clinical applications of these cells vastly. A significant problem in the field of stem cell therapy remains the inability to expand the number of multilineage long-term repopulating stem cells in vitro. In a large body of preliminary data we show that in the mouse long-term repopulating stem cells reside in the lineage-depleted, fibroblast growth factor receptor-positive cell fraction. Most importantly, fibroblast growth factor-1 (FGF1) has the unique ability to stimulate the generation of long-term repopulating stem cells in vitro in serum-free cultures. Thus, our data show for the first time that large-scale expansion of stem cells in vitro is feasible, and we provide a simple method to generate rapidly engrafting stem cells in vitro. However, we show that this expansion potential is highly mouse-strain specific, as C57BL/6 stem cells are easily expanded but DBA/2 stem cells are refractory to FGF1. Preliminary genetic linkage studies reveal that a locus on chromosome 11 is associated with the variation. It is the overall aim of the present proposal to investigate how incubation of bone marrow cells with FGF1 results in massive amplification of transplantable stem cells. To this end we defined 4 specific aims: 1. Identification of the target cell on which FGF1 exerts its activity, 2. Assessment of the clonal composition of hematopoiesis in recipients reconstituted with FGF1-expanded stem cells, 3. Determine whether the defect of DBA/2 stem cells is a cell-intrinsic trait, and 4. Investigate the genetic constrains that specify FGF1-induced stem cell expansion? In order to address these 4 issues we will use an extensive set of stem cell purification strategies to search for the FGF1-responsive cell. We will perform stem cell marking studies in which cells are retrovirally transduced prior to expansion and transplantation in lethally irradiated recipients. Using co-cultures of C57BL/6 and DBA/2 bone marrow cells we will evaluate whether DBA/2 stem cells are intrinsically impaired in their response to FGF1. Finally, using a genetical genomics approach we will search for an association between gene expression profiles and stem cell expansion potential in a set of 30 recombinant inbred BXD strains of mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FUNCTION OF STEM CELL-DERIVED NEURONS IN THE AGING BRAIN Principal Investigator & Institution: Gage, Fred H.; Salk Institute for Biological Studies 10010 N Torrey Pines Rd La Jolla, Ca 920371099 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: Cells proliferate in the inner granular zone of the dentate gyrus of the adult hippocampus of all mammals. It is hypothesized that some of the dividing cells are stem cells because they can give rise to neurons and glia in the dentate gyrus. Additionally, we have demonstrated that cells from the adult hippocampus can be isolated in vitro and induced to proliferate indefinitely. Under specific conditions the cells can be transplanted back into the adult brain where they can differentiate into neurons and
20
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glia. We demonstrated previously that there is a progressive decrease in the number of proliferative cells in the dentate gyrus of adult rodents with aging. This decrease in neurogenesis in the aged dentate gyrus can be partially reversed by environmental stimulation. We do not know whether newly born cells in the aged brain can become neurons that are anatomically and functionally similar to the new neurons in the young adult brain. Further, we do not know if environmental stimulation like voluntary exercise will affect only the proliferation rate and survival of the newly born neurons, or whether it will also affect the anatomical or physiological properties of the differentiated cells. To determine the answer to these questions in vivo we developed new methods that allow us to measure anatomical and physiological properties of individual, newly born cells in acute brain slices. Further, we developed methods to isolate adult stem cells in vitro and measure their functional and electrophysiological properties in vitro. Finally, using transplantation methods established in this lab we can directly compare the effects of the age of the host hippocampus on survival and function of grafted aged versus young adult stem cell populations propagated in vitro. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FUNCTIONAL ISOLATION OF HUMAN HEMATOPOIETIC STEM CELLS Principal Investigator & Institution: Scadden, David T.; Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-AUG-1995; Project End 31-MAR-2005 Summary: (Applicant's Description Verbatim): Hematopoietic stem cells undergo a development stage-specific translocation during ontogeny and ultimately reside in the adult bone marrow. Maintenance of this highly regenerative cell pool through adult life is dependent upon their relative quiescence. We generated a cDNA library from quiescent human hematopoietic stem-like cells derived from bone marrow and identified by subtractive cloning a seven transmembrane molecule with a signature motif of the chemokine receptor family. Antiserum raised against this gene product identified cells from human fetal bone marrow, but not other fetal hematopoietic organs and very rare cells from adult bone marrow. These cells were enriched for quiescent cells with the ability to sustain mature blood cell generation for prolonged periods on stromal feeder layers. Calcium flux was induced upon exposure of transfected cells to bone marrow stroma conditioned medium, but not medium from other hematopoietic tissue stromal sources or from a panel of recombinant chemokines. Transduction of the receptor into hematopoietic cell lines resulted in enhanced transmigration toward bone marrow stroma in vitro and to bone marrow in irradiated mice. Transduced primary CD34+ progenitors had reduced proliferative potential, but sustained LTC-IC capability. Stem cell-G protein-coupled receptor-i (SC-GPR1) is a chemokine receptor that identifies bone marrow-derived hematopoietic stem cells and mediates growth regulatory and cell localization signals. This proposal builds upon these observations to address the following specific aims: 1. Define the functional role of SC-GPR1 in development using a mouse engineered to be deficient in the gene and its role in adult hematopoiesis using transplantation of cells identified by a monoclonal antibody specific for SC-GPR1. 2. Purify and clone the ligand for SC-GPR1. 3. Determine the mechanism by which ectopic expression of SC-GPR1 induces or maintains a primitive phenotype. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GENOMIC HEMATOPOIESIS
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Principal Investigator & Institution: Papoutsakis, Eleftherios T.; Walter P. Murphy Professor; Chemical Engineering; Northwestern University 633 Clark Street Evanston, Il 60208 Timing: Fiscal Year 2003; Project Start 01-APR-1993; Project End 31-MAR-2008 Summary: (provided by applicant): High-dose chemotherapy with autologous or allogeneic stem-cell rescue results in prolonged pancytopenia that is accompanied by infectious and bleeding complications requiring antibiotic and transfusion therapy and, at times, prolonged hospitalization. Infusion of large numbers of ex vivo expanded hematopoietic cells -as a supplement to the conventional auto- or allograft - has the potential to close the window of neutropenia and/or thrombocytopenia. Furthermore, the recently discovered plasticity of hematopoietic stem cells suggests that these readily available stem cells may be used for generating autologous or allogeneic cells and tissues for non-hematopoietic cell and gene therapies. Success of such therapies depends on the ability to generate large numbers of cells with the desired, therapy-dependent state of cell differentiation. This remains an elusive task despite the great progress in basic and applied biology. Culture conditions, such as cytokine combinations and presentation, oxygen tension (pC2) and pH, alter stem- and progenitor-cell differentiation and proliferation with substantial patient-to-patient variability. Little is known about the underlying molecular biology of these effects, and specifically, about the large-scale transcriptional program during differentiation. Such knowledge has large predictive and diagnostic potential for both ex vivo and in vivo outcomes. Thus, a comprehensive examination of the transcriptional program of ex vivo expanded human primary myeloid cells - initiated with CD34+ cells - will be examined using 8,300-gene DNA microarrays, and key findings further explored using standard molecular-biology tools. Studies include examination of the temporal and differential transcriptional program of G and Mk cells cultured either under high or low pC2 and/or pH, and with different cytokine combinations. Specific issues to be examined include the extent to which apoptosis is linked to Mk differentiation; if Mk apoptosis employs a machinery similar to that of general apoptosis; and why, in contrast to Mk cultures, there is such a low level of apoptosis in G cultures. Furthermore, gone-clustering and regulatorynetwork techniques applied to DNA-microarray data may lead to the discovery of unknown Mk- and G-differentiation genes. These experiments will provide the basis for future studies in which clinical specimens could be examined in the context of clinical stem cell transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HEMATOPOIETIC STEM CELL--BIOLOGY, PRECURSORS, AND PROGEN Principal Investigator & Institution: Weissman, Irving L.; Professor; Pathology; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2005 Summary: Hematopoietic stem cells are defined as clonogenic cells that can give rise to all blood cell lineages, as well as self-renew, at least for a significant period of time. There are 3 subsets of stem cells (HSC) and multipotent progenitors, and only the longterm (LT-HSC) self-renew for the life of the host, while ST-HSC renew for up to 8 weeks, and MPP for much less. Downstream of HSC/MPP are 2 classes of oligopotent progenitors - the common lymphoid progenitor (CLP) and the common myeloid
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progenitor (CMP). Each of these progenitors have been purified and can be prospectively identified by phenotype and isolated. In the first section of the grant, dividing LT-HSC, ST-HSC, and MPP will be tested for self-renewal or differentiation to one or the other downstream fates at the bulk level and at the single cell level to determine whether the cell fate decisions these multipotent cells make are largely symmetrical or asymmetrical. HSC cannot be expanded in vitro by any known protocol, but it is relatively simple to demonstrate their ability to expand by several orders of magnitude in various in vivo settings. To determine what intrinsic or extrinsic programs might regulate LT-HSC self-renewal, enforced expression of cell survival genes such as bcl-2, telomere extending genes such as TERT and TPC3, and genes downstream of particular signal transduction pathways such as beta catenin will be tested in HSC and other multipotent progenitors, and their progeny analyzed in an in vivo setting. Within the past year a large number of stem cells ranging from totipotent stem cells to organ specific stem cells (such as for the central nervous system) have been identified or claimed, with very surprising putative transdifferentiation possibilities between them and stem cells of the hematopoietic system. In this grant an effort will be made to establish unequivocal clonogenic assays for totipotent stem cells, and the relationship between various tissue specific stem cells, totipotent stem cells, and HSC will be examined. The study of HSC biology could be enhanced if HSC could be observed in situ by means of their expression of stem cell related genes. A long-term project that is part of this proposal is to begin to identify proteins that are useful fluorochromes among a plethora of recent discovered proteins such as the green fluorescent protein, and from amongst those that appear to be useful, to "knockin" different color genes as fusion proteins for these stem cell related genes already known (ckit, Sca1, Thy- 1.1, Flk2/Flt3, SCL) as well as others recently identified as being stem cell specific in their expression (e.g., a new serpin gene cloned in this laboratory). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HEMATOPOIETIC STEM CELLS FROM TOTIPOTENT STEM CELL TYPES Principal Investigator & Institution: Daley, George Q.; Whitehead Fellow; Whitehead Institute for Biomedical Res Biomedical Research Cambridge, Ma 02142 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2005 Summary: (provided by applicant): This proposal explores the hematopoietic potential of mouse embryonic stem (ES) cells, with the ultimate goal of discovering principles that govern the differentiation of ES cells into hematopoietic stem cells (HSCs) that can be used to model transplantation in murine systems. To date, there has been no definitive demonstration that a pluripotent stem cell capable of engrafting irradiated adults arises in vitro during ES cell differentiation into embryoid bodies (EBs). Following differentiation of ES cells genetically modified to express BCR/ABL, HoxB4, or STAT5, we have succeeded in demonstrating hematopoietic engraftment of irradiated adult mice with a common lymphoid-myeloid progenitor from EBs. We are thus well positioned to investigate the nature of the common lymphoid-myeloid progenitor in EBs, and the mechanisms governing the potential for such cells to engraft in embryonic and adult hematopoietic microenvironments. We have proposed methods for isolating enriched populations of EB-derived progenitors using selectable markers driven off of hematopoietic specific promoters, and will endeavor to more carefully define the surface antigen phenotype and in vivo properties of this cell. We will determine whether the native cells have a distinct developmental potential (i.e., capacity for engraftment of fetal or newborn sites but not adult). We will test the hypotheses that engraftment is
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facilitated by homing, enhanced cell survival, or cell proliferation, and probe the molecular basis for these observations. Our results will enable methods for enhanced hematopoietic development from ES cells and reconstitution of the adult hematopoietic system as a model for hematopoietic research and cellular therapies. Future efforts will explore the similarities and differences in the hematopoietic potential of murine and human ES cells, making use of repopulation studies of human cells in NOD/Scid mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HIGH PERFORMANCE MAGNETIC CELL SORTING Principal Investigator & Institution: Chalmers, Jeffrey J.; Professor; Chemical Engineering; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2003; Project Start 21-JUL-2003; Project End 31-MAR-2007 Summary: (provided by the applicant): An area of increasing interest, and potentially significant clinical use, is performing mismatched stem cell transplants for high-risk and refractory hematological malignancies using related donors. Such patients currently undergo transplants using HLA matched sibling or unrelated donor stem cells. Using haplotype-mismatched donors from siblings, parents or children would permit the availability of suitable donors for more than 90-95% of candidate patients. However, the main limitation is graft-versus-host disease (GVHD). GVHD can be almost eliminated by extensive T-cell depletion (>5 logs). While T cell depletion increases the risk of graft rejection, this can be overcome by the use of very large doses of stem cells. Therefore, it is desirable to have a system where very large numbers of stem cells can be efficiently processed to deplete T-cells, and with minimal loss of these stem cells. A second area of increasing interest, and potentially significant clinical use, is the isolation of Natural Killer (NK) Cells for Immunotherapy. NK cells are important cells of the innate immune system that are not involved in specific antigen recognition. These cells are important in the defense against infections, but also have potent anti-tumor effects. Currently, there is growing interest in the use of both autologous and allogeneic activated NK cells for cancer immunotherapy. In particular, the use of allogeneic NK cells mismatched for HLA-C alleles of the recipient can exert very potent anti-leukemic effect in vitro. Infusion of NK cells may also assist engraftment of stem cells in the bone marrow transplant setting. This project will focus on the development/application of a high throughput, flow through immunomagnetic cell separation system currently under development for clinical scale T-cell depletion and NK isolation. While several systems have been developed, none are currently approved for these indications, and their performance is generally suboptimal. With respect to the recovery of stem cells during T-cell depletion, a significant increase in stem cell recovery is needed, from reported mean values of 41 to over 80%, to facilitate 'mega-dose' CD34 cell therapy in mismatched transplants. Less research has been carried out for clinical scale NK cell separation technology, with current methods performing sub-optimally due to loss of over 50% of the NK cells. Specifically, therefore, our objectives are: 1.To demonstrate significantly superior performance for T-cell depletion with the aim of achieving 5 log10 depletion of T cells, with >90% recovery of CD34+ cells in greater than or equal too 80% of clinical apheresis samples obtained from normal donors. 2. To demonstrate significantly superior performance of NK cell isolation with the aim of isolating CD56+ CD3- NK cells with > 90% recovery and with <1 x 10/5 CD3+ cell contamination in greater than or equal to 90% of peripheral blood apheresis products processed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HTLV INFECTION ON HEMATOPOIESIS Principal Investigator & Institution: Feuer, Gerold; Microbiology and Immunology; Upstate Medical University Research Administration Syracuse, Ny 13210 Timing: Fiscal Year 2002; Project Start 16-APR-1998; Project End 31-MAR-2003 Summary: The development of adult T cell leukemia (ATL) correlates with HTLV-1 infection at the perinatal or postnatal stage in humans and the thymus may be a critical target organ in the establishment and maintenance of infection. HTLV can productively infect human hematopoietic progenitor (CD34+) cells and these stem cells transmit viral infection when implanted into the human thymus engrafted in SCID-hu mice. The goal of this proposal is to characterize the events involved in HTLV infection in the thymus and to establish an in vivo model of viral leukemogenesis. Additionally, the HTLV tax1 or tax2 oncogenes will be transduced into hematopoietic stem cells, using retroviral expression vectors, to evaluate the effect of Tax on the differentiation of hematopoietic stem cells in vitro and in vivo. It is hypothesized that the establishment of persistent HTLV-1 or -2 infection and/or tax gene expression in CD34+ cells and prothymocytes results in the perturbation of lymphopoiesis and that this is a predisposing factor for leukemogenesis. The Specific Aims of this proposal are: 1. Establish HTLV-1 and -2 infection in human hematopoietic progenitor (CD34+) cells and characterize the effects on hematopoiesis. HTLV infection of CD34+ cells will be analyzed to quantify the effect on the differentiation of stem cells in vitro and to determine if viral gene expression is maintained in differentiated progeny cells. 2. Study the effect of HTLV infection on TIymphopoiesis in vivo. Reconstitution of SCID-hu mice with infected CD34+ cells will determine if establishment of high levels of HTLV can perturb the development of T cells in the thymus and whether these mice develop leukemia. 3. Determine the role of tax expression on the differentiation of hematopoietic progenitor cells in vitro and on transformation of human thymocytes in vivo. High-efficiency transduction of the tax genes into CD34+ cells will be accomplished by pseudotyping retroviral expression vectors with VSV-G envelope and selecting transduced stem cells to test whether Tax can transform human thymocytes in vivo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HUMAN NEURAL STEM CELLS TARGET GENE THERAPY-BRAIN TUMORS Principal Investigator & Institution: Mcgrogan, Michael P.; Vice President; Layton Bioscience, Inc. 709 E Evelyn Ave Sunnyvale, Ca 94086 Timing: Fiscal Year 2002; Project Start 26-JUN-2000; Project End 31-JUL-2004 Summary: Neural stem cells (NSCs) show a remarkable ability to migrate throughout the CNS, intermingle with host cells, and express foreign transgenes following transplantation. Intriguingly, this inherent migratory property of NSCs emulates the migratory pattern of some brain tumors, such as gliomas, characterized by invasive single cell migration. Potentially, the migratory properties of NSCs can be harnessed to disseminate therapeutic genes products to invading brain tumor cells. As the first step toward this goal, results from phase I studies demonstrated that human NSCs displayed significant tumor targeting migratory behavior toward gliomas while stable expressing a reporter gene. Phase II entails genetically modifying NSCs to express an array of therapeutic genes, and then assessing their potential to target tumor cells and elicit an anti-tumor response. It is anticipated that genetically modified NSCs will infiltrate the tumor mass, track individual tumor cells, and stably express oncolytic proteins that can destroy the cancerous cells in rodent models. These studies will advance the
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development of a potentially revolutionary treatment strategy using human NSCs as a novel, efficient delivery vehicle to target therapeutic genes to refractory brain tumors. PROPOSED COMMERCIAL APPLICATIONS: Neural stem cells represent a compelling new technology platform for the treatment of neurological diseases. Their natural migratory capacity provides a powerful vehicle to target therapeutic agents directly to refractory brain tumors. This project will evaluate an array of therapeutic genes to expedite the development of a potentially revolutionary cancer therapy strategy to treat deadly brain tumors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMMUNODEFICIENT MOUSE MODEL OF STEM CELL PLASTICITY Principal Investigator & Institution: Nolta, Jan A.; Associate Professor; Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2005 Summary: (provided by applicant): Recent intriguing observations indicate that stem cell plasticity may exist. Rodent bone marrow cells have been shown to contribute to liver, skeletal and cardiac muscle. These extremely exciting findings could impact health care in a dramatic way in the future, if applicable to the human system. Marrow stem cells could theoretically be harvested from a patient and used to repair his or her damaged heart, muscle tissue, or liver. In order to realize this potential, the scientific community must determine the phenotype(s) of the human counterparts to the murine cells that have displayed plasticity, must determine whether a single totipotent stem cell from human marrow is capable of differentiation into tissue and blood, and must optimize isolation and transplantation of the totipotent cells. We hypothesize that there are true totipotent cells that reside in the adult human and mouse bone marrow and in neonatal umbilical cord blood. We hypothesize that common stem cells exist for blood and liver, and that in the human, their phenotype will be plastic non-adherent CD34/lin-, and in the mouse their phenotype will be plastic non- adherent SP or c-kit+Thy1.1(lo)Lin-sca-1+. We predict that human and murine cells that can repair muscle are actually plastic adherent mesenchymal stem cells (MSC) and will not generate blood cells. We will use our novel immunodeficient nude/NOD/SCID mouse strain, which has a lifespan of two years, as the recipient for marked stem cells of defined phenotype, isolated from murine bone marrow, human marrow, and human umbilical cord blood. Retroviral and lentiviral vector marked MSC and HSC fractions from each source will be assessed in vivo for their capacity to form blood cells and muscle, following muscle injury, or blood cells and liver, following liver injury to the recipient. Clonal integration analysis at the single cell level, with sequencing, will determine whether the progeny were derived from the same precursor, or from discrete stem cells. We will also determine whether it is possible to modulate the survival, differentiation, and recruitment of candidate murine and human totipotent stem cells to specific tissues by expression of supraphysiological levels of Hepatocyte Growth Factor/Scatter Factor (HGF/SF). HGF is a chemoattractant and viability factor that is elevated in injured liver, cardiac, and skeletal muscle. HGF affects the motility and maintains the viability of myoblasts, hepatic oval cells, and hematopoietic stem cells. We hypothesize that HGF, secreted locally in response to tissue injury, is a major factor in recruiting totipotent stem cells from the circulation into the site of muscle or liver injury. We hypothesize that HGF may maintain the viability of recruited, totipotent stem cells, while they are directed by other inductive, tissue-specific factors in the local microenvironment to differentiate, to regenerate the damage tissue. The impact of HGF on the recruitment, survival and differentiation of human and murine totipotent stem cell candidates will
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be tested in vitro and in vivo. Our studies will provide definitive proof that stem cell plasticity exists, will identify the phenotypes of the murine and human cells that can generate liver or muscle tissue in addition to blood cells, and will determine methods to enhance the recruitment of those cells to damaged tissue. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IN UTERO STEM CELL TRANSFER IN MPS VII Principal Investigator & Institution: Barker, Jane E.; Senior Staff Scientist; Jackson Laboratory 600 Main St Bar Harbor, Me 04609 Timing: Fiscal Year 2003; Project Start 30-SEP-1994; Project End 31-JUL-2007 Summary: (provided by applicant): Progressive childhood diseases should be treated before pathological sequelae are evident. A technically promising but underdeveloped approach experimentally and clinically is in utero transplantation. Two major causes for unsuccessful human in utero therapy were identified by animal studies. They are microrather than macro-chimerism following congenic and allogeneic transfers and allogeneic donor cell rejection initiated by unexpected and inexplicable immune complications. It is critical that we understand the mechanisms behind these failures and develop alternative approaches to correct them. This is the goal of our current proposal. We investigate stem cell biology and curative interventions in Mucopolysaccharidosis type VII (MPS VII) mice, a model that mimics human lysosomal storage diseases. MPS VII mice lack the enzyme beta glucuronidase (GUSB). This allows us to track and enumerate GUSB+ donor cells by histochemistry and confirm our results by flow cytometry, biochemistry, and pathogenesis. Disease symptoms are ameliorated by enzyme replacement. We compared repopulation in genetically myeloablated and non-ablated MPS VII fetal recipients of congenic fetal GUSB+ hematopoietic cells. Results indicate that the donor cells do not have a selective advantage as previously hypothesized in the rapidly growing nonablated fetuses. Surprisingly, donor cells do amplify modestly between birth and one week of age and are maintained at a low percentage long term. Donor cells undergo rapid proliferation within 24 hours in the genetically myeloablated fetus and increase thereafter until they completely repopulate the host. We predict that donor cell amplification is directly linked to levels of stem cell implantation. Following allogeneic transfers, there are reasons to believe that the dam and fetus supply immunologically competent cells to one another and that allogeneic donor cell expansion after birth occurs in a hostile environment. We hypothesize that significant allogeneic donor cell implantation and expansion can be effected in utero without serious immune consequences. Our aims are to: Determine if donor stem cell implantation levels in utero affect subsequent stem and differentiated cell amplification; Identify procedures that increase corrective donor cells in the fetus; Define the role of dam and fetal immune response in allogeneic in utero transplantation; and Block immune responses to allogeneic cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: INDUCTION AND MAINTENANCE OF PLURIPOTENT-PLASTIC STATE Principal Investigator & Institution: Asch, Adam S.; Associate Professor of Medicine; Medicine; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2005 Summary: (provided by applicant): Recently, the traditional view that somatic stem cells remain faithful to their tissue of origin has been challenged. The capability of
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muscle-derived, and neural-derived cultures to produce cells capable of hematopoietic reconstitution following transplant, as well as the ability of hematopoietic cultures to give rise to muscle cells raises profound questions about the plasticity of somatic cells. The possibility that such plasticity might be exploited for therapeutic potential is compelling and makes a better understanding of its nature and the ways in which might be regulated of great interest. Plasticity, or the ability of cells that we think of as being lineage committed, to generate an alternative tissue or cell type must require the cells to reprogram and take an alternative developmental path. This must be true even of the stem cell populations within a tissue. An understanding of the basic mechanisms that define the pluripotent and plastic state somatic stem cells is the focus of this proposal. Our hypothesis is that the plasticity of stem cells a function of the translational repression of critical transcription factors present in the pluripotent stem cell. Plasticity, we also hypothesize, involves inhibition of expression of lineage defining transcripts already present within a cell resetting the developmental program along an alternative developmental pathway. To date, a proteomic approach to defining gene expression has not been undertaken. We have explored a novel and robust method for defining the change in translation upon the differentiation of stem cells. Using this approach we will be able to identify and study transcripts that are translationally repressed in the plastic/pluripotent state and gain an understanding of the basic mechanisms that underly plasticity and pluripotency. Specifically we will 1) identify critical translationally regulated mRNA transcripts and define an accurate picture of overall gene expression in the pluripotent cell by quantitating polysome-associated transcripts and their translational state using a rapid throughout screening assay in an in vitro model of stem cell plasticity; 2) define the mechanisms of translational regulation in transcripts critical to plasticity and pluripotency; and 3) define the role of translational regulation in modulating and maintaining pluripotency. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INITIAL CHARACTERIZATION OF PIG HEMANGIOBLASTS Principal Investigator & Institution: Quertermous, Thomas; Professor; Medicine; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 15-JUN-2001; Project End 31-MAY-2004 Summary: (Verbatim from the application): Multipotent stem cells exist in a variety of embryonic and post-embryonic tissues, and include neural and hematopoietic stem cells. These cells, which have the ability to both self-renew and differentiate in response to biological stimuli, hold great potential for replacing damaged or diseased tissues. The greatest utility for such cells will be in their application to the treatment of cardiovascular disease. Specifically, hemangioblastic stem cells will provide for cellular angiogenic therapy, and allow modulation of the immune system for cardiac xenotransplantation. There is mounting evidence that human and mouse hemangioblasts exist in embryonic life and may persist into adulthood. Understanding the conditions which control their expansion and differentiation would facilitate direct investigation of these cells in treating pathologic conditions. The full therapeutic potential of stem cells can only be realized if they are characterized and isolated to near homogeneity in animal models relevant to human disease. We propose to isolate and characterize hemangioblasts from pigs by cloning and developing antibodies to highly conserved stem cell markers. The pig has distinct advantages in applied animal research because of its size, hemodynamic similarity to humans, and breeding characteristics. Pigs are used extensively to test percutaneous vascular interventions, and they are also the most likely animal source for organ xenotransplantation. The specific aims of this
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proposal are: 1) To isolate pig blood and bone marrow cells which lack features of terminal differentiation, and which express hemagioblast-associated surface antigens using newly generated pig-specific antibodies. Isolated cell populations will be adapted to culture. 2) To characterize the vascular and hematopoietic potential of the above isolated cell populations in vitro, and assess their self-renewing potential. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ISOLATION OF INTESTINAL EPITHELIAL STEM CELLS Principal Investigator & Institution: Henning, Susan J.; Professor; Pediatrics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 02-AUG-2002; Project End 31-JUL-2004 Summary: (provided by applicant): Currently there is considerable interest in adult stem cells from a variety of tissues because of their potential to contribute to our basic understanding of differentiation and development as well as their long-term therapeutic potential. Of all adult tissues, the small intestinal epithelium has by far the most stem cells and the highest rate of turnover. The intestinal stem cells are located deep in the crypts of Leiberkuhn and have been demonstrated to be multipotent precursors of the 4 principal lineages within the epithelium. Although the in vivo behavior (e.g. kinetics) of intestinal stem cells has been studied for many years, our understanding of the properties of these cells has been greatly hampered by lack of methods to isolate, identify and characterize them. Likewise, there is currently a lack of suitable cell transplantation models in which to study proliferation and differentiation of putative intestinal epithelial stem cells. Finally, in light of recent findings in both mice and humans, the possibility that stem cells from other tissues make a quantitatively significant contribution to the intestinal epithelium appears worthy of investigation. Thus, the Specific Aims of this exploratory R21 proposal are: 1) To develop flow cytometry methods for isolation of viable stem cells from the epithelium of mouse small intestine. Specifically, to subject intestinal epithelial cells to novel sorting procedures that have been successfully used with bone marrow cells to identify a fraction which is highly enriched in stem cells; 2) To develop a mouse model with local, limited sterilization of intestinal crypts to create an ideal region for subsequent transplantation of putative epithelial stem cells; 3) To transplant putative intestinal epithelial stem cells into damaged regions of mouse small intestine and subsequently assess the morphology as well as the expression of lineage-specific markers in epithelium derived from the transplanted cells; and 4) To repeat the studies of Specific Aim 3 using bone marrow hematopoietic stem cells. These studies should set the stage for a variety of future investigations regarding both the basic biology and the therapeutic potential of intestinal epithelial stem cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ISOLATION OF LIMBAL EPITHELIAL STEM CELLS Principal Investigator & Institution: Lavker, Robert M.; Professor; Dermatology; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2004 Summary: (Applicant's Abstract) Epithelial stem cells are responsible for the homeostasis of self-renewing epithelia. Moreover they play a central role in wound repair and are the target cell for tumor initiation. My work during the past decade has contributed to the identification of stem cells within the corneal epithelium. Isolation of limbal epithelial stem cells will greatly facilitate their characterization. Furthermore,
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isolation of pure populations of limbal stem cells will provide the ultimate starting material for epithelial cells needed for transplantation in corneal reconstruction. The lack of specific markers for epithelial stem cells has become a major impediment in their isolation and subsequent biochemical characterization. The goal of this project is to identify specific markers for limbal epithelial stem cells. Towards this end we will: 1) use single cell technology in combination with molecular biology to obtain mRNA from limbal epithelial stem cells and corneal epithelial transit amplifying (TA) cells; 2) use suppressive subtractive hybridization (SSH) and cDNA microarrays to identify genes that are differentially expressed in limbal epithelial stem cells versus corneal epithelial TA cells; and 3) characterize the limbal epithelial stem cell-specific genes and investigate their potential function(s), focusing on those genes that are associated with the cell surface. Data obtained from these studies should lead to the isolation of pure populations of limbal epithelial stem cells. This will facilitate the biochemical characterization of these cells, and will provide a better understanding of the mechanisms involved in the self-renewal of stem cells, and in the mechanisms of limbal and corneal epithelial growth and differentiation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ISOLATION OF MURINE PANCREATIC LIVER STEM CELLS Principal Investigator & Institution: Grompe, Markus C.; Professor; Molecular and Medical Genetics; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2005 Summary: (provided by applicant): Many organs depend on highly regenerative stem cells for tissue renewal after injury or during normal turnover. During embryonic development a common endodermal pre-cursor/stem cell gives rise to both the hepatic and pancreatic parenchyma, including the ductular, exocrine and endocrine components of the pancreas. The isolation and purification of this hepato-pancreatic stem cell would greatly advance the understanding of the biology of the pancreas and possibly generate a therapeutic agent for the treatment of diabetes. The hematopoietic stem cell was identified by a biological assay, the ability to reconstitute the blood and immune system of a host after lethal irradiation. Unfortunately, a transplantation based in vivo repopulation assay for pancreatic stem cells has not been developed. However, several independent lines of evidence suggest that adult mouse pancreas continues to contain cells which can give rise to hepatocytes under certain experimental conditions. The fumarylacetoacetate hydrolase knockout mouse represents a robust liver repopulation assay in which permits the identification of cells that have the capacity to regenerate the liver. Preliminary data have shown that adult murine pancreas contains cells, which have high liver repopulating capacity (pancreatic liver stem cells). We hypothesize that the repopulating activity is a primitive endodermal precursor capable of giving rise to multiple cell types including hepatocytes, bile ducts, pancreatic ducts, acinar cells and endocrine cells. This application pertains to the use of liver repopulation as a surrogate assay for primitive murine pancreatic stem cells. The assay will be used to develop methods for their optimal isolation. Monoclonal antibodies useful for FACS sorting of pancreatic cells will be generated. We will apply cell-sorting methods to enrich pancreatic liver stem cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MARKING PROGENITOR CELL LINEAGES IN THE VASCULAR SYSTEM Principal Investigator & Institution: Stuhlmann, Heidi; Associate Professor; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2005 Summary: (provided by applicant): Stem cells are self-renewing, pluripotent cells that can give rise to multiple cell lineages and/or cell types of the body. The development of human and mouse embryonic stem cells and the isolation of adult stem cells have received much attention. The possibility of using stem/progenitor cells to replace damaged or diseased human tissue has been widely publicized. One application of this technology would be to repair damaged cardiac and vascular tissue; however, this will first require identification and characterization of vascular stem/progenitor cells. The goal of this project is to identify and characterize vascular stem/progenitor cells and to explore their developmental potential in vitro and in vivo. We will mark early vascular progenitor cells with an autofluorescent reporter suitable for flow cytometry, such as enhanced green fluorescent protein (EGFP). We will "knock-in" the auto fluorescent tag into the endogenous locus of early endothelial genes in mouse embryonic stem (ES) cells. Second, we will isolate and characterize marked progenitor populations from differentiating ES cells and embryonic yolk sac membranes. Third, we will examine the lineage differentiation potential of these progenitor cells in vitro and in vivo. We anticipate that this project will provide important insights into the nature of stem cells at the beginning of the vascular system, and possibly common to the hematopoietic and endothelial lineages. Ultimately, these studies will address basic questions of using stem cells for damaged or diseased blood vessels. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: METHODS DEVELOPMENT
FOR
MODULATING
HEMATO-VASCULAR
Principal Investigator & Institution: Baron, Margaret H.; Associate Professor; Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2003; Project Start 20-SEP-2003; Project End 31-JUL-2008 Summary: (provided by applicant): The first organ system to form in the developing mouse embryo is the cardiovascular system. Defects within the heart and vasculature are largely responsible for embryonic lethality in utero. Within the developing vascular network of the yolk sac as well as in certain intra embryonic regions, endothelial and hematopoietic cells arise in close spatial and temporal association and are thought to derive from a common mesodermal progenitor, the "hemangioblast." Recent work has indicated that hemangioblasts may also have smooth muscle cell potential. Regulation of hemangioblast and embryonic hematopoietic stem cell formation and cell fate specification are still not well understood. This proposal focuses on the characterization and functional analysis of specific subsets of mesodermal cells that give rise to hematopoietic, vascular endothelial, and smooth muscle cells during development. First, we will evaluate the hematopoietic potential and functional activity in vitro and in vivo of prospectively identified mesodermal stem/progenitorcell populations from differentiating embryonic stem cells (embryoid bodies) and from early mouse embryos. Cells will be isolated by flow cytometry on the basis of their expression of primitive cell surface markers and, using a GFP reporter transgene, on the basis of their expression of mMix, a homeodomain transcriptionfactor expressed in embryoid body subsets thought to contain hemangioblasts. The sorted cells will be analyzed using several different
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assays for stem/progenitor cells in culture and transplantation models in the mouse. Second, in analogous studies, we will evaluate the endothelial and smooth muscle potential and functional activity in vitro and in vivo of prospectively identified mesodermal stem/progenitor cell populations. Third, we will evaluate the role of the Mix homeodomain protein on the developmental potential and functional activity in vitro and in vivo of embryoid body derived mesodermal stem/progenitor cell populations. The origin of embryonic hematopoietic / vascular stem cells and their relationship to stem cells of the adult are unknown. With the increasing focus on regenerative medicine and interest in potential therapeutic applications of human embryonic and adult stem cells, the characterization of mesodermal stem/progenitor cell populations takes on high significance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MODEL AGAMMAGLOBULINEMIA
FOR
GENE
THERAPY
IN
X
LINKED
Principal Investigator & Institution: Rawlings, David J.; Associate Professor; Pediatrics; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-JUN-1999; Project End 31-MAR-2004 Summary: (Adapted from applicant's abstract). Human X-linked agammaglobulinemia (XLA) results from deficient function of Bruton's tyrosine kinase (Btk). In affected males, the production of B lineage cells is profoundly reduced resulting in life threatening humoral immunodeficiency. Definitive genetic therapy utilizing expression of wild type Btk in stem cells or B lineage progenitors would represent a significant advantage over the current supportive management of XLA. The Investigator proposes to establish preclinical cellular models for the genetic treatment of XLA through three aims. Aim 1. Development of a multistage human B cell culture system that can be used to evaluate reconstitution of B cell function in vitro. The Investigator will improve the derivation of B cells representing multiple stages of the B lineage from long-term human B progenitor cell cultures. This will be done by exploiting a range of culture modifications and signals that lead to activation, maturation, and production of secreted immunoglobulin by immature B cells. Soluble factors and cell surface ligands on stromal cells will be evaluated. The Investigator will also utilize in vivo transfer studies in SCID/NOD mice. Aim 2: Development and testing of the capacity of retroviral vectors capable of high level, sustained expression in hematopoietic stem cells, and of novel hybrid adenoviral/EBV episome vectors for Btk gene transfer and rescue of Btk signaling in vitro. Alternative gene transfer systems will be evaluated using a new signaling competent human B cell model developed by the Investigator's laboratory. This will allow the Investigator to rapidly test the transduction efficiency, and the levels and duration of protein expression of alternative vectors. In addition, the Investigator will directly evaluate the capacity of these vectors to rescue Btk dependent signaling events and determine the dosage of Btk required for functional reconstitution in human B cells. Aim 3. Evaluation of the capacity of those gene transfer vectors that successfully restore Btk signaling in vitro to reconstitute Btk dependent immune function in vivo in Btk-/mice, and ultimately, in vitro in long term cultured XLA B cells. The Investigator will evaluate gene transfer using hematopoietic stem cells and growth factor expanded B progenitors from Btk-/-mice as target cell populations. Reconstitution of B lineage development and function will be evaluated using multiple measures of Btk dependent immune function. Those vectors demonstrating optimal restoration of Btk function in vivo will be utilized for gene transfer into stem cells or B progenitors in pre-clinical studies of patients with XLA.
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Stem Cells
Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR & CELLULAR BIOLOGY OF HAIR FOLLICLE STEM CELLS Principal Investigator & Institution: Lyle, Stephen R.; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: (provided by applicant): The overall goal of this project is to characterize the expression of genes within hair follicle stem cells and to study the role of specific genes in maintaining the stem cell phenotype. The hair follicle is a model for studying epithelial stem cells and understanding the mechanisms which maintain the homeostasis of hair follicle stem cells and may lead to advances in the areas of tumorigenesis, wound healing and hair disorders. Similar to other self renewing tissues, such as bone marrow, gastrointestinal tract and epidermis, the hair follicle contains slowly cycling stem cells with a high proliferative capacity and the ability to produce differentiated cells to regenerate the tissue. Unlike other tissues, however, hair follicle growth (anagen) is interrupted by periods of regression (catagen) and rest (telogen), with subsequent regeneration. Since the lower follicle degenerates in the catagen phase, leaving only the telogen club structure, this residual epithelial cap surrounding the club hair represents an enriched source of stem cells which are responsible for regenerating a new lower follicle in anagen. They have extracted RNA from the stem cell rich area of telogen follicles as well as from the bulb area of anagen follicles dissected from human scalp. Through cDNA expression arrays, a number of genes appear to be expressed in the stem cell area that are not expressed in matrix keratinocytes of the anagen bulb. Several of the genes have been shown to mediate proliferative behavior and differentiation pathways in other experimental systems. The hypothesis that will be tested in this proposal is that specific genes expressed in the stem cells of the hair follicle are important in maintaining stem cell properties. The specific aims are: 1. To characterize the expression of specific genes identified by the expression array through in situ hybridization, immunohistochemistry and immunofluorescence with confocal microscopy. Three genes which likely have roles in maintaining stem cell properties will be examined. 2. To test the significance of these three genes in maintaining in vitro properties of hair follicle stem cells through retroviral transfection of human hair follicle stem cells with wild type and mutant gene constructs. Clonogenicity assays and other in vitro experiments of native and transfected stem cells will be used to study the role of these genes in clonality and other stem cell attributes. 3. To test the function of the specific genes during hair follicle development and cycling through in vitro and in vivo methods. Hair reconstitution assays performed with native and genetically altered stem cells will be used to analyze potential functions in folliculogenesis and cycling. In addition to the established mouse hair reconstitution system, they will attempt to develop a human hair follicle reconstitution system from hair follicle stem cells and microdissected dermal papillae using acellular dermal analogues with transplantation onto athymic mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MOLECULAR CONTROL OF PANCREATIC ISLET DEVELOPMENT Principal Investigator & Institution: German, Michael S.; Associate Professor of Medicine; Hormone Research Institute; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2005
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Summary: The objective of this Program Project is to bring together four research groups and to apply their complementary expertise to the problem of how undifferentiated cells develop into insulin-secreting beta-cells in organizing islets of Langerhans. Deriving data from zebrafish, chicks, mice, and humans, each project focuses on different but overlapping steps in the progression from embryonic stem cells to organized islets. Ultimately this information will be applied to the development of strategies for the production of new islets for patients with diabetes. Project 1 (Bell) will focus on the identification, characterization and purification of pancreatic stem/progenitor cells. Using progenitor-specific promoters developed by German, cells at discrete stages of differentiation will be fluorescently tagged in transgenic mice. These mouse models will be used to isolate and characterize presumptive pancreatic stem/progenitor cells. In addition, genes involved in islet development identified by German, Hebrok and Stainier will be screened for mutations in human populations. Project 2 (German) will focus on the progression of pancreatic progenitor cells to differentiated beta-cells utilizing the fluorescent transgenics derived by Cell, transcription factor knockout mice previously developed in this lab, and the microarray core. These studies will generate a picture of the gene expression changes that occur during beta-cell genesis, and provide candidate genes will be tested for their ability to affect the beta- cell fate decision in collaboration with Bell, Hebrok, and Stainer. Project 3 (Hebrok) will study endocrine cell migration and islet formation. Using mouse genetic models, he will test the role of migration guidance molecules and extracellular matrix modulators in islet morphogenesis and function. He will test the hypothesis that proper islet formation is critical for optimal islet function and homeostasis both in mice (with German) and humans (with Bell). Project 4 (Stainer) will examine the role of endoderm specification from zebrafish in activating the endodermal program in embryonic stem cells, the first step in the pathway to differentiated beta-cells. The zebrafish model will also be used in two collaborations with German: first to characterize the function of progenitor-specific promoters and second to test the role of candidate beta-cell determination genes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EXPRESSION
MOLECULAR
MECHANISMS
THAT
REGULATE
CD11D
Principal Investigator & Institution: Noti, John D.; Associate Professor; Guthrie Foundation for Education and Res Education and Research Sayre, Pa 18840 Timing: Fiscal Year 2002; Project Start 15-AUG-2001; Project End 31-JUL-2005 Summary: The development of the myeloid lineage from totipotent stem cells is the result of the expression of transcription factors that are either constitutively expressed or differentially induced at specific times during differentiation. A number of key transcription factors have been found that direct myeloid development. A number of specific genes affected by these transcription factors have been revealed and their expression contributes to the overall phenotype of myeloid cells. Understanding the process of normal myeloid development will require the identification of transcription factors and their co- factors that activate or silence lineage-specific genes. The restricted pattern of expression of the leukocyte integrin CD11d serves as an excellent model to identify some of these factors. CD11d is expressed on stem cells, myelomonocytic cells, and strongly on macrophage foam cells, and splenic red pulp and alveolar macrophages. Its expression pattern clearly differs from myeloid-specific leukocyte integrins CD11b and CD11c. We determined that CD11d is regulated during myeloid differentiation of stem cells, and during differentiation of monocytes to macrophages and foam cells. We propose that myeloid-specific transcription factors can be identified
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Stem Cells
with a study of the CD11d promoter. Further, identification of cis elements and the interacting transcription factors that control CD11d expression could provide a means to direct expression of specific genes to myeloid cells in gene therapy approaches. The goals of this project are to identify myeloid-specific transcription factors that control CD11d expression and test their role in myeloid differentiation. We present evidence for 3 sites within a region in CD11d that confer myeloid-specificity, and that transcription factors that bind this region affect myeloid differentiation. One-hybrid analysis of this region led to the isolation of two myeloid-specific cDNAs. We also present evidence that CD11d expression and foam cell development may utilize shared transcription factors. Two silencers, one being cell-specific, are also in the CD11d locus. We propose to further characterize these and possibly other essential cis elements by site-directed mutagenesis, transfection analysis, DNase I hypersensitivity, mobility shift and DNase I footprint analyses. Yeast one-hybrid technology will be used to isolate novel myeloid-specific transcription factors. Model systems in which to study the CD11d promoter and myeloid-specific factors will include embryonic stem cells, peripheral blood monocytes, and myeloid cell lines. Identified factors will be up- or downregulated through forced overexpression or antisense approaches to determine their effect on myeloid differentiation. Transgenic analysis of the CD11d cis elements will be done to complement these studies. These studies will expand our understanding of normal myeloid development and leukemogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOUSE MODELS OF EARLY INTESTINAL NEOPLASIA Principal Investigator & Institution: Shibata, Darryl K.; Professor; Pathology; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2003; Project Start 01-JAN-1999; Project End 31-MAR-2008 Summary: (provided by applicant): Human cancers contain multiple mutations and it is uncertain which mutations are necessary and sufficient, which are passive passenger mutations, and whether there are other yet undiscovered mutations crucial for transformation. One prospective approach to better understand the roles of specific mutations is to engineer these mutations in normal cells. We propose to engineer tumors in mice by sporadically and somatically creating "mutant" stem cells with defined genotypes. Unlike most mice models, our approach will better mimic sporadic tumorigenesis because Cre-mediated inactivation of floxed tumor suppressor genes (TSGs) will stochastically occur in isolated, widely scattered single cells. A nonfunctional out-of-frame (An+l) germline Cre-allele will become activated (An+l to An) in a DNA mismatch repair deficient background and subsequently recombine floxed genes to create well-defined mutant genotypes. A current An+l transgenic Cre allele will be targeted to the ubiquitously expressed ROSA26 locus to better control its activation. Similar to sporadic tumorigenesis, stochastic and somatic mutations will occur in single cells surrounded by normal cells. Our studies will examine sporadic Apc, Pten, or Trp53 inactivation in the intestines. Because it is uncertain how many mutations are required for transformation, a floxed B-galactosidase allele will be included so that "mutant" cells may be identified regardless of resultant phenotype. Certain TSGs may modulate stem cell survival, and even though loss of a single TSG may not confer a neoplastic phenotype, stem cell survival may be increased, resulting in greater numbers of blue staining "mutant" cells in otherwise normal appearing intestines. Multistep tumor progression implies that cancers arise after a series of mutations. These studies will prospectively recreate this process and define the fates of single stem cells in normal mammalian tissues that acquire one or more concomitant gene alterations. The
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success or failure of certain mutations to confer neoplastic phenotypes will challenge or confirm canonical tumor progression models. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MPTP-INDUCED HOMING OF BONE MARROW STEM CELLS TO THE BR* Principal Investigator & Institution: Cunningham, Lee A.; Associate Professor; Neurosciences; University of New Mexico Albuquerque Controller's Office Albuquerque, Nm 87131 Timing: Fiscal Year 2002; Project Start 15-FEB-2002; Project End 31-JAN-2004 Summary: Bone marrow-derived stem cells incorporate into multiple tissue types in adult mammals, where they give rise to cells of multiple lineages that cross classic embryological trilaminar boundaries [9,11,17,21,31,40,41]. This recent discovery has opened the possibility that bone marrow transplantation could be clinically useful to treat a broad spectrum of pathologies. Recently, marrow-derived progenitor cells have been shown to migrate and incorporate into the brain to give rise to cells of neuroectodermal lineage, (astrocytes and neurons), in addition to microglia [4,7,25]. Importantly, marrow-derived progenitors appear to display preferential homing to regions of CNS gliosis and degeneration [8], consistent with studies in peripheral tissues demonstrating enhanced engraftment of multi-potential marrow-derived stem cells into sites of injury [21,31] [Jackson, 2001 #360]. The focus of the current proposal is to explore the migration and differentiation of marrow-derived stem cells into the brain in a rodent model of Parkinson's disease, the MPTP-treated mouse. Questions to be addressed in this proposal include: Do marrow-derived progenitors display selective homing to the damaged nigra and striatum in response to MPTP-induced degeneration? If so, do they give rise to cells of neuroectodermal lineage? What is their contribution to the gliosis that accompanies nigrostriatal degeneration? To track marrow-derived progenitors within the CNS, we will utilize bone marrow from transgenic mice that express an enhanced green fluorescent protein (GFP) under the beta-actin promoter. The migration and differentiation of marrow-derived progenitors will be studied in chimeric mice whose endogenous hematopoietic systems have been completely reconstituted with GFP-expressing cells prior to MPTP- treatment, and in mice that receive acute intravascular injections of GFP+ expressing cells prior to MPTP-treatment, and in mice that receive acute intravascular injections of GFP+ expressing marrow following the onset of MPTP-induced degeneration. The immediate goal of the proposed studies is to delineate the relationship between marrow-derived progenitors and the brain in a rodent model of Parkinson's disease. If successful, these studies may provide the basis for future work to development new non-invasive gene therapies for Parkinson's disease, using accessible, renewable and autologous bone marrow stem cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MSC AS FACILITATORS OF TRANSPLANTION TOLERANCE Principal Investigator & Institution: Bartholomew, Amelia M.; Surgery; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 20-AUG-2001; Project End 31-JUL-2004 Summary: (provided by applicant): Transplantation tolerance, or the permanent acceptance of an allograft without the need for chronic immunosuppression, has remained clinically elusive. Strategies to induce tolerance through the production of lymphohematopoietic chimerism, though successful in small and large animal models,
36
Stem Cells
have been hampered by the toxicities involved in conditioning the recipient. Host conditioning regimens have traditionally required elements to eliminate or inactivate host-alloreactive T cells and cytoreductive treatment to liberate niches within the bone marrow microenvironment for allogeneic engraftment. Recent advances in stem cell biology have provided data indicating the requirement for cytotoxic therapy can be overcome by using very large doses of HSCs. Possible explanations of this observation have included improved competition of donor stem cells for marrow niches and diminished frequencies of cytotoxic T lymphocyte precursors by the direct interaction with hematopoietic stem cells. A component of the bone marrow that has largely been ignored and is poorly understood, is the MSC. These stromal elements, occurring in very low frequency, are multipotential cells that can be induced to differentiate into bone, muscle, adipocytes, myocytes, and brain and share many functional and phenotypical characteristics of thymic stromal cells. Further, they can provide regulatory signals that inhibit or promote lympho- and myelopoiesis, differentiation, and proliferation and secrete potent molecules, such as TGF-beta, SDF-1, IL-7, and FGF that affect T and B cell migration. Interestingly, the transplantation of bone fragments for stromal microenvironment in conjunction with HSCs has led to increased hematopoietic engraftment and transplantation tolerance. We have shown that transplantation of the bone marrow microenvironment without HSCs can also lead to the permanent acceptance of murine cardiac allografts. The separate contributions of bone and MSCs in these observations are unknown. Our preliminary studies suggest that MSCs can inhibit T cell proliferation in the mixed lymphocyte reaction, prolong skin graft survival in baboons, and home to the baboon bone marrow compartment, thereby potentially influencing the host microenvironment. These observations have led us to hypothesize that MSCs have immunomodulatory properties and play a major role in the induction of transplantation tolerance. The first specific aim will test the ability of mouse MSCs to engraft in the bone marrow and thymic microenvironments and to alter host T cell repertoire. The mechanism of effect on the host immune system will be explored to determine whether MSCs directly affect host T cells or whether MSCs induce a CD8 autoregulatory subset in the host. Specific aim 2 will test whether MSCs can function as facilitators of HSC engraftment in lethally irradiated mice. We will also test whether MSCs can eliminate the need for high dose HSC in minimally conditioned mice. Insights gained on the role donor MSCs play in allograft acceptance may then be applied to our pre-clinical baboon model for development of novel pre-clinical cellular therapies in transplantation tolerance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MUSCLE-DERIVED HEMATOPOIETIC STEM CELLS Principal Investigator & Institution: Goodell, Margaret; Assistant Professor; Pediatrics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-JUL-2005 Summary: (Investigator's abstract) Primitive stem cells are found in many adult tissues and, throughout life, replenish mature cells lost through attrition or injury. Although thought to be committed to differentiate into cells of their native tissues, some stem cells now appear capable of generating several different cell types, an indication that they have retained considerable plasticity in their genetic programs. The biologic and therapeutic implications of "transdifferentiation" potential are far reaching but will remain speculative until the concept is better substantiated and the mechanisms that might drive this process are known. Evidence from the applicant's laboratory indicates that adult murine skeletal muscle contains stem cells capable of complete hematopoietic
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regeneration. Thus, the central hypothesis to be tested is that these stem cells are a subset of myogenic stem cells known to participate in muscle regeneration, they share certain characteristics of bone marrow stem cells, have myogenic activity, are transducible with retroviral vectors, and can be found in human muscle. The major objectives of this proposal are to characterize the biologic properties and markers of muscle-derived hematopoietic stem cells by cell sorting and bone marrow transplantation experiments (Aim 1) so that the cells can be readily identified and purified, and their salient features an be compared with those of marrow-derived stem cells. It will also be important to assess the in vitro and in vivo myogenic potential of purified and clonal populations of muscle-derived hematopoietic stem cells (Aim 2). The results will establish whether or not the stem cells are bipotential precursors of both muscle and blood and therefore an extremely primitive stem cell with a flexible program of differentiation. If the muscle stem cells can be readily transduced with retroviral vectors and the modified cells shown to engraft and stably express a marker gene in transplant recipients (Aim 3), they may afford a novel means of delivering therapeutic genes of interest. Finally, results obtained in mice will need to be verified, both in vivo and in vitro, with stem cells derived from human muscle (Aim 4). Answers from these studies will be crucial in determining if human muscle could provide a source of hematopoietic stem cells for therapeutic exploitation. Successful completion of these aims will not only provide an estimate of the hematopoietic potential of adult muscle-derived stem cells, but also a foundation for future studies into the mechanisms of stem cell transdifferentiation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEUROECTODERM DIFFERENTIATION FROM MESENCHYMAL STEM CELL Principal Investigator & Institution: Verfaillie, Catherine M.; Professor; Medicine; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2005 Summary: (provided by applicant): We identified a population of primitive cells that is co-selected when MSC are purified from human or rodent marrow that have, at the single cell level, multilineage differentiation and extensive proliferation potential, which we named Multipotent Adult Progenitor Cell or MAPC. MAPC differentiate in vitro into most mesodermal cell types as well as cells with neuroectodermal and endodermal features. Using retroviral marking we have preliminary evidence that multi-lineage differentiation is derived from single cells. We have also initial evidence that MAPC engraft in vivo, persist for 2+ months, and may be able to differentiate into tissue specific cells in response to local "cues", even though single cell origin of the engrafted cells that differentiate in multiple tissue specific cells has not yet been proven. Our finding that MAPC differentiate into cells with not only mesodermal but also endodermal and neuroectodermal characteristics in vitro and engraft in multiple tissues when transplanted, is consistent with recent publications showing that marrow derived cells can acquire markers of muscle, endothelium, liver and neuroectoderm in vivo. If proven further, such previously unrecognized plasticity of post-natal stem cells opens the exciting possibility that post-natal stem cells from easily accessible sources such as marrow could be used to treat a number of degenerative or inherited disorders. However, many questions remain, including 1) What is the nature of the stem cell with plasticity? 2) Is plasticity due to co-existence of multiple tissue specific stem cells in the marrow, or can a single cell differentiate into most tissue cells? 3) What is the mechanism underlying the commitment and differentiation of presumed multipotent
38
Stem Cells
marrow derived mesenchymal stem cells to non-mesenchymal lineages? 4) Can presumed multipotent mesenchymal stem cells repopulate organs other than marrow? 5) Will high level engraftment and differentiation in vivo require that these multipotent mesenchymal stem cells are induced to commit to the host organ tissue prior to transplantation? 6) Can multipotent mesenchymal stem cells be used in stead of organ specific stem cells to repopulate an organ in vivo? We propose the following specific aims: SA1: To demonstrate that multipotent cells exist in post-natal marrow that, at the single cell level, can differentiate into cells of mesodermal and neuroectodermal lineage. Specifically, we will demonstrate using in vitro clonal assays that single cells from murine marrow can proliferate without senescence and can at the single cell level differentiate into cells of mesodermal and neuroectodermal lineage. We also plan to assess the frequency of cells with these characteristics in MSC and develop methods to purify such cells. SA2: Can MAPC differentiate into functioning neurons in vitro and what are the intermediary cell types that are generated? We plan to use neuroectodermal differentiation from MAPC to evaluate the plasticity of somatic stem cells. We will examine the degree of differentiation that can be obtained, and also examine the mechanism of commitment and differentiation of MAPC by comparing the nature and potential of intermediary progenitors and precursors that are generated from MAPC with that of brain derived neuroprogenitors. SA3: Can MAPC differentiate into functioning neurons in vivo? We will evaluate whether multipotent marrow derived stem cells or their neuroectodermal committed progeny repopulate the host brain in vivo and acquire region specific differentiation characteristics in response to local cues. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OSTEOGENIC POTENTIAL OF HUMAN BONE MARROW CELLS Principal Investigator & Institution: Long, Michael W.; Professor; Pediatrics & Communicable Dis; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2007 Summary: (provided by applicant): This proposal seeks to understand the nature and degree to which human stem cells can form cells of the osteogenic lineage. The central hypothesis is that expression of osteogenic potential resides within a single population of multipotent stem cells that phenotypically differs depending upon its locale. We will test this hypothesis by examining three populations of cells reported to have osteogenic potential: bone marrow hematopoietic cells (focusing on CD34-negative cells), mesenchymal stem cells, and a recently described population of human bone precursor cells. The first goal of this proposal is to determine whether these populations of Osteopoietic Stem Cells (OSC) are related. This is accomplished by viral based marking studies and in vitro evaluation of the osteogenic potential of these cells. We have developed isolation and purification protocols that allow us to examine the function of osteoprogenitor cells, preosteoblasts, and osteoblast. The viral marking studies will utilize both lenti- and retroviral mediated gene transfer of GFP, taking care to deplete the three populations of more mature cells via lineage-depletion. Using our clonal osteoprogenitor cell assay, we take an alternative approach in which GFP-positive OPC from each population of virally marked cells are analyzed for integration by inversePCR. As well, a Power-Analysis of large numbers of marked OPC will be use to overcome problems of OSC frequency, integration efficiency, and signal-dilution. The second aim is to examine if the osteogenic fate of OSC populations can be enhanced. Such fate decisions are hypothesized to be modulated via manipulation of cell-intrinsic and/or cell-extrinsic mechanisms. Intrinsic mechanisms are investigated by modulation
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39
of bone related transcription factors (e.g., Fral, delta-fos B and others) and evaluation of their affect on osteogenic commitment and ex vivo bone formation. Extrinsic control of osteogenic fate determine focuses on the role of an accessory cell population, recently identified in this laboratory, as well as enforced expression of bone-active cytokines by CHO cells that function as "artificial Stromal cells." The final set of experiments focuses on the fate of OSC populations in vivo. These studies will determine the degree to which OSC can "home" to the osteogenic microenvironment in immuno-compromised Nude/NOD/SCID mice. As well, we will explore the capacity of these cells to commit to the osteogenic lineage and restore bone formation in osteoporotic NOD/SCID mice, as well as mice with skeletal defects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PANCREATIC STEM CELL INDUCTION BY SMALL MOLECULES Principal Investigator & Institution: Crews, Craig M.; Associate Professor; Molecular and Cellular Physio; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2004 Summary: (provided by applicant): Recent research in stem cell biology has been driven in large part by the immense potential of stem cells in the treatment of various human diseases. Given the absence of insulin production in Type 1 diabetes, the regeneration of pancreatic beta islet cells from stem cells could have direct clinical application for diabetic patients. However, neither the isolation nor production of pancreatic stem cells is currently a viable option for pancreatic regeneration. In order to overcome these obstacles, we propose to identify small molecules capable of inducing embryonic stem (ES) cells to differentiate into pancreatic stem cells. This will involve the screening of a 15,000 compound library for compounds that induce the expression of the homeobox protein PDX-1, an early marker of pancreatic stem cells. Subsequent assays will analyze for additional pancreatic markers, (i.e., neurogenin3 and insulin). Compounds meeting these criteria will be assayed for the ability to induce pancreatic tissue in eve in the chick embryonic assay. Small molecule-generated ES-derived "islet-like" cells will then implanted in NOD mice to determine if they are functional insulin-producing cells in vivo. We anticipate that the identification of a palette of pancreatic stem cell inducers will greatly stimulate basic research in this field (e.g., identification of additional pancreatic stem cell marker proteins via differential gene analysis). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: POTENTIAL OF BLOOD PROGENITORS TO FORM NONBLOOD TISSUE Principal Investigator & Institution: Eisenberg, Carol A.; Associate Professor; Cell Biology and Anatomy; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 20-AUG-2001; Project End 31-JUL-2004 Summary: (provided by applicant): A dynamic area in biotechnology today is stem cell research. Stem cells are the precursor cells of every tissue in the body and thus, have the potential to provide replacement tissue for diseased and damaged organs. Our studies on stem cell differentiation suggest that adult and embryonic stem cells share a similar tissue potential. Specifically, we believe that stem cells from adult mammalian bone marrow have the capacity to give rise to all mesoderm derived tissue-although this potential is never realized in the normal adult environment. Initial studies have shown,
40
Stem Cells
for example, that hematopoietic stem cells (HSCs) from adult bone marrow-which normally give rise to the cellular components of the blood-can develop into cardiac myocytes under conditions developed for nondifferentiated embryonic tissue to undergo cardiac differentiation. As a first demonstration of our hypothesis on the broad potential of adult stem cells, we propose to extensively study the formation of cardiac tissue from adult mouse bone marrow stem cells. The experiments outlined in this project are designed to: (I) definitively identify this cardiac competent cell population of the bone marrow, (II) examine the capacity of this bone marrow cellular subpopulation to maintain their cardiac competence following their expansion in culture, (Ill) investigate their capabilities as cardiac cells, and (IV) examine their ability to integrate into adult cardiac tissue as functional cardiomyocytes. The development of methods to manipulate stem cell potential will have significant future medical impact, as it will provide the means to convert stem cells to pure populations of individual cell types for replacement tissue. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PROGRAM PROJECT,RESTORATION OF ENDOCRINE PANCREAS FUNCT* Principal Investigator & Institution: Habener, Joel F.; Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2004 Summary: The overall objectives of the studies proposed in this Program Project Application (PPA) are to explore the potential efficacies of using stem/progenitor cells and modified pancreatic islets as cellular therapies to restore endocrine pancreas function and to thereby cure diabetes mellitus. The motivation for this PPA is the fortuitous occurrence of several events: (1) the independent discoveries of pancreatic stem cells by three Harvard investigators, Dr. Susan Bonner-Weir (Joslin), Dr. Joel Habener (Massachusetts General Hospital), and Dr. Richard Mulligan (Childrens' Hospital); (2) the availability from Dr. Douglas Helton (Harvard University) of normalized pancreas cDNA arrays that contain all of the genes express in the pancreas; (3) the development by Dr. Dennis Sgroi (Massachusetts General Hospital) of a means to prepare gene expression profiling probes by Dr. Bennis Sgroi (Massachusetts General Hospital) of a means to prepare gene expression profiling probes from minuscule amounts of tissue obtained by laser capture microdissection; (4) the discovery by Dr. Melissa Thomas (Massachusetts General Hospital) of active hedgehog signaling in the islets of the adult pancreas and (5) the availability from Dr. Gordon Weir (Joslin) of high quality human islets from a preexisting islet transplantation core laboratory. The application proposes three scientific projects and two scientific cores that will work synergistically together to achieve the objectives. Project 1: Pancreas-derived stem/progenitor cells for the regeneration of beta cells (PI: Dr. Bonnor-Weir) has three aims: (1) analysis of distinct populations of duct-derived stem/progenitor cells; (2) gene expression profiling comparisons of human duct-derived versus islet derived stem/progenitor cells during their differentiation; (3) regeneration of beta-cells via transplantation of stem/progenitor cells in animal models of diabetes (rat partial pancreatectomy). Project 2: Modulation of pancreatic islets for transplantation (PI: Dr. Weir) has three aims: (1) evaluation of human islets by expression profiling; (2) determination of the fate of human islets after transplantation; (3) differentiation of transplanted stem/progenitor cells (NIPs, ductal progenitors, SP cells, and others. Project 3: Morphogen signaling during pancreatic islet development (PI: Dr. Thomas) has three aims: (1) mechanisms by which hedgehog signaling regulates expression of
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homeodomain protein IDX-1; (2) role of hedgehog signaling in the differentiation of pancreas-derived stem/progenitor cells into beta-cells; (3) hedgehog signaling in betacell development in vivo. The two scientific cores are: Core B: Islet isolation and transplantation (CD: Dr. Weir) and Core C: Laser capture microdissection and gene expression profiling (Co-CDs: Drs. Sgroi and Melton). All three projects will be heavy users of the two cores. In fact. The cores are the heart of the project, without which the objectives of the project could not be accomplished The two scientific cores are already established and running as components of the Harvard JDRF Islet Transplantation Center. In addition, all participants in this PPA application are members of one of the two NIDDK-funded Diabetes Endocrinology Research Centers (Joslin and MGH-based). An important aspect of this PPA is that the participants will be amongst the first to profile gene expression on cDNA arrays that incorporate all of the genes expressed in the pancreas and allow for determinations of the differences in genes expressed in healthy versus diseased islets and the genes expressed during the differentiation of stem/progenitor5 cells into beta-cells. This PPA proposes the initial studies on the way to providing a cure for diabetes via the approaches for regenerative medicine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF EMBRYONIC STEM CELLS Principal Investigator & Institution: Pera, Martin F.; Monash University Faculty of Medicine, Nursing & Health Sciences Melbourne, Vic, 3181 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2006 Summary: (provided by applicant): The derivation of human embryonic stem (ES) cell lines has opened up exciting new prospects for basic biomedical research and therapeutics in the new field of regenerative medicine. In order for human ES cells to fulfill their potential, it will be necessary to understand a good deal more about the control of their growth and differentiation. The broad goal of this project is to identify the extrinsic factors that control the growth and differentiation of human ES cells and committed progenitor cells, in order to improve in our ability to grow ES cells and produce specific types of specialized cells from them in significant quantities. Focusing on the role of cell interactions in vitro, particularly between the pluripotent stem cells and cells resembling extraembryonic endoderm, a tissue now recognized to play a key regulatory role in determining cell fate in the early mammalian embryo, the first aim is to identify growth and differentiation factors, which modulate these cell interactions. The major focus here will be members of the transforming growth factor beta superfamily and their antagonists, which play important roles in early embryo development. The second aim of the project is to study the action of these candidate factors on ES cells and cells at early stages of commitment to various differentiation lineages. The third aim of this proposal is to identify isolate and characterize committed progenitor cell populations from ES cell cultures. These cell populations will be isolated either from spontaneously differentiating ES cetl cultures or from ES cultures undergoing directed differentiation, using specific culture conditions and immunoisolation methodology developed in preliminary studies or during the course of this project. The work undertaken in this project will result in the ability to obtain and amplify committed populations of progenitor cells from human ES cultures, in particular precursors of neural and endodermal lineages, and to use these progenitors to produce specific types of differentiated cells. The ability to generate committed stem cell populations from ES cells and in turn derive highly enriched populations of end cells from these precursors will greatly enhance the utility of human ES cells in basic research (the study of human gene function in health and disease and the development of new
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drugs) and in transplantation medicine. This project will use stem cell lines ES 01 02 03 04 05 06 on the NIH Embryonic Stem Cell Registry. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF HEMATOPOIESIS BY NOTCH RECEPTORS Principal Investigator & Institution: Griffin, James D.; Professor; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 01-MAR-1984; Project End 31-DEC-2007 Summary: (provided by applicant): The events that regulate the development and proliferation of hematopoietic cells are precise, complicated, flexible, and subject to many levels of controls. The control mechanisms involve both humoral and cellassociated factors from the microenvironement as well as pre-programmed patterns of gene expression intrinsic to different progenitor and stem cells. There have been two basic goals of this project over the last 18 years. The first goal has been to understand the external signals that influence patterns of differentiation, control traffic of mature and immature cells, and influence functions of mature hematopoietic cells. The second goal has been to understand how leukemia oncogenes disrupt, conscript, or deregulate the normal mechanisms that control hematopoiesis. Over the initial five years of this grant (1984-88), our aims were to identify the major cytokines affecting myelopoiesis and determine their major biological properties first in vitro, and then in vivo in human subjects. Over the next five years of the grant (1989-93), our aims were to identify the receptors for the major myeloid growth factors, begin to understand how these cytokines interact physically with their receptors, and identify the initial elements of receptor signaling. Studies during this period also led to the discovery of the significant degree of overlap between the actions of activated tyrosine kinase oncogenes, such as BCR/ABL or TEL/ABL, with the actions of ligand-activated cytokine receptors. The similarities, and differences, between BCR/ABL and IL-3 receptor function, for example, explain many of the clinical phenotypes of CML. Over the last grant period (1994-2002) the goals were to investigate in detail how signals travel from cytokine receptors to the nucleus, how positive and negative signals are integrated in hematopoietic cells, and how these different signals are similar, or distinct, from those initiated by leukemia oncogenes such as BCR/ABL. Overall, the factors, receptors, and signals that regulate proliferation and viability of many lineages of hematopoietic cells are now fairly well understood. The signals of leukemia and myeloproliferative syndrome oncogenes that induce proliferation and viability are also becoming much more clear. The external signals that regulate differentiation and lineage commitment of immature hematopoietic cells, however, are still poorly defined. There is increasing evidence that receptors of the Notch family participate in some differentiation "decisions" of stem cells, such as commitment to the lymphoid vs. myeloid lineages at an early time point. In many tissues, and in animals from flies to humans, Notch receptors determine certain types of lineage commitment, typically forcing a stem cell to commit to one lineage at the expense of another lineage. It is proposed here to determine how the signals from Notch receptors mediate these effects, using hematopoietic cells as the model system. The goals of the proposed studies will be to determine how Notch signaling influences differentiation and lineage commitment in hematopoietic cells, better define the functions of Notch in hematopoiesis, and understand the mechanism of transformation of stem cells by the human ALL oncogene, TAN-1 (a mutant allele of the Notch 1 receptor). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REGULATION OF INNATE IMMUNITY AND HEMATOPOIESIS BY MEF Principal Investigator & Institution: Lacorazza, Hugo D.; Sloan-Kettering Institute for Cancer Res New York, Ny 10021 Timing: Fiscal Year 2003; Project Start 25-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Hematopoiesis consists of a series of regulated steps involving expansions (cell proliferation) and developmental choices (lineage commitment) that lead to the generation of mature blood cell lineages, including the cellular components of both acquired and innate immunity. Some immune cells complete their development in the bone marrow (e.g., NK cells) whereas others develop in secondary lymphoid tissues such as the thymus (e.g., T and NK-T cells). The goal of this proposal is to further study the role of MEF, a member of the ETS family of transcription factors, in innate immunity and hematopoiesis, based on our findings in MEF-deficient mice that we have generated in our laboratory. These mice exhibit greater numbers of hematopoietic stem cells (HSC), impairment in the development and function of natural killer cells (NK and NK-T cells) and lack of perforin expression. This phenotype resembles the human disease Familial Hemophagocytic Lymphohistiocytosis (NK cell dysfunction and immune deregulation). Insights into how the innate immune system and hematopoietic stem cell maintenance are regulated at a transcriptional level will provide a basis for optimizing therapeutic interventions in hematologic disorders and recovery after stem cell transplantation. Our findings raise important biological questions: What is the role of MEF in the function of natural killer cells and how does this affect the innate immune system? What is the precise role of MEF in stem cell quiescence? What MEF-target genes are involved in such processes? Can overexpression of MEF induce stem cell exhaustion or skew lineage commitment to the lymphoid compartment? Aiming to answer these questions we propose to further define the role of MEF in the innate immune system by studying the functional properties of MEFdeficient mice (Aim 1). We will characterize the role of MEF in stem cell quiescence, cell cycle and self-renewal by studying HSCs from MEF-deficient mice in vitro and in vivo (Aim 2). We will further study how MEF regulates the expression of a key target gene (perforin), define the molecular circuitry of NK cells and hematopoietic stem cells using DNA microarray technology, and evaluate the effect of ectopic expression of MEF on tumorigenesis and hematopoiesis (Aim 3). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REGULATION OF NEURONAL STEM CELL DEATH Principal Investigator & Institution: Bieberich, Erhard; Assistant Professor; Medicine; Medical College of Georgia 1120 15Th St Augusta, Ga 30912 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2007 Summary: (provided by applicant): Between gestational day E12 and 18, about half of the mitotic neuronal cells die in embryonal mouse forebrain due to apoptosis. Studies with caspase knockout mice have demonstrated that apoptosis is necessary to prevent hyperproliferation of neuronal stem cells and subsequent, severe brain malformation. It is not known, however, which factors selectively induce or prevent apoptosis in individual, differentiating neuronal stem cells. We have shown for the first time, that the peak time of apoptosis in embryonal mouse brain (E14.5) is concurrent with elevation of endogenous ceramide and activation of caspase 3. We have also shown that the concentration of ceramide is high enough to kill neuronal progenitor cells grown in culture. From these observations, we propose that elevation of ceramide may be critical
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for induction of apoptosis in differentiating neuronal stem cells. Recently, several studies have reported that the ceramide-mediated formation of an inhibitory complex between PAR-4 and atypical PKC ,induces apoptosis. Our own studies with in vitro differentiated embryonic stem (ES) cells have shown that induction of apoptosis by ceramide is concurrent with up-regulation of PAR-4. We propose that PAR-4 is one of probably several pro-apoptotic proteins that induce apoptosis when their expression and that of ceramide is elevated. Our main hypothesis is that simultaneous upregulation of endogenous ceramide and ceramide-associated proteins (CAPs) results in formation of a pro-apoptotic protein complex (PAC) that triggers apoptosis in mitotic neuronal stem cells by suppression of anti-apoptotic, cell survival signaling. We will test this hypothesis in three Specific Aims using murine ES cells as model system. In Specific Aim 1, we will test the hypothesis that up-regulation of ceramide induces apoptosis specifically in mitotic neuronal stem cells. In Specific Aim 2, we will test the hypothesis that ceramide/CAP-induced PAC formation results in activation of caspases. In Specific Aim 3, we will test the hypothesis that elevation of ceramide and down-regulation of cell survival signaling is synchronized by the cell cycle and growth factors. In conclusion, this study will identify mechanisms for regulation of apoptosis by ceramide that are critical for normal brain development and/or the etiology of subsequent, pathological disorders in adulthood. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATON OF UROTHELIAL GROWTH Principal Investigator & Institution: Sun, Tung-Tien H.; Professor; Dermatology; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-JUL-2008 Summary: (provided by applicant): The luminal surface of the entire lower urinary tract including renal pelvis, ureter, bladder and proximal urethra is lined by a cell type described in standard textbooks as the transitional epithelium or urothelium, which is characterized by a highly specialized apical cell surface covered by rigid-looking urothelial plaques consisting of hexagonally packed 16 nm uroplakin particles. It has been suggested that urothelial defects can result in a loss of the permeability barrier function allowing the penetration of some urine irritants into the bladder wall thus causing pain in interstitial cystitis. In addition, it is generally assumed that urothelial cells lining the different portions of the urinary tract are the same; hence conclusions derived from studying cells of one region should be applicable to all urothelial cells. However, urothelia of renal pelvis/ureter/trigone are known to have a different embryological origin than urothelial cells of other sites, and there are indications that urothelium is biochemically heterogeneous. In this project, we will (i) determine whether the urothelia that cover renal pelvis, ureter, bladder, and proximal urethra actually consist of several distinct cell lineages by analyzing the relative contributions of intrinsic divergence vs. extrinsic modulation to urothelial phenotypes, and (ii) identify the stem cells in various urothelial compartments using cell kinetic, cell culture and stem cell transplantation techniques. These proposed studies can yield important information because if urothelium indeed can be separated into several distinct subpopulations belonging to different cell lineages, one needs to re-examine the validity of some earlier studies in which urothelial cells from different parts of the urinary tract were used interchangeably. Since stem cells are the preferred targets of carcinogens, gene therapy, and they are particularly suited for tissue engineering and tissue reconstitution, our studies can have practical implications on the source of urothelial cells for tissue engineering of various parts of the urinary tract, the cellular origin of in
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vivo urothelial wound healing following the surgical removal of the bladder, the possible involvement of urothelial cells in interstitial cystitis and in site-specific variations in bacterium: urothelium interactions, and the cellular origin of various urothelial tumors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RETROVIRAL GENE TRANSFER TO EPIDERMAL STEM CELLS Principal Investigator & Institution: Andreadis, Stelios T.; Assistant Professor; Chemical Engineering; State University of New York at Buffalo Suite 211 Ub Commons Amherst, Ny 14228 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-JAN-2008 Summary: (provided by applicant): The current project seeks to understand retrovirusmediated gene transfer and to enhace the transduction efficiency to epidermal stem cells. Although retroviral transduction results in permanent genetic modification, differentiation and eventually loss of the transduced cells from the epidermis results in temporary transgene expression. Therefore, to achieve stable long-term gene expression, it is critical that the epidermal stem cells are transduced with high efficiency. Recent results from our laboratory show that gene transfer on fibronectin is significantly higher than on tissue culture plastic and implicate integrins in retroviral transduction of epidermal keratinocytes. Specifically, the efficiency of gene transfer correlates with the levels of alpha 5 and beta 1 integrins on the cell surface and blocking these integrins with antibodies decreases gene transfer significantly. We hypothesize that integrins may enhance gene transfer by enhancing the rate of keratinocyte migration on fibronectin and therefore the probability that itarget cells encounter the immobilized virus. We propose to develop two assays to test this hypothesis and use flow cytometry to identify other integrins that may also play a role in retroviral gene transfer. Since integr ns and attachment to extracellular matrix have been shown to characterize keratinocyte stem cell phenotype, we also propose to test the hypothesis that retroviral transduction on fibronectin increases the efficiency of gene transfer to epidermal stem cells. To this end we will use biochemical (e.g. flow cytometry) and functional assays (e.g. clonal analysis), as well as in vivo transplantation of genetically modified skin equivalents onto athymic mice. Finally we propose to engineer micropatterned surfaces and microfluidic networks to enhance deposition of retrovirus to the surface. Mathematical modeling and experiments will be employed to design the gene transfer "chips" in order to increase the efficiency of gene transfer and control the number of gene copies per target cell. Reaching these goals will have significant impact on the potential of genetically modified cells to treat short or long-term disease states. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: RHESUS HEART REGENERATION WITH EMBRYONIC STEM CELLS Principal Investigator & Institution: Kamp, Timothy J.; Assistant Professor; Medicine; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2005 Summary: (provided by applicant): Many forms of heart disease are characterized by a loss of myocytes either by apoptosis or infarction. Therefore, strategies such as cardiac cell transplantation may provide remarkable advances in therapy for a range of heart diseases. A variety of donor cells have been tested in animal models of infarction with the most promising results from adult stem cells. However, embryonic stem (ES) cells may provide the greatest opportunity for myocardial regeneration. The overall goal of
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this proposal is to utilize nonhuman primate embryonic stem (ES) cells to regenerate infarcted myocardium as an aggressive step toward clinical applications of cardiac cell transplantation. A multidisciplinary approach will provide innovative approaches to address major roadblocks in bringing cell transplantation to the clinic. First, we hypothesize that, with appropriate priming, rhesus ES cells will be able to engraft into the infarcted rhesus myocardium and regenerate multiple cell types typical of myocardium. Specific Aim 1 will test engraftment of donor ES cells labeled with the fluorescent protein EGFP in a rhesus myocardial infarction-reperfusion model. Ex vivo immunohistochemistry will provide information on the cell types regenerated from the donor cells, and isolated myocyte studies will characterize the cellular function of regenerated myocytes. Specific Aim 2 will develop novel imaging applications using Magnetic Resonance Imaging (MRI) to track donor ES cells labeled with magnetodendrimers as well as provide structural and functional details of myocardial regeneration. Next, we hypothesize that the microenvironment of the infarcted myocardium has a rich collection of signaling molecules directing progenitor cell recruitment and milieu-dependent differentiation. In Specific Aim 3, we will search for these signaling molecules in the venous effluent following infarction using antibodybased assays as well as utilizing proteomics technology with mass spectrometry. To test putative signaling molecules in a controlled microenvironment, we will develop a microfluidics bioassay system using cultured ES cells in microchannels. Overall, these developmental approaches have the potential to dramatically advance the field of myocardial regeneration and bring cardiac cell transplantation much closer to clinical reality. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE LEUKEMOGENESIS
OF
AML1/ETO
IN
HEMATOPOIESIS
AND
Principal Investigator & Institution: Mulloy, James C.; Sloan-Kettering Institute for Cancer Res New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 16-MAY-2001; Project End 31-JAN-2003 Summary: The AML 1/ETO fusion protein is causally implicated in the pathogenesis of 40% of acute myeloid leukemias of the M2 subtype, and accounts for 12% of human AMLs overall. The fusion gene is compromised of the amino-terminal portion of the AML1 (CBFA2) gene on chromosome 21 and the nearly full coding region of ETO gene on chromosome 8. Aml1/Eto interferes with the function of the transcription factor, CBF, in a dominant negative fashion, presumably by its ability to bind to the heterodimeric transcription partner CBF beta and repress transcription through CBF enhancer elements. Mice deficient in AML1 or CBF BETA lack definitive hematopoiesis, and these mice die during embryogenesis. Similarly, mice engineered to express a leukemic fusion protein that interferes with CBF function die from a similar phenotype, complicating the development of an animal model of AML. Recent advances in retroviral gene delivery systems, hematopoietic stem cell biology, and immunodeficient animal development have made it possible to overexpress genes of interest in human and murine stem cells and use these cells to reconstitute the immune system of recipient animals. The ultimate objective of this work is the development of murine model AML, specifically of AML associated with expression of AML1/ETO (Specific Aim 1). A murine retovirus optimized for expression in stem cells will be used, and the green fluorescent protein will be co-expressed from the same mRNA using an IRES element, to facilitate identification of transduced cells. Both human and murine stem cells will be used in these studies, and the appropriate animal model will be chosen to allow the
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growth of transformed cells in vivo. In vitro studies will also be performed to determine the effects of AML1/ETO over-expression on normal hematopoiesis (Specific Aim 2). Using specific combinations of cytokines and stromal layers, the investigator will determine which hematopoietic lineage is affected by AML1/ETO expression. Mutants of AML1/ETO will also be included in the system, to decipher which signaling pathways are important in AML1/ETO-induced leukemia in vivo. mRNA from human stem cells expressing AML1/ETO will be used for differential hybridization screening of high-density microarrays to identify target genes regulated by AML1/ETO (Specific Aim 3). These target genes will be evaluated for their contribution for the phenotype elicited by expression of AML1/ETO in human stem cells, using the assays mentioned above. Taken together, these data will provide detailed information on the functional role of AML1/ETO in both hematopoeisis and leukemogenesis. The establishment of a small animal model of AML will greatly enhance our ability to develop and test treatment strategies and drugs that may be useful in the therapy of AML. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SIGNAL TRANSDUCTION DETERMINING FATE OF STEM CELLS Principal Investigator & Institution: Terada, Naohiro; Assistant Professor; American Society for Cell Biology 8120 Woodmont Ave, Ste 750 Bethesda, Md 20814 Timing: Fiscal Year 2003; Project Start 20-SEP-2003; Project End 31-JUL-2004 Summary: (provided by applicant): The Conference "Signal Transduction Determining the Fate of Stem Cells" will be held from August 9 through August 12, 2003, at the Montana State University in Bozeman, Montana. This meeting is sponsored and partially funded by the American Society for Cell Biology (ASCB). This conference is the only international meeting this year that focuses on signal transduction in stem cells and is open to a significant number of young scientists who are not established members of the field. In this application we request partial funding for the 2003 conference. Clinical application of stem cells in human disease requires an understanding of the stem cell and the long-term behavior of cells derived from stem cells. Understanding the behavior and properties of stem cells requires the integration of several disciplines in biomedical research. For example, we are just beginning to understand the role of cytokines and extracellular matrices in determining the fate of stem cells. Little is known of intracellular signaling pathways that control stem cell fate. The purpose of this conference is to bring together investigators from two disciplines, stem cell biology and signal transduction, in an attempt to initiate a collaborative effort for understanding signaling pathways that control the fate of stem cells in culture and animals. In the first three scientific sessions of the 2003 ASCB Summer Conference, we will discuss signal transduction pathways regulating self-renewal, plasticity and differentiation of stem cells. In the forth session, we will focus on analogy and difference of stem cells with cancer cells, where signal transduction has been intensively studied. In addition, the final session will introduce emerging ideas and techniques that would facilitate signal transduction studies in stem cells. These sessions will consist of a mixture of invited talks and presentations to be selected based on submitted abstracts. The latter speakers will be chosen with special attention to younger investigators and exciting recent developments. There will also be a poster session. The format of the Conference, and its small size, are designed to foster interactions among the 225 participants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SKELETAL MUSCLE STEM CELLS FOR TISSUE REPAIR Principal Investigator & Institution: Kramer, Randall H.; Professor; Stomatology; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-MAY-2007 Summary: (provided by applicant): A major problem confronting craniofacial repair is the difficulty in restoring soft-tissue function and contour in patients with anomalies including hemifacial microsomia, unilateral clefts of lips and palate as well as defects in the TMJ. In particular, repair of skeletal muscle defects is limited by difficulty in its transplantation and survival. A logical approach is to use existing population of muscle satellite cells which are quiescent undifferentiated precursors found beneath the basement membrane of mature muscle fibers. Following injury, activated satellite cells regenerate muscle after initiating a differentiation program whereby they migrate along laminin-rich basement membrane, proliferate, differentiate, and integrate with preexisting myofibers. Recent evidence supports the notion that satellite cells are heterogeneous and have stem cell potential. We have shown that the laminin-binding alpha 7 integrin, which is important for myoblast migration, is expressed on a subset of satellite cells and is upregulated in terminally differentiated myotubes. In this application, we propose to examine the potential of using alpha 7-positive human satellite cells for direct repair of muscle defects. We will explore the hypothesis that alpha 7 expressing satellite cells are pluripotent stem cells capable of regenerating skeletal muscle and other tissue such as bone. The proposal represents three aims. In aim 1 we will characterize human muscle-derived satellite cells and correlate expression of alpha 7 integrin with their differentiation potential for skeletal muscle and other tissue lineages. Aim 2 will determine the expression and function of the alpha 7 integrin during human skeletal muscle development. Aim 3 is focused on the use of alpha 7expressing human skeletal muscle stem cells to engineer in vitro three-dimensional skeletal muscle myofibers. These studies will form the basis for strategies that target the mechanical reintegration of regenerating myotubes to repair orofacial muscle structures using adult skeletal muscle stem cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SPECIFIC GENE EXPRESSION PATTERNS IN SATELLITE STEM CELLS Principal Investigator & Institution: Csete, Marie E.; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: The long-term objective is to develop therapeutic strategies directed at satellite stem cells that will preserve muscle mass in the elderly. Satellite stem cells are the major source of adult skeletal muscle regeneration, and so, are important targets for preserving skeletal muscle mass in the elderly. Long known as muscle progenitors, cultured satellite stem cellscan also generate other daughter cell types, including adipocytes (fat cells). This pluripotentiality of satellite stem cells suggests that they may play a direct role in changing the phenotype of skeletal muscle, especially in the elderly. Satellite cell-derived adipogenesis in tissue culture is promoted by a high (20%) oxygen (O2) environment, conducive to production of reactive oxygen species (ROS), an environment that mimics the oxidative stress of old skeletal muscle. In lower (6%) O2 culture conditions satellite stem cells are much less likely to undergo adipogenesis. These phenotypic findings have important molecular correlates: Analysis of single satellite stem cells reveals that high O2/ROS induces increased expression of genes that
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promote fat development, while low O2 conditions are associated with up-regulation of genes that promote muscle development and differentiation. High O2/ROS induces increased expression of genes that promote fat development, while low O2 conditions are associated with up-regulation of genes that promote muscle development and differentiation. High O2/ROS culture conditions also decrease satellite cell proliferation, and this defect is pronounced in satellite stem cells derived from old mice vs. those derived from young/adult mice. Thus, aging associated ROS-induced reduction in proliferation as well as adipogenesis may remove satellite stem cells from the myogenic pool and directly contribute to the characteristic pathology of muscle aging, which is a loss of muscle mass and accumulation of muscle lipid. These data suggest that the loss of muscle with aging is more than a degenerative phenomenon, and that satellite stem cells may undergo age-associated pathologic regeneration. The working hypothesis is that the imbalance between ROS accumulation and decreased antioxidant function in old muscle induces specific gene expression patterns in satellite stem cells that result in their defective proliferation, apoptosis and myogenic differentiation when compared to satellite stem cells from young/adult animals. Proliferation, apoptosis, and differentiation patterns will be quantitated and compared for satellite stem cells from old vs. young/adult mice, and from old wild type mice vs. old antioxidant-deficient mouse models. In parallel to these cellular assays, expression patterns of satellite stem cells will be compared for these different groups with the goal of identifying potential therapeutic protein products that increase survival, proliferation and myogenic differentiation of satellite stem cells in old animals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STEEL GENE PRODUCT AND STEM CELL PROLIFERATION Principal Investigator & Institution: Williams, David A.; Lampkin Chair and Professor of Pediatric; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 45229 Timing: Fiscal Year 2002; Project Start 01-AUG-1994; Project End 31-JUL-2003 Summary: (Adapted from investigator's abstract) Hematopoiesis occurs in a complex microenvironment made up of a variety of non-hematopoietic cells including endothelial cells, stromal cells and adipocytes. These accessory cells provide regulatory signals, in the form of positive and negative growth factors and adhesive molecules, which affect the survival, proliferation and differentiation of hematopoietic stem and progenitor cells. Although a large number of hematopoietic growth factors have been identified, no combination of these factors has been shown to maintain/expand the reconstituting capacity of stem cells over an extended period of time in vitro in the absence of adhesion to microenvironment cells. Thus, analysis of blood cell formation in the context of these microenvironment cells provides additional and important information concerning the regulation of hematopoiesis. It is also increasingly clear that multiple aspects of hematopoiesis are controlled by key transcription factors. However, less well studied is how the interaction of growth factors presented in the microenvironment with growth factor receptors and other cell-cell interactions modulate transcription factor function, and thus ultimately control blood formation under physiologic conditions or in response to commonly encountered stress situations. One essential growth factor that is expressed in the hematopoietic microenvironment (HM) is stem cell factor (SCF); the interaction of SCF with the receptor tyrosine kinase, c-kit, plays a critical role in both erythroid and mast cell production in vivo, as demonstrated by the phenotypic abnormalities seen in mouse mutants of the genes encoding SCF (Steel) and c-kit (Dominant white spotting) mice. In addition, c-kit is
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expressed on both hematopoietic stem cells and multilineage progenitor cells. SCF is expressed as both soluble and membrane bound isoforms in the HM. During the previous funding period, the PI's laboratory has shown in vitro and in vivo evidence that distinct isoforms of SCF produce different cellular responses in several c-kit+ cell populations. The overall hypothesis to be tested in the proposed research utilizing transgenic and "knock-in" mice is that the biological effects of SCF are due, in part, to the adhesion of cells within the HM and the interaction of c-kit+ with cell-associated SCF, which influences the duration of activation of c-kit and downstream signaling in these cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STEM CELL FACTOR ACTION IN NEURAL CREST DEVELOPMENT Principal Investigator & Institution: Sieber-Blum, Maya F.; Professor; Cell Biol, Neurobiol/Anatomy; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532264801 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: (Adapted from applicant's abstract): The long-term goal of the proposed work is to elucidate the cellular and molecular mechanisms that control neural crest cell diversification and differentiation. The application focuses on the differentiation of neural crest stem cells into small diameter sensory neuroblasts. It is based on prior data which indicate 3 additional roles of SCF in addition to the known trophic action in pigment cell formation: (1) SCF is a survival factor for neural crest stem cells, (2) SCF is involved in the expression of the neurotrophin receptors, p75NTR and TrkC, and (3) SCF promotes differentiation of the stem cell into small diameter sensory neuroblasts. In aim 1 the role of the SCF receptor, c-kit, is investigated by knock-down and rescue of quail c-kit, and by analyzing the mouse mutants Dominant spotting (W; c-kit defect) and Steel (Sl; SCF defect) for neural crest-related deficiencies. It is hypothesized that SCF promotes expression of p75NTR with higher probability than TrkC, thus creating at least two subsets of cells (p75NTR+/TrkC+, p75NTR+/TrkC-), which possibly have restricted developmental potentials. This issue will be addressed by in vitro clonal analysis of immunoselected cells. Aim 2 is concerned with neurotrophin-mediated apoptosis, for which there is preliminary evidence, and which is suggested to function in vivo as a proof reading mechanism for the elimination of site-inappropriate precursor cells. Aim 3 deals with the mechanisms that direct p75NTR+/TrkC+ cells into the small diameter sensory neuron lineage. Initial data suggest that a subset of neural crest cells differentiates into TrkB-expressing sensory neuroblasts in a chemically defined culture medium in the presence of SCF and absence of any other added growth factors. Using antisense and mutant mouse approaches, it will be determined whether TrkB expression is mediated by SCF and/or by the other autocrine factors, NT-3 and TGF-5. Moreover, BDNF-mediated neuropeptide expression will be documented. A better knowledge of the characteristics of neural crest stem cells has implications for transplant therapy in some degenerative and familial diseases. Moreover, health relatedness pertains to human piebaldism, which is due to c-kit defects. Piebaldism is characterized by hypopigmentation and a white forelock at birth due to faulty melanogenesis. However, the newly detected additional roles of SCF in maintaining stem cells, up-regulating neurotrophin receptors and promoting sensory neurogenesis suggest additional defects in human piebaldism that remain to be elucidated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: STEM CELL GENE THERAPY FOR AIDS Principal Investigator & Institution: Johnson, R. Paul.; Associate Professor of Medicine; Immunology; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 10-FEB-1997; Project End 31-MAR-2007 Summary: (Provided by the applicant): Despite the dramatic success of highly active antiretroviral therapy (HAART) in inhibiting viral replication in HIV-infected subjects, it is increasingly clear that there is a compelling need for the development of complementary therapies. Accumulating experience with HAART is documenting a significant incidence of serious side effects, an increasing prevalence of resistant viruses, and failure rates of HAART that exceed 50 percent in some cohorts. A wide range of genetic strategies are now able to achieve potent inhibition of HIV replication in vitro, and introduction of these inhibitory genes into hematopoietic stem cells offers the potential to offer long- lived immune reconstitution. However, the successful translation of these in vitro successes to clinically- applicable therapies has been limited by the disappointing rates of gene transfer to hematopoietic cells in human gene therapy clinical trials. Multiple ethical and practical considerations significantly constrain the ability to address basic questions regarding stem cell gene therapy for AIDS in human clinical trials. Experiments in nonhuman primates offer the opportunity to rigorously address these issues in an in vivo experimental model. Experiments conducted during the initial funding period of this grant have shown that significant levels of geneticallymodified cells can be obtained in nonhuman primates following autologous bone marrow transplantation with hematopoietic stem cells transduced with murine leukemia virus (MLV) vectors. Specific aims of the current proposal are: 1. To optimize MLV and lentiviral vectors for the delivery of RNA decoys into hematopoietic stem cells and evaluate their ability to inhibit SIV/HIV replication; 2. To examine levels of gene marking in uninfected macaques transplanted with hematopoietic stem cells transduced with MLV and lentiviral vectors; 3. To determine the ability of inhibitory genes to protect hematopoietic cells from SHIV infection in vivo; and 4. To examine the ability of genetically-modified hematopoietic stem cells to reconstitute immune function in SHIV-infected macaques. These studies should yield important information regarding the efficacy and safety of stem cell gene therapy for AIDS and facilitate the development of similar trials in HIV- infected people. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: STEM CELL GENE THERAPY FOR LUNG DISORDERS Principal Investigator & Institution: Lutzko, Carolyn M.; Children's Hospital Los Angeles 4650 Sunset Blvd Los Angeles, Ca 90027 Timing: Fiscal Year 2002; Project Start 11-SEP-2002; Project End 31-JUL-2005 Summary: (provided by applicant): Gene therapy for respiratory disorders requires stable gene transfer to epithelial progenitor cells, efficient engraftment of these genetically modified progenitors in the respiratory epithelium and regulated transgene expression in differentiated progeny of these cells. Recently, cells have been identified in marrow that can contribute to tissue repair and regeneration in hematopoietic and nonhematopoietic tissues. In preliminary studies by our group, transgene expressing donor epithelial cells were detected in the lung following transplantation of retrovirally transduced bone marrow into murine recipients. At 2-5 months post-transplant, approximately 1% of cytokeratin positive epithelial cells were EGFP transgene positive donor cells. Based on these data our overall hypothesis is that cells derived from the
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bone marrow engraft in the respiratory epithelium and contribute to alveolar epithelial layer maintenance and regeneration. The hypotheses to be evaluated in this proposal are: 1) Progenitor cells in normal mouse marrow that engraft and contribute to the alveolar epithelium can be characterized and isolated based on physical properties and cell surface markers. 2) Recombinant lentiviral gone transfer vectors can be designed to efficiently transduce bone marrow derived lung epithelial progenitor cells and specifically express transgenes in respiratory epithelial cells. 3) Marrow derived multipotent stem cells can be transduced with lentiviral vectors and contribute to both respiratory epithelial and hematopoietic tissues. In the experiments proposed here we will test these hypotheses in a murine bone marrow transplant model in the following specific aims: 1) Characterize the progenitor population (s) that engraft in the lung epithelia. 2) Develop gene transfer vectors that have stable and epithelial specific transgene expression. 3) Identify and characterize the lineage potential, or plasticity, of individual, gene marked progenitor cells, that contribute to respiratory epithelia. The overall goal of these studies is to advance the development of clinical gene therapy for lung disorders by evaluating the potential of genetically modified epithelial progenitors to engraft in the lung epithelium and deliver therapeutic gene products in vivo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STEM CELL PATCH THERAPY IN HEARTS WITH LV INFARCTION Principal Investigator & Institution: Zhang, Jianyi; Associate Professor; Medicine; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2005 Summary: (provided by applicant): Following transmural myocardial infarction left ventricular remodeling (LVR) with chamber dilation and hypertrophy occurs to compensate for loss of contracting myocardium. Although stable LV remodeling may be achieved for a period of time, progressive myocardial dysfunction can develop and ultimately lead to overt congestive heart failure (CHF). The currently available therapeutic options for heart failure due to transmural left ventricular infarct are limited. Several exciting recent studies have shown that tissue specific stem cells may have the ability to generate cells of tissues from unrelated organs. We have identified a population of primitive cells in normal human post-natal bone marrow that have multipotent differentiation and extensive proliferation potential, which we have named Multipotent Adult Progenitor Cells or MAPC. The proposed research will examine the ability of a novel fibrin patch to deliver allogenic or autologous cells into myocardial infarcts to improve LV function, and to prevent the transition to heart failure. Using a swine model of postinfarction LV remodeling, the effect of cell transplantation on LV contractile function and myocardial energy metabolism will be examined using MRI and 31P-MR spectroscopy, respectively. The following hypothesis will be tested: 1) A fibrinstem cell patch can deliver a high concentration of allogenic MAPC onto the surface of ischemic myocardium. In response to myocardial ischemic signals, the stem cells will leave the fibrin patch and home to the ischemic myocardium to repair the infarct region and to prevent the formation of LV aneurysm. 2) A fibrin-thrombin patch can be used to deliver a high concentration of autologous bone marrow stem cells within 30 minutes. The autologous bone marrow cells will gradually leave the patch and migrate to the infarct area where they continue to divide and differentiate into myocytes, smooth muscle cells and endothelial cells, and replace the myocardial infarct. 3) An artificial myocardium generated by entrapping MAPC in a bipolymer fibrin gel and allowing the cells to partially differentiate and develop contractile function in vitro before implantation onto the infarct region will reestablish LV contractile function. By
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providing insight into the effects of the cellular patch transplantation, the results may lead to better preventive, diagnostic and therapeutic modalities for LV injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STEM CELL PLASTICITY AFTER BLASTOCYST IMPLANTATION Principal Investigator & Institution: Recht, Lawrence D.; Professor; Neurology; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2005 Summary: (provided by applicant): Several recent studies indicate that tissue-derived stem cells can not only differentiate into cells of the tissue from which they are obtained, but also those from other tissues. We have been interested in the range of differentiative capacity (which we term plasticity) of CNS derived stem cells and hypothesized that one way to assay this would be to implant these cells into blastocyts and assess incorporation into the resulting mice later in development. Our results indicate a robust incorporation of these cells into extraneural tissues including bone marrow, where they express lineage markers of differentiated hematopoietic cells, bone muscle and GI tract. We believe this model provides a unique insight into stem cell plasticity because of the high efficiency of implantation and production of apparently normal pups. We propose to follow-up our studies by addressing the following specific aims: 1) We will determine whether incorporation of stem cells into blastocysts varies as a function of stem cell subpopulation or type, we will create a retorviral library of neural stem cells to assess whether specific subpopulations exist as well as comparing neural stem cells with marrow stromal cells in their ability to incorporate into blastocysts; 2) We will determine whether incorporation of neural stem cells into other tissues renders them functional by performing bone marrow transplantation of cells obtained from chimeric pups into lethally irradiated mice and assessing whether neural stem cells can repair a embryonically lethal genetic defect in bone; and 3) We will assess whether neural stem cells retain their functional capacity to develop into olfactory interneurons after blastocyst transplantation and determine whether their implantation at the blastocyst stage can repair mice with an absence of myelin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: STEM CELL PROLIFERATION AND DIFFERENTIATION IN PLANARIA Principal Investigator & Institution: Newmark, Phillip A.; Cell and Structural Biology; University of Illinois Urbana-Champaign Henry Administration Bldg Champaign, Il 61820 Timing: Fiscal Year 2003; Project Start 09-JAN-2003; Project End 31-DEC-2007 Summary: (provided by applicant): The establishment of human pluripotential stem cell lines has led to a resurgence of interest in stem cell biology. This interest is largely due to the therapeutic potential of stem cells for repairing degenerative diseases and injuries. Before recent breakthroughs in studies of human stem cells can be effectively and safely applied in the clinic, many basic questions about the biology of stem cells need to be addressed. These include: how is stem cell proliferation regulated in vivo to generate the appropriate number of daughter stem cells and differentiating progeny without forming tumors? How is the developmental potential of a stem cell restricted to a particular fate? How is pluripotentiality maintained and what steps lead to loss of pluripotentiality? The work proposed here will address these fundamental questions using the freshwater planarian, Schmidt Mediterranean, as a model organism for
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studying stem cell regulation. Planarians- classic models of regeneration experiments can regenerate entire animals from small fragments of their bodies. This remarkable plasticity is based upon a stem cell population present in the adult worm. These stem cells are used both to replace cells lost during the course of cell turnover and to regenerate missing structures when the animal is transected. Recent advances permit this classic system to be re-examined in detail at both cellular and molecular levels. Thus, environmental influences on stem cell proliferation will be studied by analyzing cell cycle kinetics in intact and regenerating planarians. These experiments will determine if wounding regulates the cell cycle of planarian stem cells. If it does, these experiments will also define the phases of the cell cycle that are regulated, an important consideration for understanding the signaling pathways that lead from wounding to proliferation. The development of automated in situ hybridization techniques and the availability of over 4000 unique planarian cDNAs provide starting material for defining stem cell-specific genes and raising monoclonal antibodies to identify and study stem cells. Finally, functional analysis using double-stranded RNA-mediated genetic interference will be used to identify genes that play critical roles in stern cell regulation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STEM SPERMATOGENESIS
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Principal Investigator & Institution: Dinardo, Stephen; Professor; Anatomy; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2003; Project Start 01-AUG-1999; Project End 31-JUL-2007 Summary: (provided by applicant): Cells within many tissues and organs are continually replenished throughout our lives. This is accomplished by stem cells, which balance self-renewal with more differentiated cell types. The mechanisms that control this balance are not clear. In tissues maintained by stem cells, the differentiating daughters undergo mitotic expansion before generating tissue-specific cell types. The mechanisms that control transit amplification are also not clear. Both of these phenomena are featured in Drosophila spermatogenesis, where stem cell daughters choose between self-renewal and differentiation, and where transit amplifying gonial cells switch to spermatocyte development. Gonial cells divide four times; the counting and effector mechanisms regulating this are unknown. Aim 1 tests the hypothesis that germ cells count intrinsically, and then collaborate with surrounding somatic cells to coordinate the spermatocyte transition. We discovered that a somatic cell signal promotes differentiation of stem cell daughters, while other labs discovered a signal that promotes self-renewal. Aim 2 tests the hypothesis that self-renewal and differentiation are indeed balanced by these competing signals, and then investigate how they compete. To generate and begin to test biologically based hypotheses for other candidate factors and signaling pathways that legislate between renewal and differentiation we have conducted transcript-profiling analyses of self-renewing cells or their differentiating daughters. Aim 3 proposes to complete these studies and conduct functional tests on selected candidates. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STEM CELL SELECTION & EXPANSION VIA HOX GENE ACTIVATION Principal Investigator & Institution: Emerson, Stephen G.; Professor; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104
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Timing: Fiscal Year 2002; Project Start 16-MAY-2001; Project End 31-MAR-2005 Summary: (Applicant's Abstract) Stem cell therapies play a major and increasing role in cancer therapies. If we were able to isolate repopulating stem cells, expand them in vitro and genetically manipulate them prior to reinfusion, we would be able to explore many avenues of protective therapies, including expansion of stem cells for multi-cycle chemotherapy, protection of stem cells with chemotherapy resistance genes, and improvement in stem cell quality with DNA repair genes. Published studies indicate that the homeobox gene HOXB4 is expressed in primitive hematopoietic cells, and that its enforced expression induces stem cell symmetric cycling. Our preliminary data indicates that we have isolated the human HOXB4 gene and its promoter, and that we have isolated at least two transcription factors that activate this promoter in both leukemic cells and normal CD34+ cells. In addition, we have found that CD34+ cells activating a HOXB4 expression construct are substantially enriched in long term culture initiating cells (LTCIC). This proposal seeks to identify and stimulate the fraction of stem cells that are capable of self-renewal, as illustrated by their ability to transcribe the homeobox gene HOXB4. In particular, we propose to: 1) Test the Ability of the Activated HOXB4 Promoter to NOD/SCID Repopulating Cells following Xenotransplantation; 2) Identify the Transcription Factors Activating the HOXB4 Promoter at the HxRE-1 (NF-1) Site; and 3) Identify Additional More Distant Genetic Elements That Enhance the Activity of the HOXB4 Promoter In Vivo. Integrated together, these aims will define a new paradigm for the molecular identification and manipulation of stem cells for hematopoietic support and genetic modification. If successful, this model should be directly translatable to clinical practice in the future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STEM CELLS AND PERIODONTAL BIOENGINEERING Principal Investigator & Institution: Diekwisch, Thomas G.; Associate Professor and Head; Orthodontics; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-MAY-2008 Summary: (provided by applicant): Stem cells are a population of cells capable of providing replacement cells for a given differentiated cell type (Blau et al. 2001). In the current proposal, stem cell-based technologies are applied to generate novel tissueengineered, smart periodontal implants that use biomimetic strategies with the ultimate goal of achieving full regeneration of lost periodontal tissues. Mesenchymal periodontal tissues such as cementum, alveolar bone, and periodontal ligament are neural crestderived entities that emerge from the dental follicle at the onset of root formation (Diekwisch 2001, 2002). In order to mimic the differentiation of periodontal cells from undifferentiated progenitors we are planning to recapitulate and/or mimic the molecular and cellular events that occur during periodontal tissue differentiation in the developing periodontium. Dental follicle and bone marrow mesenchymal stem cells have been isolated to determine the differentiation conditions necessary for these cells to mimic periodontal cells. In order to test the applicability of periodontal stem cells, we have established a series of model systems in which we will test the feasibility of using stern cells in conjunction with biomimetic scaffolds to generate bioengineered periodontal implants for improved periodontal regeneration. Hypothesis to be tested: Mesenchymal stem cells have the potential to generate and regenerate periodontal tissues, cementum, alveolar bone, and periodontal ligament. To test this hypothesis, we propose studies with the following Specific Aims: 1. To identify and isolate stem cells for periodontal tissue-engineering. 2. To establish and characterize stem cell lines for
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periodontal tissueengineering. 3. To test the conditions necessary to differentiate stem cells into periodontal cells in vitro. 4. To ask the question whether stem cells will mimic existing periodontal tissues following tissue implantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STEM CELLS IN AIRWAY REPAIR Principal Investigator & Institution: Stripp, Barry R.; Associate Professor; Environ & Occupational Health; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: (Applicant's abstract): Identification of pulmonary epithelial stem cells with pluripotential differentiation capacity will significantly impact development of gene therapeutic modalities, and development of new approaches for the treatment or prevention of chronic and neoplastic lung disease. Our preliminary studies have defined the neuroepithelial body (NEB) microenvironment as a critical reservoir of proliferative cells following acute airway injury and suggest that these may have stem cell-like character. Proliferation and hyperplasia of NEB-associated cells, which is common to many types of chronic lung disease in humans, is only observed among mouse models when progenitor (Clara) cells are among those injured. Goals of this application are to test the hypothesis that injury of a progenitor cell population, such as the mature Clara cell, is a stimulus for recruitment of NEB-associated stem cells for epithelial renewal. Aims will define contributions made by proliferative cells originating from the NEB towards repair from ozone or naphthalene-induced airway injury; agents preferentially targeting terminally differentiated (ciliated) or progenitor (Clara) cells, respectively. Classification of NEB-associated cells with regenerated capacity as "stem cells" will be made by fulfilling three criteria: 1) absence of certain differentiated functions, 2) pluripotential differentiation capacity and 3) relatively slow cycling time in the quiescent lung. Preliminary data demonstrate a requirement for Clara cell secretory protein (CCSP)-expressing (CE) cells in airway repair. Aim 1 will build upon these studies by further exploring variability in functional and molecular phenotype of CE cells in the quiescent and injured adult mouse lung. Aim 2 will expand upon preliminary studies demonstrating that both CE and pulmonary neuroendocrine (PNE) cells proliferate following acute naphthalene-induced airway injury. Through use of transgenic mice allowing cell type-specific conditional ablation of either CE or PNE cells, we will identify the contribution of each group to airway homeostasis and repair. Finally, studies proposed in Aim 3 will classify NEB-associated cells with proliferative potential as either progenitor cells or stem cells through analysis of cycling time and differentiation capacity. Completion of these aims will define pulmonary stem cell populations, their contributions to airway repair, and how this may be modified by injury to either progenitor or non-progenitor epithelial cell populations. These finding will significantly impact the understanding of mechanisms of normal epithelial renewal and neoplasia, and will identify critical cells to be targeted for stable maintenance of therapeutic genes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: STEM CELLS IN PERIPHERAL NERVOUS SYSTEM DEVELOPMENT Principal Investigator & Institution: Morrison, Sean J.; Assistant Professor; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274
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Timing: Fiscal Year 2002; Project Start 01-FEB-2001; Project End 31-JAN-2006 Summary: (From the Applicant's Abstract): Stem cells are self-renewing multipotent progenitors with the broadest developmental potential in a given tissue at a given time (Morrison et al. Cell 88:287). There is great interest in neural stem cells because of their importance in neural development and their therapeutic potential. Neural crest stem cells (NCSCs) migrate out of the neural tube in early to mid-gestation, and give rise to the peripheral nervous system (PNS) as well as other tissues. In order to understand PNS formation, the process by which NCSCs differentiate into the diverse cell types of the PNS must be understood. Although neural crest cells were thought to differentiate within days of migrating, we have recently discovered that NCSCs persist into late gestation by self-renewing within peripheral nerves (Morrison et al. Cell 96:737). This observation suggests that PNS development may be more dynamic than previously thought and raises several specific questions. First, why would the self-renewal of NCSCs be promoted within peripheral nerves if, as current models suggest, the neural crest only gives rise to Schwann cells in nerves? Aim #1 is to use CRE-recombinase fate mapping to test whether the neural crest actually gives rise to multiple lineages of cells within nerves. If so, nerve development would require multilineage differentiation by stem cells rather than just overt differentiation by Schwann precursors. This would fundamentally change models of nerve development. Aim #2 is to test whether postmigratory NCSCs also persist in other areas of the fetal PNS. Aim #4 is to test whether there are cell-intrinsic differences between these NCSC populations from different regions of the PNS in terms of the types of neurons they can form. If there are cell-intrinsic differences between postmigratory NCSC populations then perhaps differences between stem cell lineages interact with environmental differences to generate neural diversity. Aim #3 is to test whether rare NCSCs also persist postnatally. The discovery of NCSCs in postnatal tissues might fundamentally alter approaches to regeneration in the PNS. Answers to these questions could change the way we think about PNS development, injury, and disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STEM CELLS IN THE CNS Principal Investigator & Institution: Temple, Sally; Associate Professor; Ctr/Neuropharmacology/Neurosci; Albany Medical College of Union Univ Union University Albany, Ny 12208 Timing: Fiscal Year 2003; Project Start 15-AUG-1995; Project End 31-JUL-2007 Summary: (provided by applicant): Damage to the central nervous system (CNS) is tragically difficult to restore: the numerous types of neurons are postmitotic, and in most CNS regions their loss is permanent. The discovery that neural stem cells generate neurons in the embryo and in a few regions in the adult raises the possibility that they can be harnessed to generate new neurons for CNS repair. The long-term objective of these studies is to understand how CNS stem cells generate different neuron types, and how this can be applied clinically. Currently, we know little about the neuron types stem cells generate. In the normal adult, neurogenesis is limited to interneuron production, and it is not known whether adult stem cells can make the variety of projection neurons born during embryogenesis and early development. The neuron types that stem cells are capable of generating at different stages - their developmental potential - needs to be elucidated. In addition, the plasticity of neural stem cells - what neuron types they produce after transplantation into different stages or regions of the CNS and into the damaged CNS - needs evaluation. These issues remain unresolved largely because of the difficulty in isolating these rare cells to permit study of an
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identified, fresh stem cell population. Unfortunately, culture-expanded stem cells largely generate gila after transplantation in vivo. Recently we discovered that the carbohydrate LeX is expressed on the surface of cortical stem cells throughout life. We can now acutely isolate neural stem cells from different stages using FACS and analyze their developmental potential and plasticity. This will be done using clonal culture analysis, which provides information about the types of progeny an individual stem cell generates. In addition, we will implant these stem cells into the embryonic brain in vivo to reveal what neurons they produce in a developing system. Fresh stem cells will also be implanted into a model of ischemic damaged cerebral cortex to assess whether they can generate appropriate neuron types after CNS damage. Given LeX is expressed by all neural stem cells, we will examine its role by up and down regulating expression of the LeX-synthesizing enzymes FucT4 and FucT9 and assessing neural stem cell behavior. Because LeX is extremely abundant in embryonic regions expressing FGF-8 and Wnts, we will examine the impact of these growth factors on neural stem cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TESTING GENE THERAPY FOR EPIDERMOLYSIS BULLOSA SIMPLEX Principal Investigator & Institution: Roop, Dennis; Professor; Molecular and Cellular Biology; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2003; Project Start 07-JUL-2003; Project End 31-MAY-2008 Summary: (provided by applicant): The Dowling-Meara variant of epidermolysis bullosa simplex (EBS-DM) is a severe blistering disease inherited in an autosomaldominant fashion. Besides symptomatic care, no effective therapeutic treatment is available for EBS. Therefore, gene therapy is the only option for a permanent corrective therapy for these patients. Prior to testing gene therapy approaches for EBS in humans, it is desirable to utilize a pre-clinical animal model to determine the safety and efficacy of these approaches. We have recently generated a transgenic mouse model that mimics EBS-DM at the genetic level. This mouse model differs from the human disease in that expression of the mutant K14 allele, which contains an Arg 131 Cys mutation equivalent to the Arg 125 Cys mutation found in the majority of EBS-DM patients, can be restricted to a small area of the skin. This mouse model has provided an explanation for the lack of mosaic forms of EBS. Patients with mostly normal skin that have patches of diseased skin are referred to as mosaics. Mosaic patients have been described for several skin diseases, but not for EBS. Focal activation of the mutant K14 gene by topical application of an inducer results in blister formation. However, after a few weeks, the blister heals and never reappears. We have demonstrated that the mutant K14 gene was activated in epidermal stern cells. However, the defective EBS stem cells were replaced by normal epidermal stem cells that migrate in from the untreated area surrounding the blister. This mouse model predicts that if a mosaic patch of EBS skin formed during development of an embryo, these defective EBS epidermal stem cells would not survive, but be replaced by normal stem cells. This explains the absence of mosaic forms of EBS. This observation also has important implications for gene therapy approaches for EBS, since it suggests that if EBS stem cells were removed from a patient, genetically corrected and then returned to a blistered area, they would have a selective growth advantage over defective EBS stem cells. Of further interest was the observation that mice which express the mutant K14 allele at levels approximately 50% of wild type K14 fail to exhibit a skin phenotype. This suggests that as long as the ratio of wild type to mutant K14 is above a threshold, possibly as low as 2:1, the skin will have a normal appearance and be fully functional. Thus, successful gene therapy approaches may not
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require correction or complete suppression of the mutant allele. This proposal will use epidermal stem cells isolated from the EBS-DM mouse model to test new gene therapy strategies that are based on these novel findings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE BIOLOGY OF PROSTATE STEM CELLS Principal Investigator & Institution: Wilson, E Lynette.; Associate Professor; Cell Biology; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2002; Project Start 10-JUL-1997; Project End 31-MAY-2006 Summary: (provided by applicant): The objective of this proposal is to identify and characterize prostatic epithelial stem cells and to define the regulators of their growth and differentiation. The isolation of stem cells is of relevance to prostate carcinoma and benign prostatic hypertrophy, as both diseases are considered to arise from the aberrant proliferation of stem cells. We have identified a quiescent, slow-cycling population of cells with high proliferative potential in the proximal region of prostatic ducts. This region also contains cells with the greatest proliferative potential and the ability to form large, branched three dimensional glandular structures in collagen gels. In addition, we find that c-kit (receptor for stem cell factor, SCF), is expressed on 25% of basal cells while being completely absent from luminal cells. As many stem cell populations express c-kit, are quiescent and have innate high proliferative potential, we propose that a small number of prostatic stem cells are located in a 'niche' in the proximal region in the basal compartment and express c-kit on their surface. We further propose that the regulation of stem cell quiescence and proliferation is mediated by reciprocal interactions between transforming growth factor-B (TGF-B), which inhibits growth and SCF, which promotes growth. These hypotheses will be tested in three aims that exploit our ability to isolate subsets of viable basal cells expressing a6 integrin and c-kit and to test their engraftment in two in vivo models. Aim I will identify and separate subsets of basal cells most enriched for cells with stem cell properties. The proliferative potential of these subsets and their ability to generate glandular structures will be determined. In addition, culture conditions that allow their expansion while preventing their differentiation will be identified. New surface markers that will allow further selection and purification of stem cells will be sought. Aim 2 will quantitate the ability of the stem cell containing subsets to proliferate in vivo, to repopulate their organ of origin and to give rise to differentiated progeny. This will be done by implanting cells under the renal capsule and by intraprostatic inoculation in a novel transplantation model. Aim 3 will determine whether the balance between quiescence and proliferation is mediated by opposing effects of TGF-B and SCF. The sites of active TGF-J3 generation along the proximal-distal ductal axis will be identified under different hormonal conditions and the ability of TGF-13 to regulate c-kit and SCF expression studied. These experiments will define the subset of proximal cells in which prostatic stem cells reside and identify the manner in which their growth is regulated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TRANSDIFFERENTIATION POTENTIAL OF BONE MARROW STEM CELLS Principal Investigator & Institution: Ogawa, Makio; Professor; Medicine; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2007
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Summary: (provided by applicant): Recent studies demonstrated that stem cells in a number of organs/tissues have the potential to differentiate into tissues other than those specified in their origins. The most striking evidence for this "transdifferentiation" has been between bone marrow and muscular, hepatic, and CNS systems. Since all of the transplantation studies have been conducted using populations of cells, it is possible that the apparent bipotentiality of the stem cells is from engraftment by two separate populations of monopotential stem cells. Our proposal seeks definitive information on the tissue/organ engrafting capabilities of the hematopoietic and stromal stem cells by using single stem cell transplantation. We will use transgenic CD45.2 C57BL/6 (B6) mice that ubiquitously express enhanced green fluorescent protein (EGFP) as the source for donor stem cells and congenic CD45.1 B6 mice as recipients. The contribution of bone marrow EGFP-labeled donor cells to various organs/tissues of the recipient mice will be assessed using laser scanning confocal microscopy (LSCM) and conventional epifluorescence microscopy in combination with differential interference contrast (DIC) microscopy. Two Specific Aims are proposed: (1) To define the potentials of individual hematopoietic stem cells by single stem cell transplantation to lethally irradiated recipient mice. (2) To define the potentials of stromal stem cells. We have developed a highly efficient technique to create mice with clonal hematopoietic engraftment by combining FACS cell sorting and short-term suspension culture of bone marrow cells. Collaboration with the laboratory of Dr. Christopher J. Drake of Department of Cell Biology and Anatomy, who has considerable expertise in the use of LSCM and DIC and epifluorescence microscopy, has already resulted in exciting preliminary information about the potentiality of a single EGFP-labeled stem cell. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSDUCTION OF HUMAN STEM AND PROGENITOR CELLS Principal Investigator & Institution: Crooks, Gay M.; Associate Professor; Children's Hospital Los Angeles 4650 Sunset Blvd Los Angeles, Ca 90027 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: The fundamental obstacle to effective gene therapy for hematopoietic diseases continues to be the difficulty in obtaining sufficiently high levels of gene transfer into Lympho-Hematopoietic Stem Cells (LHSC). At the core of this problem is the mismatch in the biology of the chosen target cell, i.e. the non-cycling LHSC, and the use of vector systems that preferentially transduce cycling cells. We hypothesize that a combination of vector modifications, alternative cell targets and selective expansion of corrected cells will be required to achieve adequate levels of gene correction for most diseases. Our goal in this proposal is to explore the potential of all three approaches. Our Specific Aims are: 1. To determine the relative capacity of Human Foamy Virus (HFV) and Human Immune-deficiency Virus-1 (HIV-1) based vectors to transduce quiescent human hematopoietic cells; 2. To determine whether lineage-committed progenitors, i.e. Common Lymphoid (CLP), and Common Myeloid Progenitors (CMP) offer advantages over pluripotent Lympho-hematopoietic Stem Cells as targets for gene therapy; 3. To determine whether expansion of transduced human LHSC and progenitors can be accomplished by conditional expression of a "cell growth switch" linked to a binding site for a chemical inducer of dimerization. This proposal brings together various complementary experimental tools, i.e. optimal vector systems for multi-lineage expression in primitive cells, the ability to isolate primitive human hematopoietic populations with defined lineage potential and the in vitro and in vivo systems to measure the lineage potential of transduced populations, perform clonal analysis and assess engraftment and in vivo expansion of each population. The
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biological interplay of the choice of vector, the type of target cells and the in vivo manipulation of the transduced target cells, will be analyzed in the context of the whole to understand the full therapeutic potential of these approaches. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: USE OF GENE THERAPY TO INDUCE TRANSPLANTATION TOLERANCE Principal Investigator & Institution: Kearns-Jonker, Mary K.; Children's Hospital Los Angeles 4650 Sunset Blvd Los Angeles, Ca 90027 Timing: Fiscal Year 2002; Project Start 15-AUG-2001; Project End 31-JUL-2004 Summary: The critical shortage of human organs available for transplantation to patients with end-stage diseases has led to an increasing amount of attention directed at developing methods to allow for the use of pigs as an alternative source of donor organs. Humans that have never been exposed to pig cells, however, have antibodies that are capable of rapidly rejecting these organs. These antibodies react predominantly with a specific sugar called the galactose tx1,3 galactose carbohydrate epitope (gal epitope) expressed on pig cells. This sugar is identified as foreign by humans or Old World primates because a mutation has occurred during evolution that prevents this carbohydrate from being expressed in humans and specific types of monkeys. Consequently, humans produce antibodies to gal when exposed to organs derived from other species (xenografts). A special strain of mice has recently been developed that serves as a good small animal model of xenograft rejection because they produce antigal antibodies similar to the antibodies that reject pig xenografts in humans. In this model, production of antibodies that reject pig cells can be prevented by introducing a single gene by bone marrow transplantation before the mouse is exposed to the pig cells. The ability to reproduce this experiment in a preclinical primate model will provide a means by which human patients may be treated prior to xenotransplantation to prevent rejection of pig organs, and will have a significant impact on the field of transplantation. This experiment has not yet been reproduced in primates because introduction of the new gene in primate stem cells of the bone marrow is more difficult compared with the mouse model using conventional methods. We have recently established a new method to introduce genes more efficiently into primate and human stem cells of the bone marrow using a new type of gene delivery vehicle (lentiviral vector). In this application, we propose to introduce the gene responsible for gal carbohydrate expression in primate stem cells and determine whether this procedure prevents anti-gal antibody production in primates. Our hypothesis is that this new vector will allow us to introduce the gene responsible for encoding the gal carbohydrate into primate stem cells at levels that are sufficient to prevent the immune response to pig cells in transplanted rhesus monkeys. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National
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Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.
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Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “stem cells” (or synonyms) into the search box. This search gives you access to fulltext articles. The following is a sample of items found for stem cells in the PubMed Central database: •
8p12 Stem Cell Myeloproliferative Disorder: the FOP-Fibroblast Growth Factor Receptor 1 Fusion Protein of the t(6;8) Translocation Induces Cell Survival Mediated by Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase/Akt/mTOR Pathways. by Guasch G, Ollendorff V, Borg JP, Birnbaum D, Pebusque MJ.; 2001 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=99978
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A molecular profile of a hematopoietic stem cell niche. by Hackney JA, Charbord P, Brunk BP, Stoeckert CJ, Lemischka IR, Moore KA.; 2002 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130586
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A nucleolar mechanism controlling cell proliferation in stem cells and cancer cells. by Tsai RY, McKay RD.; 2002 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=187487
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An empty Drosophila stem cell niche reactivates the proliferation of ectopic cells. by Kai T, Spradling A.; 2003 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153607
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An Induction Gene Trap Screen in Embryonic Stem Cells: Identification of Genes that Respond to Retinoic Acid in vitro. by Forrester LM, Nagy A, Sam M, Watt A, Stevenson L, Bernstein A, Joyner AL, Wurst W.; 1996 Feb 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40001
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Bcrp1 gene expression is required for normal numbers of side population stem cells in mice, and confers relative protection to mitoxantrone in hematopoietic cells in vivo. by Zhou S, Morris JJ, Barnes Y, Lan L, Schuetz JD, Sorrentino BP.; 2002 Sep 17; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=129446
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Biological Characteristics of the Leukemia-Associated Transcriptional Factor AML1 Disclosed by Hematopoietic Rescue of AML1-Deficient Embryonic Stem Cells by Using a Knock-in Strategy. by Okuda T, Takeda K, Fujita Y, Nishimura M, Yagyu S, Yoshida M, Akira S, Downing JR, Abe T.; 2000 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85087
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Characterization of the expression of MHC proteins in human embryonic stem cells. by Drukker M, Katz G, Urbach A, Schuldiner M, Markel G, Itskovitz-Eldor J, Reubinoff B, Mandelboim O, Benvenisty N.; 2002 Jul 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=125045
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Chipping away at stem cells. by Chu VT, Gage FH.; 2001 Jul 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=35394
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With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.
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Cyclophosphamide /granulocyte colony-stimulating factor induces hematopoietic stem cells to proliferate prior to mobilization. by Morrison SJ, Wright DE, Weissman IL.; 1997 Mar 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20016
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Direct isolation of human central nervous system stem cells. by Uchida N, Buck DW, He D, Reitsma MJ, Masek M, Phan TV, Tsukamoto AS, Gage FH, Weissman IL.; 2000 Dec 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18985
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Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. by Levesque JP, Hendy J, Takamatsu Y, Simmons PJ, Bendall LJ.; 2003 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151860
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Distinct role of gp130 activation in promoting self-renewal divisions by mitogenically stimulated murine hematopoietic stem cells. by Audet J, Miller CL, Rose-John S, Piret JM, Eaves CJ.; 2001 Feb 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=29330
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Embryonic stem cells and mice expressing different GFP variants for multiple noninvasive reporter usage within a single animal. by Hadjantonakis AK, Macmaster S, Nagy A.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=116589
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Embryonic stem cells and somatic cells differ in mutation frequency and type. by Cervantes RB, Stringer JR, Shao C, Tischfield JA, Stambrook PJ.; 2002 Mar 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122567
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Enrichment for murine keratinocyte stem cells based on cell surface phenotype. by Tani H, Morris RJ, Kaur P.; 2000 Sep 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27131
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Escaping the stem cell compartment: Sustained UVB exposure allows p53-mutant keratinocytes to colonize adjacent epidermal proliferating units without incurring additional mutations. by Zhang W, Remenyik E, Zelterman D, Brash DE, Wikonkal NM.; 2001 Nov 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=61147
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Ets1 is required for p53 transcriptional activity in UV-induced apoptosis in embryonic stem cells. by Xu D, Wilson TJ, Chan D, De Luca E, Zhou J, Hertzog PJ, Kola I.; 2002 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=126157
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Europe fragmented over embryonic stem cell research. by Birmingham K.; 2003 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=171403
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Expression of Pax4 in embryonic stem cells promotes differentiation of nestinpositive progenitor and insulin-producing cells. by Blyszczuk P, Czyz J, Kania G, Wagner M, Roll U, St-Onge L, Wobus AM.; 2003 Feb 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=298715
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Fbx15 Is a Novel Target of Oct3/4 but Is Dispensable for Embryonic Stem Cell SelfRenewal and Mouse Development. by Tokuzawa Y, Kaiho E, Maruyama M, Takahashi K, Mitsui K, Maeda M, Niwa H, Yamanaka S.; 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=152544
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Flk-2 is a marker in hematopoietic stem cell differentiation: A simple method to isolate long-term stem cells. by Christensen JL, Weissman IL.; 2001 Dec 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=64718
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Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells. by Teng YD, Lavik EB, Qu X, Park KI, Ourednik J, Zurakowski D, Langer R, Snyder EY.; 2002 Mar 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122466
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Gene Expression Profiling of Embryo-Derived Stem Cells Reveals Candidate Genes Associated With Pluripotency and Lineage Specificity. by Tanaka TS, Kunath T, Kimber WL, Jaradat SA, Stagg CA, Usuda M, Yokota T, Niwa H, Rossant J, Ko MS.; 2002 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=187571
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Generation of neural crest-derived peripheral neurons and floor plate cells from mouse and primate embryonic stem cells. by Mizuseki K, Sakamoto T, Watanabe K, Muguruma K, Ikeya M, Nishiyama A, Arakawa A, Suemori H, Nakatsuji N, Kawasaki H, Murakami F, Sasai Y.; 2003 May 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156286
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Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells. by Hori Y, Rulifson IC, Tsai BC, Heit JJ, Cahoy JD, Kim SK.; 2002 Dec 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=138572
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Hematopoietic colony-forming cells derived from human embryonic stem cells. by Kaufman DS, Hanson ET, Lewis RL, Auerbach R, Thomson JA.; 2001 Sep 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=58532
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Hematopoietic Stem Cell Expansion and Distinct Myeloid Developmental Abnormalities in a Murine Model of the AML1-ETO Translocation. by de Guzman CG, Warren AJ, Zhang Z, Gartland L, Erickson P, Drabkin H, Hiebert SW, Klug CA.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=133929
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Hematopoietic stem cells and lymphoid progenitors express different Ikaros isoforms, and Ikaros is localized to heterochromatin in immature lymphocytes. by Klug CA, Morrison SJ, Masek M, Hahm K, Smale ST, Weissman IL.; 1998 Jan 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18476
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HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34 + stem cell recruitment to the liver. by Kollet O, Shivtiel S, Chen YQ, Suriawinata J, Thung SN, Dabeva MD, Kahn J, Spiegel A, Dar A, Samira S, Goichberg P, Kalinkovich A, ArenzanaSeisdedos F, Nagler A, Hardan I, Revel M, Shafritz DA, Lapidot T.; 2003 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=164291
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HIV, but not murine leukemia virus, vectors mediate high efficiency gene transfer into freshly isolated G0 /G1 human hematopoietic stem cells. by Uchida N, Sutton RE, Friera AM, He D, Reitsma MJ, Chang WC, Veres G, Scollay R, Weissman IL.; 1998 Sep 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21744
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Host cis-Mediated Extinction of a Retrovirus Permissive for Expression in Embryonal Stem Cells during Differentiation. by Laker C, Meyer J, Schopen A, Friel J, Heberlein C, Ostertag W, Stocking C.; 1998 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109381
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Hybrid Embryonic Stem Cell-Derived Tetraploid Mice Show Apparently Normal Morphological, Physiological, and Neurological Characteristics. by Schwenk F, Zevnik B, Bruning J, Rohl M, Willuweit A, Rode A, Hennek T, Kauselmann G, Jaenisch R, Kuhn R.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155215
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Identification and isolation of candidate human keratinocyte stem cells based on cell surface phenotype. by Li A, Simmons PJ, Kaur P.; 1998 Mar 31; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19935
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Identification of a multipotent astrocytic stem cell in the immature and adult mouse brain. by Laywell ED, Rakic P, Kukekov VG, Holland EC, Steindler DA.; 2000 Dec 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17670
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Identification of a subpopulation of rapidly self-renewing and multipotential adult stem cells in colonies of human marrow stromal cells. by Colter DC, Sekiya I, Prockop DJ.; 2001 Jul 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=35429
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Identification of endoglin as a functional marker that defines long-term repopulating hematopoietic stem cells. by Chen CZ, Li M, de Graaf D, Monti S, Gottgens B, Sanchez MJ, Lander ES, Golub TR, Green AR, Lodish HF.; 2002 Nov 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137740
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Identification of Novel MyoD Gene Targets in Proliferating Myogenic Stem Cells. by Wyzykowski JC, Winata TI, Mitin N, Taparowsky EJ, Konieczny SF.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=133998
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Immortalization of a primate bipotent epithelial liver stem cell. by Allain JE, Dagher I, Mahieu-Caputo D, Loux N, Andreoletti M, Westerman K, Briand P, Franco D, Leboulch P, Weber A.; 2002 Mar 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122576
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In vitro Differentiation of Embryonic Stem Cells into Lymphocyte Precursors Able to Generate T and B Lymphocytes in vivo. by Gutierrez-Ramos JC, Palacios R.; 1992 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50087
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In vitro Generation of Hematopoietic Stem Cells from an Embryonic Stem Cell Line. by Palacios R, Golunski E, Samaridis J.; 1995 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41373
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In vitro hematopoietic and endothelial potential of flk-1[minus sign] /[minus sign] embryonic stem cells and embryos. by Schuh AC, Faloon P, Hu QL, Bhimani M, Choi K.; 1999 Mar 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26753
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In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells. by Yang L, Li S, Hatch H, Ahrens K, Cornelius JG, Petersen BE, Peck AB.; 2002 Jun 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=123023
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Integration of multiple instructive cues by neural crest stem cells reveals cell-intrinsic biases in relative growth factor responsiveness. by Shah NM, Anderson DJ.; 1997 Oct 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23470
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Interleukin 3 or Interleukin 1 Abrogates the Reconstituting Ability of Hematopoietic Stem Cells. by Yonemura Y, Ku H, Hirayama F, Souza LM, Ogawa M.; 1996 Apr 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39483
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Intrinsic Human Immunodeficiency Virus Type 1 Resistance of Hematopoietic Stem Cells Despite Coreceptor Expression. by Shen H, Cheng T, Preffer FI, Dombkowski D, Tomasson MH, Golan DE, Yang O, Hofmann W, Sodroski JG, Luster AD, Scadden DT.; 1999 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=103880
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Long-Term Culture of Lymphohematopoietic Stem Cells. by Palacios R, Bucana C, Xie X.; 1996 May 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39230
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Methylguanine methyltransferase --mediated in vivo selection and chemoprotection of allogeneic stem cells in a large-animal model. by Neff T, Horn PA, Peterson LJ, Thomasson BM, Thompson J, Williams DA, Schmidt M, Georges GE, Kalle CV, Kiem HP.; 2003 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=259127
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Mouse embryonic stem cells carrying one or two defective Msh2 alleles respond abnormally to oxidative stress inflicted by low-level radiation. by DeWeese TL, Shipman JM, Larrier NA, Buckley NM, Kidd LR, Groopman JD, Cutler RG, te Riele H, Nelson WG.; 1998 Sep 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21740
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Murine hematopoietic stem cells committed to macrophage /dendritic cell formation: Stimulation by Flk2-ligand with enhancement by regulators using the gp130 receptor chain. by Metcalf D.; 1997 Oct 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23534
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Muscle-derived hematopoietic stem cells are hematopoietic in origin. by McKinneyFreeman SL, Jackson KA, Camargo FD, Ferrari G, Mavilio F, Goodell MA.; 2002 Feb 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122192
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Natural killer cell suppression of Friend virus-induced preleukemic hemopoietic stem cells. by Eckner RJ, Bennett M, Hettrick KL, Seidler C.; 1987 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=255714
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Neural stem cell heterogeneity demonstrated by molecular phenotyping of clonal neurospheres. by Suslov ON, Kukekov VG, Ignatova TN, Steindler DA.; 2002 Oct 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137913
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Neural stem cells and cholinergic neurons: Regulation by immunolesion and treatment with mitogens, retinoic acid, and nerve growth factor. by Calza L, Giuliani A, Fernandez M, Pirondi S, D'Intino G, Aloe L, Giardino L.; 2003 Jun 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=165874
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Neural stem cells display extensive tropism for pathology in adult brain: Evidence from intracranial gliomas. by Aboody KS, Brown A, Rainov NG, Bower KA, Liu S, Yang W, Small JE, Herrlinger U, Ourednik V, Black PM, Breakefield XO, Snyder EY.; 2000 Nov 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18852
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Oxytocin induces differentiation of P19 embryonic stem cells to cardiomyocytes. by Paquin J, Danalache BA, Jankowski M, McCann SM, Gutkowska J.; 2002 Jul 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=123178
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p63 identifies keratinocyte stem cells. by Pellegrini G, Dellambra E, Golisano O, Martinelli E, Fantozzi I, Bondanza S, Ponzin D, McKeon F, De Luca M.; 2001 Mar 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=30623
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Parvovirus Infection Suppresses Long-Term Repopulating Hematopoietic Stem Cells. by Segovia JC, Guenechea G, Gallego JM, Almendral JM, Bueren JA.; 2003 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=165232
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Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. by Gronthos S, Mankani M, Brahim J, Robey PG, Shi S.; 2000 Dec 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17626
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Preferential induction of apoptosis for primary human leukemic stem cells. by Guzman ML, Swiderski CF, Howard DS, Grimes BA, Rossi RM, Szilvassy SJ, Jordan CT.; 2002 Dec 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=138592
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Preselection of retrovirally transduced bone marrow avoids subsequent stem cell gene silencing and age-dependent extinction of expression of human [beta]-globin in engrafted mice. by Kalberer CP, Pawliuk R, Imren S, Bachelot T, Takekoshi KJ, Fabry M, Eaves CJ, London IM, Humphries RK, Leboulch P.; 2000 May 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25842
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Rapid expansion of recycling stem cells in cultures of plastic-adherent cells from human bone marrow. by Colter DC, Class R, DiGirolamo CM, Prockop DJ.; 2000 Mar 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16218
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Reduced Proliferative Capacity of Hematopoietic Stem Cells Deficient in Hoxb3 and Hoxb4. by Bjornsson JM, Larsson N, Brun AC, Magnusson M, Andersson E, Lundstrom P, Larsson J, Repetowska E, Ehinger M, Humphries RK, Karlsson S.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155209
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Reelin function in neural stem cell biology. by Kim HM, Qu T, Kriho V, Lacor P, Smalheiser N, Pappas GD, Guidotti A, Costa E, Sugaya K.; 2002 Mar 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122641
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Remodeling of the postnatal mouse testis is accompanied by dramatic changes in stem cell number and niche accessibility. by Shinohara T, Orwig KE, Avarbock MR, Brinster RL.; 2001 May 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33443
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Retroviral Expression in Embryonic Stem Cells and Hematopoietic Stem Cells. by Cherry SR, Biniszkiewicz D, van Parijs L, Baltimore D, Jaenisch R.; 2000 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86295
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Serum Response Factor Is Required for Immediate-Early Gene Activation yet Is Dispensable for Proliferation of Embryonic Stem Cells. by Schratt G, Weinhold B, Lundberg AS, Schuck S, Berger J, Schwarz H, Weinberg RA, Ruther U, Nordheim A.; 2001 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86921
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SHED: Stem cells from human exfoliated deciduous teeth. by Miura M, Gronthos S, Zhao M, Lu B, Fisher LW, Robey PG, Shi S.; 2003 May 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156282
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Shiga Toxin 2 Induces Macrophage-Granulocyte Colonies from Human Bone Marrow and Cord Blood Stem Cells. by Chiyoda S, Takeda T, Aoki Y.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128287
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Somatic mosaicism in Fanconi anemia: Evidence of genotypic reversion in lymphohematopoietic stem cells. by Gregory JJ Jr, Wagner JE, Verlander PC, Levran O, Batish SD, Eide CR, Steffenhagen A, Hirsch B, Auerbach AD.; 2001 Feb 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=30172
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Spermatogonial stem cell enrichment by multiparameter selection of mouse testis cells. by Shinohara T, Orwig KE, Avarbock MR, Brinster RL.; 2000 Jul 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26950
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Spermatogonial stem cells share some, but not all, phenotypic and functional characteristics with other stem cells. by Kubota H, Avarbock MR, Brinster RL.; 2003 May 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=164473
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Synthetic small molecules that control stem cell fate. by Ding S, Wu TY, Brinker A, Peters EC, Hur W, Gray NS, Schultz PG.; 2003 Jun 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=164638
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The embryonic stem cell transcription factors Oct-4 and FoxD3 interact to regulate endodermal-specific promoter expression. by Guo Y, Costa R, Ramsey H, Starnes T, Vance G, Robertson K, Kelley M, Reinbold R, Scholer H, Hromas R.; 2002 Mar 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122580
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The human hematopoietic stem cell compartment is heterogeneous for CXCR4 expression. by Rosu-Myles M, Gallacher L, Murdoch B, Hess DA, Keeney M, Kelvin D, Dale L, Ferguson SS, Wu D, Fellows F, Bhatia M.; 2000 Dec 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18969
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The kinase MSK1 is required for induction of c-fos by lysophosphatidic acid in mouse embryonic stem cells. by Schuck S, Soloaga A, Schratt G, Arthur JS, Nordheim A.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=161794
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The Latent Transforming Growth Factor-[beta] --binding Protein-1 Promotes In Vitro Differentiation of Embryonic Stem Cells into Endothelium. by Gualandris A, Annes JP, Arese M, Noguera I, Jurukovski V, Rifkin DB.; 2000 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15073
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The primary target cells of the high-risk cottontail rabbit papillomavirus colocalize with hair follicle stem cells. by Schmitt A, Rochat A, Zeltner R, Borenstein L, Barrandon Y, Wettstein FO, Iftner T.; 1996 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190020
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Thrombopoietin expands hematopoietic stem cells after transplantation. by Fox N, Priestley G, Papayannopoulou T, Kaushansky K.; 2002 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151089
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Transduction of Human Progenitor Hematopoietic Stem Cells by Human Immunodeficiency Virus Type 1-Based Vectors Is Cell Cycle Dependent. by Sutton RE, Reitsma MJ, Uchida N, Brown PO.; 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104140
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Transgenic mice for the preparation of hygromycin-resistant primary embryonic fibroblast feeder layers for embryonic stem cell selections. by Johnson KA, Lerner CP, Di Lacio LC, Laird PW, Sharpe AH, Simpson EM.; 1995 Apr 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=306843
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Wheat germ agglutinin-positive cells in a stem cell-enriched fraction of mouse bone marrow have potent natural suppressor activity. by Sugiura K, Inaba M, Ogata H, Yasumizu R, Inaba K, Good RA, Ikehara S.; 1988 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=280528
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Wnt-5A augments repopulating capacity and primitive hematopoietic development of human blood stem cells in vivo. by Murdoch B, Chadwick K, Martin M, Shojaei F, Shah KV, Gallacher L, Moon RT, Bhatia M.; 2003 Mar 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=152308
The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with stem cells, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “stem cells” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for stem cells (hyperlinks lead to article summaries): •
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A new start for stem cells. Can bone marrow seed the brain with fresh neurons? Author(s): Sohn E. Source: U.S. News & World Report. 2003 February 10; 134(4): 84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12608330&dopt=Abstract
PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.
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A new tool in restorative neurosurgery: creating niches for neuronal stem cells. Author(s): Langmoen IA, Ohlsson M, Westerlund U, Svensson M. Source: Neurosurgery. 2003 May; 52(5): 1150-3. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12699560&dopt=Abstract
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Adenosine triphosphate induces proliferation of human neural stem cells: Role of calcium and p70 ribosomal protein S6 kinase. Author(s): Ryu JK, Choi HB, Hatori K, Heisel RL, Pelech SL, McLarnon JG, Kim SU. Source: Journal of Neuroscience Research. 2003 May 1; 72(3): 352-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12692902&dopt=Abstract
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Adenoviral transduction of mouse hematopoietic stem cells. Author(s): Bradfute SB, Goodell MA. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2003 March; 7(3): 334-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12668129&dopt=Abstract
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Adipose-derived adult stem cells: isolation, characterization, and differentiation potential. Author(s): Gimble J, Guilak F. Source: Cytotherapy. 2003; 5(5): 362-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14578098&dopt=Abstract
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Adult bone marrow stem cells regenerate myocardium in ischemic heart disease. Author(s): Orlic D. Source: Annals of the New York Academy of Sciences. 2003 May; 996: 152-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799293&dopt=Abstract
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Adult cardiac stem cells--where do we go from here? Author(s): Edelberg JM, Xaymardan M, Rafii S, Hong MK. Source: Sci Aging Knowledge Environ. 2003 July 2; 2003(26): Pe17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12844537&dopt=Abstract
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Adult mesenchymal stem cells and cell-based tissue engineering. Author(s): Tuan RS, Boland G, Tuli R. Source: Arthritis Research & Therapy. 2003; 5(1): 32-45. Epub 2002 December 11. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12716446&dopt=Abstract
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Adult stem cells and their importance in cell therapy. Author(s): Filip S, Mokry J, Hruska I. Source: Folia Biol (Praha). 2003; 49(1): 9-14. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12630663&dopt=Abstract
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Adult stem cells for tissue repair - a new therapeutic concept? Author(s): Korbling M, Estrov Z. Source: The New England Journal of Medicine. 2003 August 7; 349(6): 570-82. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12904523&dopt=Abstract
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Age-related changes of P-glycoprotein-mediated rhodamine 123 efflux in normal human bone marrow hematopoietic stem cells. Author(s): Calado RT, Machado CG, Carneiro JJ, Garcia AB, Falcao RP. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2003 April; 17(4): 816-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12682648&dopt=Abstract
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Akt helps stem cells heal the heart. Author(s): Koc ON, Gerson SL. Source: Nature Medicine. 2003 September; 9(9): 1109-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12949518&dopt=Abstract
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Allogeneic stem cells, clinical transplantation and the origins of regenerative medicine. Author(s): Strom TB, Field LJ, Ruediger M. Source: Current Opinion in Immunology. 2002 October; 14(5): 601-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12183159&dopt=Abstract
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Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation. Author(s): In 't Anker PS, Scherjon SA, Kleijburg-van der Keur C, Noort WA, Claas FH, Willemze R, Fibbe WE, Kanhai HH. Source: Blood. 2003 August 15; 102(4): 1548-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12900350&dopt=Abstract
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An experimental platform for studying growth and invasiveness of tumor cells within teratomas derived from human embryonic stem cells. Author(s): Tzukerman M, Rosenberg T, Ravel Y, Reiter I, Coleman R, Skorecki K. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 November 11; 100(23): 13507-12. Epub 2003 October 22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14573705&dopt=Abstract
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Angiogenic factors reconstitute hematopoiesis by recruiting stem cells from bone marrow microenvironment. Author(s): Rafii S, Avecilla S, Shmelkov S, Shido K, Tejada R, Moore MA, Heissig B, Hattori K. Source: Annals of the New York Academy of Sciences. 2003 May; 996: 49-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799282&dopt=Abstract
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Astrocytes as stem cells: nomenclature, phenotype, and translation. Author(s): Steindler DA, Laywell ED. Source: Glia. 2003 July; 43(1): 62-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12761868&dopt=Abstract
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Australia agonises over stem cells. Author(s): Nowak R. Source: New Scientist (1971). 2002 September 21; 175(2361): 9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12731537&dopt=Abstract
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Autologous peripheral blood stem cell transplantation of stem cells harvested in imatinib-induced complete cytogenetic remission: an example of in vivo purging in CML. Author(s): le Coutre P, Kreuzer KA, Massenkeil G, Baskaynak G, Zschieschang P, Genvresse I, Lupberger J, Mapara M, Dorken B, Arnold R. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2003 December; 17(12): 2525-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14562118&dopt=Abstract
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Autologous stem cells for functional myocardial repair. Author(s): Schwartz Y, Kornowski R. Source: Heart Failure Reviews. 2003 July; 8(3): 237-45. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12878832&dopt=Abstract
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Berashis cells in human umbilical cord blood vs. embryonic stem cells. Author(s): Ende N. Source: J Med. 2002; 33(1-4): 167-71. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12939115&dopt=Abstract
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Bio-engineering inslulin-secreting cells from embryonic stem cells: a review of progress. Author(s): Roche E, Sepulcre MP, Ensenat-Waser R, Maestre I, Reig JA, Soria B. Source: Medical & Biological Engineering & Computing. 2003 July; 41(4): 384-91. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12892359&dopt=Abstract
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Biological and mechanical quality of red blood cells cultured from human umbilical cord blood stem cells. Author(s): Maggakis-Kelemen C, Bork M, Kayser P, Biselli M, Artmann GM. Source: Medical & Biological Engineering & Computing. 2003 May; 41(3): 350-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12803302&dopt=Abstract
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Biology and plasticity of CD133+ hematopoietic stem cells. Author(s): Handgretinger R, Gordon PR, Leimig T, Chen X, Buhring HJ, Niethammer D, Kuci S. Source: Annals of the New York Academy of Sciences. 2003 May; 996: 141-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799292&dopt=Abstract
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Biology of hematopoietic stem cells and progenitors: implications for clinical application. Author(s): Kondo M, Wagers AJ, Manz MG, Prohaska SS, Scherer DC, Beilhack GF, Shizuru JA, Weissman IL. Source: Annual Review of Immunology. 2003; 21: 759-806. Epub 2002 December 17. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12615892&dopt=Abstract
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Biology of human bone marrow stem cells. Author(s): Bonnet D. Source: Clinical and Experimental Medicine. 2003 November; 3(3): 140-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14648228&dopt=Abstract
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Bioterrorism, embryonic stem cells, and Frankenstein. Author(s): Guinan P. Source: Journal of Religion and Health. 2002 Summer; 41(2): 305-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12728944&dopt=Abstract
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BM-derived stem cells for the treatment of nonhematopoietic diseases. Author(s): Krause DS. Source: Cytotherapy. 2002; 4(6): 503-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12568982&dopt=Abstract
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Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Author(s): Park IK, Qian D, Kiel M, Becker MW, Pihalja M, Weissman IL, Morrison SJ, Clarke MF. Source: Nature. 2003 May 15; 423(6937): 302-5. Epub 2003 April 20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12714971&dopt=Abstract
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Bmi1, stem cells, and senescence regulation. Author(s): Park IK, Morrison SJ, Clarke MF. Source: The Journal of Clinical Investigation. 2004 January; 113(2): 175-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14722607&dopt=Abstract
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BMP responsiveness in human mesenchymal stem cells. Author(s): Diefenderfer DL, Osyczka AM, Reilly GC, Leboy PS. Source: Connective Tissue Research. 2003; 44 Suppl 1: 305-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12952214&dopt=Abstract
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Bone induction by BMP-2 transduced stem cells derived from human fat. Author(s): Dragoo JL, Choi JY, Lieberman JR, Huang J, Zuk PA, Zhang J, Hedrick MH, Benhaim P. Source: Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society. 2003 July; 21(4): 622-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12798061&dopt=Abstract
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Bone marrow stem cells contribute to healing of the kidney. Author(s): Poulsom R, Alison MR, Cook T, Jeffery R, Ryan E, Forbes SJ, Hunt T, Wyles S, Wright NA. Source: Journal of the American Society of Nephrology : Jasn. 2003 June; 14 Suppl 1: S4854. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12761239&dopt=Abstract
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Bone marrow stem cells do not repopulate the healthy upper respiratory tract. Author(s): Davies JC, Potter M, Bush A, Rosenthal M, Geddes DM, Alton EW. Source: Pediatric Pulmonology. 2002 October; 34(4): 251-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12205565&dopt=Abstract
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Bone marrow stem cells regenerate infarcted myocardium. Author(s): Orlic D, Kajstura J, Chimenti S, Bodine DM, Leri A, Anversa P. Source: Pediatric Transplantation. 2003; 7 Suppl 3: 86-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12603699&dopt=Abstract
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Bone marrow-derived stem cells and “plasticity”. Author(s): Huttmann A, Li CL, Duhrsen U. Source: Annals of Hematology. 2003 October; 82(10): 599-604. Epub 2003 July 24. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12898189&dopt=Abstract
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Bone marrow-derived stem cells for ischemic hearts. Author(s): Kocher AA. Source: Wiener Klinische Wochenschrift. 2003 February 28; 115(3-4): 77-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12674679&dopt=Abstract
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Bone-marrow stem cells as a source for cell therapy. Author(s): Chiu RC. Source: Heart Failure Reviews. 2003 July; 8(3): 247-51. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12878833&dopt=Abstract
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Brain transplantation of genetically engineered human neural stem cells globally corrects brain lesions in the mucopolysaccharidosis type VII mouse. Author(s): Meng XL, Shen JS, Ohashi T, Maeda H, Kim SU, Eto Y. Source: Journal of Neuroscience Research. 2003 October 15; 74(2): 266-77. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14515356&dopt=Abstract
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Breast cancer stem cells revealed. Author(s): Dick JE. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 April 1; 100(7): 3547-9. Epub 2003 March 25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12657737&dopt=Abstract
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Cancer research. Mutant stem cells may seed cancer. Author(s): Marx J. Source: Science. 2003 September 5; 301(5638): 1308-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12958339&dopt=Abstract
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Cancer stem cells. Author(s): Masters JR, Foley CL, Bisson I, Ahmed A. Source: Bju International. 2003 November; 92(7): 661-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14616438&dopt=Abstract
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Cancerous stem cells can arise from pediatric brain tumors. Author(s): Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M, Kornblum HI. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 December 9; 100(25): 15178-83. Epub 2003 November 26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14645703&dopt=Abstract
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Cardiomyocyte-mediated contact programs human mesenchymal stem cells to express cardiogenic phenotype. Author(s): Rangappa S, Entwistle JW, Wechsler AS, Kresh JY. Source: The Journal of Thoracic and Cardiovascular Surgery. 2003 July; 126(1): 124-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12878947&dopt=Abstract
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CDCP1 is a novel marker for hematopoietic stem cells. Author(s): Conze T, Lammers R, Kuci S, Scherl-Mostageer M, Schweifer N, Kanz L, Buhring HJ. Source: Annals of the New York Academy of Sciences. 2003 May; 996: 222-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799299&dopt=Abstract
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Cellular cardiomyoplasty--cardiomyocytes, skeletal myoblasts, or stem cells for regenerating myocardium and treatment of heart failure? Author(s): Reffelmann T, Kloner RA. Source: Cardiovascular Research. 2003 May 1; 58(2): 358-68. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757870&dopt=Abstract
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Characterization and culture of human embryonic stem cells. Author(s): Laslett AL, Filipczyk AA, Pera MF. Source: Trends in Cardiovascular Medicine. 2003 October; 13(7): 295-301. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14522470&dopt=Abstract
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Characterization and differentiation of human embryonic stem cells. Author(s): Carpenter MK, Rosler E, Rao MS. Source: Cloning and Stem Cells. 2003; 5(1): 79-88. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12713704&dopt=Abstract
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Characterization of cord blood hematopoietic stem cells. Author(s): Mazurier F, Doedens M, Gan OI, Dick JE. Source: Annals of the New York Academy of Sciences. 2003 May; 996: 67-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799284&dopt=Abstract
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Chinese fusion method promises fresh route to human stem cells. Author(s): Dennis C. Source: Nature. 2003 August 14; 424(6950): 711. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917645&dopt=Abstract
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Clinically applicable labeling of mammalian and stem cells by combining superparamagnetic iron oxides and transfection agents. Author(s): Frank JA, Miller BR, Arbab AS, Zywicke HA, Jordan EK, Lewis BK, Bryant LH Jr, Bulte JW. Source: Radiology. 2003 August; 228(2): 480-7. Epub 2003 June 20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12819345&dopt=Abstract
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Cloning and stem cells. Author(s): Wilmut I. Source: Cloning and Stem Cells. 2002; 4(2): 103-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12171702&dopt=Abstract
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Cloning and stem cells: processes, politics, and policy. Author(s): Curtis MG. Source: Curr Womens Health Rep. 2003 December; 3(6): 492-500. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14613671&dopt=Abstract
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Cloning and stem cells--handicapping the political and scientific debates. Author(s): Daley GQ. Source: The New England Journal of Medicine. 2003 July 17; 349(3): 211-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12867604&dopt=Abstract
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Coculture and transplant of purified CD34(+)Lin(-) and CD34(-)Lin(-) cells reveals functional interaction between repopulating hematopoietic stem cells. Author(s): Hess DA, Karanu FN, Levac K, Gallacher L, Bhatia M. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2003 August; 17(8): 1613-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12886251&dopt=Abstract
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Constitutive and specific activation of STAT3 by BCR-ABL in embryonic stem cells. Author(s): Coppo P, Dusanter-Fourt I, Millot G, Nogueira MM, Dugray A, Bonnet ML, Mitjavila-Garcia MT, Le Pesteur D, Guilhot F, Vainchenker W, Sainteny F, Turhan AG. Source: Oncogene. 2003 June 26; 22(26): 4102-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821944&dopt=Abstract
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Cotransplantation of human mesenchymal stem cells enhances human myelopoiesis and megakaryocytopoiesis in NOD/SCID mice. Author(s): Angelopoulou M, Novelli E, Grove JE, Rinder HM, Civin C, Cheng L, Krause DS. Source: Experimental Hematology. 2003 May; 31(5): 413-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12763140&dopt=Abstract
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Cyclic strain enhances matrix mineralization by adult human mesenchymal stem cells via the extracellular signal-regulated kinase (ERK1/2) signaling pathway. Author(s): Simmons CA, Matlis S, Thornton AJ, Chen S, Wang CY, Mooney DJ. Source: Journal of Biomechanics. 2003 August; 36(8): 1087-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12831733&dopt=Abstract
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Cyclophosphamide, etoposide and G-CSF to mobilize peripheral blood stem cells for autologous stem cell transplantation in patients with lymphoma. Author(s): Mollee P, Pereira D, Nagy T, Song K, Saragosa R, Keating A, Crump M. Source: Bone Marrow Transplantation. 2002 September; 30(5): 273-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12209348&dopt=Abstract
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Cystatin-B is expressed by neural stem cells and by differentiated neurons and astrocytes. Author(s): Brannvall K, Hjelm H, Korhonen L, Lahtinen U, Lehesjoki AE, Lindholm D. Source: Biochemical and Biophysical Research Communications. 2003 August 22; 308(2): 369-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901878&dopt=Abstract
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Derivation and potential applications of human embryonic stem cells. Author(s): Gepstein L. Source: Circulation Research. 2002 November 15; 91(10): 866-76. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12433831&dopt=Abstract
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Development and analysis of megakaryocytes from murine embryonic stem cells. Author(s): Eto K, Leavitt AL, Nakano T, Shattil SJ. Source: Methods Enzymol. 2003; 365: 142-58. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14696343&dopt=Abstract
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Developmental origins of hematopoietic stem cells. Author(s): Robin C, Ottersbach K, de Bruijn M, Ma X, van der Horn K, Dzierzak E. Source: Oncology Research. 2003; 13(6-10): 315-21. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12725520&dopt=Abstract
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Developmental potentials of hematopoietic and neural stem cells following injection into pre-implantation blastocysts. Author(s): Harder F, Kirchhof N, Petrovic S, Schmittwolf C, Durr M, Muller AM. Source: Annals of Hematology. 2002; 81 Suppl 2: S20-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12611062&dopt=Abstract
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Differences and similarities among phenotypes of mesenchymal and neural stem cells. Author(s): Magrassi L. Source: Haematologica. 2003 February; 88(2): 121. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12604398&dopt=Abstract
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Differences in heat sensitivity between normal and acute myeloid leukemic stem cells: feasibility of hyperthermic purging of leukemic cells from autologous stem cell grafts. Author(s): Wierenga PK, Setroikromo R, Kamps G, Kampinga HH, Vellenga E. Source: Experimental Hematology. 2003 May; 31(5): 421-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12763141&dopt=Abstract
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Differential apoptosis and Fas expression on GPI-negative and GPI-positive stem cells: a mechanism for the evolution of paroxysmal nocturnal haemoglobinuria. Author(s): Ismail MM, Tooze JA, Flynn JA, Gordon-Smith EC, Gibson FM, Rutherford TR, Elebute MO. Source: British Journal of Haematology. 2003 November; 123(3): 545-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14617023&dopt=Abstract
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Differentiating embryonic stem cells: GAPDH, but neither HPRT nor beta-tubulin is suitable as an internal standard for measuring RNA levels. Author(s): Murphy CL, Polak JM. Source: Tissue Engineering. 2002 August; 8(4): 551-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12201995&dopt=Abstract
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Differentiation and genetic manipulation of human embryonic stem cells and the analysis of the cardiovascular system. Author(s): Lavon N, Benvenisty N. Source: Trends in Cardiovascular Medicine. 2003 February; 13(2): 47-52. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12586438&dopt=Abstract
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Differentiation of human antigen-presenting dendritic cells from CD34+ hematopoietic stem cells in vitro. Author(s): Ju XS, Zenke M. Source: Methods in Molecular Biology (Clifton, N.J.). 2003; 215: 399-407. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12512315&dopt=Abstract
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Differentiation of human embryonic stem cells on three-dimensional polymer scaffolds. Author(s): Levenberg S, Huang NF, Lavik E, Rogers AB, Itskovitz-Eldor J, Langer R. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 October 28; 100(22): 12741-6. Epub 2003 Oct 15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14561891&dopt=Abstract
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Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Author(s): Mummery C, Ward-van Oostwaard D, Doevendans P, Spijker R, van den Brink S, Hassink R, van der Heyden M, Opthof T, Pera M, de la Riviere AB, Passier R, Tertoolen L. Source: Circulation. 2003 June 3; 107(21): 2733-40. Epub 2003 May 12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12742992&dopt=Abstract
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Differentiation of human neural stem cells into retinal cells. Author(s): Dong X, Pulido JS, Qu T, Sugaya K. Source: Neuroreport. 2003 January 20; 14(1): 143-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12544846&dopt=Abstract
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Differentiation of pluripotent embryonic stem cells into cardiomyocytes. Author(s): Boheler KR, Czyz J, Tweedie D, Yang HT, Anisimov SV, Wobus AM. Source: Circulation Research. 2002 August 9; 91(3): 189-201. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12169644&dopt=Abstract
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Differentiation of rhesus embryonic stem cells to neural progenitors and neurons. Author(s): Calhoun JD, Lambert NA, Mitalipova MM, Noggle SA, Lyons I, Condie BG, Stice SL. Source: Biochemical and Biophysical Research Communications. 2003 June 20; 306(1): 191-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12788087&dopt=Abstract
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Differentiation, cell fusion, and nuclear fusion during ex vivo repair of epithelium by human adult stem cells from bone marrow stroma. Author(s): Spees JL, Olson SD, Ylostalo J, Lynch PJ, Smith J, Perry A, Peister A, Wang MY, Prockop DJ. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 March 4; 100(5): 2397-402. Epub 2003 February 26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12606728&dopt=Abstract
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Direct and indirect induction of apoptosis in human mesenchymal stem cells in response to titanium particles. Author(s): Wang ML, Tuli R, Manner PA, Sharkey PF, Hall DJ, Tuan RS. Source: Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society. 2003 July; 21(4): 697-707. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12798071&dopt=Abstract
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Direct selection of human bone marrow mesenchymal stem cells using an anti-CD49a antibody reveals their CD45med,low phenotype. Author(s): Deschaseaux F, Gindraux F, Saadi R, Obert L, Chalmers D, Herve P. Source: British Journal of Haematology. 2003 August; 122(3): 506-17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12877680&dopt=Abstract
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Donor-derived hematopoietic stem cells in organ transplantation: technical aspects and hurdles yet to be cleared. Author(s): Herve P. Source: Transplantation. 2003 May 15; 75(9 Suppl): 55S-57S. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12819493&dopt=Abstract
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Dramatic expansion of germinal stem cells by ectopically expressed human glial cell line-derived neurotrophic factor in mouse Sertoli cells. Author(s): Yomogida K, Yagura Y, Tadokoro Y, Nishimune Y. Source: Biology of Reproduction. 2003 October; 69(4): 1303-7. Epub 2003 June 11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12801989&dopt=Abstract
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Effect of rat Schwann cell secretion on proliferation and differentiation of human neural stem cells. Author(s): An YH, Wan H, Zhang ZS, Wang HY, Gao ZX, Sun MZ, Wang ZC. Source: Biomed Environ Sci. 2003 March; 16(1): 90-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12747012&dopt=Abstract
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Effects of peripheral benzodiazepine receptor ligands on proliferation and differentiation of human mesenchymal stem cells. Author(s): Lee DH, Kang SK, Lee RH, Ryu JM, Park HY, Choi HS, Bae YC, Suh KT, Kim YK, Jung JS. Source: Journal of Cellular Physiology. 2004 January; 198(1): 91-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14584048&dopt=Abstract
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Efficient BMP2 gene transfer and bone formation of mesenchymal stem cells by a fiber-mutant adenoviral vector. Author(s): Tsuda H, Wada T, Ito Y, Uchida H, Dehari H, Nakamura K, Sasaki K, Kobune M, Yamashita T, Hamada H. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2003 March; 7(3): 354-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12668131&dopt=Abstract
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Electrophysiological profiling of cardiomyocytes in embryonic bodies derived from human embryonic stem cells: therapeutic implications. Author(s): Vanderlaan RD, Oudit GY, Backx PH. Source: Circulation Research. 2003 July 11; 93(1): 1-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12855668&dopt=Abstract
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Embryonic stem cells generated by nuclear transfer of human somatic nuclei into rabbit oocytes. Author(s): Chen Y, He ZX, Liu A, Wang K, Mao WW, Chu JX, Lu Y, Fang ZF, Shi YT, Yang QZ, Chen da Y, Wang MK, Li JS, Huang SL, Kong XY, Shi YZ, Wang ZQ, Xia JH, Long ZG, Xue ZG, Ding WX, Sheng HZ. Source: Cell Research. 2003 August; 13(4): 251-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12974615&dopt=Abstract
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Embryonic stem cells. Stem cell programs. Author(s): Zerhouni E. Source: Science. 2003 May 9; 300(5621): 911-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12738840&dopt=Abstract
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Engineering mesenchymal stem cells for immunotherapy. Author(s): Jorgensen C, Djouad F, Apparailly F, Noel D. Source: Gene Therapy. 2003 May; 10(10): 928-31. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12732877&dopt=Abstract
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Engraftment of human cord blood-derived stem cells in preimmune ovine fetuses after ultrasound-guided in utero transplantation. Author(s): Young AJ, Holzgreve W, Dudler L, Schoeberlein A, Surbek DV. Source: American Journal of Obstetrics and Gynecology. 2003 September; 189(3): 698701. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14526296&dopt=Abstract
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Engraftment of sorted/expanded human central nervous system stem cells from fetal brain. Author(s): Tamaki S, Eckert K, He D, Sutton R, Doshe M, Jain G, Tushinski R, Reitsma M, Harris B, Tsukamoto A, Gage F, Weissman I, Uchida N. Source: Journal of Neuroscience Research. 2002 September 15; 69(6): 976-86. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12205691&dopt=Abstract
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Ethics of human stem cells and cloning - a personal view. Author(s): Ludwig H, Diedrich K. Source: Archives of Gynecology and Obstetrics. 2002 August; 266(4): 185-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12192474&dopt=Abstract
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EU will fund research on stem cells only from embryos created before June 2002. Author(s): Watson R. Source: Bmj (Clinical Research Ed.). 2003 July 19; 327(7407): 124. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12869446&dopt=Abstract
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European Union. At odds again over stem cells. Author(s): Vogel G. Source: Science. 2003 July 18; 301(5631): 289. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12869730&dopt=Abstract
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Evidence for transdifferentiation of human bone marrow-derived stem cells: recent progress and controversies. Author(s): Tao H, Ma DD. Source: Pathology. 2003 February; 35(1): 6-13. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12701678&dopt=Abstract
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Ex vivo expansion of corneal limbal epithelial/stem cells for corneal surface reconstruction. Author(s): Ramaesh K, Dhillon B. Source: Eur J Ophthalmol. 2003 July; 13(6): 515-24. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12948308&dopt=Abstract
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Ex vivo expansion of human hematopoietic stem cells by direct delivery of the HOXB4 homeoprotein. Author(s): Amsellem S, Pflumio F, Bardinet D, Izac B, Charneau P, Romeo PH, DubartKupperschmitt A, Fichelson S. Source: Nature Medicine. 2003 November; 9(11): 1423-7. Epub 2003 October 26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14578882&dopt=Abstract
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Ex vivo expansion of limbal epithelial stem cells: amniotic membrane serving as a stem cell niche. Author(s): Grueterich M, Espana EM, Tseng SC. Source: Survey of Ophthalmology. 2003 November-December; 48(6): 631-46. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14609709&dopt=Abstract
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Ex vivo gene therapy in autologous bone marrow stromal stem cells for tissueengineered maxillofacial bone regeneration. Author(s): Chang SC, Chuang HL, Chen YR, Chen JK, Chung HY, Lu YL, Lin HY, Tai CL, Lou J. Source: Gene Therapy. 2003 November; 10(24): 2013-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14566360&dopt=Abstract
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Ex vivo preservation and expansion of human limbal epithelial stem cells on amniotic membrane for treating corneal diseases with total limbal stem cell deficiency. Author(s): Tseng SC, Meller D, Anderson DF, Touhami A, Pires RT, Gruterich M, Solomon A, Espana E, Sandoval H, Ti SE, Goto E. Source: Advances in Experimental Medicine and Biology. 2002; 506(Pt B): 1323-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12614074&dopt=Abstract
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Ex vivo targeting of p21Cip1/Waf1 permits relative expansion of human hematopoietic stem cells. Author(s): Stier S, Cheng T, Forkert R, Lutz C, Dombkowski DM, Zhang JL, Scadden DT. Source: Blood. 2003 August 15; 102(4): 1260-6. Epub 2003 April 17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12702511&dopt=Abstract
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Existence of reserve quiescent stem cells in adults, from amphibians to humans. Author(s): Young HE. Source: Curr Top Microbiol Immunol. 2004; 280: 71-109. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14594208&dopt=Abstract
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Factors affecting purification of CD34(+) peripheral blood stem cells using the Baxter Isolex 300i. Author(s): Gryn J, Shadduck RK, Lister J, Zeigler ZR, Raymond JM. Source: Journal of Hematotherapy & Stem Cell Research. 2002 August; 11(4): 719-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12201961&dopt=Abstract
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Factors influencing the collection of peripheral blood stem cells in patients with acute myeloblastic leukemia and non-myeloid malignancies. Author(s): Carral A, de la Rubia J, Martin G, Molla S, Martinez J, Sanz GF, Soler MA, Jarque I, Jimenez C, Sanz MA. Source: Leukemia Research. 2003 January; 27(1): 5-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12479846&dopt=Abstract
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Failure of adult marrow-derived stem cells to generate marrow stroma after successful hematopoietic stem cell transplantation. Author(s): Awaya N, Rupert K, Bryant E, Torok-Storb B. Source: Experimental Hematology. 2002 August; 30(8): 937-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12160845&dopt=Abstract
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Failure to increase glucose consumption through the pentose-phosphate pathway results in the death of glucose-6-phosphate dehydrogenase gene-deleted mouse embryonic stem cells subjected to oxidative stress. Author(s): Filosa S, Fico A, Paglialunga F, Balestrieri M, Crooke A, Verde P, Abrescia P, Bautista JM, Martini G. Source: The Biochemical Journal. 2003 March 15; 370(Pt 3): 935-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12466018&dopt=Abstract
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Faith in stem cells. Author(s): Mack C. Source: The Oncologist. 2001; 6(4): 311-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11524546&dopt=Abstract
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Feasibility and toxicity of high-dose therapy (HDT) supported by peripheral blood stem cells in elderly patients with multiple myeloma and non-Hodgkin's lymphoma: survey from a single institution. Author(s): Magagnoli M, Castagna L, Balzarotti M, Sarina B, Timofeeva I, Bertuzzi A, Compasso S, Nozza A, Siracusano L, Santoro A. Source: American Journal of Hematology. 2003 August; 73(4): 267-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12879431&dopt=Abstract
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Feasibility study of IL-11 and granulocyte colony-stimulating factor after myelosuppressive chemotherapy to mobilize peripheral blood stem cells from heavily pretreated patients. Author(s): Goldman SC, Bracho F, Davenport V, Slack R, Areman E, Shen V, Lenarsky C, Weinthal J, Hughes R, Cairo MS. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2001 June-July; 23(5): 300-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11464987&dopt=Abstract
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Features of the engraftment of allogeneic hematopoietic stem cells using reducedintensity conditioning regimens. Author(s): Ruiz-Arguelles GJ, Ruiz-Arguelles A, Gomez-Almaguer D, Lopez-Martinez B, Abreu-Diaz G, Bravo G, Jaime-Perez JC. Source: Leukemia & Lymphoma. 2001 June; 42(1-2): 145-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11699202&dopt=Abstract
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Feeding hungry stem cells. Author(s): Pedersen RA. Source: Nature Biotechnology. 2002 September; 20(9): 882-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12205505&dopt=Abstract
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FES-Cre targets phosphatidylinositol glycan class A (PIGA) inactivation to hematopoietic stem cells in the bone marrow. Author(s): Keller P, Payne JL, Tremml G, Greer PA, Gaboli M, Pandolfi PP, Bessler M. Source: The Journal of Experimental Medicine. 2001 September 3; 194(5): 581-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11535627&dopt=Abstract
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Fetal human hematopoietic stem cells can differentiate sequentially into neural stem cells and then astrocytes in vitro. Author(s): Hao HN, Zhao J, Thomas RL, Parker GC, Lyman WD. Source: Journal of Hematotherapy & Stem Cell Research. 2003 February; 12(1): 23-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12662433&dopt=Abstract
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Flow cytometric assessment of lymphocyte subsets, lymphoid progenitors, and hematopoietic stem cells in allogeneic stem cell grafts. Author(s): Theilgaard-Monch K, Raaschou-Jensen K, Palm H, Schjodt K, Heilmann C, Vindelov L, Jacobsen N, Dickmeiss E. Source: Bone Marrow Transplantation. 2001 December; 28(11): 1073-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11781619&dopt=Abstract
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Formation of cartilage matrix proteins by BMP-transfected murine mesenchymal stem cells encapsulated in a novel class of alginates. Author(s): Weber M, Steinert A, Jork A, Dimmler A, Thurmer F, Schutze N, Hendrich C, Zimmerman U. Source: Biomaterials. 2002 May; 23(9): 2003-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11996042&dopt=Abstract
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Formation of neurospheres from human embryonal carcinoma stem cells. Author(s): Horrocks GM, Lauder L, Stewart R, Przyborski S. Source: Biochemical and Biophysical Research Communications. 2003 May 2; 304(2): 411-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12711331&dopt=Abstract
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From human genes to stem cells: new challenges for patent law? Author(s): Caulfield TA. Source: Trends in Biotechnology. 2003 March; 21(3): 101-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12628363&dopt=Abstract
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From teratocarcinomas to embryonic stem cells. Author(s): Andrews PW. Source: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 2002 April 29; 357(1420): 405-17. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12028783&dopt=Abstract
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Functional and kinetic characterization of granulocyte colony-stimulating factorprimed CD34- human stem cells. Author(s): Lemoli RM, Bertolini F, Petrucci MT, Gregorj C, Ricciardi MR, Fogli M, Curti A, Rabascio C, Pandolfi S, Ferrari S, Foa R, Baccarani M, Tafuri A, Rabascio C, Fo R. Source: British Journal of Haematology. 2003 November; 123(4): 720-9. Erratum In: Br J Haematol. 2004 January; 124(2): 256. Rabascio Cristina [corrected to Rabascio Christina] and Fo Robin [corrected to Foa Robin]. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14616978&dopt=Abstract
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Functional genomics by gene-trapping in embryonic stem cells. Author(s): Floss T, Wurst W. Source: Methods in Molecular Biology (Clifton, N.J.). 2002; 185: 347-79. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11769000&dopt=Abstract
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Further proof of the plasticity of adult stem cells and their role in tissue repair. Author(s): Prockop DJ. Source: The Journal of Cell Biology. 2003 March 17; 160(6): 807-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12642607&dopt=Abstract
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Future prospects for patient care utilizing autologous lymphoid and hematopoietic stem cells. Author(s): Lum LG, Rathore R, Quesenberry PJ, Elfenbein GJ. Source: Medicine and Health, Rhode Island. 2003 August; 86(8): 247-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14582220&dopt=Abstract
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Galanin and galanin receptors in embryonic stem cells: accidental or essential? Author(s): Tarasov KV, Tarasova YS, Crider DG, Anisimov SV, Wobus AM, Boheler KR. Source: Neuropeptides. 2002 August; 36(4): 239-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12372696&dopt=Abstract
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Gastric stem cells: an update. Author(s): Modlin IM, Kidd M, Lye KD, Wright NA. Source: The Keio Journal of Medicine. 2003 June; 52(2): 134-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12862366&dopt=Abstract
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Gene expression in human neural stem cells: effects of leukemia inhibitory factor. Author(s): Wright LS, Li J, Caldwell MA, Wallace K, Johnson JA, Svendsen CN. Source: Journal of Neurochemistry. 2003 July; 86(1): 179-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12807438&dopt=Abstract
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Gene expression patterns in human embryonic stem cells and human pluripotent germ cell tumors. Author(s): Sperger JM, Chen X, Draper JS, Antosiewicz JE, Chon CH, Jones SB, Brooks JD, Andrews PW, Brown PO, Thomson JA. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 November 11; 100(23): 13350-5. Epub 2003 October 31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14595015&dopt=Abstract
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Gene expression profiles of human bone marrow derived mesenchymal stem cells and tendon cells. Author(s): Hu Q, Piao Y, Zou F. Source: Chinese Medical Journal. 2003 August; 116(8): 1270-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12935427&dopt=Abstract
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Gene transfer in purified human hematopoietic peripheral-blood stem cells by means of electroporation without prestimulation. Author(s): Weissinger F, Reimer P, Waessa T, Buchhofer S, Schertlin T, Kunzmann V, Wilhelm M. Source: The Journal of Laboratory and Clinical Medicine. 2003 February; 141(2): 138-49. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12577050&dopt=Abstract
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Generation of cardiomyocytes from embryonic stem cells experimental studies. Author(s): Sachinidis A, Kolossov E, Fleischmann BK, Hescheler J. Source: Herz. 2002 November; 27(7): 589-97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12439631&dopt=Abstract
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Generation of hepatocyte-like cells from human embryonic stem cells. Author(s): Rambhatla L, Chiu CP, Kundu P, Peng Y, Carpenter MK. Source: Cell Transplantation. 2003; 12(1): 1-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12693659&dopt=Abstract
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Generation of islets of Langerhans from adult pancreatic stem cells. Author(s): Peck AB, Cornelius JG, Schatz D, Ramiya VK. Source: Journal of Hepato-Biliary-Pancreatic Surgery. 2002; 9(6): 704-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12658404&dopt=Abstract
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Generation of neural crest-derived peripheral neurons and floor plate cells from mouse and primate embryonic stem cells. Author(s): Mizuseki K, Sakamoto T, Watanabe K, Muguruma K, Ikeya M, Nishiyama A, Arakawa A, Suemori H, Nakatsuji N, Kawasaki H, Murakami F, Sasai Y. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 May 13; 100(10): 5828-33. Epub 2003 April 30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12724518&dopt=Abstract
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Genetic control of stem cells: implications for aging. Author(s): Van Zant G. Source: International Journal of Hematology. 2003 January; 77(1): 29-36. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12568297&dopt=Abstract
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Genetic control of stem-cell properties and stem cells in aging. Author(s): Liang Y, Van Zant G. Source: Current Opinion in Hematology. 2003 May; 10(3): 195-202. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12690286&dopt=Abstract
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Genetic manipulation of primate embryonic and hematopoietic stem cells with simian lentivirus vectors. Author(s): Hanazono Y, Asano T, Ueda Y, Ozawa K. Source: Trends in Cardiovascular Medicine. 2003 April; 13(3): 106-10. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12691674&dopt=Abstract
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Genetically modified human embryonic stem cells relieve symptomatic motor behavior in a rat model of Parkinson's disease. Author(s): Park S, Kim EY, Ghil GS, Joo WS, Wang KC, Kim YS, Lee YJ, Lim J. Source: Neuroscience Letters. 2003 December 19; 353(2): 91-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14664908&dopt=Abstract
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Glass needle-mediated microinjection of macromolecules and transgenes into primary human mesenchymal stem cells. Author(s): Tsulaia TV, Prokopishyn NL, Yao A, Carsrud ND, Carou MC, Brown DB, Davis BR, Yannariello-Brown J. Source: Journal of Biomedical Science. 2003 May-June; 10(3): 328-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12711860&dopt=Abstract
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Glial cells generate neurons--master control within CNS regions: developmental perspectives on neural stem cells. Author(s): Gotz M. Source: The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry. 2003 October; 9(5): 379-97. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14580122&dopt=Abstract
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Glucose-responsive insulin-producing cells from stem cells. Author(s): Kaczorowski DJ, Patterson ES, Jastromb WE, Shamblott MJ. Source: Diabetes/Metabolism Research and Reviews. 2002 November-December; 18(6): 442-50. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12469358&dopt=Abstract
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Gp130 activation by soluble interleukin-6 receptor/interleukin-6 enhances osteoblastic differentiation of human bone marrow-derived mesenchymal stem cells. Author(s): Erices A, Conget P, Rojas C, Minguell JJ. Source: Experimental Cell Research. 2002 October 15; 280(1): 24-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12372336&dopt=Abstract
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Graft survival assessment of MN genotype after allogeneic transplantation of hematopoietic stem cells of umbilical cord blood. Author(s): Liu Z, Lan JC, He LQ, Zhang YZ, Lu R, Fang Q, Guo XJ. Source: Di Yi June Yi Da Xue Xue Bao. 2002 October; 22(10): 912-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12377617&dopt=Abstract
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Growth factors and stem cells as treatments for stroke recovery. Author(s): Cairns K, Finklestein SP. Source: Phys Med Rehabil Clin N Am. 2003 February; 14(1 Suppl): S135-42. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12625643&dopt=Abstract
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Harvesting blood stem cells from cranial bone at craniotomy--a preliminary study. Author(s): Iwashita T, Tada T, Zhan H, Tanaka Y, Hongo K. Source: Journal of Neuro-Oncology. 2003 September; 64(3): 265-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14558603&dopt=Abstract
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Hematopoiesis from embryonic stem cells: lessons from and for ontogeny. Author(s): Kyba M, Daley GQ. Source: Experimental Hematology. 2003 November; 31(11): 994-1006. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14585361&dopt=Abstract
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Hematopoietic stem cells: can old cells learn new tricks? Author(s): Ho AD, Punzel M. Source: Journal of Leukocyte Biology. 2003 May; 73(5): 547-55. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12714568&dopt=Abstract
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Hematopoietic stem cells: generation and manipulation. Author(s): Nakano T. Source: Trends in Immunology. 2003 November; 24(11): 589-94. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14596883&dopt=Abstract
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Hematoprotection and enrichment of transduced cells in vivo after gene transfer of MGMT(P140K) into hematopoietic stem cells. Author(s): Jansen M, Sorg UR, Ragg S, Flasshove M, Seeber S, Williams DA, Moritz T. Source: Cancer Gene Therapy. 2002 September; 9(9): 737-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12189523&dopt=Abstract
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High transduction efficiency of circulating first trimester fetal mesenchymal stem cells: potential targets for in utero ex vivo gene therapy. Author(s): Campagnoli C, Bellantuono I, Kumar S, Fairbairn LJ, Roberts I, Fisk NM. Source: Bjog : an International Journal of Obstetrics and Gynaecology. 2002 August; 109(8): 952-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12197378&dopt=Abstract
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Higher doses of CD34+ peripheral blood stem cells are associated with increased mortality from chronic graft-versus-host disease after allogeneic HLA-identical sibling transplantation. Author(s): Mohty M, Bilger K, Jourdan E, Kuentz M, Michallet M, Bourhis JH, Milpied N, Sutton L, Jouet JP, Attal M, Bordigoni P, Cahn JY, Sadoun A, Ifrah N, Guyotat D, Faucher C, Fegueux N, Reiffers J, Maraninchi D, Blaise D. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2003 May; 17(5): 869-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12750699&dopt=Abstract
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Highly efficient endosomal labeling of progenitor and stem cells with large magnetic particles allows magnetic resonance imaging of single cells. Author(s): Hinds KA, Hill JM, Shapiro EM, Laukkanen MO, Silva AC, Combs CA, Varney TR, Balaban RS, Koretsky AP, Dunbar CE. Source: Blood. 2003 August 1; 102(3): 867-72. Epub 2003 April 03. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12676779&dopt=Abstract
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HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Author(s): Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringden O. Source: Experimental Hematology. 2003 October; 31(10): 890-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14550804&dopt=Abstract
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Homing and mobilization of hematopoietic stem cells and hematopoietic cancer cells are mirror image processes, utilizing similar signaling pathways and occurring concurrently: circulating cancer cells constitute an ideal target for concurrent treatment with chemotherapy and antilineage-specific antibodies. Author(s): Gazitt Y. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2004 January; 18(1): 1-10. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14574330&dopt=Abstract
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Human CD34+ hematopoietic stem cells capable of multilineage engrafting NOD/SCID mice express flt3: distinct flt3 and c-kit expression and response patterns on mouse and candidate human hematopoietic stem cells. Author(s): Sitnicka E, Buza-Vidas N, Larsson S, Nygren JM, Liuba K, Jacobsen SE. Source: Blood. 2003 August 1; 102(3): 881-6. Epub 2003 April 03. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12676789&dopt=Abstract
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Human corneal stem cells display functional neuronal properties. Author(s): Seigel GM, Sun W, Salvi R, Campbell LM, Sullivan S, Reidy JJ. Source: Molecular Vision [electronic Resource]. 2003 April 30; 9: 159-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12724646&dopt=Abstract
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Human embryonic stem cells as an in vitro model for human vascular development and the induction of vascular differentiation. Author(s): Gerecht-Nir S, Ziskind A, Cohen S, Itskovitz-Eldor J. Source: Laboratory Investigation; a Journal of Technical Methods and Pathology. 2003 December; 83(12): 1811-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14691299&dopt=Abstract
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Human embryonic stem cells for cardiovascular repair. Author(s): Nir SG, David R, Zaruba M, Franz WM, Itskovitz-Eldor J. Source: Cardiovascular Research. 2003 May 1; 58(2): 313-23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757866&dopt=Abstract
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Human embryonic stem cells for myocardial regeneration. Author(s): Kehat I, Gepstein L. Source: Heart Failure Reviews. 2003 July; 8(3): 229-36. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12878831&dopt=Abstract
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Human embryonic stem cells: research, ethics and policy. Author(s): de Wert G, Mummery C. Source: Human Reproduction (Oxford, England). 2003 April; 18(4): 672-82. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12660256&dopt=Abstract
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Human mesenchymal stem cells transduced with recombinant bone morphogenetic protein-9 adenovirus promote osteogenesis in rodents. Author(s): Dayoub H, Dumont RJ, Li JZ, Dumont AS, Hankins GR, Kallmes DF, Helm GA. Source: Tissue Engineering. 2003 April; 9(2): 347-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12740097&dopt=Abstract
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Human neural stem cells can migrate, differentiate, and integrate after intravenous transplantation in adult rats with transient forebrain ischemia. Author(s): Chu K, Kim M, Jeong SW, Kim SU, Yoon BW. Source: Neuroscience Letters. 2003 June 5; 343(2): 129-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12759181&dopt=Abstract
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Human neural stem cells: a new tool for studying cortical development in Down's syndrome. Author(s): Bhattacharyya A, Svendsen CN. Source: Genes, Brain, and Behavior. 2003 June; 2(3): 179-86. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12931791&dopt=Abstract
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Human umbilical cord blood stem cells infusion in spinal cord injury: engraftment and beneficial influence on behavior. Author(s): Saporta S, Kim JJ, Willing AE, Fu ES, Davis CD, Sanberg PR. Source: Journal of Hematotherapy & Stem Cell Research. 2003 June; 12(3): 271-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12857368&dopt=Abstract
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Identification and propagation of liver stem cells. Author(s): Suzuki A, Nakauchi H. Source: Seminars in Cell & Developmental Biology. 2002 December; 13(6): 455-61. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12468247&dopt=Abstract
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Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Author(s): Djouad F, Plence P, Bony C, Tropel P, Apparailly F, Sany J, Noel D, Jorgensen C. Source: Blood. 2003 November 15; 102(10): 3837-44. Epub 2003 July 24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12881305&dopt=Abstract
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Impact of chemotherapy regimen and hematopoietic growth factor on mobilization and collection of peripheral blood stem cells in cancer patients. Author(s): Nowrousian MR, Waschke S, Bojko P, Welt A, Schuett P, Ebeling P, Flasshove M, Moritz T, Schuette J, Seeber S. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2003; 14 Suppl 1: I29-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12736228&dopt=Abstract
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Improvement in the ability to direct the differentiation of embryonic stem cells. Author(s): Roitberg B. Source: Surgical Neurology. 2003 July; 60(1): 3-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12864994&dopt=Abstract
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In vitro expansion of hematopoietic stem cells by recombinant TAT-HOXB4 protein. Author(s): Krosl J, Austin P, Beslu N, Kroon E, Humphries RK, Sauvageau G. Source: Nature Medicine. 2003 November; 9(11): 1428-32. Epub 2003 October 26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14578881&dopt=Abstract
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In vitro expansion of human basophils by interleukin-3 from granulocyte colonystimulating factor-mobilized peripheral blood stem cells. Author(s): Takao K, Tanimoto Y, Fujii M, Hamada N, Yoshida I, Ikeda K, Imajo K, Takahashi K, Harada M, Tanimoto M. Source: Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology. 2003 November; 33(11): 1561-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14616869&dopt=Abstract
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In vitro generation of long-term repopulating hematopoietic stem cells by fibroblast growth factor-1. Author(s): de Haan G, Weersing E, Dontje B, van Os R, Bystrykh LV, Vellenga E, Miller G. Source: Developmental Cell. 2003 February; 4(2): 241-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12586067&dopt=Abstract
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Increased expansion of V alpha 24+ T cells derived from G-CSF-mobilized peripheral blood stem cells as compared to peripheral blood mononuclear cells following alphagalactosylceramide stimulation. Author(s): Asada-Mikami R, Heike Y, Harada Y, Kanai S, Ikarashi Y, Kato K, Shirakawa K, Takaue Y, Abe T, Wakasugi H. Source: Cancer Science. 2003 April; 94(4): 383-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12824909&dopt=Abstract
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Infection efficiency of human and mouse embryonic stem cells using adenoviral and adeno-associated viral vectors. Author(s): Smith-Arica JR, Thomson AJ, Ansell R, Chiorini J, Davidson B, McWhir J. Source: Cloning and Stem Cells. 2003; 5(1): 51-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12713701&dopt=Abstract
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Infusion of donor-derived hematopoietic stem cells in organ transplantation: clinical data. Author(s): De Pauw L, Toungouz M, Goldman M. Source: Transplantation. 2003 May 15; 75(9 Suppl): 46S-49S. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12819491&dopt=Abstract
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Integration and differentiation of human embryonic stem cells transplanted to the chick embryo. Author(s): Goldstein RS, Drukker M, Reubinoff BE, Benvenisty N. Source: Developmental Dynamics : an Official Publication of the American Association of Anatomists. 2002 September; 225(1): 80-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12203723&dopt=Abstract
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Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy. Author(s): Urbanek K, Quaini F, Tasca G, Torella D, Castaldo C, Nadal-Ginard B, Leri A, Kajstura J, Quaini E, Anversa P. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 September 2; 100(18): 10440-5. Epub 2003 August 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12928492&dopt=Abstract
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Intensive triathlon training induces low peripheral CD34+ stem cells. Author(s): Philip P, Bermon S. Source: British Journal of Haematology. 2003 March; 120(5): 914-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12614234&dopt=Abstract
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Interactions between human adipose stromal cells and mouse neural stem cells in vitro. Author(s): Kang SK, Jun ES, Bae YC, Jung JS. Source: Brain Research. Developmental Brain Research. 2003 October 10; 145(1): 141-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14519500&dopt=Abstract
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Introducing the concept of breast cancer stem cells. Author(s): Waterworth A. Source: Breast Cancer Research : Bcr. 2004; 6(1): 53-4. Epub 2003 November 20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14680485&dopt=Abstract
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Isolation and characterization of functional mammary gland stem cells. Author(s): Welm B, Behbod F, Goodell MA, Rosen JM. Source: Cell Proliferation. 2003 October; 36 Suppl 1: 17-32. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14521513&dopt=Abstract
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Isolation and characterization of normal adult human epithelial pluripotent stem cells. Author(s): Trosko JE, Chang CC. Source: Oncology Research. 2003; 13(6-10): 353-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12725525&dopt=Abstract
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Isolation and culture of umbilical vein mesenchymal stem cells. Author(s): Covas DT, Siufi JL, Silva AR, Orellana MD. Source: Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas / Sociedade Brasileira De Biofisica. [et Al.]. 2003 September; 36(9): 1179-83. Epub 2003 August 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12937783&dopt=Abstract
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Isolation and identification of mesenchymal stem cells from human fetal pancreas. Author(s): Hu Y, Liao L, Wang Q, Ma L, Ma G, Jiang X, Zhao RC. Source: The Journal of Laboratory and Clinical Medicine. 2003 May; 141(5): 342-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12761478&dopt=Abstract
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Isolation, characterization, and differentiation of human embryonic stem cells. Author(s): Pera MF, Filipczyk AA, Hawes SM, Laslett AL. Source: Methods Enzymol. 2003; 365: 429-46. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14696363&dopt=Abstract
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Japanese team makes stem cells. Author(s): Cyranoski D. Source: Nature. 2003 June 5; 423(6940): 577. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12789307&dopt=Abstract
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Keeper of the stem cells. Author(s): Lemonick MD. Source: Time. 2001 August 27; 158(8): 57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11534482&dopt=Abstract
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Keratin 15 promoter targets putative epithelial stem cells in the hair follicle bulge. Author(s): Liu Y, Lyle S, Yang Z, Cotsarelis G. Source: The Journal of Investigative Dermatology. 2003 November; 121(5): 963-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14708593&dopt=Abstract
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Keratinocyte stem cells: a commentary. Author(s): Potten CS, Booth C. Source: The Journal of Investigative Dermatology. 2002 October; 119(4): 888-99. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12406335&dopt=Abstract
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Keratinocytes enriched for stem cells are protected from anoikis via an integrin signaling pathway in a Bcl-2 dependent manner. Author(s): Tiberio R, Marconi A, Fila C, Fumelli C, Pignatti M, Krajewski S, Giannetti A, Reed JC, Pincelli C. Source: Febs Letters. 2002 July 31; 524(1-3): 139-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12135756&dopt=Abstract
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Knowledge and attitudes of pregnant women with regard to collection, testing and banking of cord blood stem cells. Author(s): Fernandez CV, Gordon K, Van den Hof M, Taweel S, Baylis F. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 2003 March 18; 168(6): 695-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12642424&dopt=Abstract
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Lack of telomerase activity in human mesenchymal stem cells. Author(s): Zimmermann S, Voss M, Kaiser S, Kapp U, Waller CF, Martens UM. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2003 June; 17(6): 1146-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12764382&dopt=Abstract
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Large-scale expansion of mammalian neural stem cells: a review. Author(s): Kallos MS, Sen A, Behie LA. Source: Medical & Biological Engineering & Computing. 2003 May; 41(3): 271-82. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12803291&dopt=Abstract
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Large-scale isolation of CD133+ progenitor cells from G-CSF mobilized peripheral blood stem cells. Author(s): Gordon PR, Leimig T, Babarin-Dorner A, Houston J, Holladay M, Mueller I, Geiger T, Handgretinger R. Source: Bone Marrow Transplantation. 2003 January; 31(1): 17-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12621502&dopt=Abstract
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Large-scale isolation of immature dendritic cells with features of Langerhans cells by sorting CD34+ cord blood stem cells cultured in the presence of TGF-beta1 for cutaneous leukocyte antigen (CLA). Author(s): Bartz H, Rothoeft T, Anhenn O, Bunse D, Schauer U. Source: Journal of Immunological Methods. 2003 April 1; 275(1-2): 137-48. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12667678&dopt=Abstract
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Large-scale sources of neural stem cells. Author(s): Gottlieb DI. Source: Annual Review of Neuroscience. 2002; 25: 381-407. Epub 2002 March 20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12052914&dopt=Abstract
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Large-volume leukapheresis using femoral venous access for harvesting peripheral blood stem cells with the Fenwal CS 3000 Plus from normal healthy donors: predictors of CD34+ cell yield and collection efficiency. Author(s): Sohn SK, Kim JG, Chae YS, Kim DH, Lee NY, Suh JS, Lee KB. Source: Journal of Clinical Apheresis. 2003; 18(1): 10-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12717787&dopt=Abstract
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Legislative myopia on stem cells. Author(s): Drazen JM. Source: The New England Journal of Medicine. 2003 July 17; 349(3): 300. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12867614&dopt=Abstract
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Lentiviral gene transfer and ex vivo expansion of human primitive stem cells capable of primary, secondary, and tertiary multilineage repopulation in NOD/SCID mice. Nonobese diabetic/severe combined immunodeficient. Author(s): Piacibello W, Bruno S, Sanavio F, Droetto S, Gunetti M, Ailles L, Santoni de Sio F, Viale A, Gammaitoni L, Lombardo A, Naldini L, Aglietta M. Source: Blood. 2002 December 15; 100(13): 4391-400. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453876&dopt=Abstract
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Lentiviral transfer of the LacZ gene into human endothelial cells and human bone marrow mesenchymal stem cells. Author(s): Totsugawa T, Kobayashi N, Okitsu T, Noguchi H, Watanabe T, Matsumura T, Maruyama M, Fujiwara T, Sakaguchi M, Tanaka N. Source: Cell Transplantation. 2002; 11(5): 481-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12382678&dopt=Abstract
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Lineage choice and differentiation in mouse embryos and embryonic stem cells. Author(s): Loebel DA, Watson CM, De Young RA, Tam PP. Source: Developmental Biology. 2003 December 1; 264(1): 1-14. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14623228&dopt=Abstract
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Liver regeneration with reference to stem cells. Author(s): Alison MR. Source: Seminars in Cell & Developmental Biology. 2002 December; 13(6): 385-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12468237&dopt=Abstract
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Liver stem cells: the fall and rise of tissue biology. Author(s): Theise ND. Source: Hepatology (Baltimore, Md.). 2003 October; 38(4): 804-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14512866&dopt=Abstract
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Liver-specific gene expression in cultured human hematopoietic stem cells. Author(s): Fiegel HC, Lioznov MV, Cortes-Dericks L, Lange C, Kluth D, Fehse B, Zander AR. Source: Stem Cells (Dayton, Ohio). 2003; 21(1): 98-104. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12529556&dopt=Abstract
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Location of stem cells for the enteric nervous system. Author(s): Sidebotham EL, Kenny SE, Lloyd DA, Vaillant CR, Edgar DH. Source: Pediatric Surgery International. 2002 October; 18(7): 581-5. Epub 2002 September 26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12471470&dopt=Abstract
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Long-term culture of hematopoietic stem cells - validating the stromal component of the CAFC assay. Author(s): Olesen G, Tonder H, Holm MS, Hokland P. Source: Cytotherapy. 2001; 3(2): 107-16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12028833&dopt=Abstract
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Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968-99. Author(s): Antoine C, Muller S, Cant A, Cavazzana-Calvo M, Veys P, Vossen J, Fasth A, Heilmann C, Wulffraat N, Seger R, Blanche S, Friedrich W, Abinun M, Davies G, Bredius R, Schulz A, Landais P, Fischer A; European Group for Blood and Marrow Transplantation; European Society for Immunodeficiency. Source: Lancet. 2003 February 15; 361(9357): 553-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12598139&dopt=Abstract
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Long-term survival of human spermatogonial stem cells in mouse testes. Author(s): Nagano M, Patrizio P, Brinster RL. Source: Fertility and Sterility. 2002 December; 78(6): 1225-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12477516&dopt=Abstract
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Low incidence of acute graft-versus-host disease after non-myeloablative stem cell transplantation with CD8-depleted peripheral blood stem cells: an update. Author(s): Baron F, Frere P, Baudoux E, Schaaf-Lafontaine N, Fillet G, Beguin Y. Source: Haematologica. 2003 July; 88(7): 835-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12857568&dopt=Abstract
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Low-dose (550 cGy), single-exposure total body irradiation and cyclophosphamide: consistent, durable engraftment of related-donor peripheral blood stem cells with low treatment-related mortality and fatal organ toxicity. Author(s): Blum W, Brown R, Lin HS, Zehnbauer B, Khoury H, Goodnough LT, Westervelt P, Vij R, DiPersio J, Adkins D. Source: Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. 2002; 8(11): 608-18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12463480&dopt=Abstract
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Lung epithelial stem cells. Author(s): Otto WR. Source: The Journal of Pathology. 2002 July; 197(4): 527-35. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12115868&dopt=Abstract
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Mechanism of stem cells in the central nervous system. Author(s): Johansson CB. Source: Journal of Cellular Physiology. 2003 September; 196(3): 409-18. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12891698&dopt=Abstract
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Meeting summary: International Symposium and Workshop on Hematopoietic Stem Cells IV, University of Tubingen, Germany, September 19-21, 2002. Author(s): Brummendorf TH, Orlic D, Fibbe WE, Sharkis S, Kanz L. Source: Experimental Hematology. 2003 June; 31(6): 475-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829022&dopt=Abstract
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Mesenchymal stem cells in human second-trimester bone marrow, liver, lung, and spleen exhibit a similar immunophenotype but a heterogeneous multilineage differentiation potential. Author(s): in 't Anker PS, Noort WA, Scherjon SA, Kleijburg-van der Keur C, Kruisselbrink AB, van Bezooijen RL, Beekhuizen W, Willemze R, Kanhai HH, Fibbe WE. Source: Haematologica. 2003 August; 88(8): 845-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12935972&dopt=Abstract
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Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells. Author(s): Rasmusson I, Ringden O, Sundberg B, Le Blanc K. Source: Transplantation. 2003 October 27; 76(8): 1208-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14578755&dopt=Abstract
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Methylguanine methyltransferase-mediated in vivo selection and chemoprotection of allogeneic stem cells in a large-animal model. Author(s): Neff T, Horn PA, Peterson LJ, Thomasson BM, Thompson J, Williams DA, Schmidt M, Georges GE, von Kalle C, Kiem HP. Source: The Journal of Clinical Investigation. 2003 November; 112(10): 1581-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14617759&dopt=Abstract
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Mitochondrial DNA mutations in human colonic crypt stem cells. Author(s): Taylor RW, Barron MJ, Borthwick GM, Gospel A, Chinnery PF, Samuels DC, Taylor GA, Plusa SM, Needham SJ, Greaves LC, Kirkwood TB, Turnbull DM. Source: The Journal of Clinical Investigation. 2003 November; 112(9): 1351-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14597761&dopt=Abstract
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Mobilization of Ph chromosome-negative peripheral blood stem cells in chronic myeloid leukaemia patients with imatinib mesylate-induced complete cytogenetic remission. Author(s): Drummond MW, Marin D, Clark RE, Byrne JL, Holyoake TL, Lennard A; United Kingdom Chronic Myeloid Leukaemia (UK CML) Working Party. Source: British Journal of Haematology. 2003 November; 123(3): 479-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14617010&dopt=Abstract
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Molecular biology of hematopoietic stem cells. Author(s): Steidl U, Kronenwett R, Martin S, Haas R. Source: Vitam Horm. 2003; 66: 1-28. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12852251&dopt=Abstract
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Molecular signature of human embryonic stem cells and its comparison with the mouse. Author(s): Sato N, Sanjuan IM, Heke M, Uchida M, Naef F, Brivanlou AH. Source: Developmental Biology. 2003 August 15; 260(2): 404-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12921741&dopt=Abstract
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Monitoring of residual hematopoiesis after total body irradiation in humans as a model for accidental x-ray exposure: dose-effect and failure of ex vivo expansion of residual stem cells in view of autografting. Author(s): Belkacemi Y, Bouchet S, Frick J, Huchet A, Pene F, Aigueperse J, Gourmelon P, Lopez M, Gorin NC. Source: International Journal of Radiation Oncology, Biology, Physics. 2003 October 1; 57(2): 500-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957263&dopt=Abstract
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Myoendothelial differentiation of human umbilical cord blood-derived stem cells in ischemic limb tissues. Author(s): Pesce M, Orlandi A, Iachininoto MG, Straino S, Torella AR, Rizzuti V, Pompilio G, Bonanno G, Scambia G, Capogrossi MC. Source: Circulation Research. 2003 September 5; 93(5): E51-62. Epub 2003 August 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12919944&dopt=Abstract
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Neuronal generation from somatic stem cells: current knowledge and perspectives on the treatment of acquired and degenerative central nervous system disorders. Author(s): Corti S, Locatelli F, Strazzer S, Guglieri M, Comi GP. Source: Current Gene Therapy. 2003 June; 3(3): 247-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12762483&dopt=Abstract
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Neuronal stem cells biology and plasticity. Author(s): La Russa VF, Mondal D, Miller A, Safah H, Rozans M, Curiel T, Agrawal K, Weiner R. Source: Cancer Investigation. 2003; 21(5): 792-804. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14628437&dopt=Abstract
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Neurotrophin receptor p75(NTR) characterizes human esophageal keratinocyte stem cells in vitro. Author(s): Okumura T, Shimada Y, Imamura M, Yasumoto S. Source: Oncogene. 2003 June 26; 22(26): 4017-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821936&dopt=Abstract
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New frontiers in gene targeting and cloning: success, application and challenges in domestic animals and human embryonic stem cells. Author(s): Denning C, Priddle H. Source: Reproduction (Cambridge, England). 2003 July; 126(1): 1-11. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814342&dopt=Abstract
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No differences in colony formation of peripheral blood stem cells frozen with 5% or 10% dimethyl sulfoxide. Author(s): Bakken AM, Bruserud O, Abrahamsen JF. Source: Journal of Hematotherapy & Stem Cell Research. 2003 June; 12(3): 351-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12857376&dopt=Abstract
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NOD/LtJ type I diabetes in mice and the effect of stem cells (Berashis) derived from human umbilical cord blood. Author(s): Ende N, Chen R, Mack R. Source: J Med. 2002; 33(1-4): 181-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12939117&dopt=Abstract
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Nodal-dependent Cripto signaling promotes cardiomyogenesis and redirects the neural fate of embryonic stem cells. Author(s): Parisi S, D'Andrea D, Lago CT, Adamson ED, Persico MG, Minchiotti G. Source: The Journal of Cell Biology. 2003 October 27; 163(2): 303-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14581455&dopt=Abstract
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Non-hematopoietic human bone marrow contains long-lasting, pluripotential mesenchymal stem cells. Author(s): Suva D, Garavaglia G, Menetrey J, Chapuis B, Hoffmeyer P, Bernheim L, Kindler V. Source: Journal of Cellular Physiology. 2004 January; 198(1): 110-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14584050&dopt=Abstract
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Normalization of previously shortened telomere length under treatment with imatinib argues against a preexisting telomere length deficit in normal hematopoietic stem cells from patients with chronic myeloid leukemia. Author(s): Brummendorf TH, Ersoz I, Hartmann U, Balabanov S, Wolke H, Paschka P, Lahaye T, Berner B, Bartolovic K, Kreil S, Berger U, Gschaidmeier H, Bokemeyer C, Hehlmann R, Dietz K, Lansdorp PM, Kanz L, Hochhaus A. Source: Annals of the New York Academy of Sciences. 2003 May; 996: 26-38. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799279&dopt=Abstract
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Nuclear transplantation, embryonic stem cells, and the potential for cell therapy. Author(s): Hochedlinger K, Jaenisch R. Source: The New England Journal of Medicine. 2003 July 17; 349(3): 275-86. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12867612&dopt=Abstract
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Ocular surface reconstruction using cultivated mucosal epithelial stem cells. Author(s): Nakamura T, Kinoshita S. Source: Cornea. 2003 October; 22(7 Suppl): S75-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14703711&dopt=Abstract
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Olfactory bulb core is a rich source of neural progenitor and stem cells in adult rodent and human. Author(s): Liu Z, Martin LJ. Source: The Journal of Comparative Neurology. 2003 May 12; 459(4): 368-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12687705&dopt=Abstract
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One strategy for cell and gene therapy: harnessing the power of adult stem cells to repair tissues. Author(s): Prockop DJ, Gregory CA, Spees JL. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 September 30; 100 Suppl 1: 11917-23. Epub 2003 Sep 17. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13679583&dopt=Abstract
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Ontogenic differences in human liver 4-hydroxynonenal detoxification are associated with in vitro injury to fetal hematopoietic stem cells. Author(s): Gardner JL, Doi AM, Pham RT, Huisden CM, Gallagher EP. Source: Toxicology and Applied Pharmacology. 2003 September 1; 191(2): 95-106. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12946646&dopt=Abstract
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Ontogenic emergence of definitive hematopoietic stem cells. Author(s): Dzierzak E. Source: Current Opinion in Hematology. 2003 May; 10(3): 229-34. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12690291&dopt=Abstract
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Organ- and tissue-specific stem cells and carcinogenesis. Author(s): Pathak S. Source: Anticancer Res. 2002 May-June; 22(3): 1353-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12168810&dopt=Abstract
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Origin and use of embryonic and adult stem cells in differentiation and tissue repair. Author(s): Passier R, Mummery C. Source: Cardiovascular Research. 2003 May 1; 58(2): 324-35. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757867&dopt=Abstract
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Origin of vascular smooth muscle cells and the role of circulating stem cells in transplant arteriosclerosis. Author(s): Hillebrands JL, Klatter FA, Rozing J. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2003 March 1; 23(3): 380-7. Epub 2003 January 30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12615698&dopt=Abstract
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Osteoblast recruitment from stem cells does not decrease by age at late adulthood. Author(s): Leskela HV, Risteli J, Niskanen S, Koivunen J, Ivaska KK, Lehenkari P. Source: Biochemical and Biophysical Research Communications. 2003 November 28; 311(4): 1008-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14623282&dopt=Abstract
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Outcome of transplantation of highly purified peripheral blood CD34+ cells with Tcell add-back compared with unmanipulated bone marrow or peripheral blood stem cells from HLA-identical sibling donors in patients with first chronic phase chronic myeloid leukemia. Author(s): Elmaagacli AH, Peceny R, Steckel N, Trenschel R, Ottinger H, Grosse-Wilde H, Schaefer UW, Beelen DW. Source: Blood. 2003 January 15; 101(2): 446-53. Epub 2002 September 12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12393406&dopt=Abstract
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P2Y-like receptor, GPR105 (P2Y14), identifies and mediates chemotaxis of bonemarrow hematopoietic stem cells. Author(s): Lee BC, Cheng T, Adams GB, Attar EC, Miura N, Lee SB, Saito Y, Olszak I, Dombkowski D, Olson DP, Hancock J, Choi PS, Haber DA, Luster AD, Scadden DT. Source: Genes & Development. 2003 July 1; 17(13): 1592-604. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12842911&dopt=Abstract
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Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp. Author(s): Shi S, Gronthos S. Source: Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research. 2003 April; 18(4): 696-704. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12674330&dopt=Abstract
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Personal pathways to embryonic stem cells. Author(s): Edwards RG. Source: Reproductive Biomedicine Online. 2002 May-June; 4(3): 263-78. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12709279&dopt=Abstract
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Plasticity of marrow-derived stem cells. Author(s): Herzog EL, Chai L, Krause DS. Source: Blood. 2003 November 15; 102(10): 3483-93. Epub 2003 July 31. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12893756&dopt=Abstract
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Plasticity of mesenchymal stem cells--regenerative medicine for diseased hearts. Author(s): Gojo S, Umezawa A. Source: Hum Cell. 2003 March; 16(1): 23-30. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12971622&dopt=Abstract
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Platelet-derived growth factors enhance proliferation of human stromal stem cells. Author(s): Lucarelli E, Beccheroni A, Donati D, Sangiorgi L, Cenacchi A, Del Vento AM, Meotti C, Bertoja AZ, Giardino R, Fornasari PM, Mercuri M, Picci P. Source: Biomaterials. 2003 August; 24(18): 3095-100. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12895582&dopt=Abstract
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Poor mobilization of peripheral blood stem cells is a risk factor for worse outcome in lymphoma patients undergoing autologous stem cell transplantation. Author(s): Gordan LN, Sugrue MW, Lynch JW, Williams KD, Khan SA, Wingard JR, Moreb JS. Source: Leukemia & Lymphoma. 2003 May; 44(5): 815-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12802919&dopt=Abstract
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Potential use of stem cells in neuroreplacement therapies for neurodegenerative diseases. Author(s): Sugaya K. Source: Int Rev Cytol. 2003; 228: 1-30. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14667041&dopt=Abstract
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Potentially therapeutically relevant differences of antisense oligonucleotide uptake in CD34+ hematopoietic stem cells, leukemic blasts and cancer cells from patients. Author(s): Seitz G, Kohler G, Nehmzow M, Lorenz G, Denzlinger C, Muller C, Bader P, Brischwein K, Beck JF. Source: Anticancer Res. 2002 May-June; 22(3): 1717-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12168859&dopt=Abstract
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Proteolytic enzyme levels are increased during granulocyte colony-stimulating factorinduced hematopoietic stem cell mobilization in human donors but do not predict the number of mobilized stem cells. Author(s): van Os R, van Schie ML, Willemze R, Fibbe WE. Source: Journal of Hematotherapy & Stem Cell Research. 2002 June; 11(3): 513-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12183836&dopt=Abstract
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Quantifying levels of transplanted murine and human mesenchymal stem cells in vivo by real-time PCR. Author(s): McBride C, Gaupp D, Phinney DG. Source: Cytotherapy. 2003; 5(1): 7-18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12745583&dopt=Abstract
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Quantitative assessment of contaminating tumor cells in autologous peripheral blood stem cells of B-cell non-Hodgkin lymphomas using immunoglobulin heavy chain gene allele-specific oligonucleotide real-time quantitative-polymerase chain reaction. Author(s): Yashima A, Maesawa C, Uchiyama M, Tarusawa M, Satoh T, Satoh M, Enomoto S, Sugawara K, Numaoka H, Murai K, Utsugisawa T, Ishida Y, Masuda T. Source: Leukemia Research. 2003 October; 27(10): 925-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12860013&dopt=Abstract
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Recombinant Sendai virus provides a highly efficient gene transfer into human cord blood-derived hematopoietic stem cells. Author(s): Jin CH, Kusuhara K, Yonemitsu Y, Nomura A, Okano S, Takeshita H, Hasegawa M, Sueishi K, Hara T. Source: Gene Therapy. 2003 February; 10(3): 272-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12571635&dopt=Abstract
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Reconstruction of hepatic organoid by hepatic stem cells. Author(s): Mitaka T. Source: Journal of Hepato-Biliary-Pancreatic Surgery. 2002; 9(6): 697-703. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12658403&dopt=Abstract
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Regenerative medicine through mesenchymal stem cells for bone and cartilage repair. Author(s): Noel D, Djouad F, Jorgense C. Source: Curr Opin Investig Drugs. 2002 July; 3(7): 1000-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12186258&dopt=Abstract
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Region-specific generation of cholinergic neurons from fetal human neural stem cells grafted in adult rat. Author(s): Wu P, Tarasenko YI, Gu Y, Huang LY, Coggeshall RE, Yu Y. Source: Nature Neuroscience. 2002 December; 5(12): 1271-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12426573&dopt=Abstract
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Regulation of human breast epithelial stem cells. Author(s): Clarke RB, Anderson E, Howell A, Potten CS. Source: Cell Proliferation. 2003 October; 36 Suppl 1: 45-58. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14521515&dopt=Abstract
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Researchers expand & preserve stem cells for cellular therapies. Author(s): Walczak IM. Source: Diabetes Technology & Therapeutics. 2003; 5(1): 131. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12733539&dopt=Abstract
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Restoring the brain with neural stem cells. Author(s): Copray JC. Source: Acta Neurochirurgica. 2003 June; 145(6): 425-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14570058&dopt=Abstract
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Reversibility of CD34 expression on human hematopoietic stem cells that retain the capacity for secondary reconstitution. Author(s): Dao MA, Arevalo J, Nolta JA. Source: Blood. 2003 January 1; 101(1): 112-8. Epub 2002 July 25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12393633&dopt=Abstract
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Reversible expression of CD34 by adult human bone marrow long-term engrafting hematopoietic stem cells. Author(s): Zanjani ED, Almeida-Porada G, Livingston AG, Zeng H, Ogawa M. Source: Experimental Hematology. 2003 May; 31(5): 406-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12763139&dopt=Abstract
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Role of melanoma chondroitin sulphate proteoglycan in patterning stem cells in human interfollicular epidermis. Author(s): Legg J, Jensen UB, Broad S, Leigh I, Watt FM. Source: Development (Cambridge, England). 2003 December; 130(24): 6049-63. Epub 2003 October 22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14573520&dopt=Abstract
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Side population keratinocytes resembling bone marrow side population stem cells are distinct from label-retaining keratinocyte stem cells. Author(s): Terunuma A, Jackson KL, Kapoor V, Telford WG, Vogel JC. Source: The Journal of Investigative Dermatology. 2003 November; 121(5): 1095-103. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14708612&dopt=Abstract
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Similar MLL-associated leukemias arising from self-renewing stem cells and shortlived myeloid progenitors. Author(s): Cozzio A, Passegue E, Ayton PM, Karsunky H, Cleary ML, Weissman IL. Source: Genes & Development. 2003 December 15; 17(24): 3029-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14701873&dopt=Abstract
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Stem cells and breast cancer: A field in transit. Author(s): Smalley M, Ashworth A. Source: Nature Reviews. Cancer. 2003 November; 3(11): 832-44. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14668814&dopt=Abstract
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Stem cells in the mammalian blastocyst. Author(s): Rossant J. Source: Harvey Lect. 2001-2002; 97: 17-40. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14562515&dopt=Abstract
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Stem cells. Mixing species--and crossing a line? Author(s): Boyce N. Source: U.S. News & World Report. 2003 October 27; 135(14): 58, 60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14619296&dopt=Abstract
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Stem cells: a promising source of pancreatic islets for transplantation in type 1 diabetes. Author(s): Street CN, Rajotte RV, Korbutt GS. Source: Curr Top Dev Biol. 2003; 58: 111-36. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14711014&dopt=Abstract
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Stem cells: how to make eggs and sperm. Author(s): Surani MA. Source: Nature. 2004 January 8; 427(6970): 106-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14712257&dopt=Abstract
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Stem cells: review and update. Author(s): Sylvester KG, Longaker MT. Source: Archives of Surgery (Chicago, Ill. : 1960). 2004 January; 139(1): 93-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14718284&dopt=Abstract
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Stepwise surgical approach for in vivo expansion of epithelial stem cells to treating severe acute chemical burns with total limbal deficiency. Author(s): Park GS, Je J, Kim JC. Source: Korean J Ophthalmol. 2003 December; 17(2): 75-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14717484&dopt=Abstract
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Strategies to reduce transplant-related mortality after allogeneic stem cell transplantation in elderly patients: Comparison of reduced-intensity conditioning and unmanipulated peripheral blood stem cells vs a myeloablative regimen and CD34+ cell selection. Author(s): Canals C, Martino R, Sureda A, Altes A, Briones J, Subira M, Ancin I, MartinHenao G, Brunet S, Sierra J. Source: Experimental Hematology. 2003 November; 31(11): 1039-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14585367&dopt=Abstract
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Telomeres, stem cells, senescence, and cancer. Author(s): Sharpless NE, DePinho RA. Source: The Journal of Clinical Investigation. 2004 January; 113(2): 160-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14722605&dopt=Abstract
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Temporally distinct requirements for endothelin receptor B in the generation and migration of gut neural crest stem cells. Author(s): Kruger GM, Mosher JT, Tsai YH, Yeager KJ, Iwashita T, Gariepy CE, Morrison SJ. Source: Neuron. 2003 December 4; 40(5): 917-29. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14659091&dopt=Abstract
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The continuing saga of epidermal stem cells. Author(s): Bickenbach JK. Source: The Journal of Investigative Dermatology. 2003 November; 121(5): Xv-Xvi. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14708587&dopt=Abstract
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The evolution of patents on life--transgenic animals, clones and stem cells. Author(s): Woessner WD. Source: J Pat Trademark Off Soc. 2001 November; 83(11): 830-44. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12962089&dopt=Abstract
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The in vitro myelin formation in neurospheres of human neural stem cells. Author(s): Yang LY, Zheng JK, Liu XM, Hui GZ, Guo LH. Source: Chinese Journal of Traumatology = Chung-Hua Ch'uang Shang Tsa Chih / Chinese Medical Association. 2003 December; 6(6): 341-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14642053&dopt=Abstract
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The use of adult stem cells in regenerative medicine. Author(s): Hedrick MH, Daniels EJ. Source: Clin Plast Surg. 2003 October; 30(4): 499-505. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14621298&dopt=Abstract
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The vulture and stem cells. Author(s): Garcia-Olmo D, Garcia-Olmo MA. Source: The New England Journal of Medicine. 2003 October 9; 349(15): 1480-1; Author Reply 1480-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14534345&dopt=Abstract
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Tissue engineering, stem cells, and cloning for the regeneration of urologic organs. Author(s): Atala A. Source: Clin Plast Surg. 2003 October; 30(4): 649-67. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14621312&dopt=Abstract
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Transplant graft vasculopathy: a dark side of bone marrow stem cells? Author(s): Ii M, Losordo DW. Source: Circulation. 2003 December 23; 108(25): 3056-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14691018&dopt=Abstract
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Transplantation of embryonic stem cells: possibilities and challenges. Author(s): Ringden O, Le Blanc K, Hovatta O. Source: Transplantation. 2003 October 15; 76(7): 1011-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14584499&dopt=Abstract
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U.S. approves labs with stem cells for research use. Author(s): Wade N. Source: Ny Times (Print). 2001 August 27; : A1, A12. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12155851&dopt=Abstract
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Ultraviolet light and stem cells. Author(s): Zaidi H, Weir R, Cheong-Leen R, Corbett MC, Sharkawi E, King ER. Source: Ophthalmology. 2004 January; 111(1): 196; Author Reply 196. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14711739&dopt=Abstract
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Umbilical cord blood--a rich source of haematopoietic stem cells. Author(s): Ebrahim GJ. Source: Journal of Tropical Pediatrics. 2002 April; 48(2): 64-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12022430&dopt=Abstract
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Unexpected potential of adult stem cells. Author(s): Verfaillie CM, Schwartz R, Reyes M, Jiang Y. Source: Annals of the New York Academy of Sciences. 2003 May; 996: 231-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799301&dopt=Abstract
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Unique molecular and cellular features of acute myelogenous leukemia stem cells. Author(s): Jordan CT. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2002 April; 16(4): 559-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11960332&dopt=Abstract
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Update on hepatic stem cells. Author(s): Alison MR, Poulsom R, Forbes SJ. Source: Liver. 2001 December; 21(6): 367-73. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11903879&dopt=Abstract
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Use eggs, not embryos, to derive stem cells. Author(s): Brison DR, Lieberman BA. Source: Bmj (Clinical Research Ed.). 2003 October 11; 327(7419): 872. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14551124&dopt=Abstract
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Use of primary human liver cells originating from discarded grafts in a bioreactor for liver support therapy and the prospects of culturing adult liver stem cells in bioreactors: a morphologic study. Author(s): Gerlach JC, Mutig K, Sauer IM, Schrade P, Efimova E, Mieder T, Naumann G, Grunwald A, Pless G, Mas A, Bachmann S, Neuhaus P, Zeilinger K. Source: Transplantation. 2003 September 15; 76(5): 781-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14501853&dopt=Abstract
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Use of stem cells in biotechnological research. Author(s): Paegel NS. Source: Whittier Law Rev. 2001 Summer; 22(4): 1183-221. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12774792&dopt=Abstract
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Use of stem cells. Author(s): Andrews BF. Source: J Ky Med Assoc. 2002 July; 100(7): 297. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12141197&dopt=Abstract
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Variable cytotoxicity of diphtheria toxin 388-granulocyte-macrophage colonystimulating factor fusion protein for acute myelogenous leukemia stem cells. Author(s): Feuring-Buske M, Frankel A, Gerhard B, Hogge D. Source: Experimental Hematology. 2000 December; 28(12): 1390-400. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11146161&dopt=Abstract
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Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Author(s): Rafii S, Lyden D, Benezra R, Hattori K, Heissig B. Source: Nature Reviews. Cancer. 2002 November; 2(11): 826-35. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12415253&dopt=Abstract
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Veto-like activity of mesenchymal stem cells: functional discrimination between cellular responses to alloantigens and recall antigens. Author(s): Potian JA, Aviv H, Ponzio NM, Harrison JS, Rameshwar P. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 October 1; 171(7): 3426-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14500637&dopt=Abstract
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When biology bursts into the clinic: stem cells and their potential. Author(s): Piscaglia AC, Di Campli C, Pola P, Gasbarrini A. Source: Eur Rev Med Pharmacol Sci. 2001 September-December; 5(5-6): 151-4. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12201665&dopt=Abstract
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When cells become depressed: focus on neural stem cells in novel treatment strategies against depression. Author(s): Benninghoff J, Schmitt A, Mossner R, Lesch KP. Source: Journal of Neural Transmission (Vienna, Austria : 1996). 2002 May; 109(5-6): 94762. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12111481&dopt=Abstract
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Where, oh where, have my stem cells gone? Author(s): Wexler E, Palmer T. Source: Trends in Neurosciences. 2002 May; 25(5): 225-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11972951&dopt=Abstract
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Why neurosurgeons should care about stem cells. Author(s): Bruce JN, Parsa AT. Source: Neurosurgery. 2001 January; 48(1): 243-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11152358&dopt=Abstract
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Why stem cells will transform medicine. Author(s): Fox C. Source: Fortune. 2001 June 11; 143(12): 158-62, 164, 166. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11409106&dopt=Abstract
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Will embryonic stem cells be a useful source of dopamine neurons for transplant into patients with Parkinson's disease? Author(s): Freed CR. Source: Proceedings of the National Academy of Sciences of the United States of America. 2002 February 19; 99(4): 1755-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11854478&dopt=Abstract
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Will stem cells create a market for human embryos? Author(s): Kahn J. Source: Journal of Andrology. 2001 January-February; 22(1): 12. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11191076&dopt=Abstract
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WNT helps blood stem cells tick over. Author(s): Bradbury J. Source: Lancet. 2003 May 3; 361(9368): 1528. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12737871&dopt=Abstract
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CHAPTER 2. NUTRITION AND STEM CELLS Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and stem cells.
Finding Nutrition Studies on Stem Cells The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail:
[email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “stem cells” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.
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Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.
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The following information is typical of that found when using the “Full IBIDS Database” to search for “stem cells” (or a synonym): •
All-trans-retinoic acid-mediated modulation of p53 during neural differentiation in murine embryonic stem cells. Author(s): Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens 30602-7389, USA. Source: Sarkar, S A Sharma, R P Cell-Biol-Toxicol. 2002; 18(4): 243-57 0742-2091
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Biochemical properties of a keratan sulphate/chondroitin sulphate proteoglycan expressed in primate pluripotent stem cells. Author(s): University College London, UK. Source: Cooper, Susan Bennett, William Andrade, Jessica Reubinoff, Benjamin E Thomson, James Pera, Martin F J-Anat. 2002 Mar; 200(Pt 3): 259-65 0021-8782
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Differential contributions of ERK and PI3-kinase to the regulation of cyclin D1 expression and to the control of the G1/S transition in mouse embryonic stem cells. Author(s): Laboratoire de Biologie Moleculaire et Cellulaire, CNRS UMR 5665, INRA LA913, Ecole Normale Superieure de Lyon, 46 allee d'Italie, 69364 Lyon Cedex 07, France. Source: Jirmanova, L Afanassieff, M Gobert Gosse, S Markossian, S Savatier, P Oncogene. 2002 August 15; 21(36): 5515-28 0950-9232
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Differentiation of adult bone marrow stem cells into neuroprogenitor cells in vitro. Author(s): Department of Medicine, Sungkyunkwan University, School of Medicine, Seoul, Korea 135-710. Source: Kim, B J Seo, J H Bubien, J K Oh, Y S Neuroreport. 2002 July 2; 13(9): 1185-8 0959-4965
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Differentiation of embryonic stem cell to astrocytes visualized by green fluorescent protein. Author(s): Department of Biochemistry, The College of Life Science, Peking University, People's Republic of China. Source: Tang, F Shang, K Wang, X Gu, J Cell-Mol-Neurobiol. 2002 February; 22(1): 95101 0272-4340
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Directed differentiation of embryonic stem cells into motor neurons. Author(s): Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA. Source: Wichterle, H Lieberam, I Porter, J A Jessell, T M Cell. 2002 August 9; 110(3): 38597 0092-8674
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Expression of selected apoptosis related genes, MIF, IGIF and TNF alpha, during retinoic acid-induced neural differentiation in murine embryonic stem cells. Author(s): Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, 30602, USA. Source: Sarkar, S A Sharma, R P Cell-Struct-Funct. 2002 April; 27(2): 99-107 0386-7196
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Generation of dopaminergic neurons from embryonic stem cells. Author(s): Organogenesis and Neurogenesis Group, Center for Developmental Biology, RIKEN, Kobe 650-00047, Japan.
[email protected] Source: Sasai, Y J-Neurol. 2002 September; 249 Suppl 2: II41-4 0340-5354
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Having it all? Stem cells, haematopoiesis and lymphopoiesis in adult human liver. Author(s): Education and Research Centre, St.Vincent'sUniversity Hospital and The Conway Institute, University College, Dublin, Ireland.
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Source: Golden Mason, Lucy O'Farrelly, Cliona Immunol-Cell-Biol. 2002 February; 80(1): 45-51 0818-9641 •
High activity Rhenium-186 HEDP with autologous peripheral blood stem cell rescue: a phase I study in progressive hormone refractory prostate cancer metastatic to bone. Author(s): Unit of Academic Radiotherapy and Clinical Oncology, Royal Marsden NHS Trust, Sutton, Surrey SM2 5PT, UK.
[email protected] Source: O'Sullivan, J M McCready, V R Flux, G Norman, A R Buffa, F M Chittenden, S Guy, M Pomeroy, K Cook, G Gadd, J Treleaven, J Al Deen, A Horwich, A Huddart, R A Dearnaley, D P Br-J-Cancer. 2002 June 5; 86(11): 1715-20 0007-0920
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Improved survival of children with advanced neuroblastoma treated by intensified therapy including myeloablative chemotherapy with stem cell transplantation: a retrospective analysis from the Tohoku Neuroblastoma Study Group. Author(s): Department of Pediatric Hematology and Oncology, Tohoku University School of Medicine, Sendai, Japan.
[email protected] Source: Imaizumi, M Watanabe, A Kikuta, A Takano, T Ito, E Shimizu, T Tsuchiya, S Iinuma, K Konno, T Ohi, R Hayashi, Y Tohoku-J-Exp-Med. 2001 October; 195(2): 73-83 0040-8727
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Induced dedifferentiation: a possible alternative to embryonic stem cell transplants. Author(s): Department of Orthopedic Surgery, Upstate Medical Center, State University of New York, Syracuse, NY 13210, USA. Source: Becker, Robert O NeuroRehabilitation. 2002; 17(1): 23-31 1053-8135
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Intensified PCV-chemotherapy with optional stem cell support in recurrent malignant oligodendroglioma. Author(s): Department of Neurology, University Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. Source: Zander, T Nettekoven, W Kraus, J A Pels, H Ko, Y D Vetter, H Klockgether, T Schlegel, U J-Neurol. 2002 August; 249(8): 1055-7 0340-5354
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Leptomeningeal relapse of multiple myeloma following allogeneic stem cell transplantation. Author(s): Hematology/Oncology Division, Columbia University College of Physicians and Surgeons, 177 Fort Washington Avenue, New York City, NY 10032, USA.
[email protected] Source: Savage, David G Mears, J Gregory Balmaceda, Casilda Rescigno, John Shendrik, Igor Mansukhani, Mahesh Orazi, Attilio Leuk-Res. 2002 July; 26(7): 689-92 0145-2126
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Modulation of c-myc, max, and mad gene expression during neural differentiation of embryonic stem cells by all-trans-retinoic acid. Author(s): Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens 30602, USA. Source: Sarkar, S A Sharma, R P Gene-Expr. 2002; 10(3): 125-35 1052-2166
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Resolution of stroke deficits following contralateral grafts of conditionally immortal neuroepithelial stem cells. Author(s): ReNeuron Ltd, Department of Psychology, Institute of Psychiatry, King's College, London. Source: Veizovic, T Beech, J S Stroemer, R P Watson, W P Hodges, H Stroke. 2001 April; 32(4): 1012-9 1524-4628
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Role of S2 receptors in the stimulatory effect of serotonin on hemopoietic bone marrow stem cells. Author(s): International Research Center for Extreme States, Presidium of the Krasnoyarsk Research Center, Siberian Division of the Russian Academy of Sciences.
[email protected] Source: Nefedova, V V Inzhevatkin, E V Nefedov, V P Bull-Exp-Biol-Med. 2002 May; 133(5): 419-20 0007-4888
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Stem cell growth factor: in situ hybridization analysis on the gene expression, molecular characterization and in vitro proliferative activity of a recombinant preparation on primitive hematopoietic progenitor cells. Author(s): Department of Internal Medicine, Osaka Dental University, Osaka, Japan.
[email protected] Source: Hiraoka, A Yano Ki, K Kagami, N Takeshige, K Mio, H Anazawa, H Sugimoto, S Hematol-J. 2001; 2(5): 307-15 1466-4860
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Topotecan-filgrastim combination is an effective regimen for mobilizing peripheral blood stem cells. Author(s): Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN 38105-2794, USA. Source: Yeoh, E J Cunningham, J M Yee, G C Hunt, D Houston, J A Richardson, S L Stewart, C F Houghton, P J Bowman, L C Gajjar, A J Bone-Marrow-Transplant. 2001 September; 28(6): 563-71 0268-3369
Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •
healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0
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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov
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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov
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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/
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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/
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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/
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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/
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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/
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Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats
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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html
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Google: http://directory.google.com/Top/Health/Nutrition/
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Healthnotes: http://www.healthnotes.com/
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Open Directory Project: http://dmoz.org/Health/Nutrition/
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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/
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WebMDHealth: http://my.webmd.com/nutrition
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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CHAPTER 3. ALTERNATIVE MEDICINE AND STEM CELLS Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to stem cells. At the conclusion of this chapter, we will provide additional sources.
National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to stem cells and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “stem cells” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to stem cells: •
“Homing to Niche,” a new criterion for hematopoietic stem cells? Author(s): Ema H, Nakauchi H. Source: Immunity. 2004 January; 20(1): 1-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14738758&dopt=Abstract
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Adenoviral transduction of mouse hematopoietic stem cells. Author(s): Bradfute SB, Goodell MA. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2003 March; 7(3): 334-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12668129&dopt=Abstract
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Adult bone marrow stem cells regenerate myocardium in ischemic heart disease. Author(s): Orlic D.
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Source: Annals of the New York Academy of Sciences. 2003 May; 996: 152-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799293&dopt=Abstract •
Adult stem cells and their importance in cell therapy. Author(s): Filip S, Mokry J, Hruska I. Source: Folia Biol (Praha). 2003; 49(1): 9-14. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12630663&dopt=Abstract
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Allogeneic stem cells, clinical transplantation and the origins of regenerative medicine. Author(s): Strom TB, Field LJ, Ruediger M. Source: Current Opinion in Immunology. 2002 October; 14(5): 601-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12183159&dopt=Abstract
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All-trans-retinoic acid-mediated modulation of p53 during neural differentiation in murine embryonic stem cells. Author(s): Sarkar SA, Sharma RP. Source: Cell Biology and Toxicology. 2002; 18(4): 243-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12206137&dopt=Abstract
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Asymmetric division and lineage commitment at the level of hematopoietic stem cells: inference from differentiation in daughter cell and granddaughter cell pairs. Author(s): Takano H, Ema H, Sudo K, Nakauchi H. Source: The Journal of Experimental Medicine. 2004 February 2; 199(3): 295-302. Epub 2004 January 26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14744992&dopt=Abstract
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Autologous intramyocardial injection of cultured skeletal muscle-derived stem cells in patients with non-acute myocardial infarction. Author(s): Herreros J, Prosper F, Perez A, Gavira JJ, Garcia-Velloso MJ, Barba J, Sanchez PL, Canizo C, Rabago G, Marti-Climent JM, Hernandez M, Lopez-Holgado N, Gonzalez-Santos JM, Martin-Luengo C, Alegria E. Source: European Heart Journal. 2003 November; 24(22): 2012-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14613737&dopt=Abstract
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Autologous stem cells for functional myocardial repair. Author(s): Schwartz Y, Kornowski R. Source: Heart Failure Reviews. 2003 July; 8(3): 237-45. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12878832&dopt=Abstract
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Biology of human bone marrow stem cells. Author(s): Bonnet D.
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Source: Clinical and Experimental Medicine. 2003 November; 3(3): 140-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14648228&dopt=Abstract •
Bone-marrow stem cells as a source for cell therapy. Author(s): Chiu RC. Source: Heart Failure Reviews. 2003 July; 8(3): 247-51. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12878833&dopt=Abstract
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Cardiac application of embryonic stem cells. Author(s): Xiao YF. Source: Sheng Li Xue Bao. 2003 October 25; 55(5): 493-504. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14566394&dopt=Abstract
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Characterization of cord blood hematopoietic stem cells. Author(s): Mazurier F, Doedens M, Gan OI, Dick JE. Source: Annals of the New York Academy of Sciences. 2003 May; 996: 67-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799284&dopt=Abstract
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Chinese fusion method promises fresh route to human stem cells. Author(s): Dennis C. Source: Nature. 2003 August 14; 424(6950): 711. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917645&dopt=Abstract
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Cloning, stem cells, and the current national debate: incorporating ethics into a large introductory biology course. Author(s): Fink RD. Source: Cell Biology Education [electronic Resource]. 2002 Winter; 1(4): 132-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12669102&dopt=Abstract
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Collection of peripheral blood stem cells in newly diagnosed myeloma patients without any prior cytoreductive therapy: the first step towards an 'operational cure'? Author(s): Powles R, Sirohi B, Kulkarni S, Treleaven J, Rudin C, Sankpal S, Goyal S, Horton C, Millar B, Saso R, Singhal S, Mehta J. Source: Bone Marrow Transplantation. 2002 October; 30(8): 479-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12379885&dopt=Abstract
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Cyclophosphamide, etoposide and G-CSF to mobilize peripheral blood stem cells for autologous stem cell transplantation in patients with lymphoma. Author(s): Mollee P, Pereira D, Nagy T, Song K, Saragosa R, Keating A, Crump M. Source: Bone Marrow Transplantation. 2002 September; 30(5): 273-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12209348&dopt=Abstract
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Deceptive multilineage reconstitution analysis of mice transplanted with hemopoietic stem cells, and implications for assessment of stem cell numbers and lineage potentials. Author(s): Bryder D, Sasaki Y, Borge OJ, Jacobsen SE. Source: Journal of Immunology (Baltimore, Md. : 1950). 2004 February 1; 172(3): 1548-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14734733&dopt=Abstract
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Derivation and potential applications of human embryonic stem cells. Author(s): Gepstein L. Source: Circulation Research. 2002 November 15; 91(10): 866-76. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12433831&dopt=Abstract
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Differentiation of pluripotent embryonic stem cells into cardiomyocytes. Author(s): Boheler KR, Czyz J, Tweedie D, Yang HT, Anisimov SV, Wobus AM. Source: Circulation Research. 2002 August 9; 91(3): 189-201. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12169644&dopt=Abstract
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Donor-derived hematopoietic stem cells in organ transplantation: technical aspects and hurdles yet to be cleared. Author(s): Herve P. Source: Transplantation. 2003 May 15; 75(9 Suppl): 55S-57S. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12819493&dopt=Abstract
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Early neuronal and glial determination from mouse E10.5 telencephalon embryonic stem cells: an in vitro study. Author(s): Khelfaoui M, Guimiot F, Simonneau M. Source: Neuroreport. 2002 July 2; 13(9): 1209-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12151771&dopt=Abstract
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Efficient gene transfer of a simian immuno-deficiency viral vector into cardiomyocytes derived from primate embryonic stem cells. Author(s): Nagata M, Takahashi M, Muramatsu S, Ueda Y, Hanazono Y, Takeuchi K, Okada K, Suzuki Y, Kondo Y, Suemori M, Ikeda U, Nakano I, Kobayashi E, Hasegawa M, Ozawa K, Nakatsuji N, Shimada K. Source: The Journal of Gene Medicine. 2003 November; 5(11): 921-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14601129&dopt=Abstract
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EGF-responsive rat neural stem cells: molecular follow-up of neuron and astrocyte differentiation in vitro. Author(s): Jori FP, Galderisi U, Piegari E, Cipollaro M, Cascino A, Peluso G, Cotrufo R, Giordano A, Melone MA.
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Source: Journal of Cellular Physiology. 2003 May; 195(2): 220-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12652649&dopt=Abstract •
Estrogens activate bone morphogenetic protein-2 gene transcription in mouse mesenchymal stem cells. Author(s): Zhou S, Turgeman G, Harris SE, Leitman DC, Komm BS, Bodine PV, Gazit D. Source: Molecular Endocrinology (Baltimore, Md.). 2003 January; 17(1): 56-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12511606&dopt=Abstract
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Ex vivo expansion of human hematopoietic stem cells by direct delivery of the HOXB4 homeoprotein. Author(s): Amsellem S, Pflumio F, Bardinet D, Izac B, Charneau P, Romeo PH, DubartKupperschmitt A, Fichelson S. Source: Nature Medicine. 2003 November; 9(11): 1423-7. Epub 2003 October 26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14578882&dopt=Abstract
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Functional gene screening in embryonic stem cells implicates Wnt antagonism in neural differentiation. Author(s): Aubert J, Dunstan H, Chambers I, Smith A. Source: Nature Biotechnology. 2002 December; 20(12): 1240-5. Epub 2002 November 25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12447396&dopt=Abstract
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Gene expression in human neural stem cells: effects of leukemia inhibitory factor. Author(s): Wright LS, Li J, Caldwell MA, Wallace K, Johnson JA, Svendsen CN. Source: Journal of Neurochemistry. 2003 July; 86(1): 179-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12807438&dopt=Abstract
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Gene therapy and tissue engineering based on muscle-derived stem cells. Author(s): Deasy BM, Huard J. Source: Curr Opin Mol Ther. 2002 August; 4(4): 382-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12222876&dopt=Abstract
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Genesis of embryonic stem cells. Author(s): Buehr M, Smith A. Source: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 2003 August 29; 358(1436): 1397-402; Discussion 1402. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14511487&dopt=Abstract
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Hematopoiesis from embryonic stem cells: lessons from and for ontogeny. Author(s): Kyba M, Daley GQ.
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Source: Experimental Hematology. 2003 November; 31(11): 994-1006. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14585361&dopt=Abstract •
Hematopoietic stem cells: generation and manipulation. Author(s): Nakano T. Source: Trends in Immunology. 2003 November; 24(11): 589-94. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14596883&dopt=Abstract
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HES-1 preserves purified hematopoietic stem cells ex vivo and accumulates side population cells in vivo. Author(s): Kunisato A, Chiba S, Nakagami-Yamaguchi E, Kumano K, Saito T, Masuda S, Yamaguchi T, Osawa M, Kageyama R, Nakauchi H, Nishikawa M, Hirai H. Source: Blood. 2003 March 1; 101(5): 1777-83. Epub 2002 October 24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12406868&dopt=Abstract
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Hoxb4 deficient mice have normal hematopoietic development but exhibit a mild proliferation defect in hematopoietic stem cells. Author(s): Brun AC, Bjornsson JM, Magnusson M, Larsson N, Leveen P, Ehinger M, Nilsson E, Karlsson S. Source: Blood. 2004 February 12 [epub Ahead of Print] http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14962901&dopt=Abstract
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Human CD34+ hematopoietic stem cells capable of multilineage engrafting NOD/SCID mice express flt3: distinct flt3 and c-kit expression and response patterns on mouse and candidate human hematopoietic stem cells. Author(s): Sitnicka E, Buza-Vidas N, Larsson S, Nygren JM, Liuba K, Jacobsen SE. Source: Blood. 2003 August 1; 102(3): 881-6. Epub 2003 April 03. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12676789&dopt=Abstract
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Human embryonic or adult stem cells: an overview on ethics and perspectives for tissue engineering. Author(s): Henon PR. Source: Advances in Experimental Medicine and Biology. 2003; 534: 27-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12903709&dopt=Abstract
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Human embryonic stem cells for myocardial regeneration. Author(s): Kehat I, Gepstein L. Source: Heart Failure Reviews. 2003 July; 8(3): 229-36. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12878831&dopt=Abstract
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Human reconstituting hematopoietic stem cells up-regulate Fas expression upon active cell cycling but remain resistant to Fas-induced suppression.
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Author(s): Dybedal I, Yang L, Bryder D, Aastrand-Grundstrom I, Leandersson K, Jacobsen SE. Source: Blood. 2003 July 1; 102(1): 118-26. Epub 2003 March 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12637333&dopt=Abstract •
In vitro differentiation of size-sieved stem cells into electrically active neural cells. Author(s): Hung SC, Cheng H, Pan CY, Tsai MJ, Kao LS, Ma HL. Source: Stem Cells (Dayton, Ohio). 2002; 20(6): 522-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12456960&dopt=Abstract
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In vivo differentiation of mouse embryonic stem cells into hepatocytes. Author(s): Choi D, Oh HJ, Chang UJ, Koo SK, Jiang JX, Hwang SY, Lee JD, Yeoh GC, Shin HS, Lee JS, Oh B. Source: Cell Transplantation. 2002; 11(4): 359-68. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12162376&dopt=Abstract
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Influence of mobilized stem cells on myocardial infarct repair in a nonhuman primate model. Author(s): Norol F, Merlet P, Isnard R, Sebillon P, Bonnet N, Cailliot C, Carrion C, Ribeiro M, Charlotte F, Pradeau P, Mayol JF, Peinnequin A, Drouet M, Safsafi K, Vernant JP, Herodin F. Source: Blood. 2003 December 15; 102(13): 4361-8. Epub 2003 August 28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12947003&dopt=Abstract
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Isolation and culture of umbilical vein mesenchymal stem cells. Author(s): Covas DT, Siufi JL, Silva AR, Orellana MD. Source: Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas / Sociedade Brasileira De Biofisica. [et Al.]. 2003 September; 36(9): 1179-83. Epub 2003 August 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12937783&dopt=Abstract
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Labeling embryonic stem cells with enhanced green fluorescent protein on the hypoxanthineguanine phosphoribosyl transferase locus. Author(s): Teng L, Meng G, Xing Y, Shang K, Wang X, Gu J. Source: Chinese Medical Journal. 2003 February; 116(2): 267-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12775245&dopt=Abstract
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Large-scale expansion of mammalian neural stem cells: a review. Author(s): Kallos MS, Sen A, Behie LA. Source: Medical & Biological Engineering & Computing. 2003 May; 41(3): 271-82. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12803291&dopt=Abstract
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Mechanism of stem cells in the central nervous system. Author(s): Johansson CB. Source: Journal of Cellular Physiology. 2003 September; 196(3): 409-18. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12891698&dopt=Abstract
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Mesenchymal stem cells and hematopoietic stem cell transplantation. Author(s): Fibbe WE, Noort WA. Source: Annals of the New York Academy of Sciences. 2003 May; 996: 235-44. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799302&dopt=Abstract
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Neural differentiation of mouse embryonic stem cells grown in monolayer. Author(s): Pachernik J, Esner M, Bryja V, Dvorak P, Hampl A. Source: Reproduction, Nutrition, Development. 2002 July-August; 42(4): 317-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12510873&dopt=Abstract
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Neural induction, neural fate stabilization, and neural stem cells. Author(s): Moody SA, Je HS. Source: Scientificworldjournal. 2002 April 28; 2(4): 1147-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12805974&dopt=Abstract
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Neuronal generation from somatic stem cells: current knowledge and perspectives on the treatment of acquired and degenerative central nervous system disorders. Author(s): Corti S, Locatelli F, Strazzer S, Guglieri M, Comi GP. Source: Current Gene Therapy. 2003 June; 3(3): 247-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12762483&dopt=Abstract
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New frontiers in gene targeting and cloning: success, application and challenges in domestic animals and human embryonic stem cells. Author(s): Denning C, Priddle H. Source: Reproduction (Cambridge, England). 2003 July; 126(1): 1-11. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814342&dopt=Abstract
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Nonhuman primate parthenogenetic stem cells. Author(s): Vrana KE, Hipp JD, Goss AM, McCool BA, Riddle DR, Walker SJ, Wettstein PJ, Studer LP, Tabar V, Cunniff K, Chapman K, Vilner L, West MD, Grant KA, Cibelli JB. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 September 30; 100 Suppl 1: 11911-6. Epub 2003 Sep 22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14504386&dopt=Abstract
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Nuclear transplantation, embryonic stem cells, and the potential for cell therapy. Author(s): Hochedlinger K, Jaenisch R.
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Source: The New England Journal of Medicine. 2003 July 17; 349(3): 275-86. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12867612&dopt=Abstract •
Pilot evaluation of high-dose carboplatin and paclitaxel followed by high-dose melphalan supported by peripheral blood stem cells in previously untreated advanced ovarian cancer: a gynecologic oncology group study. Author(s): Schilder RJ, Brady MF, Spriggs D, Shea T. Source: Gynecologic Oncology. 2003 January; 88(1): 3-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12504619&dopt=Abstract
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Pluripotent stem cells--model of embryonic development, tool for gene targeting, and basis of cell therapy. Author(s): Prelle K, Zink N, Wolf E. Source: Anatomia, Histologia, Embryologia. 2002 June; 31(3): 169-86. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12479360&dopt=Abstract
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Self-renewal and lineage restriction of hematopoietic stem cells. Author(s): Ema H, Nakauchi H. Source: Current Opinion in Genetics & Development. 2003 October; 13(5): 508-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14550417&dopt=Abstract
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Stem cells and cardiovascular disease. Author(s): Abbott JD, Giordano FJ. Source: Journal of Nuclear Cardiology : Official Publication of the American Society of Nuclear Cardiology. 2003 July-August; 10(4): 403-12. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12900745&dopt=Abstract
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Stem cells and regenerative medicine. Author(s): Hirai H. Source: Hum Cell. 2002 December; 15(4): 190-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12889854&dopt=Abstract
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Stem cells for cell therapy in Parkinson's disease. Author(s): Lindvall O. Source: Pharmacological Research : the Official Journal of the Italian Pharmacological Society. 2003 April; 47(4): 279-87. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12644384&dopt=Abstract
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Stem cells for the heart, are we there yet? Author(s): Timmermans F, De Sutter J, Gillebert TC.
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Source: Cardiology. 2003; 100(4): 176-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14713729&dopt=Abstract •
Stem cells in the treatment of amyotrophic lateral sclerosis (ALS). Author(s): Silani V, Fogh I, Ratti A, Sassone J, Ciammola A, Cova L. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. 2002 December; 3(4): 173-81. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12710505&dopt=Abstract
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Stem cells: articles of faith adulterated. Author(s): Pearson H. Source: Nature. 2002 December 19-26; 420(6917): 734-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12490909&dopt=Abstract
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The profile of gene expression of human marrow mesenchymal stem cells. Author(s): Silva WA Jr, Covas DT, Panepucci RA, Proto-Siqueira R, Siufi JL, Zanette DL, Santos AR, Zago MA. Source: Stem Cells (Dayton, Ohio). 2003; 21(6): 661-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14595126&dopt=Abstract
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The role of stem cells for treatment of cardiovascular disease. Author(s): Lovell MJ, Mathur A. Source: Cell Proliferation. 2004 February; 37(1): 67-87. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14871238&dopt=Abstract
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The role of stem cells in the evolution of longevity and its application to tissue therapy. Author(s): Roccanova L, Ramphal P. Source: Tissue & Cell. 2003 February; 35(1): 79-81. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12589732&dopt=Abstract
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The tao of hematopoietic stem cells: toward a unified theory of tissue regeneration. Author(s): Bunting KD, Hawley RG. Source: Scientificworldjournal. 2002 April 10; 2(4): 983-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12805953&dopt=Abstract
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Toward full restoration of synaptic and terminal function of the dopaminergic system in Parkinson's disease by stem cells. Author(s): Isacson O, Bjorklund LM, Schumacher JM.
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Source: Annals of Neurology. 2003; 53 Suppl 3: S135-46; Discussion S146-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12666105&dopt=Abstract
Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •
Alternative Medicine Foundation, Inc.: http://www.herbmed.org/
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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats
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Chinese Medicine: http://www.newcenturynutrition.com/
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drkoop.com: http://www.drkoop.com/InteractiveMedicine/IndexC.html
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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm
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Google: http://directory.google.com/Top/Health/Alternative/
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Healthnotes: http://www.healthnotes.com/
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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine
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Open Directory Project: http://dmoz.org/Health/Alternative/
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HealthGate: http://www.tnp.com/
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WebMDHealth: http://my.webmd.com/drugs_and_herbs
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/
The following is a specific Web list relating to stem cells; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •
General Overview Bone Marrow Disorders Source: Integrative Medicine Communications; www.drkoop.com Chronic Myelogenous Leukemia Source: Integrative Medicine Communications; www.drkoop.com Epstein-Barr Virus Source: Integrative Medicine Communications; www.drkoop.com Lymphoma Source: Integrative Medicine Communications; www.drkoop.com
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Mononucleosis Source: Integrative Medicine Communications; www.drkoop.com Myelofibrosis Source: Integrative Medicine Communications; www.drkoop.com Myeloproliferative Disorders Source: Integrative Medicine Communications; www.drkoop.com Polycythemia Vera Source: Integrative Medicine Communications; www.drkoop.com Thrombocytosis Source: Integrative Medicine Communications; www.drkoop.com •
Herbs and Supplements Ashwagandha Alternative names: Withania somniferum Source: Healthnotes, Inc.; www.healthnotes.com Barberry Alternative names: Berberis vulgaris Source: Healthnotes, Inc.; www.healthnotes.com Echinacea Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,775,00.html Histidine Source: Healthnotes, Inc.; www.healthnotes.com Mistletoe Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10109,00.html Thymus Alternative names: Thyme; Thymus vulgaris Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Withania Ashwagandha Alternative names: Ashwagandha; Withania somnifera L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org
General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page
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dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.
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CHAPTER 4. DISSERTATIONS ON STEM CELLS Overview In this chapter, we will give you a bibliography on recent dissertations relating to stem cells. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “stem cells” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on stem cells, we have not necessarily excluded non-medical dissertations in this bibliography.
Dissertations on Stem Cells ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to stem cells. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •
A Study of Human Homologs of Selected Drosophila Genes in Human Mammary Ductal Carcinoma, Asymmetric Cell Division of Human Neural Stem Cells and a Multiplex Microsphere Bead Assay for Comparative RNA Expression Analysis by Fuja, Tannin J., PhD from University of California, Irvine, 2003, 159 pages http://wwwlib.umi.com/dissertations/fullcit/3090268
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Characterization of the Gene for the Calcitonin Gene-Related Peptide (CGRP) Receptor Component Protein (RCP), and Generation of RCP +/- Embryonic Stem Cells by Mnayer, Laila Omar, PhD from University of Miami, 2003, 145 pages http://wwwlib.umi.com/dissertations/fullcit/3090859
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Cloning, Stem Cells and Epigenetic Reprogramming after Nuclear Transfer by Eggan, Kevin C., PhD from Massachusetts Institute of Technology, 2003 http://wwwlib.umi.com/dissertations/fullcit/f43425
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Cytological Studies of Potential of Hemopoietic Stem Cells for Differentiation by Wu, Alan Ming-Ta; AdvDeg from University of Toronto (Canada), 1968 http://wwwlib.umi.com/dissertations/fullcit/NK03347
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Effects of Surface-Immobilized Stem Cell Factor on the Differentiation and Proliferation of Hematopoietic Cells by Chow, Dominic Cheuk-Ming, PhD from Northwestern University, 2003, 231 pages http://wwwlib.umi.com/dissertations/fullcit/3087898
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Evaluating Hydroxyapatite Microcarriers for the Attachment, Proliferation, and Osteoblastic Differentiation of Human Adult Stem Cells and a Human Osteosarcoma Cell Line by Loveland, Amy N., MS from Duquesne University, 2003, 63 pages http://wwwlib.umi.com/dissertations/fullcit/1415304
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I. Expression of IGF-II and IGFBPS in Developing Fetal Rhesus Monkey (Macaca mulatta) Tissues. II. Characterization of Fetal Rhesus Monkey Hematopoietic and Mesenchymal Stem Cells by Lee, Chang Il, PhD from University of California, Davis, 2003, 164 pages http://wwwlib.umi.com/dissertations/fullcit/3097448
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Identification and Characterization of Stem Cell-Like SP Cells in the Post-Natal Myocardium by Hierlihy, Andree Michele, MSC from University of Ottawa (Canada), 2003, 87 pages http://wwwlib.umi.com/dissertations/fullcit/MQ79347
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Integrin-Mediated Adhesion of Human Mesenchymal Stem Cells to Hard-Tissue Implant Biomaterials by Kilpadi, Krista Lyn, PhD from The University of Alabama at Birmingham, 2003, 133 pages http://wwwlib.umi.com/dissertations/fullcit/3101493
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Lineage Analysis of Hematopoietic Stem Cells by Wu, Dong-dong; PhD from University of Toronto (Canada), 1990 http://wwwlib.umi.com/dissertations/fullcit/NL56915
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Mechanisms and Mediators of Hematopoietic Stem Cell Fate by Christensen, Julie Lynne, PhD from Stanford University, 2003, 197 pages http://wwwlib.umi.com/dissertations/fullcit/3085269
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Neural Progenitor Genes: Germinal Zone Expression and the Analysis of an Overlapping Stem Cell Genetic Program by Easterday, Mathew Carl, PhD from University of California, Los Angeles, 2003, 110 pages http://wwwlib.umi.com/dissertations/fullcit/3089002
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Physical Characterization of Hemopoietic Stem Cells by Worton, Ronald G; AdvDeg from University of Toronto (Canada), 1969 http://wwwlib.umi.com/dissertations/fullcit/NK04514
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Quantitative Analyses of Embryonic Stem Cell Fate Responses to Cytokine Supplementation: Mechanisms of LIF-Mediated Regulation by Viswanathan, Sowmya, PhD from University of Toronto (Canada), 2003, 185 pages http://wwwlib.umi.com/dissertations/fullcit/NQ78304
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Restriction of Cell Fates of Neural Stem Cells: How FGF-2 Modifies Chromatin to Regulate Glial-Specific Gene Expression by Song, Mi-Ryoung, PhD from The Johns Hopkins University, 2003, 107 pages http://wwwlib.umi.com/dissertations/fullcit/3080769
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Stem Cell Competition for Somatic and Germ Line Niches in the Protochordate Botryllus Schlosseri by Laird, Diana Jean, PhD from Stanford University, 2003, 144 pages http://wwwlib.umi.com/dissertations/fullcit/3085203
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The Growth and Differentiation of Hemopoietic Stem Cells in Cell Culture by Sutherland, Donald James Alan; PhD from University of Toronto (Canada), 1971 http://wwwlib.umi.com/dissertations/fullcit/NK12226
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Transduction of Hematopoietic Stem Cells Using Lentiviral Vectors in Models of Drug Resistance Gene Therapy: Determinants of Transduction and Selection by Zielske, Steven Paul, PhD from Case Western Reserve University (Health Sciences), 2003, 153 pages http://wwwlib.umi.com/dissertations/fullcit/3100026
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United States Human Stem Cell Policy Making by Fassi, Carolyn Rose, DPA from University of Southern California, 2002, 229 pages http://wwwlib.umi.com/dissertations/fullcit/3073774
Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.
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CHAPTER 5. CLINICAL TRIALS AND STEM CELLS Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning stem cells.
Recent Trials on Stem Cells The following is a list of recent trials dedicated to stem cells.8 Further information on a trial is available at the Web site indicated. •
Alemtuzumab Plus Peripheral Stem Cell Transplantation in Treating Patients With Chronic Lymphocytic Leukemia Condition(s): stage III chronic lymphocytic leukemia; stage IV chronic lymphocytic leukemia; B-cell Chronic Lymphocytic Leukemia; stage I chronic lymphocytic leukemia; stage II chronic lymphocytic leukemia Study Status: This study is currently recruiting patients. Sponsor(s): Eastern Cooperative Oncology Group; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Monoclonal antibodies such as alemtuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Peripheral stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy or radiation therapy. Combining monoclonal antibody therapy, chemotherapy, radiation therapy, and peripheral stem cell transplantation may kill more tumor cells. PURPOSE: Phase II trial to study the effectiveness of alemtuzumab plus peripheral stem cell transplantation in treating patients who have chronic lymphocytic leukemia. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006390
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These are listed at www.ClinicalTrials.gov.
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Allogeneic Peripheral Stem Cell Transplantation After Antithymocyte Globulin, High-Dose Melphalan, and Fludarabine in Treating Women With Metastatic Adenocarcinoma of the Breast Condition(s): recurrent breast cancer; stage IV breast cancer Study Status: This study is currently recruiting patients. Sponsor(s): UCSD Cancer Center; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Donor peripheral stem cell transplantation may be an effective treatment for breast cancer that has not responded to previous chemotherapy or has spread to the bone marrow. Combining antithymocyte globulin with melphalan and fludarabine before transplantation may reduce the chance of developing graftversus-host disease. PURPOSE: Phase IIpilot study of allogeneic peripheral stem cell transplantation after antithymocyte globulin, high-dose melphalan, and fludarabine in treating women who have metastaticadenocarcinoma of the breast. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00074269
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Chemoradiotherapy and Peripheral Stem Cell Transplantation Compared With Combination Chemotherapy in Treating Patients With Non-Hodgkin's Lymphoma Condition(s): adult Burkitt's lymphoma; adult diffuse large cell lymphoma; adult diffuse mixed cell lymphoma; adult diffuse small cleaved cell lymphoma; adult immunoblastic large cell lymphoma; grade 3 follicular lymphoma Study Status: This study is currently recruiting patients. Sponsor(s): Southwest Oncology Group; National Cancer Institute (NCI); Cancer and Leukemia Group B; Eastern Cooperative Oncology Group; National Cancer Institute of Canada Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage cancer cells. Peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy and radiation and kill more cancer cells. It is not yet known whether chemoradiotherapy plus peripheral stem cell transplantation is more effective than combination chemotherapy alone in treating nonHodgkin's lymphoma. PURPOSE: Randomizedphase III trial to compare the effectiveness of chemoradiotherapy plus peripheral stem cell transplantation with combination chemotherapy in treating patients who have stage II, stage III, or stage IV non-Hodgkin's lymphoma. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004031
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Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients With Myelodysplastic Syndrome Condition(s): Refractory Anemia; refractory anemia with ringed sideroblasts; de novo myelodysplastic syndromes; previously treated myelodysplastic syndromes; secondary myelodysplastic syndromes Study Status: This study is currently recruiting patients. Sponsor(s): Fred Hutchinson Cancer Research Center; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Peripheral stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy. PURPOSE: Phase II trial to study the effectiveness of chemotherapy followed by peripheral stem cell transplantation in treating patients who have myelodysplastic syndrome. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00024050
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Chemotherapy and Peripheral Stem Cell Transplantation With or Without Monoclonal Antibody Therapy in Treating Patients With Non-Hodgkin's Lymphoma Condition(s): recurrent grade 3 follicular lymphoma; recurrent adult diffuse large cell lymphoma Study Status: This study is currently recruiting patients. Sponsor(s): Commissie Voor Klinisch Toegepast Onderzoek Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Peripheral stem cell transplantation may be able to replace immune cells that were destroyed by the chemotherapy. Monoclonal antibodies can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. It is not yet known if combination chemotherapy plus peripheral stem cell transplantation is more effective with or without monoclonal antibody therapy in treating non-Hodgkin's lymphoma. PURPOSE: Randomizedphase III trial to compare the effectiveness of combination chemotherapy plus peripheral stem cell transplantation with or without monoclonal antibody therapy in treating patients who have relapsed non-Hodgkin's lymphoma. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00012051
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Chemotherapy Followed by Peripheral Stem Cell or Bone Marrow Transplantation Compared With Chemotherapy Alone in Treating Patients With Small Cell Lung Cancer Condition(s): limited stage small cell lung cancer; extensive stage small cell lung cancer Study Status: This study is currently recruiting patients.
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Sponsor(s): EBMT Solid Tumors Working Party Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation or bone marrow transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. It is not yet known whether high-dose chemotherapy plus peripheral stem cell or bone marrow transplantation is more effective than chemotherapy alone for treating small cell lung cancer. PURPOSE: Randomizedphase III trial to compare the effectiveness of chemotherapy followed by peripheral stem cell or bone marrow transplantation with that of chemotherapy alone in treating patients who have limited-stage or extensivestage small cell lung cancer. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00011921 •
Chemotherapy Followed by Radiation Therapy and Peripheral Stem Cell Transplantation Compared With Chemotherapy Plus Interferon Alfa in Treating Patients With Stage III or Stage IV Mantle Cell Lymphoma Condition(s): stage III mantle cell lymphoma; stage IV mantle cell lymphoma Study Status: This study is currently recruiting patients. Sponsor(s): German Low Grade Lymphoma Study Group; EORTC Lymphoma Cooperative Group; Gruppo Italiano Studio Linfomi; Groupe d'Etudes de Lymphomes de L'Adulte Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage cancer cells. Peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. Interferon alfa may interfere with the growth of cancer cells. It is not yet known whether chemotherapy combined with radiation therapy and peripheral stem cell transplantation is more effective than chemotherapy followed by interferon alfa in treating mantle cell lymphoma. PURPOSE: Randomizedphase III trial to compare the effectiveness of chemotherapy followed by radiation therapy, chemotherapy, and peripheral stem cell transplantation with that of chemotherapy plus interferon alfa in treating patients who have stage III or stage IV mantle cell lymphoma. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00016887
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Chemotherapy, Biological Therapy, and/or Bone Marrow or Peripheral Stem Cell Transplantation in Treating Patients With Chronic Myelogenous Leukemia Condition(s): chronic phase chronic myelogenous leukemia; Philadelphia chromosome positive chronic myelogenous leukemia; Philadelphia chromosome negative chronic myelogenous leukemia; childhood chronic myelogenous leukemia; atypical chronic myeloid leukemia
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Study Status: This study is currently recruiting patients. Sponsor(s): III. Medizinische Klinik Mannheim Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell or bone marrow transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. Interferon alfa may interfere with the growth of cancer cells. It is not yet known if chemotherapy is more effective with or without interferon alfa and/or stem cell or bone marrow transplantation in treating chronic myelogenous leukemia. PURPOSE: Randomizedphase III trial to compare the effectiveness of combination chemotherapy with or without biological therapy and/or stem cell transplantation. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00025402 •
Chemotherapy, Total-Body Irradiation, and Peripheral Stem Cell Transplantation in Treating Older Patients With Acute Myeloid Leukemia Condition(s): adult acute myeloid leukemia in remission Study Status: This study is currently recruiting patients. Sponsor(s): Southwest Oncology Group; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Peripheral stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy and radiation therapy. Sometimes the transplanted cells can make an immune response against the body's normal tissues. Cyclosporine and mycophenolate mofetil may prevent this from happening. PURPOSE: Phase II trial to study the effectiveness of chemotherapy and total-body irradiation followed by donor peripheral stem cell transplantation, cyclosporine, and mycophenolate mofetil in treating older patients who have acute myeloid leukemia. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00053014
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Combination Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients With Neuroblastoma Condition(s): localized resectable neuroblastoma; regional neuroblastoma; disseminated neuroblastoma; stage 4S neuroblastoma; localized unresectable neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): Children's Oncology Group; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. PURPOSE: Randomizedphase III trial to compare the effectiveness of peripheral stem cell transplantation using either treated or
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untreated peripheral stem cells following combination chemotherapy in treating patients who have neuroblastoma. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004188 •
Combination Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients With Relapsed Hodgkin's Lymphoma Condition(s): recurrent adult Hodgkin's lymphoma Study Status: This study is currently recruiting patients. Sponsor(s): German Hodgkin's Lymphoma Study Group; EORTC Lymphoma Cooperative Group; EBMT Solid Tumors Working Party Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Peripheral stem cell transplantation may allow the doctors to give higher doses of chemotherapy drugs and kill more cancer cells. It is not yet known which combination chemotherapyregimen given before peripheral stem cell transplantation is more effective in treating relapsedHodgkin's lymphoma. PURPOSE: Randomizedphase III trial to compare different combination chemotherapy regimens followed by peripheral stem cell transplantation in treating patients who have relapsed Hodgkin's lymphoma. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00025636
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Combination Chemotherapy Plus Peripheral Stem Cell Transplantation in Treating Patients With Newly Diagnosed Aggressive Non-Hodgkin's Lymphoma Condition(s): adult diffuse large cell lymphoma; adult diffuse mixed cell lymphoma; adult immunoblastic large cell lymphoma; anaplastic large cell lymphoma Study Status: This study is currently recruiting patients. Sponsor(s): Swiss Institute for Applied Cancer Research Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining peripheral stem cell transplantation with more than one drug regimen may kill more tumor cells. It is not known whether receiving standard combination chemotherapy alone is more effective than receiving multiple combination chemotherapy plus peripheral stem cell transplantation for aggressivenon-Hodgkin's lymphoma. PURPOSE: Randomizedphase III trial to compare the effectiveness of standard combination chemotherapy alone with that of multiple combination chemotherapy regimens plus peripheral stem cell transplantation in treating patients who have newly diagnosed aggressive nonHodgkin's lymphoma. Phase(s): Phase III Study Type: Interventional
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Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00003215 •
Combination Chemotherapy Plus Peripheral Stem Cell Transplantation With or Without Rituximab in Treating Patients With Relapsed Non-Hodgkin's Lymphoma Condition(s): recurrent grade 1 follicular lymphoma; recurrent grade 2 follicular lymphoma; recurrent grade 3 follicular lymphoma Study Status: This study is currently recruiting patients. Sponsor(s): EBMT Solid Tumors Working Party; British National Lymphoma Investigation Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. Monoclonal antibodies such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. It is not yet known if combination chemotherapy plus peripheral stem cell transplantation is more effective with or without rituximab for non-Hodgkin's lymphoma. PURPOSE: Randomizedphase III trial to compare the effectiveness of combination chemotherapy plus peripheral stem cell transplantation with or without rituximab in treating patients who have relapsed non-Hodgkin's lymphoma. Phase(s): Phase III; MedlinePlus consumer health information Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005589
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Combination Chemotherapy With or Without Monoclonal Antibody Therapy Followed by Stem Cell Transplantation in Treating Patients With Acute Myeloid Leukemia Condition(s): adult acute monocytic leukemia; adult acute myeloid leukemia Study Status: This study is currently recruiting patients. Sponsor(s): Eastern Cooperative Oncology Group; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Combining chemotherapy and monoclonal antibody therapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. It is not yet known whether combination chemotherapy is more effective with or without gemtuzumab ozogamicin followed by peripheral stem cell transplantation in treating acute myeloid leukemia. PURPOSE: Randomizedphase III trial to determine the effectiveness of combination chemotherapy with or without gemtuzumab ozogamicin followed by peripheral stem cell transplantation in treating patients who have acute myeloid leukemia. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below
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Web Site: http://clinicaltrials.gov/ct/show/NCT00049517 •
Combination Chemotherapy With or Without Peripheral Stem Cell Transplantation in Treating Men With Previously Untreated Germ Cell Cancer Condition(s): bone metastases; brain metastases; liver metastases; Mediastinal Cancer; Testicular Cancer Study Status: This study is currently recruiting patients. Sponsor(s): EORTC Genito-Urinary Tract Cancer Cooperative Group Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug may kill more cancer cells. Peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy and kill more tumor cells. It is not yet known whether chemotherapy plus peripheral stem cell transplantation is more effective than chemotherapy alone. PURPOSE: Randomizedphase III trial to compare the effectiveness of combination chemotherapy with or without peripheral stem cell transplantation in treating men who have previously untreated germ cell cancer. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00003941
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Cyclophosphamide With or Without Rituximab and Peripheral Stem Cell Transplantation in Treating Patients With Recurrent Non-Hodgkin's Lymphoma Condition(s): adult non-Hodgkin's lymphoma Study Status: This study is currently recruiting patients. Sponsor(s): Ireland Cancer Center; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Monoclonal antibodies such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. It is not yet known if combining rituximab with cyclophosphamide is more effective than cyclophosphamide alone in stimulating peripheral stem cells for transplantation. PURPOSE: Randomizedphase II trial to compare the effectiveness of cyclophosphamide with or without rituximab followed by chemotherapy and peripheral stem cell transplantation in treating patients who have recurrentnon-Hodgkin's lymphoma. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00028665
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Donor Stem Cell Transplantation in Treating Patients With Hematologic Cancer Condition(s): childhood non-Hodgkin's lymphoma; myelodysplastic and myeloproliferative diseases
Leukemia;
Lymphoma;
Study Status: This study is currently recruiting patients. Sponsor(s): Ireland Cancer Center; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage cancer cells. Combining chemotherapy and radiation therapy with donor stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and radiation to kill more cancer cells. PURPOSE: Phase II trial to study the effectiveness of chemotherapy with or without radiation therapy followed by donor stem cell transplantation in treating patients who have hematologic cancer. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00054327 •
Donor Stem Cell Transplantation in Treating Patients With Relapsed Hematologic Cancer Condition(s): childhood Hodgkin's lymphoma; childhood non-Hodgkin's lymphoma; Leukemia; Lymphoma; myelodysplastic and myeloproliferative diseases; plasma cell neoplasm Study Status: This study is currently recruiting patients. Sponsor(s): Cancer and Leukemia Group B; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Bone marrow or peripheral stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy or radiation therapy. PURPOSE: Phase II trial to study the effectiveness of donor bone marrow or peripheral stem cell transplantation in treating patients who have relapsedhematologic cancer after treatment with chemotherapy and autologousstem cell transplantation. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00053196
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Donor Stem Cell Transplantation With or Without Chemotherapy in Treating Children With Primary Myelodysplastic Syndrome Condition(s): atypical chronic myeloid leukemia; Chronic Myelomonocytic Leukemia; juvenile myelomonocytic leukemia; myelodysplastic and myeloproliferative disease; Myelodysplastic Syndromes Study Status: This study is currently recruiting patients. Sponsor(s): European Working Group of MDS in Childhood Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with stem cell transplantation may allow the doctor to give higher doses of
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chemotherapy drugs and kill more tumor cells. It is not yet known if donor stem cell transplantation is more effective with or without chemotherapy in treating myelodysplastic syndrome. PURPOSE: Phase III trial to determine the effectiveness of donor stem cell transplantation with or without chemotherapy in treating children who have primary myelodysplastic syndrome. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00047268 •
Filgrastim-Mobilized Peripheral Stem Cell Transplantation Compared With Bone Marrow Transplantation From Compatible Unrelated Donors in Treating Patients With Hematologic Malignancies Condition(s): acute leukemia; chronic leukemia; chronic myeloproliferative disorders; myelodysplastic and myeloproliferative disease Study Status: This study is currently recruiting patients. Sponsor(s): Blood and Marrow Transplant Clinical Trials Network; National Heart, Lung, and Blood Institute (NHLBI); National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Colony-stimulating factors, such as filgrastim, stimulate the production of blood cells. Peripheral stem cell transplantation or bone marrow transplantation may be able to replace immune cells that were destroyed by chemotherapy used to kill cancer cells. Giving filgrastim to stimulate peripheral stem cells that can be collected for peripheral stem cell transplant may result in fewer side effects after the transplant. Sometimes the transplanted cells from a donor can be rejected by the body's tissues. Methotrexate and cyclosporine or tacrolimus may prevent this from happening. It is not yet known whether filgrastim-mobilized donor peripheral stem cell transplantation is more effective than donor bone marrow transplantation in treating hematologic malignancies. PURPOSE: Randomizedphase III trial to compare the effectiveness of filgrastim-mobilized donor peripheral stem cell transplantation with that of donor bone marrow transplantation in treating patients who have hematologic cancer. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00075816
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Filgrastim-Mobilized Stem Cells for Transplantation Using Unrelated Donors Condition(s): Hematopoietic Stem Cell Mobilization Study Status: This study is currently recruiting patients. Sponsor(s): Warren G Magnuson Clinical Center (CC) Purpose - Excerpt: This study will test whether stem cells collected from the bloodstream (peripheral blood stem cells) can be used instead of cells collected from bone marrow for unrelated donor transplantation. Stem cells are cells produced by the bone marrow that mature into the various blood components-white and red blood cells and platelets. Unlike bone marrow, the bloodstream contains few stem cells. Therefore,
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donors are given G-CSF (also called filgrastim)-a growth factor naturally produced by the body-before cell collection. G-CSF boosts bone marrow production of stem cells and mobilizes them to enter the bloodstream, allowing enough cells to be collected for transplantation. G-CSF-mobilized blood stem cells are often used for transplantation in recipients who are related to their donors. This study will evaluate a system for using this same method in unrelated donors and recipients. The Food and Drug Administration has approved G-CSF for several uses, including collection of blood stem cells from patients who are receiving transplants of their own stem cells; for patients with cancer who are receiving chemotherapy; patients who are getting bone marrow transplants; and patients with diseases that cause very low white blood cells counts. Individuals matched by the National Marrow Donor Program with a potential recipient for blood stem cell donation are eligible for this study. Participants will receive oral and written information about all the procedures involved in both bone marrow and peripheral blood stem cell collection, from donor evaluation and testing through postdonation followup. They will then have a medical examination, including blood tests and urinalysis, electrocardiogram and chest X-ray, to make sure that neither the donor nor the recipient will incur unexpected risks from the procedure. If the evaluation confirms that the donation can proceed, the donor will receive G-CSF injections under the skin once a day for 4 or 5 days. Blood samples (1/2 to 1 tablespoon each) will be collected on the first and fourth days of G-CSF injections to measure blood cell counts. Stem cells will then be collected by a procedure called apheresis. The donor lies in a recliner chair, and a needle is placed in a vein in each arm. Blood is collected from one arm and passes through a special machine called a blood cell separator. The machine collects the stem cells in a bag and directs the rest of the blood back through the needle in the other arm. One or two donations will be needed, depending on the size of the recipient and the number of stem cells circulating in the donor's bloodstream. Each donation takes about 4 to 5 hours. One-half tablespoon of blood is drawn before and after each donation to measure blood cell counts. Two days after donation and again one week after donation, donors will be questioned about any symptoms the may experience. Another blood sample (1/2 tablespoon) will be collected 1 month after cell donation and then yearly for an indefinite number of years to measure cell counts. Phase(s): Phase III; MedlinePlus consumer health information Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005930 •
Fludarabine and Cyclophosphamide Followed by Peripheral Transplantation in Treating Patients With Leukemia or Lymphoma
Stem
Cell
Condition(s): adult non-Hodgkin's lymphoma; Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia Study Status: This study is currently recruiting patients. Sponsor(s): Cancer and Leukemia Group B; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Peripheral stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy. PURPOSE: Phase II trial to study the effectiveness of fludarabine and cyclophosphamide followed by peripheral stem cell transplantation in treating patients who have leukemia or lymphoma.
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Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006252 •
Fludarabine and Total-Body Irradiation Followed By Donor Peripheral Stem Cell Transplantation in Treating Patients With Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia That Has Responded to Treatment With Imatinib Mesylate Condition(s): recurrent childhood acute lymphoblastic leukemia; recurrent adult acute lymphoblastic leukemia; blastic phase chronic myelogenous leukemia; Philadelphia chromosome positive chronic myelogenous leukemia; childhood chronic myelogenous leukemia Study Status: This study is currently recruiting patients. Sponsor(s): Fred Hutchinson Cancer Research Center; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Imatinib mesylate may stop the growth of cancer cells by blocking the enzymes necessary for cancer cell growth. Peripheral stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy and radiation therapy used to kill cancer cells. Combining imatinib mesylate with fludarabine and total-body irradiation followed by donor peripheral stem cell transplantation may kill more cancer cells. PURPOSE: Phase II trial to study the effectiveness of fludarabine and total-body irradiation followed by donor peripheral stem cell transplantation in treating patients who have acute lymphoblastic leukemia or chronic myelogenous leukemia that has responded to previous treatment with imatinib mesylate. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00036738
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Fludarabine, Cyclophosphamide, and Alemtuzumab in Treating Patients With Recurrent or Metastatic Renal Cell Carcinoma (Kidney Cancer) Undergoing Allogeneic Stem Cell Transplantation Condition(s): stage IV renal cell cancer; recurrent renal cell cancer Study Status: This study is currently recruiting patients. Sponsor(s): Baylor College of Medicine Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy, such as fludarabine and cyclophosphamide, use different ways to stop cancer cells from dividing so they stop growing or die. Peripheral stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy. Sometimes the transplanted cells can reject the body's normal tissues. Alemtuzumab and tacrolimus may prevent this from happening. PURPOSE: Phase II trial to study the effectiveness of combining fludarabine and cyclophosphamide with alemtuzumab in treating patients who are undergoing allogeneic stem cell transplantation for recurrent or metastaticrenal cell carcinoma (kidney cancer). Phase(s): Phase II
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Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00073879 •
Immunotherapy Using Cyclosporine, Interferon gamma, and Interleukin-2 After High-Dose Myeloablative Chemotherapy With Autologous Stem Cell Transplantation in Treating Patients With Refractory or Relapsed Hodgkin's Lymphoma Condition(s): recurrent adult Hodgkin's lymphoma; recurrent/refractory childhood Hodgkin's lymphoma Study Status: This study is currently recruiting patients. Sponsor(s): Children's Oncology Group; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with autologous stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. Giving immunotherapy using cyclosporine, interferon gamma, and interleukin-2 after stem cell transplantation may help the transplanted cells kill more cancer cells. It is not yet known whether high-dose chemotherapy followed by autologous stem cell transplantation is more effective with or without immunotherapy. PURPOSE: Randomizedphase II/III trial to compare the effectiveness of high-dose chemotherapy followed by autologous stem cell transplantation with or without immunotherapy using cyclosporine, interferon gamma, and interleukin-2 in treating patients who have refractory or relapsedHodgkin's lymphoma. Phase(s): Phase II; Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00070187
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Low-Dose Chemotherapy and Radiation Therapy Before Allogeneic Stem Cell Transplantation in Treating Patients With Refractory Chronic Lymphocytic Leukemia Condition(s): refractory chronic lymphocytic leukemia Study Status: This study is currently recruiting patients. Sponsor(s): Fred Hutchinson Cancer Research Center; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Fludarabine may suppress the immune system and reduce the chance of developing graft-versus-host disease following allogeneic stem cell transplantation. Combining fludarabine with total-body irradiation may be effective in killing cancer cells before stem cell transplantation. PURPOSE: Phase II trial to study the effectiveness of low-dose fludarabine and total-body irradiation before allogeneic stem cell transplantation in treating patients who have refractorychronic lymphocytic leukemia. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00060424
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Peripheral Stem Cell Transplantation in Treating Patients With Multiple Myeloma Condition(s): refractory plasma cell neoplasm; stage I multiple myeloma; stage II multiple myeloma; stage III multiple myeloma Study Status: This study is currently recruiting patients. Sponsor(s): Cancer and Leukemia Group B; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Peripheral stem cell transplantation may be able to replace immune cells that were destroyed by the chemotherapy or radiation therapy used to kill tumor cells. PURPOSE: Phase II trial to study the effectiveness of autologous peripheral stem cell transplantation followed by donor peripheral stem cell transplantation in treating patients who have multiple myeloma. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00028600
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Peripheral Stem Cell Transplantation Plus Monoclonal Antibody Therapy in Treating Patients With High-Risk Hematologic Cancer, Refractory Breast or Kidney Cancer, or Melanoma Condition(s): Breast Cancer; hematopoietic and lymphoid cancer; kidney and urinary cancer; skin tumor Study Status: This study is currently recruiting patients. Sponsor(s): Duke Comprehensive Cancer Center; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Peripheral stem cell transplantation replaces immune cells that were destroyed by chemotherapy used to kill tumor cells. Sometimes the transplanted cells can make an immune response against the body's normal tissues. Treatment of the cells with a monoclonal antibody may prevent this from happening. PURPOSE: Phase II trial to study the effectiveness of peripheral stem cell transplantation plus monoclonal antibody therapy in treating patients who have highrisk hematologic cancer, refractory breast or kidney cancer, or melanoma. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004143
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Radiolabeled Monoclonal Antibody Therapy Combined With Total-body Irradiation, Allogeneic Peripheral Stem Cell Transplantation, and Immunosuppression Therapy in Treating Older Patients Who Have Advanced Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Condition(s): adult acute myeloid leukemia; atypical chronic myeloid leukemia; Chronic Myelomonocytic Leukemia; Graft Versus Host Disease; Myelodysplastic Syndromes Study Status: This study is currently recruiting patients. Sponsor(s): Fred Hutchinson Cancer Research Center; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Monoclonal antibodies can locate cancer cells and either kill them or deliver radioactive cancer-killing substances to them without
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harming normal cells. Peripheral stem cell transplantation may be able to replace immune cells that were destroyed by radiation therapy used to kill cancer cells. Sometimes the transplanted cells can make an immune response against the body's normal tissues. Treatment with cyclosporine may prevent this from happening. PURPOSE: Phase I trial to study the effectiveness of radiolabeled monoclonal antibody therapy combined with total-body irradiation, allogeneic peripheral stem cell transplantation, and immunosuppression therapy in treating older patients who have advanced acute myeloid leukemia, myelodysplastic syndrome, or chronic myelomonocytic leukemia. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00008177 •
Stem Cell Transplantation With or Without Rituximab in Treating Patients With Relapsed or Progressive Large Cell Lymphoma Condition(s): recurrent adult diffuse large cell lymphoma Study Status: This study is currently recruiting patients. Sponsor(s): Eastern Cooperative Oncology Group; National Cancer Institute (NCI); Cancer and Leukemia Group B Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. Monoclonal antibodies such as rituximab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. It is not yet known if stem cell transplantation is more effective with or without rituximab in treating relapsed or progressiveB-cell diffuse large cell lymphoma. PURPOSE: Randomizedphase III trial to compare the effectiveness of stem cell transplantation with or without rituximab in treating patients who have relapsed or progressive B-cell diffuse large cell lymphoma. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00052923
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Study of Gelonin Purging of Autologous Stem Cells for Transplantation Condition(s): Acute Myelogenous Leukemia; Myelodysplastic Syndrome Study Status: This study is currently recruiting patients. Sponsor(s): M.D. Anderson Cancer Center Purpose - Excerpt: Patients with Acute Myelogenous Leukemia or Myelodysplastic are able to achieve a complete remission but fail to achieve a prolonged disease-free survival. High dose chemotherapy and autologous bone marrow transplantation has been shown to be effective in this group of patients but hematopoietic recovery is slow, and infectious or bleeding complications are common. The delay in hematopoietic recover is accentuated by the use of purging techniques. This is a novel purging
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approach for autologous stem cell transplantation in patients with Acute Myelogenous Leukemia or Myelodysplastic syndrome to allow for rapid engraftment with a lower relapse rate therefore improving the therapeutic outcomes Phase(s): Phase I; Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00043810 •
Study of Peripheral Stem Cell Transplantation After Chemotherapy and Radiation Therapy in Treating Patients With Metastatic Kidney Cancer Condition(s): stage IV renal cell cancer Study Status: This study is currently recruiting patients. Sponsor(s): Fred Hutchinson Cancer Research Center; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Peripheral stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy or radiation therapy used to kill tumor cells. Donor white blood cellinfusions may decrease the body's immune response to transplanted peripheral stem cells. PURPOSE: Phase I/II trial to study the effectiveness of combining chemotherapy, radiation therapy, peripheral stem cell transplantation, and donor white blood cells in treating patients who have metastatickidney cancer. Phase(s): Phase I; Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005851
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Tandem Autologous Stem Cell Transplantation With or Without Maintenance Therapy After the Second Transplantation Compared With Autologous Stem Cell Transplantation Followed By Matched Sibling Allogeneic Stem Cell Transplantation in Patients With Stage II Condition(s): stage II multiple myeloma; stage III multiple myeloma; refractory plasma cell neoplasm Study Status: This study is currently recruiting patients. Sponsor(s): Blood and Marrow Transplant Clinical Trials Network; National Heart, Lung, and Blood Institute (NHLBI); National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy work in different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with autologous peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. Giving maintenance therapy after stem cell transplantation may kill more cancer cells. Peripheral stem cell transplantation from a brother or sister may be able to replace immune cells that were destroyed by chemotherapy. Sometimes the transplanted cells can be rejected by the body's tissues. Cyclosporine, total-body irradiation, and mycophenolate mofetil may prevent this from happening. It is not yet known whether
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autologous stem cell transplantation followed by maintenance therapy is more effective than autologous stem cell transplantation followed by allogeneic stem cell transplantation in treating multiple myeloma. PURPOSE: Randomizedphase III trial to compare the effectiveness of tandem (two) autologous stem cell transplantation with or without maintenance therapy with that of autologous stem cell transplantation followed by matched sibling (brother or sister) allogeneic (donor) stem cell transplantation in treating patients who have stage II or stage III multiple myeloma. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00075829 •
Tandem cycles of high dose chemotherapy followed by stem cell support for ovarian cancer Condition(s): Ovarian Neoplasms Study Status: This study is currently recruiting patients. Sponsor(s): Columbia Presbyterian Medical Center; Bristol-Myers Squibb; SmithKline Beecham Purpose - Excerpt: The patient will receive paclitaxel and carboplatin in high dose before one stem cell infusion. When the patient has recovered sufficiently from this first cycle they will be given high dose topotecan and etopophos in combination and then given a second stem cell infusion. When the patient has recovered sufficiently from this second cycle, they will be given high dose thiotepa and then given a third stem cell infusion. Following these procedures, the doctor will assess several forms of data which are routinely analyzed after high dose chemotherapy, including recovery of marrow function, side effects of the treatment, possible relapse of the cancer, and survival. Phase(s): Phase I; Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00034320
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Thalidomide, Chemotherapy, and Peripheral Stem Cell Transplantation in Treating Patients With Multiple Myeloma Condition(s): stage I multiple myeloma; stage II multiple myeloma; stage III multiple myeloma Study Status: This study is currently recruiting patients. Sponsor(s): Southwest Oncology Group; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Thalidomide may stop the growth of cancer cells by stopping blood flow to the cancer. Drugs used in chemotherapy work in different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. Giving thalidomide before and after peripheral stem cell transplantation may be effective in treating newly diagnosedmultiple myeloma. PURPOSE: Phase II trial to study the effectiveness of
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combining thalidomide with chemotherapy and peripheral stem cell transplantation in treating patients who have newly diagnosed multiple myeloma. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00040937 •
Total-Body Irradiation With Or Without Fludarabine Followed By Allogeneic Hematopoietic Stem Cell Transplantation in Treating Patients With Hematologic Malignancies Condition(s): childhood Hodgkin's lymphoma; childhood non-Hodgkin's lymphoma; Leukemia; Lymphoma; plasma cell neoplasm Study Status: This study is currently recruiting patients. Sponsor(s): Fred Hutchinson Cancer Research Center; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy, such as fludarabine, work in different ways to stop cancer cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage cancer cells. Donor peripheral stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy and radiation therapy. Sometimes the transplanted cells can reject the body's normal tissues. Mycophenolate mofetil and cyclosporine may prevent this from happening. It is not yet known whether total-body irradiation followed by donor stem cell transplantation is more effective with or without fludarabine in treating hematologic malignancies (cancer). PURPOSE: Randomizedphase III trial to study the effectiveness of total-body irradiation with or without fludarabine followed by allogeneichematopoietic stem cell transplantation in treating patients who have hematologic cancer. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00075478
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Ultraviolet-B Light Therapy and Allogeneic Stem Cell Transplantation in Treating Patients With Hematologic Malignancies Condition(s): chronic myeloproliferative disorders; Leukemia; myelodysplastic and myeloproliferative diseases; plasma cell neoplasm
Lymphoma;
Study Status: This study is currently recruiting patients. Sponsor(s): Ireland Cancer Center; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Peripheral stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy. Sometimes the transplanted cells from a donor are rejected by the body's normal cells. Ultraviolet-B light therapy given before and after allogeneic stem cell transplantation may help prevent this from happening. PURPOSE: Clinical trial to study the effectiveness of combining ultraviolet-B light therapy with allogeneic stem cell transplantation in treating patients who have hematologic malignancies. Study Type: Interventional
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Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00068523 •
Chemotherapy and Surgery Followed by Peripheral Stem Cell Transplantation in Treating Patients With Metastatic Neuroblastoma Condition(s): stage 4S neuroblastoma Study Status: This study is no longer recruiting patients. Sponsor(s): United Kingdom Children's Cancer Study Group; Societe Francaise Oncologie Pediatrique Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs to kill more tumor cells. Chemotherapy, given before and after surgery, followed by peripheral stem cell transplantation may be an effective treatment for metastatic neuroblastoma. PURPOSE: Phase II trial to study the effectiveness of chemotherapy, given before and after surgery, followed by peripheral stem cell transplantation in treating patients who have metastatic neuroblastoma. Phase(s): Phase II; MedlinePlus consumer health information Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00024193
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Chemotherapy, Vaccine Therapy, and Peripheral Stem Cell Transplantation in Treating Patients With Newly Diagnosed Multiple Myeloma Condition(s): stage I multiple myeloma; stage II multiple myeloma; stage III multiple myeloma Study Status: This study is no longer recruiting patients. Sponsor(s): Sidney Kimmel Cancer Center; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Vaccines made from a person's cancer cells may make the body build an immune response to kill cancer cells. Peripheral stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy. Combining chemotherapy with vaccine therapy and peripheral stem cell transplantation may be effective in treating multiple myeloma. PURPOSE: Phase I/II trial to study the effectiveness of chemotherapy followed by vaccine therapy and peripheral stem cell transplantation in treating patients who have newly diagnosed multiple myeloma. Phase(s): Phase I; Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00024466
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Combination Chemotherapy With or Without Peripheral Stem Cell Transplantation in Treating Men With Stage III or Stage IV Hodgkin's Disease Condition(s): adult Hodgkin's disease Study Status: This study is no longer recruiting patients. Sponsor(s): National Cancer Institute (NCI); Eastern Cooperative Oncology Group; Cancer and Leukemia Group B; Southwest Oncology Group Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. It is not yet known if combination chemotherapy is more effective with or without peripheral stem cell transplantation in treating Hodgkin's Disease. PURPOSE: Randomized phase III trial to compare the effectiveness of combination chemotherapy with or without peripheral stem cell transplantation in treating men who have stage III or stage IV Hodgkin's disease. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005090
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Combination Chemotherapy, Amifostine, and Peripheral Stem Cell Transplantation in Treating Patients With Stage II, Stage III, or Stage IV Breast Cancer Condition(s): stage IIIB breast cancer; stage IIIA breast cancer; stage IV breast cancer; stage II breast cancer Study Status: This study is no longer recruiting patients. Sponsor(s): National Cancer Institute (NCI); Beckman Research Institute Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. Amifostine may protect normal cells from the side effects of chemotherapy. PURPOSE: Phase II trial to study the effectiveness of combination chemotherapy, amifostine, and peripheral stem cell transplantation in treating patients who have stage II, stage III, or stage IV breast cancer. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00003927
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Comparison of Fludarabine Plus Total-body Irradiation With Combination Chemotherapy Followed by Donor Peripheral Stem Cell Transplantation in Treating Patients With Relapsed Non-Hodgkin's Lymphoma or Chronic Lymphocytic Leukemia Condition(s): Waldenstrom's Macroglobulinemia; refractory chronic lymphocytic leukemia; recurrent grade I follicular small cleaved cell lymphoma; recurrent grade II follicular mixed cell lymphoma; recurrent adult diffuse small cleaved cell lymphoma; recurrent diffuse small lymphocytic/marginal zone lymphoma
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Study Status: This study is no longer recruiting patients. Sponsor(s): Simmons Cancer Center Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Peripheral stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy or radiation therapy. Sometimes the transplanted cells are rejected by the body's normal tissues. Cyclosporine, mycophenolate mofetil, methotrexate, and tacrolimus may prevent this from happening. PURPOSE: Randomized phase II trial to compare the effectiveness of fludarabine plus total-body irradiation with that of combination chemotherapy followed by donor peripheral stem cell transplantation in treating patients who have relapsed non-Hodgkin's lymphoma or chronic lymphocytic leukemia. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00041288 •
Filgrastim-Treated Donor Peripheral Stem Cell Transplantation in Treating Patients With Acute Leukemia Condition(s): adult acute lymphoblastic leukemia in remission; recurrent adult acute myeloid leukemia; acute undifferentiated leukemia; recurrent childhood acute myeloid leukemia; recurrent adult acute lymphoblastic leukemia; secondary acute myeloid leukemia; recurrent childhood acute lymphoblastic leukemia; childhood acute lymphoblastic leukemia in remission Study Status: This study is no longer recruiting patients. Sponsor(s): National Cancer Institute (NCI); Fred Hutchinson Cancer Research Center Purpose - Excerpt: RATIONALE: Transplanted peripheral stem cells can sometimes be rejected by the body's tissues. Treating donor peripheral stem cells with filgrastim may increase the number of donor white blood cells. This may help to decrease the rejection of the transplanted cells in patients receiving them as treatment for acute leukemia. PURPOSE: Phase II trial to study the effectiveness of filgrastim-treated donor peripheral stem cells in treating patients with acute leukemia who are undergoing peripheral stem cell transplantation. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00025545
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Pegfilgrastim Compared With Filgrastim To Increase Peripheral Stem Cells Before Autologous Stem Cell Transplantation in Treating Patients With Lymphoma Condition(s): adult Hodgkin's lymphoma; adult non-Hodgkin's lymphoma; Cutaneous T-Cell Lymphoma Study Status: This study is no longer recruiting patients. Sponsor(s): Jonsson Comprehensive Cancer Center; National Cancer Institute (NCI)
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Purpose - Excerpt: RATIONALE: Colony-stimulating factors such as filgrastim and pegfilgrastim may increase the number of peripheral stem cells that can be collected during leukapheresis. Autologous stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. PURPOSE: Randomized phase II trial to compare the effectiveness of pegfilgrastim with that of filgrastim in increasing the number of peripheral stem cells in patients who are undergoing autologous stem cell transplantation for Hodgkin's lymphoma or non-Hodgkin's lymphoma. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00060229 •
Peripheral Stem Cell Transplantation With Specially Treated Stem Cells in Treating Patients With Non-Hodgkin's Lymphoma or Hodgkin's Disease Condition(s): Hodgkin's Disease; Lymphocytic Lymphoma Study Status: This study is no longer recruiting patients. Sponsor(s): National Cancer Institute (NCI); University of Minnesota Cancer Center Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage cancer cells. Combining chemotherapy and radiation therapy with peripheral stem cell transplantation using specially treated stem cells may allow the doctor to give higher doses of chemotherapy drugs and radiation therapy and kill more cancer cells. PURPOSE: Phase II trial to study the effectiveness of peripheral stem cell transplantation using specially treated stem cells in treating patients who have non-Hodgkin's lymphoma or Hodgkin's disease. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005998
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Rituximab and Combination Chemotherapy Followed by Bone Marrow or Peripheral Stem Cell Transplantation in Treating Patients With Relapsed or Refractory NonHodgkin's Lymphoma Condition(s): recurrent diffuse small lymphocytic/marginal zone lymphoma; recurrent adult diffuse small cleaved cell lymphoma; recurrent grade III follicular large cell lymphoma; recurrent adult immunoblastic large cell lymphoma; recurrent adult diffuse small noncleaved cell/Burkitt's lymphoma; recurrent adult diffuse mixed cell lymphoma; recurrent mantle cell lymphoma; recurrent adult diffuse large cell lymphoma; recurrent grade I follicular small cleaved cell lymphoma; recurrent grade II follicular mixed cell lymphoma Study Status: This study is no longer recruiting patients. Sponsor(s): University of Nebraska Purpose - Excerpt: RATIONALE: Monoclonal antibodies such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without
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harming normal cells. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation or bone marrow transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. PURPOSE: Phase II trial to study the effectiveness of rituximab and combination chemotherapy followed by bone marrow or peripheral stem cell transplantation in treating patients who have relapsed or refractory non-Hodgkin's lymphoma. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00007852 •
Chemotherapy and Filgrastim Followed by Peripheral Stem Cell Transplantation in Treating Patients With Chronic Myelogenous Leukemia Condition(s): accelerated phase chronic myelogenous leukemia; Philadelphia chromosome positive chronic myelogenous leukemia; chronic phase chronic myelogenous leukemia Study Status: This study is suspended. Sponsor(s): University of Minnesota Cancer Center Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. Colony-stimulating factors such as filgrastim may increase the number of immune cells found in bone marrow or peripheral blood and may help a person's immune system recover from the side effects of chemotherapy. PURPOSE: Phase II trial to study the effectiveness of chemotherapy and filgrastim followed by peripheral stem cell transplantation in treating patients who have chronic myelogenous leukemia. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005986
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Chemotherapy Plus Peripheral Stem Cell Transplantation in Treating Patients With Multiple Myeloma Condition(s): refractory plasma cell neoplasm; stage I multiple myeloma; stage II multiple myeloma; stage III multiple myeloma; Graft Versus Host Disease Study Status: This study is suspended. Sponsor(s): Eastern Cooperative Oncology Group; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Peripheral stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy. Sometimes the transplanted cells are rejected by the body's tissues. Peripheral stem cell transplantation with the person's own stem cells followed by donor peripheral stem cell transplantation may prevent this from happening. PURPOSE:
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Phase II trial to study the effectiveness of chemotherapy plus autologous peripheral stem cell transplantation followed by donor peripheral stem cell transplantation in treating patients who have multiple myeloma. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00014508 •
Combination Chemotherapy, Total-Body Irradiation, Peripheral Stem Cell Transplantation, and Lymphocyte Infusion in Treating Patients With Stage IV Melanoma Condition(s): Stage IV Melanoma; Recurrent Melanoma Study Status: This study is completed. Sponsor(s): Fred Hutchinson Cancer Research Center; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Peripheral stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy or radiation therapy. Sometimes the transplanted cells can reject the body's normal tissues. Donor lymphocytes that have been treated in the laboratory may prevent this. PURPOSE: Phase II trial to study the effectiveness of combination chemotherapy, total-body irradiation, peripheral stem cell transplantation, and lymphocyte infusion in treating patients who have stage IV melanoma. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006233
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Stem Cell Factor Medication for Aplastic Anemia Condition(s): Aplastic Anemia; Pancytopenia Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: This trial, sponsored by Amgen, Inc., which produces the recombinant methionyl human stem cell factor (r-metHuSCF), also involves two other institutions. The primary objective is determination of the safety of administering multiple doses of r-metHuSCF in the setting of acquired aplastic anemia and evaluation of the effect of r-metHuSCF on peripheral blood counts. Potential effects of r-metHuSCF on frequency of need for red cell or platelet transfusions and on bone marrow morphology/cellularity will also be evaluated. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001398
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Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “stem cells” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •
For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/
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For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html
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For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/
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For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm
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For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm
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For trials on aging, visit and search the Web site of the National Institute on Aging: http://www.grc.nia.nih.gov/studies/index.htm
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For rare diseases, visit and search the Web site sponsored by the Office of Rare Diseases: http://ord.aspensys.com/asp/resources/rsch_trials.asp
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For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm
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For trials on infectious, immune, and allergic diseases, visit the site of the National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov/clintrials/
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For trials on arthritis, musculoskeletal and skin diseases, visit newly revised site of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health: http://www.niams.nih.gov/hi/studies/index.htm
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For hearing-related trials, visit the National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/clinical/index.htm
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For trials on diseases of the digestive system and kidneys, and diabetes, visit the National Institute of Diabetes and Digestive and Kidney Diseases: http://www.niddk.nih.gov/patient/patient.htm
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For drug abuse trials, visit and search the Web site sponsored by the National Institute on Drug Abuse: http://www.nida.nih.gov/CTN/Index.htm
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For trials on mental disorders, visit and search the Web site of the National Institute of Mental Health: http://www.nimh.nih.gov/studies/index.cfm
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For trials on neurological disorders and stroke, visit and search the Web site sponsored by the National Institute of Neurological Disorders and Stroke of the NIH: http://www.ninds.nih.gov/funding/funding_opportunities.htm#Clinical_Trials
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CHAPTER 6. PATENTS ON STEM CELLS Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.9 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “stem cells” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on stem cells, we have not necessarily excluded non-medical patents in this bibliography.
Patents on Stem Cells By performing a patent search focusing on stem cells, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We
9Adapted
from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.
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will tell you how to obtain this information later in the chapter. The following is an example of the type of information that you can expect to obtain from a patent search on stem cells: •
Antibodies against flt3 ligand Inventor(s): Beckmann; Patricia M. (Poulsbo, WA), Lyman; Stewart D. (Seattle, WA) Assignee(s): Immunex Corporation (seattle, Wa) Patent Number: 6,630,143 Date filed: June 24, 1996 Abstract: Ligands for flt3 receptors capable of transducing self-renewal signals to regulate the growth, proliferation or differentiation of progenitor cells and stem cells are disclosed. The invention is directed to anti-flt3-L antibodies and enzyme-linked immunosorbent assays comprising such antibodies. Excerpt(s): The present invention relates to antibodies, and in particular, monoclonal antibodes, against mammalian flt3-ligands and kits incorporating the antibodies. Blood cells originate from hematopoietic stem cells that become committed to differentiate along certain lineages, i.e., erythroid, megakaryocytic, granulocytic, monocytic, and lymphocytic. Cytokines that stimulate the proliferation and maturation of cell precursors are called colony stimulating factors ("CSFs"). Several CSFs are produced by T-lymphocytes, including interleukin-3 ("IL-3"), granulocyte-monocyte CSF (GM-CSF), granulocyte CSF (G-CSF), and monocyte CSF (M-CSF). These CSFs affect both mature cells and stem cells. Heretofore no factors have been discovered that are able to predominantly affect stem cells. Tyrosine kinase receptors ("TKRs") are growth factor receptors that regulate the proliferation and differentiation of a number of cells (Yarden, Y. & Ullrich, A. Annu. Rev. Biochem., 57, 443-478, 1988; and Cadena, D. L. & Gill, G. N. FASEB J., 6, 2332-2337, 1992). Certain TKRs function within the hematopoietic system. For example, signaling through the colony-stimulating factor type 1 ("CSF-1"), receptor c-fms regulates the survival, growth and differentiation of monocytes (Stanley et al., J. Cell Biochem., 21, 151-159, 1983). Steel factor ("SF", also known as mast cell growth factor, stem cell factor or kit ligand), acting through c-kit, stimulates the proliferation of cells in both myeloid and lymphoid compartments. Web site: http://www.delphion.com/details?pn=US06630143__
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Anti-transforming growth factor Beta (TGF-.beta.) treated stem cell composition and method Inventor(s): Bartelmez; Stephen H. (Seattle, WA), Ruscetti; Frank (New Market, MD), Sitnicka; Ewa (Lund, SE) Assignee(s): Seattle Biomedical Research Institute (seattle, Wa) Patent Number: 6,627,191 Date filed: January 25, 2000 Abstract: The invention relates to stem cell compositions comprising anti-TGF-.beta. treated stem cells which are viable for at least 14 days in culture without replication or differentiation and methods for rapid and long term in vitro hematopoiesis and in vivo hematopoietic reconstitution using such anti-TGF-.beta. treated stem cells.
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Excerpt(s): The present invention relates to stem cell compositions and methods for preparing them in vitro or ex vivo by culturing stem cells in medium containing antiTGF-.beta. antibodies in the absence of exogenously provided cytokines. Such treatment facilitates the survival of long term repopulating hematopoietic stem cells (LTR-HSC) within the culture for at least 14 days without replication or differentiation, the rapid engraftment of such LTR-HSC following in vivo administration to a mammal or the rapid proliferation of such LTR-HSC following transfer to in vitro culture conditions effective to result in such expansion. The hematopoietic stem cell (HSC) is a pluripotent progenitor cell that has been characterized as a cell that is transplantable, can selfreplicate or generate daughter cells that are destined to commit to mature cells of different specific lineages. Self-replication of the most primitive HSC produces daughter cells that possess a long (possibly unlimited) clonal lifespan, while differentiation of HSCs results in a loss of such multilineage potential, and corresponding lineage commitment with a progressive reduction of their clonal lifespan. Previous studies indicated that survival of HSC ex vivo in the absence of growth factors is limited, resulting in a complete loss of HSC after about 0.5-4 days in culture (Bartelmez S, unpublished data; Ploemacher R E et al. Stem Cells 11:336-347, 1993; Li and Johnson, Blood 15;84(2):408-14, 1994). Web site: http://www.delphion.com/details?pn=US06627191__ •
Biological material containing bone marrow stem cells partially or completely differentiated into connective tissue cells and a hyaluronic acid ester matrix Inventor(s): Abatangelo; Giovanni (Saccolongo, IT), Callegaro; Lanfranco (Thiene, IT) Assignee(s): Fidia Advanced Biopolymers S.r.l. (brindisi, It) Patent Number: 6,596,274 Date filed: March 12, 1998 Abstract: A biological material comprising two components is provided containing a first component comprising alternatively (1) a culture of autologous or homologous bone marrow stem cells partially or completely differentiated into specific connective tissue cellular lines or (2) a sole extracellular matrix free from any cellular component secreted by the specific connective tissue cellular lines; and a second component containing a three-dimensional biocompatible and biodegradable matrix consisting of a hyaluronic acid ester having a degree of esterification comprised between 25 and 100%. The specific tissue cell lines are selected from fibroblasts, osteoblasts, myoblasts, adipocytes, chondrocytes and endothelial cells. The biological material is suitable for use as a dermal substitute in cutaneous lesions as well as repairing damaged connective tissue. Excerpt(s): The present invention relates to a biologic material, a process for its preparation and the use thereof in tissue grafts. The loss of cutaneous material due to various causes, traumatic or metabolic for example, can sometimes prove to be very slow-healing. This can be due to metabolic or local circulatory causes, the patient's poor state of health or to the size of the wound, as in the case of extensive burns. The ineffectiveness of pharmacological therapy has led physicians to resort to reconstructive surgery, using skin grafts from the same patient whenever possible. An important breakthrough in the treatment of such lesions is the use of techniques for in vitro cell culture. Another problem involved in the preparation of skin substitutes is represented by the supply of fibroblasts to seed onto the biocompatible matrices. Indeed, it is not always easy to isolate fibroblasts from dermal tissues, especially in the case of elderly or
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severely weakened subjects. One solution to this problem is offered by the mesenchymal cells present in bone marrow tissue. These cells are very active and can be suitably differentiated into various cell lines when placed in the correct conditions. From these stem cells it is possible to obtain differentiated cells such as fibroblasts, adipocytes, myoblasts, osteoblasts, chondrocytes. Web site: http://www.delphion.com/details?pn=US06596274__ •
Biological pacemaker and implantation catheter Inventor(s): Leonhardt; Howard J. (2400 N. Commerce Pkwy., Suite 498, Weston, FL 33326), Taheri; Syde A. (1275 Delaware Ave., Buffalo, NY 14209) Assignee(s): None Reported Patent Number: 6,690,970 Date filed: October 6, 2000 Abstract: A biological pacemaker and implantation catheter for restoring normal or near normal heartbeat function without a mechanical pacemaker. The biological pacemaker is provided by a bridge of implantation cells, such as nerve cells, stem cells or ganglion cells, that are introduced into an area of electrical malfunction, such as an impaired SA node or a blocked AV node. The implantation cells grow to form a conductive cell bridge around the malfunction area so that a new pathway is provided for the electrical signals responsible for triggering heart beat contractions. The implantation catheter has a central nerve cell injection needle connected to a syringe or the like via a cell injection tube, and two elongated lateral stabilizing needles. The catheter is inserted into a blood vessel in a patient's leg, arm, shoulder or the like, and advanced until the catheter's distal end is located above the malfunction area. The distal end of the catheter is bent so that the three needles are facing the malfunction area. The two stabilizing needles are advanced into the heart wall to stabilize the catheter and the nerve cell injection needle is advanced for injection of the implantation cells. Excerpt(s): This invention relates to cardio myopathy and its effect on electrical activity of the heart. More particularly, the invention concerns a pacemaker and related instrumentation for restoring heart rhythtn functionality to a heart. By way of background, the human heart is a large muscle consisting of a series of pumping chambers that are carefully controlled by a specialized electrical system designed to deliver timed contraction signals to the muscle cells associated with each chamber. This electrical system attempts to regulate the heart rate between a range of about 60-100 beats per minute. At the beginning of a heart beat, an electrical signal originates near the top of the right atrium. A network of specialized nerve cells, known as the "sino-atrial" or SA node, generates the electrical signal. Conduction pathways carry the electrical signal to the muscle cells of the left and right atria, causing them to contract and pump blood into the ventricles. Additional conduction pathways carry the electrical signal in a downward fashion to additional nerve tissue known as the "atrio-ventricular" or AV node. Here the electrical signal is slowed slightly as the ventricles fill with blood. The AV node electrically separates the upper and lower chambers of the heart and acts as a gateway to an additional bundle of conductor cells known as the "bundle of His." The bundle of His divides into right and left branches in the lower chambers of the heart to carry the electrical signal to two final groups of nerve tissue, known as the Purkinje fibers. The Purkinje fibers on the left and rights side of the heart respectively deliver the electrical signal to the muscle cells of the left and right ventricles. Because of the specialized way in which the electrical signal is transmitted, the ventricles contract
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almost simultaneously. With normal electrical conduction, the cardiac contractions are very organized and timed so that the atria contract before the ventricles, and the heart rate is maintained between about 60 and 100 beats per minute. This provides the major pumping action of the heart, allowing blood supply to reach the tissues of the body. Web site: http://www.delphion.com/details?pn=US06690970__ •
Bone morphogenetic protein-16 (BMP-16)antibodies Inventor(s): Celeste; Anthony J. (Hudson, MA), Murray; Beth L. (Arlington, MA) Assignee(s): Genetics Institute, Llc. (cambridge, Ma) Patent Number: 6,623,934 Date filed: November 26, 2001 Abstract: Purified BMP-16 proteins and processes for producing them are disclosed. DNA molecules encoding the BMP-16 proteins are also disclosed. The proteins may be used in the treatment of bone, cartilage, other connective tissue defects and disorders, including tendon, ligament and meniscus, in wound healing and related tissue repair, as well as for treatment of disorders and defects to tissues which include epidermis, nerve, muscle, including cardiac muscle, and other tissues and wounds, and organs such as liver, lung, cardiac, pancreas and kidney tissue. The proteins may also be useful for the induction of growth and/or differentiation of undifferentiated embryonic and stem cells. Excerpt(s): The present invention relates to a novel family of purified proteins designated as Bone Morphogenetic Protein-16 (BMP-16) and BMP-16-related proteins, DNA encoding them, and processes for obtaining them. These proteins may be used to induce bone and/or cartilage or other connective tissue formation, and in wound healing and tissue repair. These proteins may also be used for augmenting the activity of other bone morphogenetic proteins. The search for the molecule or molecules responsible for the bone-, cartilage-, and other connective tissue-inductive activity present in bone and other tissue extracts has led to the discovery of a novel set of molecules called the Bone Morphogenetic Proteins (BMPs). The structures of several proteins., designated BMP-1 through BMP-15 have previously been elucidated. The unique inductive activities of these proteins, along with their presence in bone, suggests that they are important regulators of bone repair processes, and may be involved in the normal maintenance of bone tissue. There is a need to identify whether additional proteins, particularly human proteins, exist which play a role in these processes. The present invention relates to the identification of such a novel human protein, which the inventors have designated human BMP-16. Human BMP-16 is the human homolog of a( murine protein called Nodal. The nucleotide and amino acid sequences of Nodal are described in Zhou et al., Nature, 361:543-547 (1993). The murine Nodal gene has been described as being expressed in the mouse node during gastrulation. A retrovirally induced insertional mutation of the murine Nodal gene results in the absence of mesodermal cell types normally associated with the primitive streak, and is embryonic lethal. Conlon et al., Development 120:1919-1928 (1994); Conlon et al., Development 111:969-981 (1991). Web site: http://www.delphion.com/details?pn=US06623934__
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cDNA libraries reflecting gene expression during growth and differentiation of human pluripotent stem cells Inventor(s): Carpenter; Melissa K. (Foster City, CA), Funk; Walter D. (Hayward, CA), Gold; Joseph D. (San Francisco, CA), Inokuma; Margaret S. (San Jose, CA), Xu; Chunhui (Cupertino, CA) Assignee(s): Geron Corporation (menlo Park, Ca) Patent Number: 6,667,176 Date filed: October 10, 2000 Abstract: This disclosure provides a system for obtaining expression libraries from primate pluripotent stem (pPS) cells. pPS cells can be maintained in vitro without requiring a layer of feeder cells to inhibit differentiation. The role of the feeder cells is replaced by several other culture conditions provided in a suitable combination. Conditions that promote pPS cell growth without differentiation include supporting the culture on an extracellular matrix, and culturing the cells in a medium conditioned by another cell type. The cDNA libraries from such cultures are devoid of transcripts of feeder cell origin, relatively uncontaminated by transcripts from differentiated cells, and can have a high proportion of full-length transcripts. Subtraction libraries can also be produced that are enriched for transcripts modulated during differentiation. Excerpt(s): This invention relates generally to the field of cell biology of embryonic cells. More specifically, it relates to the propagation of human pluripotent stem cells, culture conditions that facilitate propagation, and the use of such cultures for producing cDNA libraries. Recent discoveries have raised expectations that stem cells may be a source of replacement cells and tissue for cells and tissues that are damaged in the course of disease, infection, or as a result of congenital abnormalities. Various types of putative stem cells differentiate when they divide, maturing into cells that can carry out the unique functions of particular tissues, such as the heart, the liver, or the brain. A particularly important discovery has been the development of pluripotent stem cells, which are thought to have the potential to differentiate into almost any cell type. Early work on pluripotent stem cells was done in mice (reviewed in Robertson, Meth. Cell Biol. 75:173, 1997; and Pedersen, Reprod. Fertil. Dev. 6:543, 1994). Mouse stem cells can be isolated both from early embryonic cells and germinal tissue. Desirable characteristics of pluripotent stem cells are that they be capable of indefinite proliferation in vitro in an undifferentiated state, retain a normal karyotype, and retain the potential to differentiate to derivatives of all three embryonic germ layers (endoderm, mesoderm, and ectoderm). Web site: http://www.delphion.com/details?pn=US06667176__
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Compositions and methods for use in affecting hematopoietic stem cell populations in mammals Inventor(s): Peschle; Cesare (Rome, IT), Ziegler; Benedikt L. (Tuebingen, DE) Assignee(s): Instituto Superiore DI Sanita (rome, It), Thomas Jefferson University (philadelphia, Pa) Patent Number: 6,586,192 Date filed: May 28, 1999
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Abstract: The invention relates to a methods of obtaining and expanding a purified population of long-term repopulating hematopoietic stem cells. The invention also relates to the uses of a purified population of long-term repopulating hematopoietic stem cells. Excerpt(s): Hematopoiesis in mammals is maintained by a pool of self-renewing hematopoietic stem cells (HSCs) (Ogawa, 1993, Blood 81:2844-2853). HSCs feed into lineage(s)-committed undifferentiated hematopoietic progenitor cells (HPCs) with little or no self-renewal capacity (Ogawa, 1993, Blood 81:2844-2853). The HPCs in turn generate morphologically recognizable differentiated precursors and terminal cells circulating in peripheral blood. Human HSCs are identified on the basis of their capacity for long-term hematopoietic repopulation in vitro and in vivo. Specifically, in vitro repopulation of an irradiated allogeneic stromal adherent layer in long term culture (LTC) of Dexter type has been observed. In Dexter type LTC, primitive HPCs and HSCs are assessed as five to eight week and twelve week LTC initiating cells (LTC-ICs; Sutherland et al., 1990, Proc. Natl. Acad. Sci. U.S.A. 87:3584-3588; Valtieri et al., 1994, Cancer Res. 54:4398-4404; Hao et al., 1996, Blood 88:3306-3313), or cobblestone area forming cells (CAFCs; Breems et al., 1996, Blood 87:5370-5378). Particularly, short term repopulating primitive HPCs have been identified in five to eight week LTC (Sutherland et al., 1990, Proc. Natl. Acad. Sci. U.S.A. 87:3584-3588; Larochelle et al., 1996, Nature Med. 2:1329-1337), whereas long-term repopulating putative HSCs have been identified in twelve week LTC (Hao et al., 1996, Blood 88:3306-3313). Moreover, in vivo repopulation of severe combined immunodeficiency (SCID) mice at two months (Nolta et al., 1994, Blood 83:3041-3047) or non-obese diabetic SCID (SCID-NOD) mice at one and a half months (Bock et al., 1995, J. Exp. Med. 182:2037-2043) after irradiation and HSC injection has been observed. In murine embryonic life (day 7.5 of gestation), a close developmental association of the hematopoietic and endothelial lineages takes place in the yolk sack blood islands, leading to the hypothesis that the two lineages share a common ancestor referred to as the hemoangioblast (Flamme et al., 1992, Development 116:435-439; Risau et al., 1995, Ann. Rev. Cell. Dev. Biol. 11:73-91). Web site: http://www.delphion.com/details?pn=US06586192__ •
Compositions for identification and isolation of stem cells Inventor(s): Makarovskiy; Andrew N. (58 Bellingham St., Mendon, MA 01756) Assignee(s): Makarovskiy; Andrew N. (mendon, Ma) Patent Number: 6,632,620 Date filed: June 22, 2000 Abstract: The invention provides monoclonal antibodies that selectively bind to ectodermally- and endodermally-derived stem cells and methods for the diagnosis of a neoplasm in a subject by contacting a tissue sample from the subject with the antibodies. Also disclosed are methods for isolating such stem cells from a heterogeneous cell population by contacting the population with antibodies which selectively bind to stem cells. Excerpt(s): The invention relates to stem cells. Stem cell populations have been identified in many tissues and are thought to constitute a source of tissue renewal in quiescent, regenerative and pathological conditions. Tumor stem cells are the cell renewal source of a neoplasm and also serve as the seeds of metastatic spread of cancer. While rapidly proliferating tissues such as bone marrow, gut, and epidermis are known
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to be organized into stem cells and lineages of maturing descendants, the evidence for parallel phenomena in other tissues has been debatable. Stem cell markers are useful to diagnose cancers and to treat pathological conditions characterized by abnormal or insufficient function of differentiated cells of a mature organ. However, stem cells have been difficult to identify and isolate. Web site: http://www.delphion.com/details?pn=US06632620__ •
Conditioned media for propagating human pluripotent stem cells Inventor(s): Gold; Joseph D. (San Francisco, CA), Xu; Chunhui (Cupertino, CA) Assignee(s): Geron Corporation (menlo Park, Ca) Patent Number: 6,642,048 Date filed: July 6, 2001 Abstract: This invention provides media that support the growth of primate pluripotent stem cells in feeder-free culture, and cell lines useful for producing such media and other purposes. Conventionally, it has been necessary to grow pluripotent embryonic cells on feeder layers of primary embryonic fibroblasts, in order to prevent them from differentiating. It has now been discovered that standard culture media conditioned by special cell lines can be used to support proliferation of pluripotent stem cells while inhibiting differentiation in an environment free of feeder cells. This invention includes mesenchymal and fibroblast-like cell lines obtained from embryonic tissue or differentiated from embryonic stem cells. Methods for deriving such cell lines, processing media, and growing stem cells using the conditioned media are described and illustrated in this disclosure. Excerpt(s): This invention relates generally to the field of cell biology of embryonic cells. More specifically, it relates to the derivation of cell lines producing conditioned culture media, which in turn can be used to propagate human pluripotent stem cells in feederfree culture. A number of recent discoveries have raised expectations that stem cells may be a source of replacement cells and tissue for cells and tissues that are damaged in the course of disease, infection, or because of congenital abnormalities. Various types of putative stem cells differentiate when they divide, maturing into cells that can carry out the unique functions of particular tissues, such as the heart, the liver, or the brain. A particularly important discovery has been the development of human pluripotent stem (hPS) cells (reviewed by R. A. Pedersen, Scientif. Am. 280(4):68, 1999). These cells have the capacity to differentiate into essentially all types of cells in the body. For example, hPS cells have been used to generate cells that are committed to a number of different cell lineages, which retain their capacity to proliferate. Since these embryonic cells are truly pluripotent, they have the potential to provide a stock supply of different types of cells for regeneration of essentially any type of failed tissue. Web site: http://www.delphion.com/details?pn=US06642048__
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Cord blood-derived activated lymphocytes, preparations containing said lymphocytes as main ingredient and method and kit for producing said preparations Inventor(s): Bamba; Kenzo (Ibaraki, JP), Ito; Kiminari (Hokkaido, JP), Kuroiwa; Yasuyuki (Ibaragi, JP), Sekine; Teruaki (Tokyo, JP), Shimizu; Norio (Yamanashi, JP), Yamaguchi; Tomohiro (Saitama, JP) Assignee(s): Humantec Ltd. (ibaraki-ken, Jp) Patent Number: 6,692,958 Date filed: December 4, 2001 Abstract: Activated lymphocytes derived from cord blood are excellently effective for preventing and treating various types of tumors and various types of infection. With interleukin 2 and/or anti-CD3 antibody, the lymphocytes derived from the cord blood is prepared by segregating lymphocytes from the cord blood and proliferating the segregated lymphocytes directly in vitro or segregating monocytes from cord blood and proliferating the monocytes in vitro. Also, the cord blood-derived activated lymphocytes can be effectively used for preventing recurrence of the diseases and promoting the take of stem cells or other organs. Excerpt(s): This invention relates to activated lymphocytes derived from cord blood, pharmaceutical preparations containing the aforesaid activated lymphocytes as a main ingredient, and a method and kit for producing the aforesaid preparations for the purpose of treating various tumors and infection diseases and preventing these diseases from developing and redeveloping and hastening take of stem cells of various organs and so on. Lately, intense interest has been shown toward lymphocytes bearing an immune system for biophylaxis. Specifically, T-lymphocytes are one of the important cells having an efficient cellular immunity and sorted into the following groups in accordance with the reactivity of monoclonal antibodies. For example, the Tlymphocytes having reactivity with anti-CD3 antibodies ("CD" is short for "cluster of differentiation) belong to CD3 positive cells. There have been performed a number of studies of the relationship between the antigen manifested from these lymphocytes and their functions. The lymphocyte manifesting CD45 RA-antigen among the CD3 positive cells is a naive T-lymphocyte, which is deemed not to have antitumor activity. On the contrary, the lymphocyte manifesting CD45 RO-antigen among the aforesaid CD3 positive cells is a memory T-lymphocyte, which is recognized to have the function of antitumor activity. Sekine, one of the inventors, has already reported that it is possible to proliferate the lymphocytes with a solidus anti-CD3 antibody and interleukin 2, so that autologous lymphocytes obtained as the result of proliferation can possess an antitumor function (Japanese Patent Public Disclosure HEI 03-80076(A)). Web site: http://www.delphion.com/details?pn=US06692958__
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Delivery of therapeutic biologicals from implantable tissue matrices Inventor(s): Donahoe; Patricia K. (Boston, MA), MacLaughlin; David T. (Saugus, MA), Masiakos; Peter T. (Boston, MA), Vacanti; Joseph P. (Winchester, MA) Assignee(s): The General Hospital Corporation (boston, Ma) Patent Number: 6,692,738 Date filed: January 26, 2001
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Abstract: Normal cells, such as fibroblasts or other tissue or organ cell types, are genetically engineered to express biologically active, therapeutic agents, such as proteins that are normally produced in small amounts, for example, MIS, or other members of the TGF-beta family Herceptin.TM., interferons, andanti-angiogenic factors. These cells are seeded into a matrix for implantation into the patient to be treated. Cells may also be engineered to include a lethal gene, so that implanted cells can be destroyed once treatment is completed. Cells can be implanted in a variety of different matrices. In a preferred embodiment, these matrices are implantable and biodegradable over a period of time equal to or less than the expected period of treatment, when cells engraft to form a functional tissue producing the desired biologically active agent. Implantation may be ectopic or in some cases orthotopic. Representative cell types include tissue specific cells, progenitor cells, and stem cells. Matrices can be formed of synthetic or natural materials, by chemical coupling at the time of implantation, using standard techniques for formation of fibrous matrices from polymeric fibers, and using micromachining or microfabrication techniques. These devices and strategies are used as delivery systems via standard or minimally invasive implantation techniques for any number of parenterally deliverable recombinant proteins, particularly those that are difficult to produce in large amounts and/or active forms using conventional methods of purification, for the treatment of a variety of conditions that produce abnormal growth, including treatment of malignant and benign neoplasias, vascular malformations (hemangiomas), inflammatory conditions, keloid formation, abdominal or plural adhesions, endometriosis, congenital or endocrine abnormalities, and other conditions that can produce abnormal growth such as infection. Efficacy of treatment with the therapeutic biologicals is detected by determining specific criteria, for example, cessation of cell proliferation, regression of abnormal tissue, or cell death, or expression of genes or proteins reflecting the above. Excerpt(s): The present invention is generally in the area of methods and systems for treatment of disorders such as cancer with biologically active agents produced naturally by cells in extremely small quantities, using genetically engineered host cells or natural cells that secrete a substance naturally implanted in biodegradable polymeric matrices. One of the difficulties in treatment of conditions such as cancer using protein or other biological modifiers is the need for large quantities of the therapeutic agent to be delivered over an extended period of time. For most of the compounds discovered during research on complex pathways or unique tissues, it has not been possible, or has not been commercially feasible, to produce the compounds in sufficient quantity to treat the disorders. Numerous examples of these compounds, especially proteins, have been reported. One prominant example is angiostatin, a naturally occurring anti-angiogenic peptide identified by researchers at Children's Medical Center in Boston, Mass. Although extremely promising in mice (O'Reilly et al., Science 285(5435):1926-8 1999), the inability of the developers to produce large quantities of the peptide has proven to be a major stumbling block to conducting clinical trials for treatment of cancer. Mullerian Inhibiting Substance (MIS) is another biological with great potential for treatment of cancer. MIS is produced by the fetal testis and causes the regression in males of the Muillerian duct, the forerunner of the female reproductive ducts. MIS has been shown to have great potential as a treatment for ovarian carcinomas (Chin et al, Cancer Research. 51:2101-2106, 1991; Masiakos, et al, Clinical Cancer Research, 5(11):3488-99 1999) which are derived from embryonic Mullerian structures. Recombinant human MIS (rhMIS) produced in Chinese hamster ovary cells (CHO) in multiple roller bottles has antiproliferative activity against several human carcinoma cell lines (Chin, et al, 1991). Recently, it was also reported that rhMIS specifically binds to a functional heteromeric serine threonine (Teixeira, et al., Androl. 17(4):336-41 1996;
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Teixeira et al., Endocrinology Jan;137(1):160-5 1996) receptor on the surface of human ovarian cancer ascites cells and inhibits the growth in vitro of these cells and of cells obtained directly from women with Stage III and IV disease (Masiakos et al., 1999). See also, U.S. Pat. Nos. 4,404,199, 4,487,833, 4,510,131, 4,753,794, 4,792,601, 5,011,687, 5,198,420 and 5,661,126 to Donahoe, et al., the teachings of which are incorporated by reference herein. Web site: http://www.delphion.com/details?pn=US06692738__ •
Devices and methods for harvesting limbal stem cells Inventor(s): Chuck; Roy S. (Irvine, CA) Assignee(s): The Regents of the University of California (oakland, Ca) Patent Number: 6,679,898 Date filed: September 27, 2001 Abstract: A system, apparatus and method for harvesting from the eye of a mammilian (e.g., cadaveric) donor a disc-shaped graft or lenticle consisting of corneal tissue and a quantity of scleral or pericorneal tissue wherein limbal stem cells are located. This graft or lenticle is then transplanted onto the eye of a human or veterinary patient to treat a disorder caused by the absence or deficiency of limbal stem cells in the patient's eye. The system of the present invention comprises a) an eye-contacting ring and cutter guide apparatus and b) a cutter apparatus. The eye-contacting ring and cutter guide apparatus is initially placed in contact with the donor eye such that a portion of the cornea and adjacent scleral or pericorneal tissue containing limbal stem cells protrudes upwardly through the center of the ring. The cutter is then engaged with guide member(s) formed on the ring and the cutter is advanced, severing the protruding cornea and stem-cell-containing pericorneal tissue. In this manner the desired lenticle is obtained for subsequent transplantation. Excerpt(s): The present invention relates generally to medical devices and methods and more particularly to a device and method for harvesting a quantity of transplantable corneal tissue along with adjacent, stem-cell-containing scleral tissue. The anterior portion of the human eye normally contains corneal, limbal, and conjunctival epithelial tissue. Along with a film of tears, these tissues cover and protect the eye. The limbus is the marginal region of the cornea of the eye by which the cornea is continuous with the sclera. There is experimental and clinical evidence that limbal epithelial stem cells are located in the limbal area, presumably in the basal epithelium allowing the cells to be harvested as a lamellar eye tissue section. These dynamic cells maintain the corneal epithelial cell population and thus, the corneal surface integrity. Thus, the presence of functioning limbal stem cells is critical to the health and functioning of the eye. In the event the limbal stem cells become damaged or depleted, chronic inflammation, cloudy vision, and even blindness may result. Damage or depletion to the limbal epithelial (stem) cells can result from a number of causes, including trauma, chemical or thermal burns, a disorder known as Stevens-Johnson syndrome, improper fitting or improper use of contact lenses, infections and/or scarring due to prior surgical procedures. In some cases, severe damage may lead to complete loss of the limbal epithelial cells. Web site: http://www.delphion.com/details?pn=US06679898__
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Directed maturation of CD34 negative stem cells to programmable antigen presenting cells Inventor(s): Cezayirli; Cem (801 Princeton Ave. Suite 310, Birmingham, AL 35211), Silvers; Mel (18970 NE. 21st Ave., North Miami Beach, FL 33179) Assignee(s): None Reported Patent Number: 6,586,243 Date filed: December 20, 2000 Abstract: A method is described whereby dendritic cells derived from the CD34+ and CD 34- hematopoietic cell lineages are directed to become programmable antigen presenting cells. The programmed cells may be pulsed with tumor cell RNA or tumor cell RNA expression products. The protocol provides for directing the maturation of dendritic cells to become antigen presenting cells. The protocol further provides for isolating tumor cell RNA from biopsy material that has been prepared in paraffin block storage. The directed dendritic cell is provided with a plurality of tumor markers by using tumor RNA in toto, the poly A+RNA fraction or the expression product of such RNA. Once activated the dendritic cells are incubated with T4 and T8 lymphocytes to stimulate and sensitize the T lymphocytes which upon introduction either into a donor host or a nondonor recipient will provide immune response protection. Excerpt(s): In recent years there have been numerous advances in the level of understanding of how cancer cells grow inside a host. Generally, it is known that where a tumor or cancer becomes manifest, either there is a deficiency in the host's immune system and/or the tumor cells secrete or express agents which block the normal response of the host's immune system. In any event, there is a failure on the part of the host's immune system to recognize the presence of the cancer cell as "non-self". Because of this failure, the tumor cell and its progeny are allowed to grow without the benefit of predatory attack from the host's immune system cells which are normally responsible for detection of abnormal conditions. Primarily, the immune cells responsible for such predatory attack are the white blood cells of the CD34 lineage including the lymphocyte-activated killer macrophages and the T8 killer cells. Cells derived from CD34 lineage naturally become differentiated to ten or more mature cell types dedicated to specific functions. The functionality is believed to be determined by factors, such as cytokines, leading to the next differentiated stage. Although seemingly much is known of specific hematopoietic cells which have become differentiated into identifiable discrete cell types, little is known about the physiologic control mechanisms involved in such differentiation process. Thus, contemporary research has centered primarily on examination of specifically known cell types and the cell surface "markers" recognizable at each such differentiation stage. Conspicuously lacking in the art has been clearly useful information or understanding of physiological events taking place within the cells as they metamorphosized from one state to the next differentiated state. Consistent with the current state of understanding such cell differentiation is the methodology utilized by leading physicians and researchers in treatment protocols for cancerous diseases. Over the past several decades, cancer treatment methodologies have centered on conventional therapies such as surgical excision, radiation, and the injection of potent chemical agents. Such methodologies have well recognized limitations and have, in many cases, been proved to cause much additional pain and suffering to the patient as well as unreliable long-term effectiveness. Web site: http://www.delphion.com/details?pn=US06586243__
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Double mutants of dihydrofolate reductase and methods of using same Inventor(s): Banerjee; Debabrata (New York, NY), Bertino; Joseph R. (New York, NY), Ercikan-Abali; Emine A. (New York, NY), Mineishi; Shin (New York, NY), Sadelain; Michel (New York, NY) Assignee(s): Sloan-kettering Institute for Cancer Research (new York, Ny) Patent Number: 6,642,043 Date filed: January 20, 1999 Abstract: New mutant forms of human dihydrofolate reductase (DHFR) which have properties superior to the previously disclosed mutants have mutations at both amino acid 22 and amino acid 31. Specific mutant forms are Ser31Tyr22, Ser31Phe22, Gly31Tyr22, Gly31Phe22, Ala31Tyr22 and Ala31Phe22. The mutant DHFR of the invention maybe used as a selectable marker, and to modify the genome of human cells, particularly bone marrow cells or peripheral blood stem cells, to render them resistant to chemotherapy using antifolate agents. Excerpt(s): This application relates to a new mutants of the enzyme dihydrofolate reductase, and to the use of these mutants as selectable markers and for gene therapy to produce drug resistant bone marrow or peripheral stem cells. Dihydrofolate reductase (DHFR, 5,6,7,8-tetrahydrofolate:NADP+oxidoreductase, EC 1.5.1.3) catalyzes the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate, an essential carrier of one-carbon units in the biosynthesis of thymidylate, purine nucleotides, serine and methyl compounds. DHFR is an essential enzyme in both eukaryotes and prokaryotes. In rapidly dividing cells, the inhibition of DHFR results in the depletion of cellular tetrahydrofolates, inhibition of DNA synthesis and cell death. Because of this, folate analogs which inhibit DHFR, for example methotrexate (MTX), are used as antineoplastic agents. The utility of "antifolate" treatments of this type is limited by two factors. First, tumor tissues may rapidly develop resistance to the antifolate, rendering the treatment ineffective. Second, the treatment may be toxic to rapidly dividing normal tissues, particularly to bone marrow or peripheral stem cells. Web site: http://www.delphion.com/details?pn=US06642043__
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Electroactive materials for stimulation of biological activity of stem cells Inventor(s): Langer; Robert (Newton, MA), Martin; Ivan (Oberwil, CH), Rahman; Nahid (Boston, MA), Shastri; Venkatram (Lower Gwynedd, PA) Assignee(s): Massachusetts Institute of Technology (cambridge, Ma) Patent Number: 6,569,654 Date filed: January 2, 2001 Abstract: Compositions, methods and systems are provided for the stimulation of biological activities within stem cells by applying electromagnetic stimulation to an electroactive material, wherein the electromagnetic stimulation is coupled to the electromagnetic material. In general the present invention involves attaching or associating the desired cells to or with a surface comprising an electroactive material, and applying electromagnetic radiation directly to the desired area. In preferred embodiments, the stimulation of biological activities within cells results from inducing one or more activities including, but not limited to, gene expression, cell growth, cell differentiation, signal transduction, membrane permeability, cell division, contraction,
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and cell signaling. In exemplary embodiments, the electroactive materials used in the present invention are either two-dimensional substrates such as thin films having at least one surface of an electroactive material, or in alternative embodiments, the electroactive materials are three-dimensional substrates comprising a matrix having at least one surface of an electroactive material. Excerpt(s): Tissue engineering is a field in which the principles of biology, engineering, and materials science are applied to the development of functional substitutes for damaged tissue. (See, Langer, et al., "Tissue Engineering", Science, 1993, 260, 920). In general, three different strategies have been adopted for the creation of new tissue: (i) isolated cells or cell substrates, in which only those cells that supply the needed function are replaced; (ii) tissue-inducing substances, such as signal molecules and growth factors, and (iii) cells placed on or within matrices. Researchers have been interested in applying these novel techniques to find replacements for tissues such as ectodermal, endodermal, and mesodermal-derived tissue. In particular, researchers are invested the replacement of tissues in the nervous system, cornea, skin, liver, pancreas, cartilage, bone, and muscle to name a few. Stem cells have shown tremendous potential for treatment of diseased and damaged tissue. Stem cells are cells that have the potential to both divide for indefinite periods in vitro and to differentiate into more specialized cells. Pluripotent stem cells are a potential source for the development of replacement tissues to treat a variety of medical conditions. For example, nerve stem cells transplanted into the brain may develop into healthy nerves that can counteract the affect of Alzheimer or Parkinson's disease. Tissue engineering applications have long exploited fully differentiated cells seeded onto biocompatible matrices that may be implanted in a wound site to regenerate damaged tissue. The incorporation of stem cells into tissue engineering matrices may increase the therapeutic potential of this technique. Clearly, there remains a need to develop systems and methods whereby biological activities of cells can be stimulated by direct application of electromagnetic stimulation. This would be particularly important in applications to tissue engineering. Web site: http://www.delphion.com/details?pn=US06569654__ •
Engraftable human neural stem cells Inventor(s): Kim; Seung U. (Vancouver, CA), Snyder; Evan Y. (Jamaica Plain, MA), Wolfe; John H. (Philadelphia, PA) Assignee(s): The Children's Medical Center Corporation (boston, Ma), University of British Columbia (vancouver, Gb), University of Pennsylvania (philadelphia, Pa) Patent Number: 6,680,198 Date filed: September 20, 1999 Abstract: Stable clones of neural stem cells (NSCs) have been isolated from the human fetal telencephalon. In vitro, these self-renewing clones (affirmed by retroviral insertion site) can spontaneously give rise to all 3 fundamental neural cell types (neurons, oligodendrocytes, astrocytes). Following transplantation into germinal zones of the developing newborn mouse brain, they, like their rodent counterparts, can participate in aspects of normal development, including migration along well-established migratory pathways to disseminated CNS regions, differentiation into multiple developmentallyand regionally-appropriate cell types in response to microenvironmental cues, and nondisruptive, non-tumorigenic interspersion with host progenitors and their progeny. Readily genetically engineered prior to transplantation, human NSCs are capable of expressing foreign transgenes in vivo in these disseminated locations. Further
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supporting their potential for gene therapeutic applications, the secretory products from these NSCs can cross-correct a prototypical genetic metabolic defect in abnormal neurons and glia in vitro as effectively as do murine NSCs. Finally, human cells appear capable of replacing specific deficient neuronal populations in a mouse model of neurodegeneration and impaired development, much as murine NSCs could. Human NSCs may be propagated by a variety of means--both epigenetic (e.g., chronic mitogen exposure) and genetic (transduction of the propagating gene vmyc)--that are comparably safe (vmyc is constitutively downregulated by normal developmental mechanisms and environmental cues) and effective in yielding engraftable, migratory clones, suggesting that investigators may choose the propagation technique that best serves the demands of a particular research or clinical problem. All clones can be cryopreserved and transplanted into multiple hosts in multiple settings. Excerpt(s): Neural stem cells (NSCs) are postulated to be relatively primordial, uncommitted cells that exist in the developing and even adult nervous system and are responsible for giving rise to the array of more specialized cells of the mature CNS.sup.1-12. They are operationally defined by their ability (a) to differentiate into cells of all neural lineages (neurons--ideally of multiple subtypes, oligodendroglia, astroglia) in multiple regional and developmental contexts (i.e., be multipotent); (b) to self-renew (i.e., also give rise to new NSCs with similar potential); (c) to populate developing and/or degenerating CNS regions. An unambiguous demonstration of monoclonal derivation is obligatory to the definition--i.e., a single cell must possess these attributes. With the earliest recognition that rodent neural cells with stem cell properties, propagated in culture, could be reimplanted into mammalian brain where they could reintegrate appropriately and stably express foreign genes.sup.13-16, gene therapists and restorative neurobiologists began to speculate how such a phenomenon might be harnessed for therapeutic advantage as well as for understanding developmental mechanisms. These, and the studies which they spawned (reviewed elsewhere.sup.2,9-11,17-21) provided hope that the use of NSCs--by virtue of their inherent biology--might circumvent some of the limitations of presently available graft material and gene transfer vehicles and make feasible a variety of novel therapeutic strategies.sup.20-22. Neural cells with stem cell properties have been isolated from the embryonic, neonatal and adult rodent CNS and propagated in vitro by a variety of equally effective and safe means--both epigenetic (e.g., with mitogens such as epidermal growth factor [EGF] or basic fibroblast growth factor [bFGF].sup.1,5,16,23-27 or with membrane substrates.sup.7) and genetic (e.g., with propagating genes such as vmyc or SV40 large T-antigen.sup.1,9-15,17-19,28-32). Maintaining such NSCs in a proliferative state in culture does not appear to subvert their ability to respond to normal developmental cues in vivo following transplantation--to withdraw from the cell cycle, interact with host cells, differentiate appropriately.sup.9-16,29-33. These extremely plastic cells migrate and differentiate in a temporally and regionally appropriate manner particularly following implantation into germinal zones throughout the brain. They participate in normal development along the murine neuraxis, intermingling nondisruptively with endogenous progenitors, responding similarly to local microenvironmental cues for their phenotypic determination and appropriately differentiating into diverse neuronal and glial cell types. In addition, they can express foreign genes (both reporter genes and therapeutic genes) in vivo.sup.9-21,29-32, and are capable of specific neural cell replacement in the setting of absence or degeneration of neurons and/or glia.sup.9,11,31,32. We present evidence that neural cells with rigorously defined stem cell features, may, indeed, be isolated from the human brain and may emulate the behavior of NSCs in lower mammals. Not only do these observations vouchsafe conservation of certain neurodevelopmental principles to the
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human CNS, but they suggest that this class of neural cells may ultimately be applied as well to research and clinical problems in the human. Indeed, not only might the actual human NSC clones described in this report serve that function, but our data suggest that other investigators may readily obtain and propagate such cells from other sources of human material through a variety of equally safe and effective methods (both epigenetic and genetic) with the expectation that such cells will fulfill the demands of multiple research and/or therapeutic problems. Web site: http://www.delphion.com/details?pn=US06680198__ •
Genetically altered mammalian embryonic stem cells, their living progeny, and their therapeutic application for improving cardiac function after myocardial infarction Inventor(s): Morgan; James P. (56 Norwood Ave., Newton Centre, MA 02459), Xiao; Yong-Fu (26 Paquot Rd., Wayland, MA 01778) Assignee(s): None Reported Patent Number: 6,607,720 Date filed: October 7, 2000 Abstract: The present invention provides genetically altered mammalian embryonic stem cells, their living descendent progeny having an altered genomic DNA, and therapeutic methods using these cells for improving cardiac function in a living subject after myocardial infarction. The genetically altered embryonic stem and progenitor cells may be maintained in-vitro as a stable cell line; and transplanted as active, mitotic cells to an infarcted area of the myocardial using any surgical procedure. After transplantation at a chosen anatomic site within the heart of the subject, these genetically altered cells will differentiate in-site, cause a regeneration of myocardocytes, and will effect a marked improvement in cardiac function for the subject. Excerpt(s): The present invention is concerned generally with cellular compositions and methods for improving cardiac function in a living subject after the occurrence of a myocardial infarction; And is focused in particular upon the preparation and therapeutic use of novel genetically altered mammalian embryonic stem cells and their direct descendent progeny as cells for in-vivo transplantation into the infarcted areas of the myocardium in a living host subject. Myocardial infarction (MI) is a life-threatening event and may cause cardiac sudden death or heart failure. Despite considerable advances in the diagnosis and treatment of heart disease, cardiac dysfunction after MI is still the major cardiovascular disorder that is increasing in incidence, prevalence, and overall mortality (Eriksson et al., 1995). After acute myocardial infarction, the damaged cardiomyocytes are gradually replaced by fibroid nonfunctional tissue. Ventricular remodeling results in wall thinning and loss of regional contractile function. The ventricular dysfunction is primarily due to a massive loss of cardiomyocytes. It is widely accepted that adult cardiomyocytes have little regenerative capability. Therefore, the loss of cardiac myocytes after MI is irreversible. Each year more than half million Americans die of heart failure. The relative shortage of donor hearts forces researchers and clinicians to establish new approaches for treatment of cardiac dysfunction in MI and heart failure patients. Cell transplantation has emerged as a potential novel approach for regeneration of damaged myocardium in recent several years. Transplanted cardiomyocytes have been shown to survive, proliferate, and connect with the host myocardium (Soonpaa et al., 1994). Engrafted cells may regenerate new cardiomyocytes to replace infarcted myocardium or serve as a source for therapeutic gene transfer to infarct areas (Leor et al., 1997). Li and his coworkers (Li et al., 1996)
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demonstrated that transplanted fetal cardiomyocytes could form new cardiac tissue within the myocardial scar induced by cryoinjury and significantly improve heart function (Li et al. 1997). Bishop et al. (Bishop et al., 1990) reported that embryonic myocardium of rats could be implanted or cultured. They suggested that the engrafted embryonic cardiomyocytes proliferated and differentiated in host myocardium. In a recent review, Hescheler et al. (Hescheler et al., 1997) pointed out that pluripotent ES cells cultivated within embryonic bodies reproduce highly specialized phenotypes of cardiac tissue. Most of the biological and pharmacological properties of cardiac-specific ion currents were expressed in cardiomyocytes developed in vitro from pluripotent ES cells. Electrophysiological characteristics of these cells developed from ES cells were similar to those previously described in adult cardiomyocytes or neonatal mammalian heart cells (Kilborn et al., 1990; Hescheler et al., 1997). Web site: http://www.delphion.com/details?pn=US06607720__ •
Hematopoietic differentiation of human embryonic stem cells Inventor(s): Kaufman; Dan S. (Madison, WI), Thomson; James A. (Madison, WI) Assignee(s): Wisconsin Alumni Research Foundation (madison, Wi) Patent Number: 6,613,568 Date filed: August 27, 2001 Abstract: Disclosed herein are methods of obtaining human hematopoietic cells from human embryonic stem cells using mammalian stromal cells. Hematopoietic cells derived in this way are useful for creating cell cultures suitable for transplantation, transfusion, and other purposes. Excerpt(s): The present invention relates to the use of human embryonic stem cells to create blood-related cells, and the use of those blood-related cells for various purposes. Techniques for isolating stable cultures of human embryonic stem cells have recently been described by our laboratory. See U.S. Pat. No. 5,843,780 and J. Thomson et al., 282 Science 1145-1147 (1998). The disclosure of these publications and of all other publications referred to herein are incorporated by reference as if fully set forth below. We have deposited two of our human embryonic stem cell lines with the American Type Culture Collection, 10801 University Boulevard, Manassas, Va. 20110-2209 U.S.A. on Jul. 7, 1999 and Jul. 15, 1999 respectively (with accession numbers PTA-313 and PTA353 respectively). These deposits are under the conditions of the Budapest Treaty. Taxonomic descriptions of these deposits are human embryonic stem cell lines H1 and H9 respectively. It has been proposed in these publications that such cell lines may be used for, among other things, providing a source of specified cell lines of various types for research, transplantation and other purposes. Web site: http://www.delphion.com/details?pn=US06613568__
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High efficiency gene targeting in mouse embryonic stem cells Inventor(s): Berns; Anton (Spaarndam, NL), Robanus Maandag; Els (Haarlem, NL), te Riele; Hein (Amsterdam, NL) Assignee(s): Genpharm International, Inc. (mountain View, Ca) Patent Number: 6,653,113 Date filed: February 19, 1999 Abstract: The present invention provides novel methods for modifying the genome of an animal cell which typically comprise the steps of: constructing a DNA molecule in which desired sequence modifications are contained in a segment of DNA (a "targeting DNA") that is substantially isogenic with a DNA in the cell genome (a "target DNA"); introducing the targeting DNA construct into the cell (e.g., by microinjection, electroporation, transfection, or calcium phosphate precipitation); and selecting cells in which the desired sequence modifications have been introduced into the genome via homologous recombination. Excerpt(s): The present invention relates generally to methods for modifying the genome of animal cells, including human cells, and more particularly, to methods for modifying a genomic DNA sequence by homologous recombination using substantially isogenic DNA constructs. Targeted gene disruption by homologous recombination has met with variable success in higher eukaryotes. While it has been possible to isolate cells which have stably incorporated exogenously prepared DNA sequences, in the vast majority of these cells, the DNA has integrated randomly into the genome rather than at the desired target site via homologous recombination. The ratio of the number of homologous recombinants to the total number of integration events varies, but typically, when there is no direct selection or enrichment for homologous recombinants, less than 1% of the integration events result from homologous recombination and ratios as low as 1 in 40,000 have been observed. Variations in the relative targeting efficiency have not been clearly attributable to differences in the length of homologous sequence present in the targeting constructs. Nor has any unequivocal correlation been documented between recombination efficiency and transcriptional activity of the target gene or chromosomal location of the target gene. If the homologous recombinants can only be obtained amidst a large background of random integration events, then : it may be impractical, if not impossible, to effectively target many genomic sequences. The approaches taken to overcoming this problem have focused on developing special strategies to screen or select homologous recombinants from the large background of non-homologous or random integration events. In a few situations in which the targeted gene is itself a dominant selectable marker, it may be feasible to select directly for homologous recombinants. For example, knocking out the hprt gene (encoding hypoxanthine phosphoribosyl transferase) results in increased tolerance of the base analog 6-thioguanine (Thomas, K. and M. Capecchi, Cell 51:503-512 (1987). However, such particularized methods are not widely applicable. Other selection procedures aim at the enrichment for the desired homologous recombination event by suppressing colony formation due to random integrations of the targeting construct. In single selection protocols, the targeting constructs contain a marker gene, typically conferring drug resistance, deprived of transcriptional and/or translational start signals, in 'such a way that the juxtaposition of the marker gene and functional expression signals would be obtained on homologous recombination but only rarely on random integration. Sedivy, J., and P. Sharp, Proc. Nat'l Acad. Sci. USA 86:227-231 (1989). The double or "positive/negative" selection procedure developed by Capecchi and co-workers makes use of an autonomously expressed marker gene, but the targeting construct is flanked
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by a second gene which is detrimental to the cell and which tends to be lost on homologous recombination but not on random integration. Mansour, S., at al., Nature 336:348-352 (1988). Web site: http://www.delphion.com/details?pn=US06653113__ •
Human brain endothelial cells and growth medium and method for expansion of primitive CD34+CD38-bone marrow stem cells Inventor(s): Chute; Dennis J. (Los Angeles, CA), Chute; John P. (San Francisco, CA), Davis; Thomas A. (Newton, PA), Saini; Abha A. (Collegeville, PA) Assignee(s): The United States of America AS Represented by the Secretary of the Navy (washington, Dc) Patent Number: 6,642,049 Date filed: December 3, 1999 Abstract: A novel co-culture system using human brain endothelial cells (HUBEC) which promotes the expansion of human CD34.sup.+ CD38.sup.- cells consistent with the PMVEC system is disclosed. HUBEC were isolated from cadaveric donors, passed in primary culture, cloned and found to be Von Willebrand Factor positive. Cultivation of purified bone marrow CD34.sup.+ cells on HUBEC monolayers supplemented with GM-CSF+IL-3+IL-6+SCF+flt-3 ligand caused a 14.5-fold increase in total cells, an 6.6fold increase in CD34.sup.+ cells, and, most remarkably, a 440-fold increase in CD34.sup.+ CD38.sup.- cells after 7 days. Further, CFU-GM production increased 15.1fold, BFU-E increased 8-fold, and CFU-Mix increased 5.2-fold. Optimal generation was dependent upon the continued presence of exogenous supplied cytokines. Moreover, we found that non-brain human endothelial cells isolated from the same donors supported neither the expansion nor the maintenance of human CD34.sup.+ CD38.sup.- cells. Excerpt(s): This invention relates to a growth medium derived from human brain endothelial cells (HUBEC) and the methods of utilizing said growth medium to expand bone marrow stem cells. The development of an ex-vivo system which supports the proliferation and expansion of the most primitive hematopoietic stem cells (HSC) would have direct application to the fields of gene therapy and stem cell transplantation. Identification and characterization of the optimal culture conditions for the expansion of long-term repopulating cells is a requirement for gene therapy protocols and other stem cell-based therapies. Various cytokine combinations and liquid culture methods have been shown to support the proliferation of CD34.sup.+ HPC in vitro, but the most primitive CD34.sup.+ CD38.sup.- cells are frequently lost due to differentiation and cell death [1-6]. In contrast, other investigations have demonstrated that when human HPC are co-cultured in contact with autologous, allogeneic, and xenogeneic bone marrow stroma, a small percentage of long term culture initiating cells (LTC-IC) can be maintained over several weeks [7-9]. Similarly, others have reported the expansion and differentiation of LTC-IC and CFC in stroma-free liquid suspension cultures using exogenous cytokines plus conditioned medium from bone marrow stromal cultures [10-12]. Most recently, it was reported that human cord blood CD34.sup.+ cells could be maintained in stroma-free liquid cultures in the presence of flt-3 ligand, megakaryocyte growth and development factor (MGDF), SCF, and IL-6 for up to 10 weeks without losing their ability to repopulate NOD/SCID mice [13]. Web site: http://www.delphion.com/details?pn=US06642049__
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Inducible HSV-TK in transformed cell populations Inventor(s): Borrelli; Emiliana (Strasbourg Cedex, FR), Evans; Ronald M. (La Jolla, CA), Heyman; Richard Alan (Encinitas, CA) Assignee(s): The Salk Institute for Biological Studies (la Jolla, Ca) Patent Number: 6,677,311 Date filed: June 5, 1995 Abstract: The present invention discloses a new selective method for inducibly and genetically ablating specific cell lineages in transgenic cell populations, e.g., in transgenic animals. The new method, which permits the production of stable transgenic perigees, and thus can be used at various stages of development of a transgenic cell population, allows both the timing and the degree of cellular ablation to be controlled. As a result the method can be used for a variety of therapeutic applications, as well as to study cell lineages and organogenesis, plus the capacity that residual stem cells have for regeneration. Excerpt(s): The present invention relates to transgenic cell populations, e.g., transgenic cell lines and transgenic animals. More particularly, the invention relates to negative selection methods, chimeric gene constructs useful therefor, methods for establishing stable transgenic cell populations and then selectively ablating (i.e., negatively selecting for) specific cell types and/or cell lineages in such transgenic cell populations at desired stages of development or differentiation. Positive selection procedures or negative selection procedures can be used to differentiate various cell types of a given cell population. In a positive selection situation, cells having desirable properties have one or more growth and/or maintenance advantages over cells which do not have such properties. The cells having such desirable properties out-compete the remaining cells in the cell population, and eventually overtake the remaining cells in the population. Thus, the ultimate cell population is determined, in large part, by specific features possessed by the surviving cells (but which features were not possessed by the cells which were eliminated). In contrast, negative selection involves removing from a cell population (or destroying) those cells which do not have the specific features desired for the ultimate cell population. Thus, in the negative selection situation, the ultimate cell population is determined by one or more specific features possessed by the cells which are no longer a part of the surviving cell population. Web site: http://www.delphion.com/details?pn=US06677311__
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I-Sce I induced gene replacement and gene conversion in embryonic stem cells Inventor(s): Babinet; Charles (Paris, FR), Choulika; Andre (Paris, FR), Cohen-Tannoudji; Michel (Paris, FR), Jaisser; Frederic (Malakoff, FR), Louvard; Daniel (Sceaux, FR), Robine; Sylvie (Vanves, FR) Assignee(s): Centre Nationale DE LA Recherche Scientifique (paris, Fr), Institut Curie (paris, Fr), Institut Pasteur (paris, Fr) Patent Number: 6,566,579 Date filed: July 17, 1998 Abstract: The invention relates to methods of introducing a heterologous DNA sequence into a mouse embryonic stem cell wherein the DNA sequence is inserted by homologous recombination into a villin gene/I-SceI hybrid by creating a double strand
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break with I-SceI meganuclease. Subsequently, the mouse embryonic stem cells can be used to generate a transgenic mouse comprising the heterologous DNA sequence. Additionally, the methods can be used for gene replacement in ovo where a mouse oocyte containing a villin gene/I-SceI hybrid within its genome exists or is first generated. More generally, the methods can be used for the targeted insertion of a heterologous DNA sequence into any cell containing a villin gene/I-SceI hybrid sequence within its genome. Excerpt(s): The ability to introduce specific alterations of endogenous genes into the germline of mice via targeted mutagenesis in embryonic stem cells (ES) has represented a major breakthrough in mouse genetics. Thus gene inactivation has been widely used to examine the effect of loss of function in various biological processes and has already permitted to accumulate a wealth of new insights into gene function and also to create mouse models of human genetic diseases. However it would also be useful to introduce subtle mutations, in order to refine the genetic analysis and to better approximate the models of genetic diseases which do not necessarily result from null mutations. Thus several strategies have been developped, aimed at generating subtle mutations in a given gene. However, one common limitation to all the current gene targeting procedures is the low frequency of correct targeting, which becomes a serious problems especially when using two successive rounds of targeting. Therefore, efforts have been made to increase the efficiency of gene targeting by several means like increasing the size of the region of homologies with the target locus, using isogenic genomic DNA, or improving the selection procedures. Strategy for the induction of gene conversion and gene replacement upon DSB repair in the natural villin locus. (A) Gene targeting on the I-SceI restriction site in the villin locus by homologous recombination (B) Cotransfection of the pI-SceI expression plasmid and of the replacement construct confering hygromycine resistance. Resulting recombinants represent gene conversion events, with return to the wild-type genotype, or homologous gene replacement in the villin locus. Southern blot analysis of gene targeting of the I-SceI restriction site in the villin locus. Experiments were performed as described in ref X. (A). Targeting of the ISceI restriction site in the villin locus of CK35 ES cells. Genomic DNAs of ES WT and ES59 clone were digested with (lanes 2 and 4) or without (lanes 1 and 3) the I-SceI meganuclease, followed by ScaI digestion and probed with A (0.4 kb BamHI-HincII, 3' external probe). The 7.5 kb band represents the targeted allele that resulted in a 4.5 kb band when digested by I-SceI. (B) Restriction maps for (from top to bottom) the 3' portion of the mouse villin locus, the targeting construct, the homologous recombinant. The dark rectangles represent the three first exons of the villin gene. The black bar represents the probe A used for hybridization. Restriction sites of Sca I (S), BamH1 (B) and I-SceI are indicated. Numbers on the right side of the blot indicates the sizes of the bands in kb. Web site: http://www.delphion.com/details?pn=US06566579__ •
Isolated mammalian neural stem cells, methods of making such cells Inventor(s): Kukekou; Valery G. (Memphis, TN), Laywell; Eric D. (Memphis, TN), Steindler; Dennis A. (Memphis, TN), Thomas; L. Brannon (Johnson City, TN) Assignee(s): University of Tennessee Research Foundation () Patent Number: 6,638,763 Date filed: October 1, 1999
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Abstract: Using a novel culture approach, previously unknown populations of neural progenitor cells have been found within an adult mammalian brain. By limiting cell-cell contact, dissociated adult brain yields at least two types of cell aggregates. These aggregates or clones of stem/precursor cells can be generated from adult brain tissue with significantly long postmortem intervals. Both neurons and glia arise from stem/precursor cells of these cultures, and the cells can survive transplantation to the adult mammalian brain. Excerpt(s): This invention relates generally to novel mammalian brain cell types and methods of culturing such cells. The methods of the instant invention, which utilize suspension cultures and factors that limit cell contacts, result in an amplification of the production of neural stem and progenitor cells, and clones of such cells, from the adult mammalian brain, including the human brain and from tissue with significant (e.g. 1 day) postmortem intervals. Propagation of neural stem and progenitor cells is relevant to the large-scale production of glial and neuronal cells, and clones of such cells, as well as self-repair of the brain in neurological disease. Prior to the present invention, cells from numerous tissues have been described that have attributes of stem or germ cells (i.e., spermatozoon or an ovum), and that are extremely well-suited for rapid selfrenewal. Brain-derived stem cells have only recently been a major focus of attention, using a variety of lineage tracing and culture methodologies. See for example, Gage et al., Ann. Rev. Neurosci., 18:159-192 (1995); Svendsen et al., Trends Neurosci., 18:465-467 (1995); Alvarez-Buylla et al., Stem Cells, 13:263-272 (1995); Weiss et al., Trends Neurosci., 19:387-393 (1996); Steindler et al., Prog. Brain Res., 108:349-363 (1996); and Brustle et al., Neuron, 15:1275-1285 (1995). Previous studies showed the presence of a dense extracellular matrix ("ECM") on and around subependymal zone ("SEZ") cells of the adult rodent (see, Gates et al., J. Comp. Neurol., 361:249-266 (1995); and Thomas et al., Glia, 17:1-14 (1996)). ECM molecules may facilitate cell movement and aspects of differentiation during development, and they are also implicated in a number of neuropathological conditions. Glycoproteins such as tenascin-C (TN) and proteoglycans such as the chondroitin sulfate-containing proteoglycans (CSPG) are expressed in high levels in the young brain, where they seem to have a role in forming glycoconjugate-rich boundaries around different functional groups of neurons, such as the somatosensory whisker barrel fields and striosomes in the striatum. They are then down-regulated in later stages of development (e.g. postnatal days 14-21) and normal adulthood, but their expression is enhanced in neuropathologic conditions, such as traumatic brain injury, where they are an important component of glial scar formation. In the astroglial/mesonchymal scar, they may create a barrier that inhibits the growth of neurites into the scar, although it has been proposed that some ECM molecules may actually encourage neuritic growth under some circumstances. It has also been suggested that ECM molecules regulate cell proliferation, differentiation, migration, and survival through cell-cell and cell-ECM interactions. Stem cells have been described in embryonic and postnatal mouse brain and in proliferative "neurospheres" that can be harvested and cultured from different brain areas, including the developing subventricular zone. See, for example, Cattaneo et al., Nature 347:762 (1990); Richards et al., Proc. Nat'l Acad. Sci. (USA), 89:8591-8595 (1992); Reynolds et al., Science, 255:17071710 (1992); Reynolds et al., J. Neurosci. 12:4565-4574 (1992); Reynolds et al., Dev. Biol., 175:1-13 (1996); Vescovi et al., Neuron, 11:951-966 (1993); Kirschenbaum et al., Cerebral Cortex, 6:576-589 (1994); Kirschenbaum et al., Proc Nat'l Acad. Sci. (USA), 92:210-214 (1995) Fillmore et al., Neurosci Abs., 21:1528 (1996); and Gritti et al., J. Neurosci., 16:1091-1100 (1996). Evidence from immunolabeling and cell birthday analyses has pointed to the existence of such cells in the adult SEZ. See, for example, Luskin et al., Neuron, 11:173-189 (1993); Menezes et al., J. Neurosci. 14:5399-5416 (1994); Levison et al.,
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Neuron. 10:201-212 (1993); Gates et al., J. Comp. Neurol., 361:249-266 (1995), Zerlin et al., J. Neurosci. 15:7238 (1995); Thomas et al., Glia, 17:1-14 (1996); and Jankovski et al., J. Comp. Neurol., 371:376 (1996). The combination of stem/precursor cells, and a dense ECM in the peri-ventricular SEZ throughout the neuraxis has prompted the inventors of the instant invention to refer to this area as being the neuropoietic "Brain Marrow" (Steindler et al, Pros. Brain Res. 108: 349, (1996)) since it contains elements in common with hematopoietic bone marrow. Web site: http://www.delphion.com/details?pn=US06638763__ •
Isolation and preservation of fetal and neonatal hematopoietic stem and progenitor cells of the blood Inventor(s): Boyse; Edward A. (Tucson, AZ), Broxmeyer; Hal E. (Indianapolis, IN), Douglas; Gordon W. (New York, NY) Assignee(s): Pharmastem Therapeutics, Inc. (del Mar, Ca) Patent Number: 6,569,427 Date filed: May 16, 1995 Abstract: The present invention relates to hematopoietic stem and progenitor cells of neonatal or fetal blood that are cryopreserved, and the therapeutic uses of such stem and progenitor cells upon thawing. In particular, the present invention relates to the therapeutic use of fetal or neonatal stem cells for hematopoietic (or immune) reconstitution. Hematopoietic reconstitution with the cells of the invention can be valuable in the treatment or prevention of various diseases and disorders such as anemias, malignancies, autoimmune disorders, and various immune dysfunctions and deficiencies. In another embodiment, fetal or neonatal hematopoietic stem and progenitor cells which contain a heterologous gene sequence can be used for hematopoietic reconstitution in gene therapy. In a preferred embodiment of the invention, neonatal or fetal blood cells that have been cryopreserved and thawed can be used for autologous (self) reconstitution. Excerpt(s): 1. Introduction. 2. Background of the Invention. 2.1. Hematopoietic Stem and Progenitor Cells. Web site: http://www.delphion.com/details?pn=US06569427__
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Method for composite cell-based implants Inventor(s): Bloom; Leonard (Owings Mills, MD), Domb; Abraham J. (Efrat, IL), Fink; David J. (Baltimore, MD), Frondoza; Carmelita G. (Woodstock, MD), Hungerford; David S. (Cockeysville, MD), Shikani; Alan H. (Ruxton, MD) Assignee(s): Chondros, Inc. (), The Johns Hopkins University () Patent Number: 6,662,805 Date filed: August 6, 2001 Abstract: This invention is a method for the implantation of a combination of cells or cell-microcarrier aggregates wherein one component comprises a solid implantable construct and a second component comprises an injectable formulation. For example, in one embodiment, the solid implant may be first implanted to fill the majority of the cavity receiving the implant, and then cells or cell-microcarrier aggregates in an
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injectable format, with or without the addition of gelling materials to promote rapid gelling in situ, may be injected into spaces surrounding the solid implant in order to secure the solid implant in the site and/or to promote rapid adherence and/or integration of the solid implant to surrounding tissues. Also contemplated in this embodiment is that the cellular composition of the injectable component may differ from that of the solid component. For example, the solid implant may result from the culturing of chondrocytes on microcarriers or scaffolds, thereby resulting in an implant having cartilage-like properties, whereas the injectable cells or aggregates may result from the culturing of stem cells, resulting thereby in cells capable of producing cells of a chondrogenic, fibroblastic, myoblastic or osteoblastic phenotype. In this example, cells in the injectable aggregates may promote the fixation to or rapid integration of the solid cartilage implant into surrounding cartilage, connective tissue, muscle or bone, respectively. Excerpt(s): The herein disclosed invention finds applicability in the field of preparation and implantation of tissue substitutes for tissue replacement and for prosthesis. The present inventors have previously described a microcarrier spinner culture system that facilitated maintenance of chondrocytic phenotype while enhancing proliferation. Articular chondrocytes were grown on dextran or crosslinked collagen microcarrier beads under controlled pH, oxygen levels, nutrient supply and mechanical agitation conditions. This represents a great advantage over the traditional static monolayer culture system, which facilitates proliferation but leads to a fibroblastic shift in phenotype. Likewise, it offers an alternative to the battery of three-dimensional gel or scaffold systems, which include agarose or collagen gels, calcium alginate gel, mixed fibrin-alginate gels, three-dimensional meshes of resorbable polymers such as polylactides or polyglycolides, and encapsulation in alginate beads. These latter culture techniques facilitate the maintenance of a chondrocytic phenotype, but are limited in maximizing proliferation. In another embodiment of the PTO Ser. No. 09/825,632 invention, cell-microcarrier aggregates are cultured to provide a suspension of individual aggregates that may be implanted by injection by syringe or by other endoscopic or arthroscopic instruments suitable for their implantation into a diseased or damaged anatomic site. In this embodiment, cell-microcarrier aggregates may be implanted without any additional material to bind the aggregates together after implantation. Alternatively, a material capable of polymerizing or gelling after implantation may be mixed with the aggregate suspension prior to implantation in order to improve the fixation and localization of the aggregates after implantation, to stimulate more rapid consolidation of the aggregates in vivo, or to promote more rapid integration of the aggregates into the surrounding tissue. Web site: http://www.delphion.com/details?pn=US06662805__ •
Method for detecting hematopoietic stem cells Inventor(s): Belyavsky; Alexander (New York, NY), Shmelkov; Sergey (Union City, NJ), Visser; Jan (New York, NY) Assignee(s): New York Blood Center, Inc. (new York, Ny) Patent Number: 6,670,123 Date filed: November 3, 2000 Abstract: The present invention provides an isolated nucleic acid encoding KIAA0918, an isolated nucleic acid that hybridizes under high stringency conditions to a nucleic acid that is complementary to a nucleic acid encoding KIAA0918, a purified KIAA0918
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protein, a purified protein encoded by a nucleic acid that hybridizes under high stringency conditions to a nucleic acid that is complementary to a nucleic acid encoding KIAA0918, a method of making KIAA0918 protein, an antibody specific for KIAA0918, a method for producing an antibody specific for KIAA0918 protein, a vector comprising a nucleic acid encoding KIAA0918, and a host cell transformed with a vector comprising a nucleic acid encoding KIAA0918. Also provided are methods for detecting the presence of and isolating hematopoietic stem cells in a heterogeneous cell suspension and for assessing gene expression in a tissue sample. Excerpt(s): In vertebrates, most tissues are composed of differentiated cells that no longer divide. Nevertheless, there are tissues which retain an `embryonic` cell population within themselves. The cellular composition of such embryonic populations is always changing, even in adult animals. This phenomenon is most evident in the mammalian hematopoietic system. This system, which is organized hierarchically, consists of a heterogeneous mixture of many different kinds of blood cells at all stages of differentiation--some morphologically recognizable and some not [23]. Mature, functional blood cells are divided into several lines, including erythroid, lymphoid, and myeloid, each possessing its own morphology, characteristics, and function. Each blood line derives from restricted progenitor cells, which become committed to a particular line of differentiation. However, despite this diversity, the various developing blood cells and progenitor cells derive from one discreet source: the embryonic cell population of multipotential, self-renewing hematopoietic stem cells [21, 22]. A stem cell is a cell capable of extensive proliferation: it generates more stem cells (through self-renewal) in addition to its differentiated progeny [20, 21]. In mammals and birds, a multipotential hematopoietic stem cell can give rise to red blood cells (erythrocytes), white blood cells (granulocytes), macrophages, platelets, and immunocompetent cells (lymphocytes) [22]. Thus, a single hematopoietic stem cell can generate a clone containing millions of differentiated cells, as well as a few stem cells. The continuous formation of new blood cells is accomplished in bone marrow by hematopoietic stem cells. Stem cells mature into progenitor cells, which then become lineage-committed, although not yet terminally-differentiated. Once committed, progenitor cells are no longer capable of maturing into all of the cell lineages which comprise the hematopoietic system [22]. Hematopoietic stem cells currently find use in a myriad of clinical settings. Indeed, with the recent remarkable progress in cell processing technology, there has been a rapid increase in the number of patients and types of diseases that are now treated with hematopoietic stem-cell transplantation, in both autologous and allogeneic cases. For example, autologous peripheral stem-cell support has largely replaced bone marrow transplantation as a means of regenerating the hematopoietic system of myeloma patients undergoing myeloablative chemotherapy. Stem cell transplantation is also used to treat patients with non-Hodgkin's lymphomas [25]. Moreover, peripheral blood autografting has been widely used in trials for the treatment of chemosensitive tumors [26]. Web site: http://www.delphion.com/details?pn=US06670123__
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Methods for enhanced virus-mediated DNA transfer using molecules with virus-and cell-binding domains Inventor(s): Williams; David A. (Indianapolis, IN) Assignee(s): Advanced Research and Technology Institute, Inc. (indianapolis, In) Patent Number: 6,670,177 Date filed: June 19, 1998 Abstract: A method to increase the efficiency of transduction of hematopoietic and other cells by retroviruses includes infecting the cells in the presence of fibronectin or fibronectin fragments. The fibronectin and fibronectin fragments significantly enhance retroviral-mediated gene transfer into the cells, particularly hematopoietic cells including committed progenitors and primitive hematopoietic stem cells. The invention also provides improved methods for somatic gene therapy capitalizing on enhanced gene transfer, hematopoietic cellular populations, and novel constructs for enhancing retroviral-mediated DNA transfer into cells and their use. Excerpt(s): The present invention relates generally to methods for increasing the efficiency of transduction of cells by viruses, and more particularly to methods for enhancing viral-mediated gene transfer into cells utilizing molecules, such as polypeptides, which contain an area which binds the virus and an area which binds the cells. Progress in understanding the molecular basis of many human diseases as well as improvement in gene transfer technology has led to recent attempts to develop protocols for somatic gene therapy for severe genetic diseases. Currently, promising disease candidates for human gene therapy include those in which an enzymne or other protein is defective or missing, where the level of enzyme or protein does not need to be exactly regulated, especially those that are constitutively regulated, and those defects which are found in the patient'bone marrow. For example, one disease candidate for gene therapy is adenosine deaminase (ADA) deficiency which results in severe combined immunodeficiency disease (SCID). ADA deficient patients have little or no detectable enzyme in bone marrow cells. However, ADA deficiency has been cured by matched bone marrow transplantation. ADA normal cells have a selective advantage over ADA deficient cells and will normally repopulate the patients bone marrow. Web site: http://www.delphion.com/details?pn=US06670177__
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Methods for modulation and inhibition of telomerase Inventor(s): Chen; Shih-Fong (San Antonio, TX), Fletcher; Terace M. (San Antonio, TX), Kerwin; Sean M. (Round Rock, TX), Maine; Ira (San Antonio, TX), Mamiya; Blain (Austin, TX), Salazar; Miquel (Austin, TX), Wajima; Makoto (San Antonio, TX), Windle; Bradford E. (San Antonio, TX) Assignee(s): Board of Regents, the University of Texas Systems (austin, Tx), Ctrc Research Foundation (san Antonio, Tx) Patent Number: 6,593,306 Date filed: December 21, 1999 Abstract: It was found that normal human stem cells produce a regulated nonprocessive telomerase activity, while cancer cells produce a processive telomerase activity. Nucleotide analogs, such as 7-deaza-2'-deoxyquanosine-5'-triphosphate (7deaza-dGTP) were found to be substrates for processive telomerase and incorporated
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into telomeric sequence. The incorporation of this nucleotide subsequently affected the processivity of telomerase, converting processive telomerase to non-processive telomerase. The incorporation of this nucleotide analogs was also found to inhibit formation of G-quartets by telomeric sequence. Other methods for converting cancer processive telomerase to the more benign non-processive telomerase include partially cleaving the telomerase RNA. The nucleoside analogs were found to be capable of a variety of activities including mediating allosteric-like inhibition of telomerase, premature termination and shortening of telomeric DNA, destabilization of telomeric structure and function and eventually cell death. Understanding the mechanisms of telomerase modulation by the 7-deaza-nucleotides has allowed the design of new telomerase inhibitors, modulators and agents for affecting telomere structure and function. These discoveries have application in the treatment of cancer. Excerpt(s): The present invention relates generally to the field of molecular biology. More particularly, certain embodiments concern methods and compositions useful in modulating or inhibiting human telomerase activity. In certain embodiments, the invention concerns the use of these agents in treatment of proliferative cell disorders, particularly for cancers whose proliferation is determined by processive telomerase activity. Telomeres play an important role in chromosome organization and stability. Human telomerase is a terminal transferase that adds TTAGGG units onto the telomere end. In general, telomerase activity is not detected in normal somatic cells leading to the implication of telomerase in cancer and the impetus to develop agents that selectively target telomerase activity. One of the general characteristics of cancer cells is genomic instability. Though it is still unclear what causes this instability, a hypothesis gaining increasing attention is that free chromosome ends, either from chromosome breakage or from loss of the telomere sequences which cap the ends, are prone to illegitimate recombination events. Thus, telomeres provide stability to the chromosomes. However, there appears to be a gradual loss of telomere sequences with each cell division, perhaps because of the end-replication problem. Tumor cells have shortened telomeres, but they also possess greatly elevated levels of the enzyme telomerase to overcome the endreplication problem, while normal cells do not. Thus, telomerase is an attractive-target for new anti-cancer agents because of the expected selectivity for neoplastic cells. Web site: http://www.delphion.com/details?pn=US06593306__ •
Methods for promoting growth of bone using zvegf3 Inventor(s): Gilbertson; Debra G. (Seattle, WA), Hart; Charles E. (Woodinville, WA) Assignee(s): Zymogenetics, Inc. (seattle, Wa) Patent Number: 6,663,870 Date filed: March 29, 2001 Abstract: Methods for promoting growth of bone, ligament, or cartilage in a mammal are disclosed. The methods comprise administering to said mammal a composition comprising a pharmacologically effective amount of a zvegf3 protein in combination with a pharmaceutically acceptable delivery vehicle. Also disclosed are methods for promoting proliferation or differentiation of osteoblasts, osteoclasts, chondrocytes, or bone marrow stem cells comprising culturing the cells in an effective amount of a zvegf3 protein. Excerpt(s): Bone remodeling is the dynamic process by which tissue mass and skeletal architecture are maintained. The process is a balance between bone resorption and bone
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formation, with two cell types, the osteoclast and osteoblast, thought to be the major players. Osteoblasts synthesize and deposit new bone into cavities that are excavated by osteoclasts. The activities of osteoblasts and osteoclasts are regulated by many factors, systemic and local, including growth factors. Many of the proteins that influence the proliferation, differentiation, and activity of osteoblasts, osteoclasts, and their precursors also affect these processes in chondrocytes, the cells responsible for cartilage formation (chondrogenesis). These proteins include platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), basic fibroblast growth factor (bFGF), transforming growth factor beta (TGF-.beta.), bone morphogenetic proteins (BMPs), and cartilagederived growth factor (CDGF). The exact mode by which PDGF affects the growth of osteoblasts is not yet clearly understood, however, this growth factor is generally believed to play a key role in the regulation of both normal skeletal remodeling and fracture repair. Biologically active PDGF is found as a homodimer or a heterodimer of the component A and B chains. In vitro studies have shown PDGF to be mitogenic for osteoblasts (Abdennagy et al., Cell Biol. Internat. Rep. 16(3):235-247, 1992). Mitogenic activity as well as chemotactic activities associated with PDGF have been demonstrated when the growth factor is added to normal osteoblast-like cells (Tuskamota et al., Biochem. Biophys. Res. Comm. 175(3):745-747, 1991) and primary osteoblast cultures (Centrella et al. Endocrinol. 125(1):13-19, 1989). Recent studies have demonstrated that the osteoblast produces the AA isoform of PDGF (Zhang et al., Am. J. Physiol. 261:c348c354, 1991). Web site: http://www.delphion.com/details?pn=US06663870__ •
Methods for providing differentiated stem cells Inventor(s): Gold; Joseph D. (San Francisco, CA), Lebkowski; Jane S. (Portola Valley, CA) Assignee(s): Geron Corporation (menlo Park, Ca) Patent Number: 6,576,464 Date filed: February 13, 2001 Abstract: This invention provides a system for producing differentiated cells from a stem cell population for use wherever a relatively homogenous cell population is desirable. The cells contain an effector gene under control of a transcriptional control element (such as the TERT promoter) that causes the gene to be expressed in relatively undifferentiated cells in the population. Expression of the effector gene results in depletion of undifferentiated cells, or expression of a marker that can be used to remove them later. Suitable effector sequences encode a toxin, a protein that induces apoptosis, a cell-surface antigen, or an enzyme (such as thymidine kinase) that converts a prodrug into a substance that is lethal to the cell. The differentiated cell populations produced according to this disclosure are suitable for use in tissue regeneration, and nontherapeutic applications such as drug screening. Excerpt(s): This invention relates generally to the field of cell biology of embryonic cells, and the molecular biology of promoter controlled viral vectors. More specifically, it describes a technology for removing undifferentiated cells from populations derived from pluripotent stem cells using selectively expressed lytic vectors. Precursor cells have become a central interest in medical research. Many tissues in the body have a back-up reservoir of precursors that can replace cells that are senescent or damaged by injury or disease. Considerable effort has been made recently to isolate precursors of a number of different tissues for use in regenerative medicine. U.S. Pat. No. 5,750,397
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(Tsukamoto et al., Systemix) reports isolation and growth of human hematopoietic stem cells which are Thy-1+, CD34+, and capable of differentiation into lymphoid, erythroid, and myelomonocytic lineages. U.S. Pat. No. 5,736,396 (Bruder et al.) reports methods for lineage-directed differentiation of isolated human mesenchymal stem cells, using an appropriate bioactive factor. The derived cells can then be introduced into a host for mesenchymal tissue regeneration or repair. Web site: http://www.delphion.com/details?pn=US06576464__ •
METHODS FOR REGULATING THE SPECIFIC LINEAGES OF CELLS PRODUCED IN A HUMAN HEMATOPOIETIC CELL CULTURE, METHODS FOR ASSAYING THE EFFECT OF SUBSTANCES ON LINEAGE-SPECIFIC CELL PRODUCTION, AND CELL COMPOSITIONS PRODUCED BY THESE CULTURES Inventor(s): Armstrong; R. Douglas (Ann Arbor, MI), Clarke; Michael F. (Ann Arbor, MI), Emerson; Stephen G. (Ann Arbor, MI), Palsson; Bernhard O. (La Jolla, CA) Assignee(s): The Regents of the University of Michigan (ann Arbor, Mi) Patent Number: 6,667,034 Date filed: May 16, 1997 Abstract: Methods, including culture media conditions, which provide for in vitro human stem cell division and/or the optimization of human hematopoietic progenitor cell cultures and/or increasing the metabolism or GM-CSF secretion or IL-6 secretion of human stromal cells and/or a method for assaying the effect of a substance or condition on a human hematopoietic cell population, and/or depleting the malignant cell or T-cell and B-cell content of a human hematopoietic cell population are disclosed. The methods rely on culturing human stem cells and/or human hematopoietic progenitor cells and/or human stromal cells in a liquid culture medium which is replaced, preferably perfused, either continuously or periodically, at a rate of 1 ml of medium per ml of culture per about 24 to about 48 hour period, and removing metabolic products and replenishing depleted nutrients while maintaining the culture under physiologically acceptable conditions. Optionally, growth factors are added to the culture medium. The disclosed culture conditions afford improved methods for bone marrow transplantation. Excerpt(s): The present invention relates to methods and compositions for the growth of mammalian cells in culture, particularly the growth of hematopoietic cell cultures. The present invention also relates to a functioning in vitro human tissue system, which may serve as a model for hematopoiesis. The present invention further relates to a method for assaying the effect of a substance and/or physical condition on a human hematopoietic cell mass or the hematopoietic process. The present invention also relates to a method for controlling the lineage development in an in vitro human tissue system and cultures of cells in which the population of a particular cell type has been enhanced relative to the total cell population in the culture or depleted. In addition, the present invention relates to a method of bone marrow tranplantation, in which the tissue implanted into the donee has been cultured by the present method. All of the circulating blood cells in the normal adult, including erythrocytes, leukocytes, platelets and lymphocytes, originate as precursor cells within the bone marrow. These cells, in turn, derive from very immature cells, called progenitors, which are assayed by their development into contiguous colonies of mature blood cells in 1-3 week cultures in semisolid media such as methylcellulose or agar. Progenitor cells themselves derive from a class of progenitor cells called stem cells. Stem cells have the capacity, upon division, for both self-renewal and differentiation into progenitors. Thus, dividing stem
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cells generate both additional primitive stem cells and somewhat more differentiated progenitor cells. In addition to the generation of blood cells, stem cells also may give rise to osteoblasts and osteoclasts, and perhaps cells of other tissues as well. This document describes methods and compositions which permit, for the first time, the successful in vitro culture of human hematopoietic stem cells, which results in their proliferation and differentiation into progenitor cells and more mature blood cells of a specific lineage. Web site: http://www.delphion.com/details?pn=US06667034__ •
Methods for use of delivery composition for expanding, activating, committing or mobilizing one or more pluripotent, self-renewing and committed stem cells Inventor(s): Etter; Jeffrey B. (Boulder, CO), Rosenthal; Gary J. (Louisville, CO), Talmadge; James E. (Bellevue, NE) Assignee(s): Rxkinetix, Inc. (louisville, Co) Patent Number: 6,649,189 Date filed: June 26, 2001 Abstract: A hematopoietic growth factor delivery composition includes a hematopoietic growth factor, a liquid vehicle, a first biocompatible polymer and a second biocompatible polymer. The composition exhibits reverse-thermal viscosity behavior, due to interaction between the first biocompatible polymer and the liquid vehicle. The second biocompatible polymer helps to protect the first biocompatible polymer from being dissolved in vivo following administration to a host. Excerpt(s): The present invention relates to methods for expanding, activating, committing or mobilizing pluripotent self-renewing and committed stem cells. Functionally, hematopoietic growth factors can be considered to belong to one of three groups. The first or multilineage group includes interleukin 3 (IL-3) and granulocyte macrophage colony stimulating factor (GM-CSF) which act on early colony forming units (CFU's) including colony forming unit-granulocyte, erythrocyte, megakaryocyte, macrophage (CFU-GEMM), colony forming unit-granulocyte-macrophage (CFU-GM), burst forming units erythrocyte (BFU-E) or megakaryocytes, (BFU-MK). The second or unilineage group includes erythropoietin (EPO), granulocyte colony stimulating factor (G-CSF), interleukin 5 (IL-5), macrophage colony stimulating factor (M-CSF) and thrombopoietin (TPO), and act on later hematopoietic progenitors (i.e., colony forming unit erythrocyte (CFU-E), colony forming unit megakaryocyte (CFU-Mk), and colony forming unit eosinophil (CFU-Eo). The third or "potentiating" group includes interleukin 6 (IL-6), interleukin 11 (IL-11), lymphocyte inhibitory factor (LIF), fibroblast growth factor basic (FGFb), stem cell factor (SCF) and Flt3 ligand (Flt3-L), and act to potentiate the activities of other hematopoietic factors. Within the third group, SCF and Flt3-L both show marked activity on hematopoietic stem cells and thus have been considered special circumstance/stem cell growth factors. G-CSF and GM-CSF are two commonly used hematopoietic growth factors. The principal action of G-CSF is the stimulation of colony forming unit granulocyte (CFU-G), which in vivo manifests into an augmented production of polymorphonuclear leukocyte (neutrophil) as well as enhancing the phagocytic and cytotoxic functions of neutrophils in general. G-CSF has been shown to be effective in the treatment of severe neutropenia following autologous bone marrow transplantation and high-dose chemotherapy. GM-CSF and G-CSF are each used to decrease the period of neutropenia seen during this type of therapy and thereby reduces morbidity secondary to bacterial and fungal infections. When used as a
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part of an intensive chemotherapy regimen, G-CSF can decrease the frequency of both hospitalization for febrile neutropenia and interruptions in life-saving chemotherapy protocols. G-CSF also has proven to be effective in the treatment of severe congenital neutropenias. In patients with cyclic neutropenia, G-CSF therapy, while not eliminating the neutropenic cycle, will increase the level of neutrophils and shorten the length of the cycle sufficiently to prevent recurrent infections. G-CSF therapy can improve neutrophil counts in some patients with myelodysplasia or marrow damage. The neutropenia of AIDS patients receiving AZT also can be partially or completely reversed. Web site: http://www.delphion.com/details?pn=US06649189__ •
Nuclear targeted peptide nucleic acid oligomer Inventor(s): Lane; Kirk B. (Brentwood, TN) Assignee(s): Vanderbilt University (nashville, Tn) Patent Number: 6,623,966 Date filed: August 22, 2001 Abstract: A composition comprising a nuclear localization sequence and a peptide nucleic acid oligomer (NLS-PNA) is described. Uses of the composition include, but are not limited to: regulation of gene expression, gene therapy, and the production of pharmaceutical nucleic acids and proteins. In addition, the NLS-PNA is useful for scientific and therapeutic transfection and expression of nucleic acids in cells types that previously were resistant to transfection and therapy including quiescent cells, differentiated cells, embryonic stem cells, and eukaryotic cells with intact nuclear membranes. The NLS-PNA can be combined with a membrane transport sequence (MTS) forming a novel compound referred to as an MTS-NLS-PNA wherein the MTS provides transport through the cytoplasmic membrane of a cell. A nuclear targeted peptide nucleic acid oligomer is useful for the treatment of genetic based diseases and diseases that can be treated genetically including heart disease, cancer, cerebrovascular diseases, chronic pulmonary diseases, human immunodeficiency virus, and other diseases, conditions and disorders. Excerpt(s): The present invention relates generally to the transfection of eukaryotic cells, the regulation of gene expression, and gene therapy. In particular, the present invention relates to novel compositions and uses thereof including, but not limited to: the regulation of nucleic acid expression, the transfection of eukaryotic cells, gene therapy, the creation of transgenic animals, the biological production of pharmaceuticals, and the treatment of a variety of human diseases and disorders. One of the most utilized and important techniques employed in the biological sciences today is the transfer of foreign nucleic acids into cells in vitro and in vivo. This technology is the foundation for gene therapy. A primary obstacle to the successful implementation of gene transfer technology is that cellular membranes provide a significant barrier to the translocation of nucleic acid. Currently, techniques exist for the transfer of nucleic acids across the cytoplasmic membrane of prokaryotic (transformation) and eukaryotic cells (transfection) including chemical, physical, and biological methods such as: calcium phosphate co-precipitation, DEAE dextran treatment, electroporation, microinjection, biolistic bombardment, viral infection, and liposomal based methods. The nuclear membrane of eukaryotic cells, however, proves to be a more formidable challenge. This membrane is a barrier to the passive movement of macromolecules larger than 15,000 kDa. Empirically, transfection protocols are limited to rapidly dividing cells. The hypothesis for these observations is that transfected nucleic acids have access to the
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nuclear compartment only when the nuclear membrane is dissolved during mitosis. Without a nuclear membrane, the transfected nucleic acids are thought to distribute throughout the volume of the cell, and a portion of these nucleic acids might remain in the nucleus after the nuclear membrane reforms. Various strategies have been attempted to circumvent an intact nuclear membrane during transfection. Several viral vectors are under study as gene transfer agents, but all of them have major disadvantages. Viral vectors are a biohazard, it is usually necessary to employ procedures to limit viral replication by eliminating certain viral genes and using helper virus strains, the gene of interest must be cloned into the viral vector, and adeno-associated vectors (AAV) are difficult to produce in large quantities and have a limited capacity for accepting large transgenes. The transfection efficiency of most viral vectors is dependent upon proliferation of the host cell which, again, limits the utility of such vectors. Replication deficient adenoviral vectors have been used extensively in the lungs, but trigger an acute inflammatory response and a chronic immune response. Retroviral vectors, which insert randomly into the host genome, have the potential to disrupt normal genes and carry a risk of inducing malignancies. Thus, viral vectors show limited utility for in vivo therapy. Web site: http://www.delphion.com/details?pn=US06623966__ •
Peptide, apoEp 1.B, compositions and uses thereof Inventor(s): Rider; Beverley (Palo Alto, CA), Singh; Bhagirath (London, CA) Assignee(s): University of Western Ontario (london, Ca) Patent Number: 6,652,860 Date filed: August 7, 2000 Abstract: A peptide derived from apolipoprotein E termed apoEp1.B which includes amino acids 239-252 of the apolipoprotein E is described. The apoEp1.B peptide is a potent immune modulator that acts on a variety of immune cells. Interestingly, apoEp1.B is a dual modulator, capable of both inducing and suppressing an immune response. In particular, apoEp1.B has been shown to induce differentiation of stem cells into dendritic cells, to induce tumor cell differentiation and activation, to inhibit inflammation and to inhibit autoimmune disease. Excerpt(s): The invention relates to methods and compositions for immune modulation. The immune system is a complex, multifactorial defense system that protects the body from a wide range of infectious diseases including viruses, bacteria, parasites and fungi. Although critical for our survival, in certain instances, such as autoimmune disease, transplant rejection, allergies and inflammation, the immune system can be the cause of illness. In such instances it is desirable to suppress or tolerize the immune response. The immune system is comprised of a large variety of cells derived from undifferentiated hematopoietic stem cells and includes phagocytes (such as neutrophil polymorphs, monocytes, macrophages and dendritic cells) and lymphocytes such as T cells and B cells and natural killer cells. Web site: http://www.delphion.com/details?pn=US06652860__
Patents 197
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Reconstructed laminae of human epithelium corneae and method of producing the same Inventor(s): De Luca; Michele (Ardea, IT), Pellegrini; Graziella (Ardea, IT) Assignee(s): Provincia Italiana Della Congregazione Dei Figli Dell' Immacolata (rome, It) Patent Number: 6,610,538 Date filed: September 25, 2001 Abstract: A method of reconstructing laminae of human epithelium corneae in vitro to be used in grafts from cultures of limbar stem cells as well as a method of selecting and transferring such cells to fibrin substrate. Excerpt(s): The present invention relates to the grafts in the oculistics and more particularly the production in vitro of laminae of human epithelium corneae containing stem cells from cultured limbar stem cells to be grafted directly to patients. As known, stem cells of epithelium corneae are confined to the layer between cornea and conjunctiva, so-called limbus, and allow the upper layers to be continuously renewed. In the severe ocular burns the loss of corneal tissue and the total or subtotal depletion of the limbar cells causes the missing epithelium to be replaced by the conjunctival cells forming naturally an opaque layer that causes the loss of sight. Web site: http://www.delphion.com/details?pn=US06610538__
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Serum free medium for chondrocyte cells Inventor(s): Cancedda; Ranieri (Genoa, IT), Dozin; Beatrice (Rapallo, IT) Assignee(s): Consorzio Per LA Gestione Del Centro DI Biotechnologie Avanzate (genoa, It), Istituto Nazionale Per LA Ricerca Sul Cancro (genoa, It) Patent Number: 6,617,159 Date filed: June 11, 2001 Abstract: Serum free media for growth and proliferation of chondrocytes and mesenchymal stem cells in culture are provided. A serum free medium for growth of chondrocytes includes a serum free composition comprising FGF-2, linoleic acid, ascorbic acid, B-mercaptoethanol, transferrin and dexamethasone. Further the composition comprises EGF, PDGFbb, insulin and albumin. A method for growing chondrocytes in a serum free medium comprising the composition is also provided. Also provided for mesenchymal stem cell growth, is a serum free medium which includes a composition comprising FGF-2, LIF, SCF, pantotenate, biotin and selenium and method, therefore. Excerpt(s): Bone and cartilage transplantation is an absolute need in reconstruction of bone and cartilage segments in plastic surgery, traumatic surgery or after the removal of neoplastic lesions, etc. Typically, material of human (autologous, from donors or from cadavers) or animal origin has been used for this purpose. Given the increased demand from clinicians for transplant tissues, the increased need for microbial safety in tissue transplantation, the advances in cell biology, cell differentiation and tissue engineering, the concept of rebuilding tissues from autologous or allogeneic cells expanded in vitro has become a growing field in the world of biomedical sciences. Cellular sources for skeletal repair include chondrocytes and cells committed to the chondrocyte lineage, and mesenchymal stem cells, the former specific for cartilage, the latter multipotential and therefore having the potential to be used to replace bone, cartilage and other tissues.
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Mesenchymal stem cells (MSCs) are found in bone marrow as well as in blood, dermis and periosteum. Although these cells are normally present at very low frequencies in bone marrow, these cells can be isolated purified and culturally expanded, for example, as described in U.S. Pat. No. 5,486,359. Typically, the ill vitro expansion of chondrocytes and MSCs takes place in culture medium supplemented with bovine serum or optimally with autologous serum from the patient. However, the presence of animal or autologous serum in chondrocyte and MSC cultures has certain disadvantages and limitations in view of the potential therapeutical applications of these cultures. Web site: http://www.delphion.com/details?pn=US06617159__ •
Soluble human flk-2 protein Inventor(s): Lemischka; Ihor R. (Princeton, NJ) Assignee(s): The Trustees of Princeton University (princeton, Nj) Patent Number: 6,677,434 Date filed: June 1, 2001 Abstract: Isolated mammalian nucleic acid molecules encoding receptor protein tyrosine kinases expressed in primitive hematopoietic cells and not expressed in mature hematopoietic cells are provided. Also included are the receptors encoded by such nucleic acid molecules; the nucleic acid molecules encoding receptor protein tyrosine kinases having the sequences shown in FIG. 1a (murine flk-2), FIG. 1b (human flk-2) and FIG. 2 (murine flk-1); the receptor protein tyrosine kinases having the amino acid sequences shown in FIG. 1a, FIG. 1b and FIG. 2; ligands for the receptors; nucleic acid sequences that encode the ligands; and methods of stimulating the proliferation and/or differentiation of primitive mammalian hematopoietic stem cells comprising contacting the stem cells with a ligand that binds to a receptor protein tyrosine kinase expressed in primitive mammalian hematopoietic cells and not expressed in mature hematopoietic cells. Excerpt(s): The present invention relates to hematopoietic stem cell receptors, ligands for such receptors, and nucleic acid molecules encoding such receptors and ligands. The mammalian hematopoietic system comprises red and white blood cells. These cells are the mature cells that result from more primitive lineage-restricted cells. The cells of the hematopoietic system have been reviewed by Dexter and Spooncer in the Annual Review of Cell Biology 3, 423-441 (1987). The white blood cells contain the mature cells of the lymphoid and myeloid systems. The lymphoid cells include B lymphocytes and T lymphocytes. The B and T lymphocytes result from earlier progenitor cells referred to by Dexter and Spooncer as preT and preB cells. Web site: http://www.delphion.com/details?pn=US06677434__
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Storage system, particularly with automatic insertion and retrieval Inventor(s): Richard; Daniel D. (Sedona, AZ), Vago; Robert (Palm Harbor, FL) Assignee(s): Cryo-cell International, Inc. (clearwater, Fl) Patent Number: 6,564,120 Date filed: May 11, 2000
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Abstract: A storage system particularly for storing biological materials such as blood, stem cells, and DNA includes a storage unit having at least three vertical sides, at least two of the three vertical sides each being provided with a plurality of individually accessible storage receptacles. A plurality of boxes or cassettes are removably disposed in respective ones of the storage receptacles. At least one robot mechanism is movable along a track section or path extending to the two vertical sides of the unit, the robot mechanism having a robotic arm for accessing the storage receptacles. A computer is operatively connected to the robot mechanism for controlling movement and access operations thereof and for registering the contents of the storage receptacles. Where the storage unit is disposed in a room, additional storage receptacles may be disposed in a rectangular array inside a wall of the room. The boxes or cassettes contain a multiplicity of vials at least some of which may be segmented, with a plurality of separable compartments. Excerpt(s): This invention relates to a computer-controlled robotically operated storage system. More particularly, this invention relates to a storage system with automatic insertion and retrieval of samples from a storage container or unit. The invention is especially useful in the preservation of biological specimens at various temperatures, including room temperature and the temperature of liquid nitrogen. This invention also relates to an associated method for inventory control and storing samples or specimens such as DNA, blood, stem cells, as well as pharmaceutical compounds. When properly treated, biological specimens can be stored almost indefinitely at temperatures approaching that of liquid nitrogen so long as that temperature is maintained. However, once the temperature of a specimen is raised, especially to a level where thawing occurs, the integrity of the specimen might suffer if the specimen is then refrozen. Many conventional cryogenic storage units are simple containers with removable racks having multiple shelves. Specimens are inserted and removed from the storage units manually through a door in the top of the unit. Web site: http://www.delphion.com/details?pn=US06564120__ •
Suppressor cells induced by culture with mesenchymal stem cells for treatment of immune responses in transplantation Inventor(s): Klyushnenkova; Elena (Baltimore, MD), McIntosh; Kevin (Ellicott City, MD) Assignee(s): Osiris Therapeutics, Inc. (baltimore, Md) Patent Number: 6,685,936 Date filed: October 12, 1999 Abstract: A method of reducing an immune response to a transplant in a recipient by treating said recipient with an amount of suppressor T cells effective to reduce or inhibit host rejection of the transplant. The suppressor T cells can be administered before, at the same time as, or after the transplant. Also disclosed is a method of inducing a reduced immune response against a host by foreign tissue, i.e., graft versus host disease, by treatment with suppressor T cells. Excerpt(s): The present invention relates to inhibiting an immune response to an alloantigen and further relates to inhibiting and/or preventing reactivation of previously activated T cells. More particularly, the present invention relates to the field of preventing, reducing or treating an immune response caused by immune effector cells to foreign tissue and/or cells and/or organs. The invention further relates to preventing, reducing or treating transplant rejection and/or graft versus host reaction.
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Tolerance is the acquired lack of specific responsiveness to an antigen to which an immune response would normally occur. Typically, to induce tolerance, there must be an exposure to a tolerizing antigen, which results in the death or functional inactivation of certain lymphocytes. Complete tolerance is characterized by the lack of a detectable immune response to the second antigenic challenge. Partial tolerance is typified by the quantitative reduction of an immune response. Unfortunately, the immune system does not distinguish beneficial intruders, such as transplanted tissue, from those that are harmful, and thus the immune system rejects transplanted tissue or organs. Rejection of transplanted organs is significantly mediated by alloreactive T cells present in the host which recognize donor alloantigens or xenoantigens. Web site: http://www.delphion.com/details?pn=US06685936__ •
Therapeutic uses for nitric oxide inhibitors Inventor(s): Cline; Hollis (Cold Spring Harbor, NY), Enikolopov; Grigori N. (Cold Spring Harbor, NY), Kuzin; Boris A. (Moscow, RU), Michurina; Tatyana (Moscow, RU), Peunova; Natalia I. (Cold Spring Harbor, NY) Assignee(s): Cold Spring Harbor Laboratory (cold Spring Harbor, Ny) Patent Number: 6,593,372 Date filed: October 25, 2001 Abstract: The present invention is based on the discovery that nitric oxide (NO) is an important growth regulator in an intact developing organism. In particular, the present invention relates to a method of increasing in a mammal a population of hematopoietic stem cells which are capable of undergoing normal hematopoiesis, differentiation and maturation in hematopoietic tissue, wherein the hematopoietic tissue is contacted with multiple doses of at least one inhibitor of NO, such as one or more inhibitors of nitric oxide synthase (NOS), thereby producing hematopoietic tissue having an increased population of hematopoietic stem cells which are capable of undergoing normal hematopoiesis, differentiation and maturation. The present invention also relates to a method of increasing a population of cells in S phase in a tissue of a mammal, comprising contacting the tissue with multiple doses of at least one inhibitor (one or more) of NO, such as an inhibitor of NOS. The invention also pertains to a method of regenerating tissue in an adult mammal comprising contacting a selected tissue (e.g., blood, skin, bone and digestive epithelium), or precursor cells of the selected tissue, with multiple doses of at least one inhibitor (one or more) of NO, thereby inhibiting differentiation and inducing proliferation of cells of the tissue. Excerpt(s): Organ development requires a tightly controlled program of cell proliferation followed by growth arrest and differentiation and, often, programmed cell death. The balance between the number of cell divisions and the extent of subsequent programmed cell death determines the final size of an organ (reviewed by Bryant and Simpson, Quart. Rev. of Biol., 59:387-415 (1984); Raft, Nature, 356:397-400 (1992)). Although much of the cellular machinery that determines the timing of onset and cessation of cell division per se is well understood (reviewed by Hunter and Pines, Cell, 79:573-582 (1994); Morgan, Nature, 374:131-134 (1995); Weinberg, Cell, 81:323-330 (1995)), little is known about the signals that cause discrete groups of cells and organs to terminate growth at the appropriate cell number and size. A better understanding of the signals involved provides possible targets for manipulating the cellular machinery resulting in therapeutic benefits for a number of conditions. The present invention is based on the discovery that nitric oxide (NO) is an important growth regulator in an
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intact developing organism. In particular, the present invention relates to a method of increasing in a mammal a population of hematopoietic cells (e.g., hematopoietic stem cells), including precursors to myeloid, lymphoid and erythroid cells, which are capable of undergoing normal hematopoiesis, differentiation and maturation in hematopoietic tissue, wherein the hematopoietic tissue is contacted with multiple doses of at least one inhibitor of NO, such as multiple doses of one or more inhibitors of nitric oxide synthase (NOS), thereby producing hematopoietic tissue having an increased population of hematopoietic stem cells which are capable of undergoing normal hematopoiesis, differentiation and maturation. In one embodiment, the present invention relates to a method of increasing in a mammal a population of hematopoietic stem cells which are capable of undergoing normal hematopoiesis, differentiation and maturation in hematopoietic tissue, comprising contacting the hematopoietic tissue with two inhibitors of nitric oxide synthase, thereby producing hematopoietic tissue having an increased population of hematopoietic stem cells which are capable of undergoing normal hematopoiesis, differentiation and maturation. The method can be carried out in vivo or ex vivo. In addition, the method can be used to prevent differentiation of erythroid cells and/or myeloid cells in the mammal. The method can further comprise contacting the hematopoietic tissue with at least one agent (e.g., a hematopoietic growth factor) which induces differentiation of a selected hematopoietic stem cell population. The present invention also relates to a method for treating a mammal to increase a population of hematopoietic stem cells which are capable of undergoing normal hematopoiesis, differentiation and maturation in hematopoietic tissue of the mammal. In the method, the hematopoietic tissue of the mammal is contacted with multiple doses of at least one inhibitor of NOS, thereby producing hematopoietic tissue having an increased population of hematopoietic stem cells which are capable of undergoing normal hematopoiesis, differentiation and maturation. In one embodiment, the present invention relates to a method for treating a mammal to increase a population of hematopoietic stem cells which are capable of undergoing normal hematopoiesis, differentiation and maturation in hematopoietic tissue of the mammal, comprising contacting the hematopoietic tissue of the mammal with two inhibitors of nitric oxide synthase, thereby producing hematopoietic tissue having an increased population of hematopoietic stem cells which are capable of undergoing normal hematopoiesis, differentiation and maturation. The method can further comprise contacting the hematopoietic tissue with at least one agent which induces differentiation of a selected hematopoietic stem cell population. Web site: http://www.delphion.com/details?pn=US06593372__ •
Use of delta-like protein to inhibit the differentiation of stem cells Inventor(s): Lemischka; Ihor R. (Princeton, NJ), Moore; Kateri A. (Princeton, NJ), Pytowski; Bronislaw (New York, NY), Witte; Larry (Stormville, NY) Assignee(s): Imclone Systems Incorporated (new York, Ny), Trustees of Princeton University (princeton, Nj) Patent Number: 6,613,565 Date filed: December 8, 1998 Abstract: Primitive hematopoietic stem cells are closely associated with discrete in vivo microenvironments. These "niches" are thought to provide the molecular signals that mediate stem cell differentiation and self renewal. We have dissected the fetal liver microenvironment into distinct cellular components by establishing an extensive panel
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of stromal cell lines. One particular cell line maintains repopulating stem cells for prolonged in vitro culture periods. A subtraction cloning strategy has yielded a cDNA which encodes a cell surface glycoprotein with a restricted pattern of expression among stromal cell lines. This molecule, previously identified as dlk/Pref-1, contains EGF-like repeats which are related to those in the Notch/Delta/Serrate family of proteins. We have investigated the potential role of this molecule in hematopoietic stem/progenitor cell regulation. We show that the dlk protein displays activity on purified stem cells by promoting the formation of "cobblestone areas" of proliferation. These cobblestone areas contain both primitive high-proliferative potential progenitors as well as in vivo repopulating stem cells. Excerpt(s): The present invention is directed to the use of Delta-like protein (dlk) to inhibit the rate of differentiation of stem cells. The differentiated cells of some biological systems mature in stages from a common progenitor cell, usually called a stem cell. Such cells include, for example, hematopoietic, neural, epithelial, endothelial, and mesodermal cells. Stem cells are able to differentiate into mature cells within one of these systems. Differentiation may occur through uncommitted or committed progenitor cell intermediates. Web site: http://www.delphion.com/details?pn=US06613565__ •
Use of multipotent neural stem cell progeny to augment non-neural tissues Inventor(s): Bjornson; Christopher R. (Calgary, CA), Reynolds; Brent A. (Saltspring, CA), Rietze; Rod L. (Calgary, CA), Vescovi; Angelo L. (Milan, IT) Assignee(s): Neurospheres Holdings Ltd. (alberta, Ca) Patent Number: 6,638,501 Date filed: June 19, 1998 Abstract: Multipotent neural stem cell (MNSC) progeny are transplanted into a recipient wherein they augment host tissue. The stem cells have a universal lineage potential and are capable of producing progeny that, in response to appropriate environmental signals, can differentiate into a variety of differentiated cell types, and not just neural lineages. MNSCs can be proliferated ex vivo to provide an unlimited supply of stem cells and stem cell progeny which give rise to the differentiated cell types of various tissues. The stem cells are readily amenable to genetic modification, if desired. They also have the advantage that they can be obtained from autologous adult human tissue and thus overcome prior art problems of transplant rejections. Excerpt(s): Cell transplantation is increasingly becoming a therapy of choice for a variety of cell-based disorders ranging from sickle cell anemia and diabetes to Parkinson's disease. For example, cell lines may be transplanted to deliver a biologically active agent such as insulin, for the treatment of diabetes; parathyroid hormone, for treatment of hypoparathyroidism; erythropoietin, for treatment of anemia; and gamma-aminobutyric acid, for treatment of epilepsy. The cells may naturally secrete the biologically active molecule, or be genetically modified to do so. There are several obstacles that prevent cell transplantation therapy from realizing its full potential. For example, obtaining quantities of cells suitable for transplantation is often a problem. Cell lines transformed with oncogenes can pose a risk of unwanted cell migration, unrestricted proliferation, and possibly tumor formation. Transplant rejection is also a potential problem. These problems have been addressed by encapsulating the transplanted cells in immunoisolatory vehicles which retain the cells at a desired location within the
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transplant recipient, where the cells secrete the biologically active substances. The immunoisolatory vehicle prevents unwanted cell migration, possible tumor formation, and reduces the possibility of transplant rejection. Methods of transplanting encapsulated cells are disclosed in U.S. Pat. No. 5,550,050. For some cell-based disorders, it is necessary for the transplanted cells to become integrated with the host tissue being treated. In these cases, encapsulation methods cannot be used. Thus, it is important that the transplanted cells are human leukocyte antigen (HLA) matched to the patient's tissue to reduce the likelihood of transplant rejection. Hematopoietic stem cell transplantation, is an example of a therapy where donor cells become integrated with the patient's own tissue. It is an effective therapy for a number of diseases, such as sickle cell anemia, aplastic anemia, and a variety of immunodeficiency disorders, including those which result from treatments for other disorders such as chemo- and radiotherapy treatment for cancer (reviewed in Amos and Gordon, Cell Transplantation 4(6):547-569 (1995)). Hematopoietic stem cells, are present in adult bone marrow and blood (in smaller numbers), and are capable of giving rise to all of the cells of the hematopoietic cell lineage. Fetal sources of hematopoietic stem cells in umbilical cord blood and liver, have also been reported. Lu et al., Critical Rev. in Oncol./Hemataol. 22:61-78 (1996). Certain neurological disorders treated by cell transplantation, also require that the cells become integrated with the host tissue. For example, in the treatment of myelin deficiencies, it is necessary for the transplanted cells to reform the insulating cellular sheaths around the axons of demyelinated neurons. Animal models of myelin deficiencies have shown promising results from the transplantation of undifferentiated neural stem cell progeny into demyelinated regions of the central nervous system. Hammang et al., Experimental Neurology 147:84-95 (1997). Web site: http://www.delphion.com/details?pn=US06638501__ •
Variant of C6.beta.-chemokine leukotactin-1(shLkn-1) with enhanced biological activity Inventor(s): Ahn; Ju-Hyung (Kyounggi-do, KR), Baek; Seung Jae (Kyounggi-do, KR), Chung; Soo-Il (Kyounggi-do, KR), Kwon; Byoung S. (Carmel, IN), Lee; Eun-Kyoung (Seoul, KR), Lee; Kong-Ju (Kyounggi-do, KR), Park; Doo-Hong (Seoul, KR), Youn; Byung S. (Seoul, KR) Assignee(s): Korea Green Cross Corporation (kyounggi-do, Kr), Mogam Biotechnology Research Institute (kyounggi-do, Kr) Patent Number: 6,692,735 Date filed: July 21, 1999 Abstract: The present invention relates to a variant of Lkn-1(shLkn-1) with enhanced biological activity, which is a truncated form of Lkn-1, a process for preparing a recombinant shLkn-1 by employing expression vector therefor and pharmaceutical application of the said protein. shLkn-1 is generated by missing 26 amino acid residues from the amino terminus of Lkn-1 to contain 66 amino acids. Recombinant shLkn-1 inhibits colony formation and cell proliferation in vivo, which suggests that it can be used as a potential drug for the antibody production, the treatment during HIV-1 infection, the protection of bone marrow stem cells during chemotherapy or radiotherapy, and the inhibition of leukemia. Excerpt(s): The present invention relates to a variant of C6.beta.-chemokine (shLkn-1) with enhanced biological activity, more specifically, to a variant of Lkn-1 which belongs to C6.beta.-chemokine, a process for preparing a recombinant shLkn-1 by employing
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expression vector therefor, and pharmaceutical application of the said protein. Chemokines, a family of small cytokines consisting of basic proteins of low molecular weight, have four cysteine residues commonly, which are classified into four subfamilies of CXC(.alpha.), CC(.beta.), C(.gamma.) and CX.sub.3 C depending on the position of the first and the second cysteines, i.e., whether they lie adjacent or an amino acid intervenes between the two cysteines (see: Baggiolini, M. and Dahinden, C. A., Immunol. Today, 15:127(1994); Kelner, S. G. et al., Science, 266:1395(1994); Bazan, J. F. et al., Nature, 385:640(1997)). Genes of chemokine subfamilies locate on a same chromosome in a cluster, for example,.alpha.-chemokine genes locate on the human chromosome 4q12-21 and.beta.-chemokine genes exist on the human chromosome 17q11-32 and the mouse chromosome 11. Broxmeyer, H. E. et al., Blood, 76:1110(1990); Youn, B.-S. et al., J. Immunol., 155:2661-2667(1995)). Web site: http://www.delphion.com/details?pn=US06692735__
Patent Applications on Stem Cells As of December 2000, U.S. patent applications are open to public viewing.10 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to stem cells: •
Cancer models Inventor(s): Bachoo, Robert M.; (Roslindale, MA), Depinho, Ronald A.; (Brookline, MA) Correspondence: Fish & Richardson PC; 225 Franklin ST; Boston; MA; 02110; US Patent Application Number: 20030226159 Date filed: April 15, 2003 Abstract: The invention provides chimeric non-human animals, methods for making and using chimeric non-human animals, isolated stem cells, and methods for identifying agents that reduces cancer in a non-human animal. For example, the invention relates to using stem cells to make chimeric non-human animals having cancer or the ability to develop cancer. Such animals can be used to evaluate tumorigenesis, tumor maintenance, and tumor regression in vivo. In addition, the chimeric non-human animals provided herein can be used to identify agents that reduce or prevent tumor formation or growth in vivo. Excerpt(s): This application claims the benefit of U.S. Provisional Application Serial No. 60/373,139, filed Apr. 16, 2002 and U.S. Provisional Application Serial No. 60/374,791, filed Apr. 22, 2002. The invention relates to methods and materials involved in making and using animal models. Specifically, the invention relates to using stem cells to make chimeric non-human animals having tumors or the ability to develop tumors. Transgenic and knock-out technology involves producing an animal where the germline of that animal has been genetically altered. Such technology has had a significant impact on all areas of the biological sciences. For example, transgenic mice have been used extensively in such areas as immunology, oncology, and neurobiology to study the roles particular polypeptides play in immunity, cancer development, and brain function.
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This has been a common practice outside the United States prior to December 2000.
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Likewise, knock-out mice have been instrumental to identifying the function of numerous polypeptides. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Cellular trans-differentiation Inventor(s): Yang, Lijun; (Gainesville, FL) Correspondence: Margaret J. Mclaren, PH.D. ESQ.; Akerman Senterfitt; Suite 400; 222 Lakeview Avenue; West Palm Beach; FL; 33402-3188; US Patent Application Number: 20030223974 Date filed: February 24, 2003 Abstract: Highly purified hepatic stem cells are trans-differentiated into pancreatic endocrine hormone-producing cells by culturing them in vitro in a medium containing high levels of glucose. These trans-differentiated cells express insulin, glucagon, and pancreatic polypeptide, but not hepatocyte protein Hep-par. When stimulated with glucose, these cells synthesize and secrete insulin, a response enhanced by nicotinamide. Transplantation of these trans-differentiated cells into a hyperglycemic animal normalizes blood sugar levels in the animal. Excerpt(s): This application claims priority from U.S. provisional patent application Serial No. 60/358,864, filed Feb. 22, 2002. The invention relates generally to the fields of developmental biology, stem cells, endocrinology, and medicine. More particularly, the invention relates to pancreatic endocrine hormone-producing cells made from hepatic stem cells, and methods of making and using such endocrine hormone-producing cells. The pancreas is composed of two distinctly different tissues. The bulk of the pancreas consists of exocrine tissue that produces a fluid that facilitates the digestion of proteins, fats, and carbohydrates. Located in discrete clusters throughout the exocrine tissue are aggregates of endocrine cells that produce the several different hormones, notably including insulin and glucagon. These aggregates, termed Islets of Langerhans, are composed of several different cell types. Among these are alpha cells that secrete glucagon; beta cells that secrete insulin; gamma cells that produce pancreatic polypeptide (PP); and delta cells that secrete somatostatin. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Chimeric mouse having immunity constructed by using human cd34-positive cells and use thereof Inventor(s): Ando, Kiyoshi; (Kanagawa, JP), Habu, Sonoko; (Tama-shi, JP), Hotta, Tomomitsu; (Aichi, JP) Correspondence: Fish & Richardson; 225 Franklin Street; Boston; MA; 02110-2804; US Patent Application Number: 20040016007 Date filed: June 27, 2003 Abstract: Chimeric mice were constructed by transferring human CD34.sup.+ cells (hematopoietic stem cells) into a SCID mouse. In these chimeric mice, hematopoietic stem cells persistently differentiated into immune cells. Consequently, the chimeric mice can be immunized over a long time and enable one to obtain human antibodies against arbitrary antigens containing a human self-component.
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Excerpt(s): This invention relates to chimeric mice capable of producing human antibodies, methods for producing the human antibodies using the chimeric mice, and the human antibodies prepared by the methods. Since Kohler and Milstein established the cell fusion technology in 1975 (Kohler, Nature 256: 495-497 (1975)), a variety of monoclonal antibodies have been made and used to measure a variety of samples and to diagnose and treat diseases. The original monoclonal antibodies were prepared in most cases from non-human animals, especially from mice, and, thus, when they were used as therapeutic agents for treating diseases in humans, there was concern about the immunogenicity of the antibodies and their short half-life in the blood. In particular, when they were administered for a chronic disease, frequent administration was required. Thus, application of the antibodies to therapeutic agents was limited. Later, to reduce the immunogenicity, a chimeric antibody comprising the variable region of a mouse antibody and the constant region of a human antibody was made, and further, a humanized antibody, which is obtained by replacing into a human antibody only the complementarity determining region (CDR), essential for antigen-binding activity, was developed. However, the lowest antigenicity can be achieved by an antibody derived from human antibody producing cells. Accordingly, a human monoclonal antibody, a homogeneous human antibody, is useful in the field of therapeutic agents. There is a known method for producing a human monoclonal antibody in which human antibody producing cells are isolated from a human having a desired antibody in the blood and then immortalized to obtain cell clones producing the human antibody (Unexamined Published Japanese Patent Application No. Hei 5-25058). However, it is difficult to arbitrarily obtain a desired human antibody by the method because it requires the step of isolating a cell producing an antibody possessing a desired activity. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Composition for the protection and regeneration of nerve cells containing the extract of Scutellaria Radix Inventor(s): Chang, Chi-Young; (Bucheon-si, KR), Choe, Byung-Kil; (Seo-gu, KR), Kim, Hyo-Sup; (Namdong-gu, KR), Kim, Soo-Kyung; (Jung-gu, KR), Kim, Yun-Hee; (Seoul, KR), Lim, Jung-Su; (Seoul, KR), Park, Dae-Sung; (Seoul, KR) Correspondence: Heslin Rothenberg Farley & Mesiti PC; 5 Columbia Circle; Albany; NY; 12203; US Patent Application Number: 20030224074 Date filed: March 14, 2003 Abstract: Disclosed is a composition for protecting nerve cells, promoting nerve cell growth and regenerating nerve cells comprising a Scutellaria Radix extract. The composition has excellent protective effects against apoptosis of neuronal stem cells and differentiated nerve cells, a positive effect of inducing the regeneration of nerve cells, a regenerative effect on neurites, a neuroregenerative effect on brain nerves and peripheral nerves, a reformation effect on neuromuscular junctions, and a protective effect agaisnt apoptosis of nerve cells and a neuroregenerative effect in animals suffering from dementia and brain ischemia. Therefore, the composition can be used as a therapeutic agent for the prevention and treatment of nerodegenerative diseases, ischemic nervous diseases or nerve injuries, and for the improvement of learning capability. Excerpt(s): The present invention relates to a composition for protecting nerve cells, promoting nerve cell growth and regenerating nerve cells comprising a Scutellaria
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Radix extract. Further, the present invention relates to a composition for drugs and functional foods useful in the prevention and treatment of nervous diseases or nerve injuries comprising a Scutellaria Radix extract. The composition according to the present invention can be used as therapeutic agents for the prevention and treatment of neurodegenerative diseases, ischemic nervous diseases or brain injuries, and for the improvement of learning capability. Synapses are the connection points between nerve cells, and one nerve cell connects to 1000.about.5000 other nerve cells on average. It is estimated that since at least 10.sup.11 nerve cells exist in the human brain, there are at least 10.sup.14 synapses in the human brain. All complex and various brain functions, for example thoughts, sensations, memory, learning and actions, cannot be understood without consideration of these neural networks. Synaptic connections are essential to nerve cell survival. Special functions according to the connections between nerve cells make it possible to express high-level brain functions intrinsic to humans. In particular, it is known that once the central nervous system is damaged, its regeneration is very difficult. Many ideas and attempts for treating damaged nerve tissues or chronic degenerative diseases have been made in various ways. In the 1940's, Hamburger and Levi-Montalcini discovered an unidentified substance indispensable for survival of motor neurons in the differentiation process of Chick embryo limb, and proposed the neurotrophic factor hypothesis. Based on the hypothesis, NGF (nerve growth factor) was first discovered, and discoveries of neurotrophic factors such as BDNF (brainderived neurotrophic factor), NT-3 (neurotrophic factor-3), etc., followed. Further, it was found in some transgenic animal experiments which types of nerve growth factors are necessary for survival of each differentiated nerve cell population. Also, it was found that not only neurotrophins but also some cytokines are involved in nerve cell survival. When neurotrophins or cytokines are not supplied or receptors for these neurotrophins or cytokines are not expressed in the cells, nerve cells die. There are two nerve cell death pathways, like all other cells: necrosis and apoptosis. Necrosis and apoptosis have different morphological and molecular biological characteristics. When an axon is cut (axotomy), a part attached to the cell body and a terminal forming a synapse are separated each other. Such axotomy leads to not only synaptic denaturation due to cut off of supply of protein factors from target cell body, but also synaptic detachment. That is, regeneration is a key to nerve cell survival. Dead nerve cells are replaced with glial cells in the peripheral nervous system, and astrocytes or microglias in the central nervous system, in a process called "synaptic stripping". In addition, immune system cells such as monocytes, macrophages, etc., can replace the dead nerve cells, depending on the extent of damages. Many theories explaining mechanisms of physical injuries to nerve cells, acute neurotoxicity, acute and chronic nervous disorders, dementia, epilepsy., etc. have been introduced, but these theories all have a common point. That is, these diseases affect nerve cells and supporting tissue cells thereof. These cells extend horizontally and perpendicularly to form many dendrites and axons, which form many neural networks. Abnormalities in the neural nets lead to deregulation in signal transmission and cause various cranial nervous system diseases. The glutamatergic neural net responding to glutamate, an excitatory neurotransmitter, is a neural net to which has drawn attention in terms of development of acute and chronic cranial nervous diseases. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Compositions and methods for modulating cell differentiation Inventor(s): Brott, Barbara; (Boston, MA), Gupta, Ruchika; (San Diego, CA), Lassar, Andrew B.; (Newton Center, MA), Marvin, Martha; (Brookline, MA), Mercola, Mark; (Del Mar, CA), Schneider, Valerie; (Philadelphia, PA), Sokol, Sergei; (Boston, MA), Tzahor, Eldad; (Brookline, MA) Correspondence: Foley Hoag, Llp; Patent Group, World Trade Center West; 155 Seaport Blvd; Boston; MA; 02110; US Patent Application Number: 20040014209 Date filed: January 23, 2003 Abstract: The present invention relates to compositions and methods for stimulating differentiation of stem cells into cardiac cells. The methods of the invention involve contacting a population cells comprising stem cells with at least one Wnt antagonist, such as a polypeptide or polypeptide fragment. In certain embodiments, the methods of the invention involve Dkk proteins or fragments, homologs, derivatives, variants, or peptidomimetics thereof. Excerpt(s): This application claims the benefit of priority to Provisional Patent Application Nos. 60/351,126, filed Jan. 23, 2002, 60/352,456, filed Jan. 28, 2002, and 60/352,665, filed Jan. 29, 2002, which applications are hereby incorporated by reference in their entirety. The heart and the derivatives of the blood islands are the first mesodermal tissues to differentiate after gastrulation in amniote embryos. Cells that migrate anterior and lateral to the primitive streak in early gastrulation contribute to heart tissue, whereas cells that move into the posterior lateral plate form the extraembryonic blood islands (Rosenquist and DeHaan, 1966. Carnegie Inst. Washington Contrib. Embryol. 38: 111-121; Schoenwolf et al. 1992. Dev. Dyn. 193: 235248; Garcia-Martinez and Schoenwolf 1993. Dev. Biol. 159: 706-719). Precardiac cells residing in the primitive streak at stage 3 are uncommitted (Inagaki, et al., 1993. Dev. Dyn. 197: 57-68;) but become specified in response to signals from surrounding tissues after their migration into the lateral plate (Antin, et al. 1994. Dev. Dyn. 200: 144-154; Montgomery, et al., 1994. Dev. Biol. 164: 63-71; Sugi and Lough 1994. Dev. Dyn. 200: 155162; Schultheiss, et al. 1995. Development 121: 4203-4214; Schultheiss, et al., 1997. Genes & Dev. 11: 451-462). The cardiac mesoderm precursors are in contact with presumptive anterior endoderm throughout their migration from the streak into the lateral plate (Garcia-Martinez and Schoenwolf 1993, supra). Anterior endoderm is required for cardiac specification in Xenopus (Nascone and Mercola 1995. Development 121: 515523). Moreover, blood precursors from the posterior primitive streak develop into cardiac myocytes when cultured with anterior but not posterior endoderm (Schultheiss et al. 1995, supra). These findings suggest that the anterior endoderm secretes a heartinducing signal that influences the fate of nascent mesodermal cells. Bone morphogenetic protein (BMP) signals from the lateral regions of the embryo are also required for heart formation (Schultheiss et al. 1997, supra; Andre, et al., 1998. Mech. Dev. 70: 119-131). The BMP antagonist noggin blocks cardiogenesis in explants of stage 4 precardiac mesoendoderm and blocks cardiogenesis in vivo when ectopically expressed through stage 7 (Schultheiss and Lassar 1997. Cold Spring Harbor Symp. Quant. Biol. 62: 413-419; Schultheiss et al. 1997, supra; Schlange, et al. 2000. Mech. Dev. 91: 259-270). Conversely, anterior paraxial mesoderm, which lies medial to the heart-forming region and normally gives rise to head mesenchyme, can be induced to express cardiac genes and to form beating cardiac myocytes in explant culture by exposure to BMP-2 at stages 5-6 (Schultheiss et al. 1997, supra; Andre et al. 1998, supra). In vivo, implantation of a BMP-2-soaked bead into the anterior paraxial mesoderm induces the expression of Nkx-
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2.5 and GATA-4 (Schultheiss et al. 1997, supra; Schlange et al. 2000 Mech. Dev. 91: 259270). While BMP signals can induce robust cardiac differentiation from anterior gastrula stage mesendoderm, posterior mesoderm fails to activate heart markers in response to BMP signals (Schultheiss et al. 1997, supra). These findings led us to propose a twofactor model for heart induction, in which a signal from the anterior endoderm induces a field of cardiogenic competence, and a BMP signal specifies the lateral portion of this field to develop into heart tissue (Schultheiss and Lassar 1997, supra; Schultheiss et al. 1997, supra). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Compositions and methods for the use of Bcl-2 transfected neurons Inventor(s): Haglid, Kenneth; (Hovas, SE), Wang, Shu; (Singapore, SG) Correspondence: Kramer Levin Naftalis & Frankel Llp; Intellectual Property Department; 919 Third Avenue; New York; NY; 10022; US Patent Application Number: 20040001808 Date filed: June 7, 2002 Abstract: The use of Bcl-2 transfected neurons and/or stem cells for the production of a pharmaceutical preparation for in vivo treatment of neurological conditions such as Parkinson's disease is disclosed. Also disclosed is a method for treatment of neurological conditions, wherein Bcl-2 transfected neurons are transplanted to a patient. Excerpt(s): The present invention relates to compositions and methods for treating neurological conditions. Neurological disease and injury affect millions of people in the U.S. and abroad. The cost in treating these patients is many billions of dollars annually. In fact, according to the Parkinson's Foundation as many as 1.5 million people suffer from Parkinson's disease in the U.S. alone. About 50,000 Americans are diagnosed with Parkinson's each year and the total cost of health care for Parkinson's patients exceeds $5 billion annually. Other countries have even higher rates of Parkinson's disease. The incidence and associated costs of other neurological conditions are similarly severe. Strategies of treatment of neurological disease or injury have been largely unsuccessful. For example, the use of a variety of pharmaceutical preparations for the treatment of Parkinson's disease has done little to provide long-term relief to these patients. Standard pharmaceutical treatments eventually result in ineffective treatment of symptoms and/or unacceptable side effects. Moreover, these traditional treatments are intended purely to alleviate symptoms rather than to resolve the underlying disease or injury. Treatment of other neurological conditions is similarly symptom oriented. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Dedifferentiated, programmable stem cells of monocytic origin, and their production and use Inventor(s): Faendrich, Fred; (Kiel, DE), Kremer, Bernd Karl Friedrich; (Kiel, DE), Ruhnke, Maren nee Schulze; (Kiel, DE) Correspondence: Arnold & Porter; IP Docketing Department; RM 1126(b); 555 12th Street, N.W.; Washington; DC; 20004-1206; US Patent Application Number: 20040009595 Date filed: March 28, 2003 Abstract: The invention relates to the production of adult dedifferentiated, programmable stem cells from human monocytes by cultivation of monocytes in a culture medium which contains M-CSF and IL-3. The invention further relates to pharmaceutical preparations, which contain the dedifferentiated, programmable stem cells and the use of these stem cells for the production of target cells and target tissue. Excerpt(s): This application is a continuation-in-part of U.S. Ser. No. 10/372,657 filed Feb. 25, 2003. This application claims priority under 35 U.S.C.sctn.sctn. 119 and 120 to German application No. 102 14 095.2 filed Mar. 28, 2002, International Application No. PCT/EP03/02121 filed Feb. 25, 2003, and U.S. patent application Ser. No. 10/372,657 filed Feb. 25, 2003, each of which is hereby incorporated by reference in its entirety. The term "stem cells" designates cells which (a) have the capability of self-renewal and (b) the capability to form at least one and often a number of specialized cell types due to their asymmetrical division capability (cf. Donovan, P. J., Gearhart, J., Nature 414: 92-97 (2001)). The term "pluripotent" designates stem cells, which can essentially be differentiated into all possible cell types of the human and animal body. Such stem cells have hitherto only been obtainable from embryonic tissue or embryonic carcinoma (testicular tumor) (cf. Donovan, P. J., Gearhart, J., loc cit). The use of embryonic stem cells has been the subject of extensive public discussion, especially in Germany, and is regarded as extremely problematical. Besides the ethical and legal problems connected with embryonic stem cells, the therapeutic use of such cells also comes up against difficulties. By nature, embryonic stem cells are obtained from donor organisms, which are heterologous vis--vis the potential recipients of differentiated cells or tissue (hereafter referred to as somatic target cells or target tissue) developed from these cells. It is therefore to be expected, that such target cells will trigger an immediate immunological response in the potential recipients in the form of rejection. Stem cells can be also isolated from different tissues of adult, i.e., from differentiated individuals. Such stem cells are referred to in the state of the art as "multipotent adult stem cells". In the body they play a role in tissue regeneration and homeostasis. The essential difference between embryonic pluripotent stem cells and adult multipotent stem cells lies in the number of differentiated tissues, which can be obtained from the respective cells. Presumably, this is due to the fact that pluripotent stem cells come from sperm cells, or from cells which can produce sperm, while adult multipotent stem cells come from the body or soma of adult individuals (cf. Donovan, P. J., Gearhart, J., loc cit, Page 94), which are not capable of sperm production. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Disease prevention by reactivation of the thymus Inventor(s): Boyd, Richard; (Victoria, AU) Correspondence: Hale And Dorr, Llp; 60 State Street; Boston; MA; 02109 Patent Application Number: 20040013641 Date filed: April 18, 2003 Abstract: The present disclosure provides methods for gene therapy utilizing hematopoietic stem cells, lymphoid progenitor cells, and/or myeloid progenitor cells. The cells are genetically modified to provide a gene that is expressed in these cells and their progeny after differentiation. In one embodiment the cells contain a gene or gene fragment that confers to the cells resistance to HIV infection and/or replication. The cells are administered to a patient in conjunction with treatment to reactivate the patient's thymus. The cells may be autologous, syngeneic, allogeneic or xenogeneic, as tolerance to foreign cells is created in the patient during reactivation of the thymus. In an embodiment the hematopoictic stem cells are CD34.sup.+. The patient's thymus is reactivated by disruption of sex steroid mediated signaling to the thymus. In another embodiment, this disruption is created by administration of LHRH agonists, LHRH antagonists, anti-LHRH receptor antibodies, anti-LHRH vaccines or combinations thereof. Excerpt(s): This application is a continuation-in-part of U.S. Ser. No. 09/976,598, filed Oct. 12, 2001, which is a continuation-in-part of U.S. Ser. No. 09/965,395, filed Sep. 26, 2001, which is a continuation in part of each of U.S. Ser. No. 09/755,965, filed Jan. 5, 2001, U.S. Ser. No. 09/755,646, filed Jan. 5, 2001, U.S. Ser. No. 09/755,98, filed Jan. 5, 2001, and U.S. Ser. No. 09/758,910, filed Jan. 10, 2001, each of which is a continuation-inpart of U.S. Ser. No. 09/795,286 filed, Oct. 13, 2000 which is a continuation-in-part of AU provisional application PR0745, filed Oct. 13, 2000, and of U.S. Ser. No. 09/795,30,2 filed Oct. 13, 2000, which is a continuation-in-part of PCT AU00/00329, filed Apr. 17, 2000, which is a PCT filing of AU provisional application PP9778 filed Apr. 15, 1999, each of which is incorporated herein by reference. The present disclosure is in the field of disease prevention. In particular a patient's thymus is stimulated and reactivated, and the patient's immune system by reactivating the functional status of the peripheral T cells, which, in turn is useful in preventing disease and illness. Gene therapy of hematopoietic stem cells (HSC), hematopoietic progenitor cells, epithelial stem cells or bone marrow is optionally used. The major function of the immune system is to distinguish "foreign" (that is derived from any source outside the body) antigens from "self" (that is derived from within the body) and respond accordingly to protect the body against infection. In more practical terms, the immune response has also been described as responding to "danger" signals. These "danger" signals may be any change in the property of a cell or tissue which alerts cells of the immune system that this cell/tissue in question is no longer "normal." Such alterations may be very important in causing, for example, rejection of tumors. However, this "danger" signal may also be the reason why some autoimmune diseases start, due to either inappropriate cell changes in the "self" cells targeted by the immune system (e.g., the.beta.-islet cells targeted in Diabetes mellitus), or inappropriate cell changes in the immune cells themselves, leading these cells to target normal "self" cells. In normal immune responses, the sequence of events involves dedicated antigen presenting cells (APC) capturing foreign antigen and processing it into small peptide fragments which are then presented in clefts of major histocompatibility complex (MHC) molecules on the APC surface. The MHC molecules can either be of class I expressed on all nucleated cells (recognized by cytotoxic T cells (Tc)) or of class II expressed primarily by cells of the immune system
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(recognized by helper T cells (Th)). Th cells recognize the MHC II/peptide complexes on APC and respond; factors released by these cells then promote the activation of either of both Tc cells or the antibody producing B cells which are specific for the particular antigen. The importance of Th cells in virtually all immune responses is best illustrated in HIV/AIDS where their absence through destruction by the virus causes severe immune deficiency eventually leading to death. Inappropriate development of Th (and to a lesser extent Tc) can lead to a variety of other diseases such as allergies, cancer and autoimmunity. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Embryonic or stem-like cell lines produced by cross species nuclear transplantation and methods for enhancing embryonic development by genetic alteration of donor cells or by tissue culture conditions Inventor(s): Cibelli, Jose; (US), West, Michael D.; (US) Correspondence: Crowell & Moring, L.L.P.; Intellectual Property Group; P.O. Box 14300; Washington; DC; 20044-4300; US Patent Application Number: 20030229908 Date filed: December 27, 2002 Abstract: An improved method of nuclear transfer involving the transplantation of differentiated donor cell nuclei into enucleated oocytes of a species different from the donor cell is provided. The resultant nuclear transfer units are useful for the production of isogenic embryonic stem cells, in particular human isogenic embryonic or stem cells. These embryonic or stem-like cells are useful for producing desired differentiated cells and for introduction, removal or modification, of desired genes, e.g., at specific sites of the genome of such cells by homologous recombination. These cells, which may contain a heterologous gene, are especially useful in cell transplantation therapies and for in vitro study of cell differentiation. Also, methods for improving nuclear transfer efficiency by genetically altering donor cells to inhibit apoptosis, select for a specific cell cycle and/or enhance embryonic growth and development are provided. Excerpt(s): This application is a continuation-in-part of application Ser. No. 09/467,076 filed Dec. 20, 1999, which is a continuation-in-part of application Ser. No. 09/395,368, filed Sep. 14, 1999, which is a continuation-in-part of application Ser. No. 09/260,468, filed Mar. 2, 1999, which is a continuation-in-part of application Ser. No. 09/032,945, filed Mar. 2, 1998, which is a continuation-in-part of application Ser. No. 08/699,040, filed Aug. 19, 1996, each of which is incorporated by reference in its entirety herein. application Ser. No. 09/467,076 filed Dec. 20, 1999, also claims priority under 35 U.S.C.sctn. 119 to PCT/US99/04608, filed on Mar. 2, 1999, which is incorporated by reference in its entirety herein. This application is also a continuation-in-part of application Ser. No. 09/685,061, filed Oct. 6, 2000, which is a continuation-in-part of application Ser. No. 09/260,468, filed Mar. 2, 1999, and which is incorporated by reference in its entirety herein. This application is also a continuation-in-part of application Ser. No. 09/874,040, filed Jun. 6, 2001, which is a continuation-in-part of application Ser. No. 08/699,040, filed Aug. 19,1996, and which is incorporated by reference in its entirety herein. This application is also a continuation-in-part of application Ser. No. 09/809,018, filed Mar. 16, 2001, which is a continuation-in-part of application Ser. No. 09/032,945, filed Mar. 2, 1998, and which is incorporated by reference in its entirety herein. This application claims priority to provisional application 60/342,358 filed Dec. 27, 2001, and to provisional application 60/357,848,
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filed Feb. 21, 2002, each of which is incorporated by reference in its entirety herein. The present invention generally relates to the production of embryonic or stem-like cells by the transplantation of cell nuclei derived from animal or human cells into enucleated animal oocytes of a species different from the donor nuclei. The present invention more specifically relates to the production of primate or human embryonic or stem-like cells by transplantation of the nucleus of a primate or human cell into an enucleated animal oocyte, e.g., a primate or ungulate oocyte. In a preferred embodiment the donor cell or nuclei will be human or non-human primate and the recipient cell will be an oocyte from a Lagomorph, e.g., rabbit, hare or a bovine oocyte. The present invention further relates to the use of the resultant embryonic or stem-like cells, preferably primate or human embryonic or stem-like cells for therapy, for diagnostic applications, for the production of differentiated cells which may also be used for therapy or diagnosis, and for the production of transgenic embryonic or transgenic differentiated cells, cell lines, tissues and organs. Also, the embryonic or stem-like cells obtained according to the present invention may themselves be used as nuclear donors in nuclear transplantation or nuclear transfer methods for the production of chimeras or clones, preferably transgenic cloned or chimeric animals. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Endothelial cells derived from human embryonic stem cells Inventor(s): Amit, Michal; (Misgav, IL), Itskovitz-Eldor, Joseph; (Haifa, IL), Langer, Robert; (Newton, MA), Levenberg, Shulamit; (Brighton, MA) Correspondence: Valarie B. Rosen; Choate, Hall & Stewart; 53 State Street; Exchange Place; Boston; MA; 02109; US Patent Application Number: 20040009589 Date filed: March 25, 2003 Abstract: The invention is a population of embryonic endothelial cells produced in vitro from human embryonic stem cells. The cells produce platelet endothelial cell adhesion molecule-1 and are vasculogenic. The cells may be combined with a cell support substrate, seeded on a polymer matrix, or combined with a cell-support substrate that is infused into a polymer matrix. The cells may also be injected directly into a tissue site. Excerpt(s): This application claims priority from U.S. Provisional Application No. 60/367,689, filed Mar. 26, 2002, the entire contents of which are incorporated herein by reference. This invention pertains to the use of embryonic stem cells, and, more specifically, to the differentiation, isolation, characterization and use of human embryonic endothelial cells. Human vascular endothelial cells are important for developing engineered vessels for treatment of vascular disease and may also be useful for augmenting vessel growth to areas of ischemic tissue or following implantation (Niklason, et al., (1999) Science 284, 489-93; Kawamoto, et al., (2001) Circulation 103, 6347). Endothelial progenitor cells from adults have vasculogenic potential (Kawamoto, 2001). Vasculogenesis is defined as the in situ assembly of capillaries from undifferentiated endothelial cells, as opposed to angiogenesis, the sprouting of capillaries from preexisting blood vessels (Yancopoulos, et al., (1998) Cell 93, 661-4). This potential can be exploited in tissue engineering for induction of tissue vascularization, especially for complex tissues where vascularization of regenerating tissue is essential. For example, it is often desirable to vascularize engineered tissue in vitro prior to transplantation (Black, et al., (1998) FASEB J 12, 1331-40; Kaihara, et al., (2000) Tissue Eng 6, 105-17). Vascularization in vitro is important to enable cell viability during tissue
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growth, induce structural organization and promote integration upon implantation. The use of embryonic stem cells in tissue engineering and other applications in place of adult endothelial progenitor or endothelial cells would be particularly exciting, since ES cells can be expanded without apparent limit and ES cell-derived cells could be created in virtually unlimited amounts and available for potential clinical use (Amit, et al., (2000) Dev Biol 227, 271-8). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Expansion of cells using thrombopoietin and anti-transforming growth factor-beta Inventor(s): Bartelmez, Stephen H.; (Seattle, WA) Correspondence: Clark & Elbing Llp; 101 Federal Street; Boston; MA; 02110; US Patent Application Number: 20040028661 Date filed: August 7, 2002 Abstract: The invention features a method for the expansion of hematopoietic stem cells using a combination of a thrombopoietin agonist and a transforming growth factor-beta blocking agent in the absence of stem cell factor. The invention also features a hematopoictic stem cell composition that has been expanded using a combination of a thrombopoietin agonist and a transforming growth factor-beta blocking agent in the absence of stem cell factor, as well as methods of using an expanded hematopoietic stem cell composition to restore or supplement an immune system and/or blood forming system compromised by, for example, radiation or chemotherapy. Excerpt(s): The invention relates to expansion of relatively undifferentiated cells. The origin of all the cells in blood and in the immune system is the hematopoietic stem cell (HSC). Each HSC has the potential to differentiate into at least eight separate blood cell lineages within the myeloid and lymphoid blood cell compartments. It has been estimated through successive generational analysis that one HSC has the potential to produce millions of differentiated progeny each day for the lifetime of the animal. This enormous potential could be exploited if, starting from a small number of HSCs, a large pool of HSCs could be produced in an ex vivo expansion system. This pool of HSCs could then be used to restore or supplement an immune system and/or blood forming system compromised by, e.g., radiation or chemotherapy, and as a valuable tool in the design, development and testing of diagnostic and therapeutic agents used in the treatment of immune system and/or blood forming disorders. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Generation of xenogeneic antibodies Inventor(s): Brenner, Daniel G.; (Redwood City, CA), Capon, Daniel J.; (Hillsborough, CA), Jakobovits, Aya; (Menlo Park, CA), Klapholz, Sue; (Stanford, CA), Kucherlapati, Raju; (Darien, CT) Correspondence: Fish & Neave; 1251 Avenue OF The Americas; 50th Floor; New York; NY; 10020-1105; US Patent Application Number: 20030229905 Date filed: April 21, 2003
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Abstract: The subject invention provides non-human mammalian hosts characterized by inactivated endogenous Ig loci and functional human Ig loci for response to an immunogen to produce human antibodies or analogs thereof. The hosts are produced by multiple genetic modifications of embryonic cells in conjunction with breeding. Different strategies are employed for recombination of the human loci randomly or at analogous host loci. Chimeric and transgenic mammals, particularly mice, are provided, having stably integrated large, xenogeneic DNA segments. The segments are introduced by fusion with yeast spheroplasts comprising yeast artificial chromosomes (YACs) which include the xenogeneic DNA segments and a selective marker such as HPRT, and embryonic stem cells. Excerpt(s): This application is a continuation-in-part of application Ser. No. 07/919,297 filed Jul 24, 1992 which was a continuation-in-part of application Ser. No. 07/610,515 filed Nov 8, 1990 which was a continuation-in-part of application Ser. No. 07/466,008 filed Jan 12, 1990, the entire disclosures of which are all incorporated herein by reference. The field of this invention is the production of xenogeneic specific binding proteins in a viable mammalian host. The ability to produce transgenic animals has been revolutionized with the advent of the ability to culture murine embryonic stem cells, and to introduce genetic modifications in these cells for subsequent transmission to the mouse germline. Thus one has the opportunity to modify endogenous genes to produce animal strains capable of producing novel products by introduction of foreign genes into the host, particularly human genes to produce xenogeneic binding proteins. The expression of such genes in vivo in an animal model may provide for investigation of the function of the gene, the regulation of gene expression, its processing, response to various agents and the like. In addition, animals with new phenotypes, including those that mimic a variety of diseases, may be produced. For example, there is interest in introducing a dominant mutation or complementing a recessive mutation. Depending on the particular gene, the difficulty of achieving the desired mutation will vary greatly. While some gene targets have proven to be relatively amenable to modification, other targets have proven to be extremely resistant to modification. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Genes that are up- or down-regulated during differentiation of human embryonic stem cells Inventor(s): Brandenberger, Ralph; (Menlo Park, CA), Gold, Joseph D.; (San Francisco, CA), Irving, John M.; (San Mateo, CA), Mandalam, Ramkumar; (Union City, CA), Mok, Michael; (Palo Alto, CA), Shelton, Dawne; (Salt Lake City, UT), Stanton, Lawrence W.; (Singapore, SG) Correspondence: Geron Corporation; 230 Constitution Drive; Menlo Park; CA; 94025 Patent Application Number: 20030224411 Date filed: March 13, 2003 Abstract: Genes that are up- or down-regulated during differentiation provide important leverage by which to characterize and manipulate early-stage pluripotent stem cells. Over 35,000 unique transcripts have been amplified and sequenced from undifferentiated human embryonic stem cells, and three types of differentiated progeny. Statistical analysis of the assembled transcripts identified genes that alter expression levels as differentiation proceeds. The expression profile provides a marker system that has been used to identify particular culture components for maintaining the undifferentiated phenotype. The gene products can also be used to promote
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differentiation; to assess other relatively undifferentiated cells (such as cancer cells); to control gene expression; or to separate cells having desirable characteristics. Manipulation of particular genes can be used to forestall or focus the differentiation process, en route to producing a specialized homogenous cell population suitable for human therapy. Excerpt(s): This invention relates generally to the field of cell biology of stem cells. More specifically, it relates to phenotypic markers that can be used to characterize, qualify, and control differentiation of pluripotent cells, and to evaluate clinical conditions associated with marker expression. A promising development in the field of regenerative medicine has been the isolation and propagation of human stem cells from the early embryo. These cells have two very special properties: First, unlike other normal mammalian cell types, they can be propagated in culture almost indefinitely, providing a virtually unlimited supply. Second, they can be used to generate a variety of tissue types of interest as a source of replacement cells and tissues for use in therapy. Thomson et al. (Science 282:114, 1998; U.S. Pat. No. 6,200,806) were the first to successfully isolate and propagate embryonic stem cells from human blastocysts. Gearhart and coworkers derived human embryonic germ cell lines from fetal gonadal tissue (Shamblott et al., Proc. Natl. Acad. Sci. USA 95:13726, 1998;U.S. Pat. No. 6,090,622). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Growth of human Mesenchymal Stem Cells (hMSC) using umbilical cord blood serum and the method for the peparation thereof Inventor(s): Bhat, Aravind Venkatrao; (Mumbai, IN) Correspondence: Lackenbach Siegel; One Chase Road; Scarsdale; NY; 10583; US Patent Application Number: 20030232432 Date filed: April 8, 2003 Abstract: A method of isolating and growing human mesenchymal stem calls (hMSC) by culturing human stem cells in human umbilical cord blood serum. For this purpose blood is collected from the umbilical cord at the time of birth, after the infant is separated from the umbilical cord, and the blood is collected from an umbilical vein free of anticoagulants. The blood is collected in a blood bag having a collecting needle which is inserted into the umbilical vein and the blood is allowed to flow from the vein into the blood bag, and the blood is allowed to clot at room temperature and the bag is transported to a processing area which is a cGMP clean room. The method also includes aspirating Human Mesenchymal Stem Cells (hMSC) present in bone marrow, diluting bone marrow aspirate with tissue culture medium; plating cell suspension into tissue culture flasks so that Human Mesenchymal Stem Cells (hMSC) can adhere for 24 hours; transferring the resulting supernatant to fresh flasks for the remaining Human Mesenchymal Stem Cells (hMSC) to adhere, feeding cultures every 3 days using the medium and cultures reach confluence by 3 weeks, adding 5-aza cytidine reagent to these cultures at final concentration of 5-20 micro molars and allowing the culture to grow for another 3 days. Excerpt(s): This application claims priority from provisional U.S. provisional patent application filed Apr. 9, 2002 under Serial No. 60,371,137. The present invention provides the use of sera or serum separated from the clotted umbilical cord blood for growing human stem cells and adult cells for therapeutic purposes in regenerative
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medicine. In particular, the present invention relates to the growth of Human Mesenchymal Stem Cells (hMSC) and a method for preparation thereof using cord blood serum, for therapeutic purposes. Stem cells are special cells that have the ability to develop into many different types of tissue: bone, muscle, nerve, etc. In theory, they could be grown into replacements for almost any part of the human body. Stem cells are typically found in the embryo and umbilical cord of an organism, and in reservoirs within the human body. Researchers hope that stem cells will provide a solution to cure diseases caused by cell failure, and for repairing tissues that do not repair themselves. Heart damage, spinal cord injuries, Parkinson's disease, leukemia, and diabetes are among diseases named in relation to stem cell research. Hence, researchers are of the opinion, if these stem cells are controlled, they could cure a variety of debilitating diseases in the years to come. Stem cells are separated into three (3) distinct categories viz. Totipotent, Pluripotent, and Multipotent. Stem cells are best described in relation to normal human development. Thus, a fertilized egg is totipotent. It produces an entire organism. After several cycles of cell division, these totipotent cells begin to specialize, becoming pluripotent. As the embryo begins to develop, these pluripotent cells become multipotent, specifically producing blood, skin, nerve, or other types of body cells. While stem cells are extraordinarily important in early human development, multipotent stem cells are also found in children and adults. For example, one of the best understood stem cells are the blood stem cells. Blood stem cells reside in the bone marrow of every child and adult, and in fact, they can be found in very small numbers circulating in the blood stream. Blood stem cells perform the critical role of continually replenishing the supply of blood cells--red blood cells, white blood cells, and platelets throughout the life span. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Human growth hormone to stimulate mobilization of pluripotent hematopoietic stem cells Inventor(s): Gianni, Alessandro; (Milan, IT) Correspondence: Browdy And Neimark, P.L.L.C.; 624 Ninth Street, NW; Suite 300; Washington; DC; 20001-5303; US Patent Application Number: 20040028649 Date filed: July 21, 2003 Abstract: The invention relates to the field of hematopoietic cell mobilization. In particular, the invention relates to uses and methods for increasing the mobilization of CD34 negative pluripotent hematopoietic from the bone marrow into the peripheral blood by administration of human growth hormone or one of its derivatives to an individual. In a preferred embodiment of the invention, a combination of growth hormone and G-CSF are administered. Excerpt(s): The invention relates to the use of growth hormone and derivatives thereof including any factor inducing human growth hormone release for the manufacture of a medicament to increase the number of CD34 negative pluripotent peripheral blood cells capable of regenerating hematopoiesis, in particular to increase the number of long-term culture-initiating cells (LTC-IC). The invention further relates to the use of a combination of growth hormone and G-CSF (granulocyte-colony stimulating factor) to increase the number of CD34 negative pluripotent peripheral blood cells capable of regenerating hematopoiesis in vivo. Bone marrow transplantation (BMT) is a clinical procedure in which pluripotent hematopoietic cells obtained from bone marrow are
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transplanted to a patient. BMT is the treatment of choice in several hematological disorders, including malignancies, Severe Combined Immune Deficiencies (SCIDs), congenitally or genetically determined hematopoietic abnormalities, anemia, aplastic anemia, leukemia and osteopetrosis (Fischer et al., 1998). In the last ten years, the use of BMT grew from less than 5'000 to more than 40'000 annually (Waters et al., 1998). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Identification and high-yield isolation of human pancreatic islet progenitor and stem cells Inventor(s): Goldman, Steven A.; (South Salem, NY), Keyoung, Hansoo Michael; (New York, NY) Correspondence: Michael L. Goldman; Nixon Peabody Llp; Clinton Square; P.O. Box 31051; Rochester; NY; 14603-1051; US Patent Application Number: 20040005301 Date filed: February 10, 2003 Abstract: The present invention relates to a method of separating pancreatic Islet cells or progenitor or stem cells thereof from a mixed population of cells from the pancreas. This involves selecting an enhancer/promoter which functions in the pancreatic Islet cells or progenitor cells thereof and introducing a nucleic acid molecule encoding a fluorescent protein under control of the enhancer/promoter into the mixed population of cells. The pancreatic Islet cells or progenitor or stem cells thereof are then allowed to express the fluorescent protein. The fluorescent cells (i.e. the said pancreatic Islet cells or progenitor or stem cells thereof) are then separated from the mixed population of cells. Also disclosed is an enriched or purified preparation of isolated human pancreatic Islet cells or progenitor or stem cells and the use of these cells in a method of treating a diabetic condition by transplanting the cells into a subject. Excerpt(s): This application claims benefit of U.S. Provisional Patent Application Serial No. 60/356,556, filed Feb. 12, 2002. The present invention relates to a method of separating pancreatic Islet cells or progenitor or stem cells thereof, the resulting separated cells, and their use in treating a diabetic condition. Beta cells of the human pancreas have been envisioned as a potential cellular vector for cell-based therapy of type 1 diabetes, in which beta cells are specifically lost. However, these cells have not been amenable to therapeutic use, since they are a lineage-restricted phenotype capable of limited expansion once isolated. This limitation has led to efforts to raise Islet cell progenitors, capable of both expansion and beta cell production. However, these studies have hitherto been limited by the lack of any effective means of prospectively identifying Islet progenitor cells, which, as a result, have never been selectively isolated or purified as such. To circumvent this problem, current strategies for beta cell replacement have focused on the transplantation of mechanically-sorted whole Islets extracted from cadaveric adult pancreas (Calafiore R. "Perspectives in Pancreatic and Islet Cell Transplantation for the Therapy of IDDM," Diabetes Care 20(5):889-96 (1997); Soria et al. "From Stem cells to Beta Cells: New Strategies in Cell Therapy of Diabetes Mellitus," Diabetologia 44(4):407-15 (2001)). However, these strategies are limited by the scarcity of appropriate cadaveric samples, the inconsistent tissue and cell quality of these samples, the need to use these fully differentiated.beta. cells soon after harvest, the very limited capability of adult pancreatic neuroendocrine cells for mitotic expansion, and the impure and heterogenous nature of mechanically-sorted Islets, which include stromal and endothelial cells and attached acinar cells, as well as neuroendrocine cells.
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Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Ligand/lytic peptide compositions and methods of use Inventor(s): Elzer, Philip H.; (Baton Rouge, LA), Enright, Frederick M.; (Baton Rouge, LA), Foil, Lane D.; (Baton Rouge, LA), Hansel, William; (Baton Rouge, LA), Jaynes, Jesse M.; (Raleigh, NC), Koonce, Kenneth L.; (Baton Rouge, LA), McCann, Samuel M.; (Baton Rouge, LA), Melrose, Patricia A.; (Baton Rouge, LA), Yu, Wen H.; (Baton Rouge, LA) Correspondence: Patent Department; Taylor, Porter, Brooks & Phillips, L.L.P; P.O. Box 2471; Baton Rouge; LA; 70821-2471; US Patent Application Number: 20040018967 Date filed: July 11, 2003 Abstract: Amphipathic lytic peptides are ideally suited to use in a ligand/cytotoxin combination to specifically inhibit cells that are driven by or are dependent upon a specific ligand interaction; for example, to induce sterility or long-term contraception, or to attack tumor cells, or to selectively lyse virally-infected cells, or to attack lymphocytes responsible for autoimmune diseases. The peptides act directly on cell membranes, and need not be internalized. Administering a combination of gonadotropin-releasing hormone (GnRH) (or a GnRH agonist) and a membrane-active lytic peptide produces long-term contraception or sterilization in animals in vivo. Administering in vivo a combination of a ligand and a membrane-active lytic peptide kills cells with a receptor for the ligand. The compounds are relatively small, and are not antigenic. Lysis of gonadotropes has been observed to be very rapid (on the order of ten minutes.) Lysis of tumor cells is rapid. The two components--the ligand and the lytic peptide--may optionally be administered as a fusion peptide, or they may be administered separately, with the ligand administered slightly before the lytic peptide, to activate cells with receptors for the ligand, and thereby make those cells susceptible to lysis by the lytic peptide. The compounds may be used in gene therapy to treat malignant or nonmalignant tumors, and other diseases caused by clones or populations of "normal" host cells bearing specific receptors (such as lymphocytes), because genes encoding a lytic peptide or encoding a lytic peptide/peptide hormone fusion may readily be inserted into hematopoietic stem cells or myeloid precursor cells. Excerpt(s): The benefit of the Mar. 27, 1997 filing date of provisional application serial No. 60/041,009 and of the Sep. 3, 1997 filing date of provisional application 60/057,456 are claimed under 35 U.S.C.sctn. 119(e) in the United States, and are claimed under applicable treaties and conventions outside the United States. The benefit of the Jun. 4, 1997 filing date of U.S. non-provisional application Ser. No. 08/869,153 is claimed under 35 U.S.C.sctn. 120 in the United States, and is claimed under applicable treaties and conventions outside the United States. This invention pertains to compositions and methods for specifically inhibiting cells that are driven by or are dependent on specific ligand interactions. Examples are compositions and methods for long-term contraception or sterilization; compositions and methods for inhibiting or killing malignant and non-malignant, hormone-dependent tumors; compositions and methods for selectively killing virally infected cells; and compositions and methods for selectively destroying lymphocytes responsible for autoimmune disorders. Compositions that have sometimes been used for long-term contraception include those based upon natural or synthetic steroidal hormones to "trick" the female reproductive tract into a "false pregnancy." These steroidal hormones must be administered repeatedly to prevent
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completion of the estrous cycle and conception. Steroids have side effects that can be potentially dangerous. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Meningeal-derived stem cells Inventor(s): Ogle, Roy C.; (Earlysville, VA), Tholpady, Sunil; (Charlottesville, VA) Correspondence: Pillsbury Winthrop Llp; Intellectual Property Group; Suite 2800; 725 South Figueroa Street; Los Angeles; CA; 90017-5406; US Patent Application Number: 20040014211 Date filed: June 10, 2003 Abstract: Described herein are stem cells derived from the meninges; specifically, the dura mater, pia mater or arachnoid mater. Methods for isolating, differentiating and explanting these cells are described, as well. In particular embodiments, the stem cells of the present invention are differentiated into nerve cells, bone cells, cartilage cells and Schwann cells. The stem cells of the invention can be taken from a small biopsy, and rapidly expanded to large populations of cells using specially defined media that maintain their undifferentiated state. Use of the stem cells of the present invention in biomedical applications is also described. Excerpt(s): This application claims the benefit of priority under 35 U.S.C.sctn.119 of provisional U.S. application serial No. 60/387,793, filed Jun. 11, 2002, the contents of which are hereby incorporated by reference. The present invention is directed to stem cells and methods of preparing populations of progenitor cells that differentiate into a preselected cell type with high efficiency. Moreover, there is extensive interest in developing methods for using pluripotential stem cell populations for a wide variety of potential therapeutic applications, including delivery of therapeutic genes, correction of gene defects, replacement/augmentation of existing dysfunctional cell populations (e.g., dopaminergic neurons in Parkinsons Disease), and generation of organs/tissues for surgical repair/replacement. However, existing methods in the field have a number of major limitations that relate to obtaining purified populations of the desired cell types from pluripotent stem cells. By way of example, embryonic stem cells pose interesting possibilities as several studies show that these cells are pluripotent, however, the use of these cells is mired in ethical and political considerations. It is therefore likely that this technology will not be available for use in the near future. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Method and apparatus for sorting biological cells with a MEMS device Inventor(s): Foster, John Stuart; (Santa Barbara, CA) Correspondence: John S. Foster; Innovative Micro Technology; 75 Robin Hill Road; Goleta; CA; 93117; US Patent Application Number: 20040005628 Date filed: July 8, 2002 Abstract: A micromechanical actuator for sorting hematopoietic stem cells for use in cancer therapies. The actuator operates by diverting cells into one of a number of possible pathways fabricated in the fabrication substrate of the micromechanical
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actuator, when fluorescence is detected emanating from the cells. The fluorescence results from irradiating the cells with laser light, which excites a fluorescent tag attached to the cell. The micromechanical actuator thereby sorts the cells individually, with an operation rate of 3.3 kHz, however with the massively parallel 1024-fold device described herein, a throughput of 3.3 million events/second is achievable. Excerpt(s): This invention relates to the sorting of biological cells. More particularly, this invention relates to the use of a MEMS device for performing the sorting by physically separating the component of interest from the rest of the fluid sample. Many new therapies for cancer patients relate to enabling them to better withstand the challenge made to their bodies by the chemotherapies. In particular, it has recently been found that the inability of some patients to cope with chemotherapies has to do with the destruction of hematopoietic stem cells (HSCs), as ancillary damage of the chemotherapy. HSCs are the progenitor cells found in bone marrow, peripheral blood and many lymphoid organs. HSCs are responsible for generating the immune system components, such as T-cells, as well as the vital components of blood. When HSCs are destroyed in sufficient numbers, it becomes difficult for patients to replace blood cells, resulting in anemia often suffered by patients. The destruction of HSC's is also a leading cause of death in radiation victims, as the progenitor cells are destroyed, thereby destroying the ability to regenerate the vital components of the blood and immune systems. Recent research has indicated however that if the HSCs are removed from the patients' bodies prior to their receiving chemotherapy, and then replaced after the chemotherapy, the HSCs are shielded from the effects of the chemotherapy. By reinfusing the HSCs after the chemotherapy is finished, the patients' ability to regenerate their blood cells is regained and their resilience to the therapy is greatly enhanced. As a result, higher dosages of the chemotherapy can be administered to patients with better chances of diminishing the viability of the cancer cells, and yet the patients are able to regraft their blood-forming HSCs, which have been protected from exposure to the chemotherapy. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method for amplifying natural killer t cells Inventor(s): Wakasugi, Hiro; (Tokyo, JP) Correspondence: Foley And Lardner; Suite 500; 3000 K Street NW; Washington; DC; 20007; US Patent Application Number: 20040009594 Date filed: December 6, 2002 Abstract: Human V.alpha.24.sup.+ natural killer T cells are expanded by culturing a mononuclear cell fraction obtainable from human peripheral blood in which hemopoietic stem cells are mobilized by granulocyte colony-stimulating factor, in the presence of a cytokine, such as interleukin 2, effecting proliferation and/or activation of lymphocytes and.alpha.-glycosylceramide. A cell fraction comprising human V.alpha.24.sup.+ natural killer T cells expanded by the method, is useful as a cancertreating agent. Excerpt(s): The present invention relates to a method for expanding human V.alpha.24.sup.+ natural killer T (NKT) cells, and uses of human V.alpha.24.sup.+ NKT cells obtained by the method and a fraction comprising the human V.alpha.24.sup.+ NKT cells. NKT cells are an exceptional subset of mature lymphocytes that bear both
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NK and T cell receptors (Annu. Rev. Immunol., 15, 535-562, 1997; J. Exp. Med., 182, 633638, 1995). Murine NKT cells express NK1.1 and TCR.alpha.beta. receptors and are especially dense in the bone marrow (J. Immunol., 145, 3209-3215, 1990) and liver (J. Exp. Med., 180, 699-704, 1994). The cells express a very limited TCR repertoire (J. Exp. Med., 180, 1097-1106, 1994; Int. Immunol., 7, 1157-1161, 1995), including an invariant.alpha.-chain. These suggest that the ligand for NKT cells is non-polymorphic, and a non-classical MHC class I molecule that appear to present a specific antigen processed via TAP (transporter associated with antigen processing)-independent pathway. A recent study determined that one the MHC class Ib molecules, CD1d, is a ligand for NKT cells. Human T cells expressing the invariant V.alpha.24J.alpha.Q TCR with canonical rearrangements without N regions have recently been reported to be analogous to the murine V.alpha.14-J.alpha.281.sup.+ NKT cells (J. Exp. Med., 180, 10971106, 1994). Moreover, murine V.alpha.14-J.alpha.281.sup.+ cells and human V.alpha.24J.alpha.Q TCR.sup.+ NKT cells have been shown to proliferate upon stimulation with CD1d antigen presenting cells (APCs) pretreated with.alpha.galactosylceramide (.alpha.-GalCer). Activated NKT cells reportedly display an NK-like perforin-dependent cytotoxicity against various tumor cell lines (Cancer Res., 59, 51025105, 1999) and inhibit tumor metastasis in certain experimental animal models (Pro. Natl. Acad. Sci. USA, 95, 5690-5693, 1998). In the 1980's, numerous immunotherapy clinical trials were carried out, including those investigating LAK (lymphokineactivated killer) cell therapy and TIL (tumor-infiltrating lymphocytes) therapy, with or without cytokine injection. However, the findings of these clinical trials demonstrated that these cell-therapies fall short of expectations in terms of their clinical effect, with not obvious clinical benefit being detected. Significant progress has been made in the 1990's in identifying the molecular components of the immune response to human cancer. Some different immunotherapeutic approaches, such as dendritic cell (DC) therapy and cytotoxic T lymphocyte (CTL) therapy are currently being explored in clinical trails. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method for generating primate trophoblasts Inventor(s): Thomson, James A.; (Madison, WI), Xu, Ren-He; (Madison, WI) Correspondence: Nicholas J. Seay; Quarles & Brady Llp; P O Box 2113; Madison; WI; 53701-2113; US Patent Application Number: 20040005701 Date filed: March 14, 2003 Abstract: The first method to cause a culture of human and other primate stem cells to directly and uniformly differentiate into a committed cell lineage is disclosed. Treatment of primate stem cells with a single protein trophoblast induction factor causes the cells to transform into human trophoblast cells, the precursor cells of the placenta. Several protein factors including bone morphogenic protein 4 (BMP4), BMP2, BMP7, and growth and differentiation factor 5 can serve as trophoblast-inducting factors. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/365,136 filed Mar. 15, 2002. Not applicable. Modern cell biology includes a variety of techniques to manipulate various cells of living organisms in vitro. Of particular interest is a category of cell known as a stem cell. Stem cells are undifferentiated or only partially differentiated cells that have the capability to differentiate into a number of progenitor and mature cell lineages and types. The term "stem cells" can be used to refer to a cell type which is the progenitor of a differentiation cellular lineage in a larger
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organism, such as hematopoietic stem cell, or can refer to totally undifferentiated stem cells which, at least in theory, have the ability to differentiate into any of the tissues of the body. Stem cells are, at a minimum, pluripotent, meaning that they have the potential to differentiate into many different cell types, and may be totipotent, meaning have the potential to differentiate into any cell type of a mature organism of the species. Stem cell cultures have been developed from a variety of tissue types and from a number of different animals. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method for isolating and measuring proliferation of long-term label retaining cells and stem cells Inventor(s): Hellerstein, Marc K.; (Kensington, CA), Kim, Sylvia Jeewon; (Sunnyvale, CA) Correspondence: Michael R. Ward; Morrison & Foerster Llp; 425 Market Street; San Francisco; CA; 94105-2482; US Patent Application Number: 20030224420 Date filed: April 4, 2003 Abstract: This invention relates to a method for separating long-term label retaining cells or stem cells. In particular, this invention relates to a method for separating longterm label retaining cells and/or stem cells from tissues or individuals and for measuring proliferation rates of long-term label retaining cells and stem cells, as well as determining clonal expansion (proliferative history) of cell lineages from the tissues of the individual. The cells may be double-labeled with a cell-lineage marking label and isotopically labeled DNA synthesis precursor prior to physical separation. Excerpt(s): This application claims priority to U.S. Provisional Application No. 60/370,599 filed on Apr. 5, 2002, which is hereby incorporated by reference in its entirety. This invention relates to a method of separating long-term label retaining cells and/or stem cells from non-label retaining cells and/or non-stem cells. In particular, this invention relates to methods of separating stem cells from a tissue or individual, and methods of determining the proliferation rate of long-term label retaining cells and/or stem cells, as well as identifying the clonal expansion (proliferative history) of cell lineages of tissues and individuals. The number of cell divisions undergone by a particular lineage of cells is of fundamental importance in a number of diseases as well as normal physiologic processes. Cell divisions within a particular lineage, also termed the clonal expansion or proliferative history of a particular cell line, particularly stem cells, influence the risk of cancer (i.e. carcinogenesis), rate of fixation of DNA damage as permanent mutations (i.e., mutagenesis, teratogenesis, carcinogenesis, evolutionary rate), response of T cells to antigenic stimuli (i.e., vaccine efficacy), spermatogenesis (i.e. male fertility), adipogenesis from pre-adipocytes (i.e. body fat accrual), maintenance of epithelial cell populations (i.e. tissue homeostasis), neurogenesis in brain, and other medical conditions and diseases. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Method of inactivating micro-organisms Inventor(s): Brand, Agatha; (Amsterdam, NL), Dubbelman, Thomas Martinus Albert Remko; (Alphen a/d Rijn, NL), Lagerberg, Johannes Wilhelmus Maria; (Leiden, NL), Trannoy, Laurence Lilianne Annette; (Den Haag, NL) Correspondence: Peacock Myers And Adams P C; P O Box 26927; Albuquerque; NM; 871256927 Patent Application Number: 20040014738 Date filed: August 5, 2003 Abstract: The invention relates to a method of inactivating micro-organisms present in a liquid containing stem cells, where the method comprises the steps of -combining said liquid with a photosensitiser, and -activating the photosensitiser. In accordance with the present invention, a positively-charged sensitizer is used having a defined structure. Surprisingly, the use of these compounds minimize the damage to the stem cells. Excerpt(s): activating the photosensitiser. Stem cells are more and more used to grow desired cell types, for example for transplantation purposes and after chemotherapeutic interventions. A major source of stem cells is the umbilical cord. The solution containing the stem cells may be contaminated with various micro-organisms such as viruses (HIV, hepatitis B and C), fungi and bacteria. 10% of the umbillical blood samples appear to be contaminated (unpublished data, submitted for publication). This severely limits or even rules out their use for the desired purpose. It is known to inactivate organisms present in a blood product, such as plasma, red cells, platelets, leukocytes and bone marrow. For example, U.S. Pat. No. 5,360,734 describes a method comprising the addition of the photosensitiser to the blood product and irradiation with light to activate the photosensitiser, thereby inactivating viral pathogens. Such a method causes damage to the cells, which is, for example, demonstrated by the hemolysis of erythrocytes. The method disclosed in U.S. Pat. No. 5,360,734 is in particular aimed at and reducing the influence of plasma proteins in order to increase the stability of the red cells. Given the intended use of stem cells, damage to the cells should be avoided as much as possible. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Method of isolating stem cells Inventor(s): Colvin, O. Michael; (Chapel Hill, NC), Ludeman, Susan M.; (Durham, NC), Smith, Clayton A.; (Tampa, FL), Storms, Robert W.; (Durham, NC) Correspondence: Alston & Bird Llp; Bank OF America Plaza; 101 South Tryon Street, Suite 4000; Charlotte; NC; 28280-4000; US Patent Application Number: 20040023318 Date filed: August 1, 2003 Excerpt(s): The present invention relates, in general, to stem cells, and in particular, to a method of isolating stem cells and to reagents suitable for use in such a method. The invention further relates to stem cell populations isolatable in accordance with the present method. The most primitive hematopoietic stem cells (HSC) will reconstitute all of the hematopoietic lineages for an entire lifespan. These pluripotent hematopoietic stem cells (PHSC) are the transplantable cells that are ultimately the targets for gene delivery in stem cell-based gene therapies. One defining characteristic for PHSC is that they will survive most cytoablative conditioning regimens. The mechanisms for their
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resistance to these toxic agents suggest potential strategies by which these cells can be selected in vitro. One mechanism for drug resistance lies in the ability to efflux toxic substances out of the cell via the multiple drug resistance (MDR) pump. Fluorescent substrates for the MDR pump have permitted the isolation of PHSC based on their high capacity for dye efflux in a variety of assay systems. Drug resistances may also be conferred by more specific mechanisms. For example, a cytosolic aldehyde dehydrogenase (ALDH) mediates resistance to cyclophosphamide (CPA), an alkylating agent used in cytoreductive regimens in preparation for bone marrow transplant. Thus, expression of ALDH can be considered a selectable marker for true PHSC. The therapeutic effectiveness of CPA has been attributed largely to the ability of PHSC and intestinal crypt cells to survive the drug regimen. Human hematopoietic progenitors express a cytosolic ALDH and primitive human HSC derived from mobilized peripheral blood stem cells can be selected when placed in culture with cyclophosphamide for 7 days. Jones et al have demonstrated that long-term reconstituting murine PHSC can be isolated by providing a membrane-permeable fluorescent-substrate for ALDH and by then selecting cells with the highest levels of ALDH activity (Jones, Blood 85:2742 (1995); Jones et al, Blood 88:487 (1996)). In these studies, dansyl aminoacetaldyde (DAAA) was used to stain murine bone marrow cells prepared by countercurrent elutriation. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method of making embryoid bodies from primate embryonic stem cells Inventor(s): Marshall, Vivienne S.; (Madison, WI), Swiergiel, Jennifer J.; (Roscoe, IL), Thomson, James A.; (Madison, WI) Correspondence: Nicholas J. Seay; P O Box 2113; Madison; WI; 53701-2113; US Patent Application Number: 20040023376 Date filed: August 1, 2003 Abstract: Primate embryoid bodies are formed from primate ES cells. The ES cells form clumps. One then removes the clumps, as clumps, and permits incubation under nonadherent conditions. The development of embryoid bodies from primate ES cells is dependent on maintaining the aggregation of cells, as individualized cells will rapidly die. Excerpt(s): Not applicable. Undifferentiated primate embryonic stem ("ES") cells can be cultured indefinitely and yet maintain the potential to form differentiated cells of the body. See U.S. Pat. No. 5,843,780; J. Thomson, et al., 282 Science 1145-1147 (1998); and J. Thomson, et al., 38 Biology 133-165 (1998). The disclosure of these publications and of all other publications referred to herein are incorporated by reference as if fully set forth herein. Primate ES cells thus provide an exciting new model for understanding the differentiation and function of human tissue, and offer new strategies for drug discovery and testing. They also promise new therapies based on the transplantation of ES cell-derived tissues. For example, human and rhesus monkey ES cells injected into immunocompromised mice form benign teratomas with advanced differentiated derivatives representing all three embryonic germ layers. Easily identified differentiated cells in human ES cell teratomas include smooth muscle, striated muscle, bone, cartilage, gut and respiratory epithelium, keratinizing squamous epithelium, hair, neural epithelium, and ganglia. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Methods for enhancing engraftment of purified hematopoietic stem cells in allogeneic recipients Inventor(s): Ildstad, Suzanne T.; (Prospect, KY) Correspondence: Hogan & Hartson Llp; One Tabor Center, Suite 1500; 1200 Seventeenth ST; Denver; CO; 80202; US Patent Application Number: 20040005300 Date filed: May 14, 2003 Abstract: This invention provides a method of achieving a higher rate of allogeneic hematopoietic stem cell engraftment by either (i) matching the major histocompatibility complex class I K locus between donors and recipients or (ii) identifying how class I K on HSC interact with FC (CD8/33Kd receptor complex) works thus allowing one to bypass the need for FC. The MHC loci which are essential for curable engraftment of purified allogeneic HSC are identified by the methods of this invention. This invention further demonstrates that the MHC class I K molecule is essential for maintaining the self-renewal capability of purified HSC. Moreover, interaction between the HSC and FC via the MHC class I K molecule provides a regulatory function to promote engraftment and survival of allogeneic HSC. Excerpt(s): This application is a Section 371 filing of PCT/US01/45303, filed Nov. 14, 2001, which claims priority to U.S. Provisional Application Serial No. 60/248,889, filed Nov. 14, 2000, the disclosures of which are incorporated herein by reference. The present invention relates to a specific major histocompatibility complex (MHC) molecule that strongly influences engraftment of hematopoietic stem cells (HSC) mediated by facilitating cells and more particularly that this MHC molecule is essential for maintaining the self-renewal capability of purified HSC. The transfer of living cells, tissues, or organs from a donor to a recipient, with the intention of maintaining the functional integrity of the transplanted material in the recipient defines transplantation. Transplants are categorized by site and genetic relationship between the donor and recipient. An autograft is the transfer of one's own tissue from one location to another; a syngeneic graft (isograft) is a graft between identical twins; an allogeneic graft (homograft) is a graft between genetically dissimilar members of the same species; and a xenogeneic graft (heterograft) is a transplant between members of different species. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Methods for inducing differentiation of embryonic stem cells and uses thereof Inventor(s): Jessell, Thomas M.; (Bronx, NY), Lieberam, Ivo; (New York, NY), Wichterle, Hynek; (New York, NY) Correspondence: Leslie Gladstone Restaino, ESQ.; Brown Raysman Millstein Felder & Steiner Llp; 163 Madison Avenue; P.O. Box 1989; Morristown; NJ; 07962-1989; US Patent Application Number: 20040014210 Date filed: July 16, 2002 Abstract: The present invention provides a method for inducing differentiation of an embryonic stem cell into a differentiated neural cell. The present invention further provides a method for producing differentiated neural cells, and a population of cells comprising the differentiated neural cells. Additionally, the present invention provides a method for repopulating a spinal cord in a subject, and a method for treating nervous
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tissue degeneration in a subject in need of treatment. The present invention further provides neural progenitor cells, differentiated neural cells, and uses of same. Also provided is a transgenic non-human animal containing the differentiated neural cells. The present invention is further directed to a method for isolating a population of differentiated neural cells. Finally, the present invention provides a method for identifying an agent for use in treating a condition associated with neuron degeneration. Excerpt(s): Hundreds of distinct neuronal types are generated during the development of the vertebrate central nervous system (CNS), establishing a cellular diversity that is essential for the formation of neuronal circuits. The selective degeneration of specific types or classes of CNS neurons underlies many neurological disorders. This realization has generated interest in defining populations of progenitor cells that may serve as replenishable sources of neurons, with a view to treating neurodegenerative disorders. Directing such progenitor cells along specific pathways of neuronal differentiation in a systematic manner has proved difficult, not merely because the normal developmental pathways that generate most classes of CNS neurons remain poorly defined. Studies of the neurogenic potential of progenitor cells have focused on three major classes of cells: (1) neural progenitors derived from embryonic or adult nervous tissue (Alvarez-Buylla et al., A unified hypothesis on the lineage of neural stem cells. Nat. Rev. Neurosci., 2:287-93, 2001; Gage, F. H., Mammalian neural stem cells. Science, 287:1433-38, 2000; Temple, S., The development of neural stem cells. Nature, 414:112-17, 2001; Uchida et al., Direct isolation of human central nervous system stem cells. Proc. Natl. Acad. Sci. USA, 97:14720-725, 2000); (2) non-neural progenitor cells derived from other tissues and organs (Brazelton et al., From marrow to brain: expression of neuronal phenotypes in adult mice. Science, 290:1775-79, 2000; Mezey et al., Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science, 290:1779-82, 2000; Terada et al., Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature, 416:542-45, 2002; Ying et al., Changing potency by spontaneous fusion. Nature, 416:545-48, 2002); and (3) embryonic stem (ES) cells (Bain et al., Embryonic stem cells express neuronal properties in vitro. Dev. Biol., 168:342-57, 1995; Reubinoff et al., Neural progenitors from human embryonic stem cells. Nat. Biotechnol., 19:1134-40, 2001; Schuldiner et al., Induced neuronal differentiation of human embryonic stem cells. Brain Res., 913:201-05, 2001; Zhang et al., In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat. Biotechnol., 19:1129-33, 2001; Rathjen et al., Directed differentiation of pluripotent cells to neural lineages: homogenous formation and differentiation of a neurectoderm population. Development, 129:2649-61, 2002). ES cells possess the capacity to generate both neurons and neuroglial cells, and, in some instances, express cell-type markers characteristic of specific classes of neurons, including midbrain dopaminergic neurons (Kawasaki et al., Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity. Neuron, 28:31-40, 2000; Lee et al., Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nat. Biotechnol., 18:675-79, 2000). Despite these advances, however, it was not known, prior to the present invention, that ES cells can readily generate specific neuronal cell types, nor that they can recapitulate normal programs of neurogenesis. Spinal motor neurons represent one CNS neuronal subtype for which many of the relevant pathways of neuronal specification have been defined (Jessell et al., Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nat. Rev. Genet., 1:20-29, 2000; Lee et al., Transcriptional networks regulating neuronal identity in the developing spinal cord. Nat. Neurosci., 4 Suppl.:1183-91, 2001). The generation of spinal motor neurons appears to involve several developmental steps. Initially, ectodermal cells acquire a rostral neural character--a process achieved through the regulation of BMP, FGF, and Wnt
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signalling (Munoz-Sanjuan et al., Neural induction, the default model and embryonic stem cells. Nat. Rev. Neurosci., 3:271-80, 2002; Wilson et al., Neural induction: toward a unifying mechanism. Nat. Neurosci., 4 Suppl.:1161-68, 2001). These rostral neural progenitors acquire a spinal positional identity in response to caudalizing signals that include retinoic acid (RA) (Blumberg et al., An essential role for retinoid signaling in anteroposterior neural patterning. Development, 124:373-79, 1997; Durston et al., Retinoids and related signals in early development of the vertebrate central nervous system. Curr. Top. Dev. Biol., 40:111-75, 1998; Muhr et al., Convergent inductive signals specify midbrain, hindbrain, and spinal cord identity in gastrula stage chick embryos. Neuron, 23:689-702, 1999). Subsequently, spinal progenitor cells acquire a motor neuron progenitor identity in response to the ventralizing action of Sonic Hedgehog protein (SHh) (Briscoe et al., Specification of neuronal fates in the ventral neural tube. Curr. Opin. Neurobiol., 11:43-49, 2001). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Methods for making and using reprogrammed human somatic cell nuclei and autologous and isogenic human stem cells Inventor(s): Campbell, Keith; (Loughborough, GB), Cibelli, Jose; (Holden, MA), West, Michael; (Southborough, MA) Correspondence: Crowell & Moring, L.L.P.; Intellectual Property Group; P.O. Box 14300; Washington; DC; 20044-4300; US Patent Application Number: 20030232430 Date filed: November 26, 2002 Abstract: Activated human embryos produced by therapeutic cloning can give rise to human totipotent and pluripotent stem cells from which autologous cells for transplantation therapy are derived. The present invention provides methods for producing activated human embryos that can be used to generate totipotent and pluripotent stem cells from which autologous cells and tissues suitable for transplantation can be derived. In one embodiment, the invention provides methods for producing activated human embryos by parthenogenesis; in another embodiment, the invention provides methods for producing activated human embryos by somatic cell nuclear transfer whereby the genetic material of a differentiated human donor cell is reprogrammed to form a diploid human pronudeus capable of directing a cell to generate the stem cells from which autologous, isogenic cells for transplantation therapy are derived. The ability to create autologous human embryos represents a critical step towards generating immune-compatible stem cells that can be used to overcome the problem of immune rejection in regenerative medicine. The activated human embryos produced by the present invention also provide model systems for identifying and analyzing the molecular mechanisms of epigenetic imprinting and the genetic regulation of embryogenesis and development. Excerpt(s): This application claims priority to U.S. provisional application 60/332,510 filed Nov. 26, 2001 incorporated by reference in its entirety. The present invention relates to the field of therapeutic cloning, the production of activated human embryos from which totipotent and pluripotent stem cells can be generated, and the derivation from these of cells and tissues suitable for transplantation that are autologous to a patient in of such transplant. In particular, the present invention relates to therapeutic cloning of human cells by parthenogenetic activation of a human embryo, and by nuclear transfer into an oocyte to effect the reprogramming of the genetic material of a
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human somatic cell to form a diploid human pronucleus capable of directing a cell to generate the stem cells from which autologous, isogenic cells for transplantation therapy are derived. The present invention also relates to the fields of study of the molecular mechanisms of epigenetic imprinting and the genetic regulation of embryogenesis and development. Until recently, it was thought that the differentiation of stem cells into the different somatic cell types of a mammal is associated with irreversible structural changes in chromatin structure and function that commit the differentiating cells to patterns of genetic expression characteristic of particular somatic cell types. The idea that the genome of somatic cells is irreversibly programmed during differentiation was discredited when nuclear transfer (NT)-derived bovine blastocysts were generated using cumulus cells (4). That the nucleus of a differentiated somatic cell could be reprogrammed to a state capable of directing embryogenesis was later confirmed by Wilmut et al. with the cloning of an adult sheep from a quiescent mammary gland-derived cell (5); and by Cibelli et al. with the cloning of an adult bovine from actively dividing fetal fibroblasts (6). Following these pioneering results, protocols for NT using somatic cells have been improved and extended to new mammalian species; however, little is understood of the mechanisms underlying, and the parameters controlling, the process whereby the genetic material (i.e., the genomic DNA and proteins that form chromatin, the nuclear matrix, nucleoplasm, genetic regulatory factors and complexes, etc.) of a differentiated cell is "reprogrammed" by ooplasm to form a diploid pronucleus that is capable of directing the generation of daughter cells that are, or give rise to, totipotent, near totipotent, or pluripotent stem cells. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Methods of identifying and isolating stem cells and cancer stem cells Inventor(s): Ailles, Laurie Elizabeth; (Stanford, CA), Jamieson, Catriona Helen M.; (Palo Alto, CA), Reya, Tannishtha; (Mountain View, CA), Weissman, Irving; (Redwood City, CA) Correspondence: Bozicevic, Field & Francis Llp; 200 Middlefield RD; Suite 200; Menlo Park; CA; 94025; US Patent Application Number: 20040018531 Date filed: May 30, 2003 Abstract: Methods and compositions are provided for the identification of stem cells and cancer stem cells.beta.-catenin is also identified as a target for the development of therapeutic moieties against hematopoietic tumors, i.e. leukemia and lymphoma cells, which may include screening assays directed at.beta.-catenin, or members of the.beta.catenin signaling pathway. Cellular proliferation in hematopoietic cells can be altered by introducing stabilized.beta.-catenin into a hematopoietic cell that is altered in its ability to undergo apoptosis but which is not fully transformed. The immortalized cells are useful in screening assays, and in the analysis of pathways by which hematopoietic cells undergo transformation. Excerpt(s): Basic cancer research has focused on identifying the genetic changes that lead to cancer. This has led to major advances in understanding of the molecular and biochemical pathways that are involved in tumorigenesis and malignant transformation. But understanding of the cellular biology has lagged. While the effect of particular mutations on the proliferation and survival of model cells may be known, it is not known what the effects of such mutations will be on the actual cells involved in particular cancers. In fact, many observations suggest that analogies between normal
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stem cells and tumorigenic cells may be appropriate. Both normal stem cells and tumorigenic cells have extensive proliferative potential and the ability to give rise to new (normal or abnormal) tissues. Both tumors and normal tissues are composed of heterogeneous combinations of cells, with different phenotypic characteristics and different proliferative potentials. Because most tumors have a clonal origin, tumorigenic cancer cells must give rise to phenotypically diverse progeny, including cancer cells with indefinite proliferative potential, as well as cancer cells with limited or no proliferative potential. This suggests that tumorigenic cancer cells undergo processes that are analogous to the self-renewal and differentiation of normal stem cells. It is well documented that many types of tumors contain cancer cells with heterogeneous phenotypes reflecting aspects of the differentiation that normally occurs in the tissues from which the tumors arise. The variable expression of normal differentiation markers by cancer cells in a tumor suggests that some of the heterogeneity in tumors arises as a result of the anomalous differentiation of tumor cells. Thus, tumorigenic cells can be thought of as cancer stem cells that undergo an aberrant and poorly regulated process of organogenesis analogous to that of normal stem cells. Many pathways that are classically associated with cancer may also regulate normal stem cell development. For example, the prevention of apoptosis by enforced expression of the oncogene bcl-2 results in increased numbers of hematopoietic stem cells (HSC) in vivo, suggesting that cell death has a role in regulating the homeostasis of HSCs. Other signaling pathways associated with oncogenesis, such as the Notch, Sonic hedgehog (Shh) and Wnt signalling pathways, may also regulate stem cell self-renewal. One particularly interesting pathway that has also been shown to regulate both self-renewal and oncogenesis in different organs is the Wnt signalling pathway. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Methods of inducing or enhancing connective tissue repair Inventor(s): Eberle, Peter; (Braunschweig, DE), Gazit, Dan; (Jerusalem, IL), Gross, Gerhard; (Braunschweig, DE), Hoffmann, Andrea; (Hannover, DE), Pelled, Gadi; (Rishon Leziyon, IL), Turgeman, Gadi; (Jerusalem, IL) Correspondence: Eitan, Pearl, Latzer & Cohen Zedek Llp; 10 Rockefeller Plaza, Suite 1001; New York; NY; 10020; US Patent Application Number: 20030228292 Date filed: December 26, 2002 Excerpt(s): This application claims priority of provisional application U.S. Serial No. 60/342,375, filed Dec. 27, 2001, which is hereby incorporated herein. This invention provides method for repairing, regenerating, treating, or inducing the repair of an injury, a defect or a condition of a connective tissue of a subject. This invention provides a method of regenerating, enhancing, inducing repair and/or development of connective tissue as a result of a defect, injury or condition of the connective tissue of a subject comprising the step of inserting an engineered cell which comprises a nucleic acid encoding a SMAD protein or variant thereof, so as to induce regeneration, repair and/or development of the connective tissue. This invention further provides methods of ex-vivo implantation of engineered cells into an injury, defect or condition of the connective tissue. This invention also provides a nucleic acid encoding a SMAD 8 protein variant, cells comprising such SMAD 8 variant, include mesenchymal stem cells, progenitor cells or cells derived from a connective tissue. Lastly, this invention provides SMAD 8 protein variant. Repair techniques for lacerated or severed tendons and
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ligaments ("connective tissues" or "cords") vary widely depending on the nature of the injury and the particular cord affected. There are large differences in the extent to which access can be obtained in the at least obtrusive manner, in the amount of cord excursion, in the surrounding environment, in the stresses to which different cords are normally subjected, and in the healing characteristics of different cords. In addition, often there is no consensus of the overall best way to repair a given cord. Examples of often injured cords having different accepted repair techniques are flexor tendons of the hand and the anterior cruciate ligament (ACL) of the knee. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Methods of using JNK or MKK inhibitors to modulate cell differentiation and to treat myeloproliferative disorders and myelodysplastic syndromes Inventor(s): Hariri, Robert J.; (Florham Park, NJ), Stirling, David I.; (Warren, NJ), Zeldis, Jerome B.; (Princeton, NJ) Correspondence: Pennie And Edmonds; 1155 Avenue OF The Americas; New York; NY; 100362711 Patent Application Number: 20040028660 Date filed: May 30, 2003 Abstract: The present invention provides methods of modulating mammalian, particularly human, stem cell and progenitor cell differentiation to regulate and control the differentiation and maturation of these cells along specific cell and tissue lineages. The methods of the invention relate to the use of certain small organic molecules to modulate the differentiation of stem cell populations along specific cell and tissue lineages, particularly embryonic-like stem cells originating from a postpartum placenta or stem cells isolated form sources such as cord blood. The invention also relates to the treatment or prevention of myelodysplastic syndrome or myeloproliferative syndrome, or symptoms thereof, comprising administration of JNK or MKK inhibitors, alone or in combination, as well as with or without the use of unconditioned cells or cells conditioned in accordance with other aspects of the invention. Finally, the invention relates to the use of such differentiated stem cells in transplantation and other medical treatments. Excerpt(s): This application claims benefit of U.S. provisional application No. 60/384,250, filed May 30, 2002 and U.S. provisional application No. 60/434,833, filed Dec. 19, 2002, each of which is incorporated by reference herein in its entirety. The present invention relates to methods of modulating mammalian stem cell and progenitor cell differentiation, comprising exposing a stem or progenitor cells to compounds that inhibit c-Jun N-terminal kinase (JNK) or mitogen-activated protein kinase kinase (MKK) activity. The methods of the invention are useful for regulating or controlling the differentiation or maturation of mammalian, particularly human, stem cells along specific cell and tissue lineages. The methods of the invention relate to the use of certain small organic molecules to modulate the differentiation of stem cell populations along specific cell and tissue lineages, and in particular, to the differentiation of embryonic-like stem cells originating from a postpartum placenta or for the differentiation of stem cells isolated form sources such as cord blood. The present invention also provides methods of treating or preventing a myeloproliferative disorder ("MPD") or a myclodysplastic syndrome ("MDS"), comprising administering to a patient in need thereof an effective amount of a JNK inhibitor or a MKK inhibitor, alone or in combination. Finally, the invention relates to the use of such differentiated
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stem cells in transplantation and other medical treatments. Human stem cells are totipotential or pluripotential precursor cells capable of generating a variety of mature human cell lineages. This ability serves as the basis for the cellular differentiation and specialization necessary for organ and tissue development. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Modulation of neural stem cells and neural progenitor cells Inventor(s): Lindquist, Per; (Staltradsvagen 21, SE), Mercer, Alex; (Staltradsvagen 15, SE), Ronnholm, Harriet; (Tornslingan 8, 1tr, SE), Wikstrom, Lilian; (Stjarnfallsvagen 9, SE) Correspondence: Ivor R. Elrifi; Mintz, Levin, Cohn, Ferris,; Glovsky And Popeo, P.C.; 666 Third Avenue, 24th Floor; New York; NY; 10017; US Patent Application Number: 20040014662 Date filed: May 8, 2003 Abstract: The invention relates generally to methods of influencing central nervous system cells to produce progeny useful in the treatment of CNS disorders. More specifically, the invention includes methods of exposing a patient suffering from such a disorder to a reagent that modulates the proliferation, migration, differentiation and survival of central nervous system cells via S1P or LPA signaling. These methods are useful for reducing at least one symptom of the disorder. Excerpt(s): This application claims the benefit of U.S. Ser. No. 60/379,114 filed May 8, 2002 and U.S. Ser. No. 60/393,159 filed Jul. 2, 2002. The contents of these applications are incorporated herein by reference in their entirety. The invention relates generally to methods of influencing adult neural stem cells and neural progenitor cells to produce progeny that can replace damaged or missing neurons or other central nervous system (CNS) cell types. More specifically, the invention includes methods of exposing a patient suffering from a disorder to a reagent that regulates the differentiation, proliferation, survival and migration of central nervous system cells via modulation of sphingosine-1phosphate (S1P) or lysophosphatidic acid (LPA) signaling. These methods are useful for reducing at least one symptom of a neurological disorder. Throughout this specification, various patents, published patent applications and scientific references are cited to describe the state and content of the art. Those disclosures, in their entireties, are hereby incorporated into the present specification by reference. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Modulation of stem and progenitor cell differentiation, assays, and uses thereof Inventor(s): Chan, Kyle W.H.; (San Diego, CA), Hariri, Robert J.; (Florham Park, NJ), Moutouh-De Parseval, Laure A.; (San Diego, CA), Stirling, David I.; (Warren, NJ) Correspondence: Pennie And Edmonds; 1155 Avenue OF The Americas; New York; NY; 100362711 Patent Application Number: 20030235909 Date filed: April 11, 2003 Abstract: The present invention relates to methods of modulating mammalian stem cell and progenitor cell differentiation. The methods of the invention can be employed to
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regulate and control the differentiation and maturation of mammalian, particularly human stem cells along specific cell and tissue lineages. The methods of the invention relate to the use of certain small organic molecules to modulate the differentiation of stem or progenitor cell populations along specific cell and tissue lineages, and in particular, to the differentiation of embryonic-like stem cells originating from a postpartum placenta or for the differentiation of early progenitor cells to a granulocytic lineage. Finally, the invention relates to the use of such differentiated stem or progenitor cells in transplantation and other medical treatments. Excerpt(s): This application claims benefit of U.S. Provisional Application Nos. 60/372,348, filed Apr. 12, 2002; 60/437,348, filed Dec. 31, 2002; and 60/437,350, filed Dec. 31, 2002, each of which is incorporated herein in its entirety. The present invention relates to methods of modulating mammalian stem and/or progenitor cell differentiation. The methods of the invention can be employed to regulate and control the differentiation and maturation of mammalian, particularly human, stem and progenitor cells along specific cell and tissue lineages. The methods of the invention relate to the use of certain small organic molecules to modulate the differentiation of stem cell populations along specific cell and tissue lineages, and in particular, to the differentiation of embryonic-like stem cells originating from a postpartum placenta or the modulation of early hematopoietic progenitor cells along a specific differentiation pathway, particularly a granulocytic differentiation pathway. The invention also relates to the use of these organic molecules to modulate the differentiation of particular lineages of progenitor cells, such as CD34+, CD45+ and CD133+ progenitor cells. The invention also relates to the temporal aspects of progenitor cell development, and in vitro models based upon these temporal aspects. The invention further relates to the use of these modulated cells in prophylactic and therapeutic methods, including in pharmaceutical compositions of such cells and/or small organic compounds. Finally, the invention relates to the use of such differentiated cells in transplantation and other medical treatments. There is considerable interest in the identification, isolation and generation of human stem and progenitor cells. Stem cells are totipotential or pluripotential precursor cells capable of generating a variety of mature cell lineages, and precursor cells are cells capable of generating cells of specific cell lineages. These abilities serve as the basis for the cellular differentiation and specialization necessary for organ and tissue development. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Novel compositions and methods for the regulation of proliferation of stem cells Inventor(s): Rameshwar, Pranela; (Maplewod, NJ) Correspondence: Perkins Coie Llp; Post Office Box 1208; Seattle; WA; 98111-1208; US Patent Application Number: 20030225010 Date filed: May 21, 2002 Abstract: The present invention establishes the fact that the degradation of SP to SP(1-4) by endogenous NEP in BM stroma can be a mediator of hematopoietic stimulation by stem cell factor (SCF) and induce the production of TGF-.beta. and TNF-.alpha. in BM stroma. The present invention establishes that compositions containing the SP(1-4) polypeptide, or NEP genetic elements, can be used to slow and or stop the rapid growth of stem and progenitor cells thus protecting them from the deleterious effects of cancer therapy. Hence, the polynucleotides and proteins of the present invention may be used to protect stem cells from the toxic effects of chemo- and radio-therapy, in those
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undergoing, or about to undergo such cancer related treatments. Also provided are compositions containing NEP antisense sequences and antibodies used for the increased proliferation and differentiation of stem and/or progenitor cells in those whom have already undergone chemo- and/or radio-therapy. Excerpt(s): The present utility patent application claims priority to patent application U.S. Ser. No. 10/039,272 (Rameshwar et al.), filed Oct. 20, 2001, the disclosure of which is incorporated by reference in its entirety herein. The present invention relates to the field of molecular biology, immunology, and the regulation of stem cell proliferation and differentiation. In particular, this invention provides novel compositions and methods for protecting stem cells from chemo- and radio-therapeutic treatment. Specifically, this invention provides a novel composition of a Substance-P tetrapeptide, SP(1-4), which can be used to inhibit hemopoietic stem cell proliferation and differentiation into the various blood cells of the mature peripheral blood system and thereby act to protect stem cells from the toxic effects of chemo- and radio-therapy that targets rapidly dividing cells. Cells in the body are continually replaced. This can occur over a period of several hours up to many months. The presence of stem cells of various tissue types are present to grow and differentiate as a source of replacement cells for those cells that die. For example, the majority of blood cells are destined to die within a period of hours to weeks, depending on the specific blood cell type, and so must be continuously replaced. Bone Marrow (BM) is the major source of blood cells, including both white (lymphocytes, i.e., immune cells) and red blood cells (erythrocytes) in the adult. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Oligodendrocytes derived from human embryonic stem cells for remyelination and treatment of spinal cord injury Inventor(s): Keirstead, Hans S.; (Irvine, CA), Nistor, Gabriel I.; (Placentia, CA) Correspondence: Bozicevic, Field & Francis Llp; 200 Middlefield RD; Suite 200; Menlo Park; CA; 94025; US Patent Application Number: 20040009593 Date filed: April 4, 2003 Abstract: This invention provides populations of neural cells bearing markers of glial cells, such as oligodendrocytes and their precursors. The populations are generated by differentiating pluripotent stem cells such as human embryonic stem cells under conditions that promote enrichment of cells with the desired phenotype or functional capability. Various combinations of differentiation factors and mitogens can be used to produce cell populations that are over 95% homogeneous in morphological appearance, and the expression of oligodendrocyte markers such as GalC. The cells are capable of forming myelin sheaths, and can be used therapeutically improve function of the central nervous system. Excerpt(s): This application claims the benefit of U.S. Provisional Application Serial No. 60/395,382, filed Jul. 11, 2002, which application is incorporated herein by reference. This invention relates generally to the field of cell biology of embryonic cells and neural progenitor cells. More specifically, this invention provides enriched populations of oligodendrocytes and their precursors, suitable for use in biological research, drug screening, and human therapy. Oligodendrocytes play a vital physiological role in support of the central nervous system. Availability of oligodendrocytes for human
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therapy may facilitate healing of disabling conditions that result from defects in the myelin sheath that insulates nerve cells. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Placental derived stem cells and uses thereof Inventor(s): Miki, Toshio; (Pittsburgh, PA), Strom, Stephen C.; (Allison Park, PA) Correspondence: Foley Hoag, Llp; Patent Group, World Trade Center West; 155 Seaport Blvd; Boston; MA; 02110; US Patent Application Number: 20030235563 Date filed: April 21, 2003 Abstract: The present invention features novel placental derived stem cells and provides methods and compositions for the therapeutic uses of placental derived stem cells or placental derived stem cells that have been induced to differentiate into a desired tissue type into a recipient host in amounts sufficient to result in production of the desired cell type, i.e., hepatic, pancreatic, neuronal, or nervous tissue. Excerpt(s): The present invention provides novel placental derived stem cells capable of differentiating into a variety of different cell types. The invention also provides methods for prolonged culturing of placental derived stem cells with the capacity for differentiation into a variety of different cell type. The methods and compositions of the invention provide stem cells, or stem cells that have been induced to differentiate, that may be used in transplantation, development of bioartificial organs or drug screening assays designed to test the effectiveness and safety of drugs. Embryonic stem cells have long been recognized as a source of totipotent stem cells, able to give rise to different cell types. These cells are derived from the inner cell mass of fertilized and developing embryos. The use of such cells has been controversial on both ethical and religious grounds. Furthermore, federal regulation currently limits the use of embryonic stem cells to a few established cell lines which are difficult to obtain. Recent studies have focused on alternative sources of stem cells. These include hematopoietic stem cells obtained from bone marrow or peripheral blood. However the isolation of such stem cells from individuals can be invasive and painful. The developing embryo requires the interaction between mother and embryo mediated by the placenta and extraembryonic membranes for survival. The placenta and chorion is derived from the trophoblast, which begins to differentiate from the inner cell mass as early as day 8 following fertilization while the amniotic cavity originates in the ectoderm of the inner cell mass and consists of a single layer of extraembryonic mesoderm. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Preparation of dendritic cells from spinal cord stem cells Inventor(s): Weickmann, Dirk; (Munchen, DE) Correspondence: Jenkins & Wilson, PA; 3100 Tower Blvd; Suite 1400; Durham; NC; 27707; US Patent Application Number: 20040001806 Date filed: November 12, 2002
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Abstract: The present invention describes a method for the preparation of dendritic cells wherein spinal cord stem cells grow in a nutrient medium in the presence of the growth factors GM-CSF and IL-4 and optionally in addition in the presence of the interleukin receptor sIL-4R until dendritic cells have formed. The thus prepared dendritic cells are preferably loaded with toxins, cytokins and/or cytokin receptors and are used in the treatment of tumor patients. Excerpt(s): The invention relates to the preparation of dendritic cells from spinal cord stem cells by the addition of the growth factors GM-CSF and IL-4 as well as optionally in the presence of the interleukin receptor sIL-4R in vitro for therapeutic use in the case of tumor diseases, preferably cutaneous tumor diseases. The term dendritic cells refers to cells of the immune system which have differentiated from stem cells and carrying dendrites which track and destroy genetically transformed cells. The destruction may for example occur by pumping of immune peptide toxins into the genetically transformed cell by means of the dendrites following docking to this cell. In this case the dendritic cell functions as a transport cell. The immune peptide toxin leads to the lysis of the transformed cell. In the case of a weakened immune state the number of dendritic cells present within the body in a joint effort with the rest of the immune system is insufficient to effectively control transformed cells. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Primitive and proximal hepatic stem cells Inventor(s): Bruce, Andrew T.; (Holly Springs, NC), Furth, Mark E.; (Chapel Hill, NC), Ludlow, John W.; (Carrboro, NC), Moss, Nick; (Chapel Hill, TX), Reid, Lola; (Chapel Hill, NC) Correspondence: Patent Adminstrator; Katten Muchin Zavis Rosenman; 525 West Monroe Street; Suite 1600; Chicago; IL; 60661-3693; US Patent Application Number: 20040018621 Date filed: March 14, 2003 Abstract: Hepatic progenitors comprise two populations of human hepatic stem cells, primitive and proximal hepatic stem cells, and two populations of committed progenitors, one for biliary cells and one for hepatocytes. Human primitive hepatic stem cells are a very small fraction of the liver cell population and give rise to proximal hepatic stem cells constituting a much larger fraction of the liver. Human proximal hepatic stem cells give rise to biliary and hepatocyte committed progenitors. Primitive and proximal stem cells are the primary stem cells for the human liver. Human primitive hepatic stem cells may be isolated by immunoselection from human livers or culturing human liver cells under conditions which select for a human primitive hepatic stem cell. Proximal hepatic stem cells may be isolated by immunoselection, or by culturing human liver cells under conditions which include a developmental factor. Proximal hepatic stem cells may also be isolated by culturing colonies comprising a primitive hepatic stem cell under conditions which include a developmental factor. Resulting compositions may be used for treating liver disorders and for producing bioartificial organs. Excerpt(s): The present invention relates to human hepatic stem cells, pluripotent cells that give rise to mature liver cells. These include two stem cell populations: a very primitive progenitor, ductal plate stem cells, that give rise to proximal hepatic stem cells, the proximal stem cells that give rise to hepatocytes and biliary cells. The present
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invention also relates to methods of isolating the human hepatic ductal plate stem cells and to isolating proximal hepatic stem cells and committed hepatocytic progentitors and committed biliary progenitors. Compositions comprising cells of the present invention can be used for cell and gene therapies and for the establishment of bioartificial organs. The primary structural and functional unit of the mature liver is the acinus, which in cross section is organized like a wheel around two distinct vascular beds: 3-7 sets of portal triads (each with a portal venule, hepatic arteriole, and a bile duct) for the periphery, and with the central vein at the hub. The liver cells are organized as cell plates lined on both sides by fenestrated endothelia, defining a series of sinusoids that are contiguous with the portal and central vasculature. Recent data have indicated that the Canals of Hering, small ducts located around each of the portal triads, produce tiny ductules that extend and splice into the liver plates throughout zone 1 forming a pattern similar to that of a bottle brush (Theise, N. 1999 Hepatology. 30:1425-1433). A narrow space, the Space of Disse, separates the endothelia from hepatocytes all along the sinusoid. As a result of this organization, hepatocytes have two basal domains, each of which faces a sinusoid, and an apical domain which is defined by the region of contact between adjacent hepatocytes. The basal domains contact the blood, and are involved in the absorption and secretion of plasma components, while the apical domains form bile canaliculi, specialized in the secretion of bile salts, and are associated through an interconnecting network with bile ducts. Blood flows from the portal venules and hepatic arterioles through the sinusoids to the terminal hepatic venules and the central vein. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Proliferated cell lines and uses thereof Inventor(s): Cameron, Don F.; (Lutz, FL), Caviedes, Pablo; (Santiago, CL), Caviedes, Raul; (Santiago, CL), Freeman, Thomas B.; (Tampa, FL), Sanberg, Paul R.; (Spring Hill, FL) Correspondence: Saliwanchik Lloyd & Saliwanchik; A Professional Association; 2421 N.W. 41st Street; Suite A-1; Gainesville; FL; 326066669 Patent Application Number: 20030232752 Date filed: February 7, 2003 Abstract: The subject invention pertains to tumor cell lines useful for increasing the proliferation potential of any human or animal cell in culture, thereby providing immortalized or continuous cell lines and cultures. The invention also concerns proliferation factors, and compositions containing the factors, which are capable of increasing the proliferation potential of any human or other animal cell in culture. The subject invention further pertains to a method for proliferation cells in culture by contacting cells with the proliferation factors. The proliferated cells can range in plasticity and can include, for example, blast cells, fertilized ova, non-fertilized gametes, embryonic stem cells, adult stem cells, precursor or progenitor cells, and highly specialized cells. Optionally, the cells can be induced to cease proliferation. The proliferation cells of the subject invention are useful for cell therapy, cell/gene therapy, biological production of molecules, and as in vitro models for research, toxicity testing, and drug development. Excerpt(s): Most cells can be cultured in vitro to a limited extent using conventional cell culture technology, provided that suitable nutrients and other conditions for growth are supplied. Such cultures have been used to study genetic, physiological, and other
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phenomena, as well as to manufacture certain biomolecules using various fermentation techniques. In studies of mammalian cell biology, cell cultures derived from lymph nodes, muscle, connective tissue, kidney, dermis, and other tissue sources have been used, for example. However, most normal cells have a limited growth potential in culture. After a certain number of cell divisions (the Hayflick limit), they can no longer proliferate (Hayflick L., Exp. Cell. Res., 1965, 37:614-636). This limited life span, termed replicative senescence, likely arose as a protective mechanism against unfettered clonal evolution and cancer in long-lived animals. Therefore, while it has long been a goal of scientists to be able to maintain all types of cells in vitro, standard culture conditions do not promote the long-term survival or proliferation of most cells. "Immortalization" is the escape from the normal limitation on growth of a finite number of division cycles. Therefore, once immortalized, a cell line can be continuously cultured. However, immortal cell lines very rarely emerge spontaneously under usual culture conditions. In order to increase the life span of cells in culture, published techniques have included the use of embryonic cells. The strategy of starting with embryonic cells is based on the fact that embryonic cells are relatively less differentiated than adult cells, and thus can be expected to go through several cycles of cell division before becoming terminally differentiated. It is an axiom of biology that undifferentiated cells proliferate at a greater rate than differentiated cells. It is generally believed that by the time a cell has developed the necessary intra-cellular machinery for hormone synthesis and secretion, for example, it is no longer able to divide rapidly, if at all. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Screening assays for identifying differentiation-inducing agents and production of differentiated cells for cell therapy Inventor(s): Chapman, Karen; (SouthBorough, MA), Page, Raymond; (Southbridge, MA), Scholer, Hans; (Kennett Square, PA), West, Michael D.; (Southborough, MA) Correspondence: Pillsbury Winthrop Llp; Intellectual Property Group; P.O. Box 10500; Mclean; VA; 22102; US Patent Application Number: 20030224345 Date filed: August 26, 2002 Abstract: The invention relates to assays for screening growth factors, adhesion molecules, immunostimulatory molecules, extracellular matrix components and other materials, alone or in combination, simultaneously or temporally, for the ability to induce directed differentiation of pluripotent and multipotent stem cells. Excerpt(s): The present invention relates to methods for the in vitro culture and differentiation of totipotent, nearly totipotent, and pluripotent cells, and cells derived therefrom. Examples of such cells are embryonic cells, embryonic stem cells, embryonic germ cells, embryoid bodies, inner cell mass cells, morula-derived cells-derived cells, non-embryonic stem cells of embryonic, fetal, and adult animals, such as mesenchymal, hematopoietic, and neuronal stem cells, and cells derived from any of these. In one aspect, the invention provides efficient, high-throughput assays for screening and identifying chemical and biological agents and physical conditions that may be used to induce and direct the differentiation of totipotent, nearly totipotent, and pluripotent cells, and cells therefrom along particular developmental lineages. Examples of such differentiation-inducing agents and conditions are growth factors, cytokines and extracellular matrix components, cell-cell interactions, environmental conditions (temperature, oxygen pressure, etc.), and other extracellular factors or components, and
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combinations thereof, to which the target stem cells may be exposed simultaneously or sequentially to induce and direct differentiation. In another aspect, the invention provides a means of making genetically modified stem cell lines, e.g., gene trap stem cell lines, that facilitate the production, isolation, and therapeutic use of differentiated cell types for cell therapy. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Stem cell culture medium and culture method by using the same Inventor(s): Bhatia, Mick; (Ontario, CA), Sakano, Seiji; (Shizuoka, JP) Correspondence: Young & Thompson; 745 South 23rd Street 2nd Floor; Arlington; VA; 22202 Patent Application Number: 20040023324 Date filed: August 5, 2003 Abstract: A novel culture medium for stem cells. A culture medium containing a human notch ligand protein as the active ingredient and a method of culturing human stem cells by using this medium. The human notch ligand protein may be used together with a growth factor. According to this culture method, the cell count or the frequency of human stem cells having an SRC (Scid Repopulating Cells) activity, human stem cells characterized by being CD34-positive CD38-negative differentiation antigen-negative, etc. can be amplified. Excerpt(s): The present invention relates to a culture medium for human stem cells and a culture method by using the same. There are many types of cells in human blood and lymph, each of which plays an important role. For example, red blood cells transfer oxygen, platelets have hemostatic actions, and white blood cells and lymphocytes prevent infections. These various types of cells are driven from hematopoietic stem cells in bone marrow. It has been discovered that hematopoietic stem cells are differentiated into various types of blood cells, osteoclasts and mast cells, stimulated by various types of cytokines and environmental factors in a living body. Cytokines, such as erythropoietin (EPO) for differentiation into red blood cells, granulocyte colonystimulating factor (G-CSF) for differentiation in to white blood cells, and thrombopoietin (TPO) for differentiation into megakaryocytes that are platelet-producing cells have been discovered. The former two of these cytokines have already been applied to clinical uses. Bone marrow transplant that is performed as a therapeutic method for various types of hematopoietic disorderhemodyscrasia represents transplantation of hematopoietic stem cells. The method of using peripheral blood-derived or cord bloodderived hematopoietic stem cells has been adopted, and at present these methods are referred to as hematopoietic stem cell transplants. In these methods, cord blood-derived hematopoietic stem cell transplants are supposed to completely replace bone marrow transplant in the future, due to the burden placed on donors and the high quality of hematopoietic stem cells obtained. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Stem cell-derived endothelial cells modified to disrupt tumor angiogenesis Inventor(s): West, Michael; (Southborough, MA) Correspondence: Crowell & MORING. L.L.P.; P.O. Box 14300; Washington; DC; 200444300; US Patent Application Number: 20040018178 Date filed: January 22, 2003 Excerpt(s): This Application claims priority to U.S. Provisional Application Serial No. 60/349,345filed on Jan. 22, 2002, which is incorporated herein by reference in its entirety. The present invention provides cloned, genetically modified, endothelial cells, and the stem cells from which they are derived, which are produced by somatic cell nuclear transfer. The invention further provide novel therapeutic methods in which such cells are administered to a patient with tumors to inhibit and/or disrupt angiogenesis of the tumors, thereby inhibiting tumor growth and killing tumor cells. Angiogenesis is the process by which new blood vessels grow from the endothelium of existing blood vessels in a developed animal; it is an essential for wound healing and for reproduction. Angiogenesis is also rate-limiting step in tumor development. In the absence of the blood supply provided by angiogenesis, tumor growth is limited to 1-2 mm.sup.3. Tumors larger than this that are deprived of their blood supply become necrotic and apoptotic (Neithammer et al., 2002, Nature Medicine 8(12):1369). Much attention has focused recently on the notion that tumor growth can be inhibited by blocking or disrupting angiogenesis with agents that target vascular endothelial cell surface proteins or their ligands. (For example, see Folkman, 1997, "Angiogenesis and angiogenesis inhibition," EXS, 79:1-8; Huang et al., 1997, "Tumor infarction in mice by antibodydirected targeting of issue factor to tumor vasculature," 275:547; and Wei et al., 2000, "Immunotherapy of tumors with xenogeneic endothelial cells as a vaccine," 6:1160-6). Because tumor cells require a blood supply, local interruption of the tumor vasculature produces "an avalanche of tumor cell death" (Huang et al., supra). The strategy of targeting endothelial cells of tumor vasculature is also advantageous because, unlike the tumor cells, vascular endothelial cells are not transformed to have resistance to therapy, and the vascular endothelium is in direct contact with the blood and is relatively accessible to therapeutic agents and cells and factors of the patients immune system (Huang et al., supra). Examples of inhibitors of angiogenesis that are being developed for use as antitumor agents include endostatin and angiostatin, which are naturally occurring angiogenesis inhibitors, and neutralizing antibodies targeted to endothelial cell growth factor reECPtors, such as the Vascular Endothelial Growth Factor Receptors (VEGFR). Specific targets are VEGFR-1 (also known as Flt-1), VEGFR-2 (also known as KDR, Flkl), and VEGFR-3 (also known as Flt-4). Current strategies to inhibit angiogenesis by soluble factors suffer from the disadvantage that they typically require frequent (often daily) dosing. The proteinaceous factors cannot be administered orally, so the cost of administration is generally relatively high, and there is a risk of poor compliance. Many of the current strategies of inhibiting tumor angiogenesis through the administration of soluble factors are directed by the model that tumor angiogenesis resulted from the recruitment of neighboring capillary endothelial cells that simply "branched" into the growing tumor mass. However, recent studies suggest that tumor angiogenesis may proceed, at least in part, through a unique and unexpected pathway. Endothelial cell precursors have been shown to circulate in the blood and selectively migrate, or "home," to sites of active angiogenesis (U.S. Pat. No. 5,980,887 (Isner et al., the contents of which are incorporated herein by reference in their entirety). Circulating bone marrow-derived endothelial cell precursors are also recruited to contribute to
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angiogenesis by vascularizing tumors. Bone marrow-derived endothelial cells are a major component of the endothelium of a tumor mass, and impairment of the ability to recruit these bone marrow-derived endothelial cells for tumor angiogenesis has been shown to block tumor growth (Lyden et al., 2001, "Impaired recruitment of bone marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth," Nature Medicine, 7(11): 1194-1201). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
System and method for forming a non-ablative cardiac conduction block Inventor(s): Lee, Randall J.; (Hillsborough, CA) Correspondence: John P. O'banion; O'banion & Ritchey Llp; 400 Capitol Mall Suite 1550; Sacramento; CA; 95814; US Patent Application Number: 20040002740 Date filed: May 7, 2003 Abstract: A system forms a conduction block in a regions of cardiac tissue at a location associated with a cardiac arrhythmia by delivering a material that is non-ablative into the region. The material include living cells that do not form sufficient gap-junctions with cardiomyocytes to conduct, e.g. myoblasts, stem cells, or fibroblasts. The material may be a non-living agent, such as a polymer agent, e.g. fibrin glue agent or collagen agent. The material may be a combination of living and non-living material that enhances the cellular conduction block. A contact member delivers the material over a patterned region of tissue, such as arcuate, linear, or circumferential patterns. The contact member may include an expandable member or balloon. A guidewire may be used for delivery. Cells used may be autologous, prepared for injection with a kit. Conduction blocks are thus formed without substantially ablating cardiac tissue in the region. Excerpt(s): This invention pertains generally to systems and methods for treating medical conditions associated with the heart, and more particularly to surgical devices and procedures for forming conduction blocks at locations associated with the heart that include cardiac tissue. Cellular therapy for treating cardiac conditions has been the topic of significant research and development in recent years, generally for the purpose of increasing cardiac conduction or function. In fact, certain types of injected cells have been observed to couple poorly with indigenous cardiac cell tissues, and various prior disclosures have cited a related decrease in conduction transmission as a significant obstacle to the intended cellular therapy. Some disclosures have cited a desire to in fact modify the properties of injected cells to increase the cardiac tissue coupling for enhanced conduction or contractility. Tissue engineering techniques utilizing skeletal myoblast transplantation for myocardial repair has in particular gained increased attention with the demonstration that skeletal myoblasts survive and form contractile myofibers in normal and injured myocardium. However, the emphasis of myocardial repair has focused on the preservation of myocardial contractility with little attention given to the effects of tissue engineering on cardiac conduction or effects on cardiac arrhythmias. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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The use of stem cells and CD6 depleted stem cells for the induction of tolerance to allogenic transplants and/or for the treatment of leucemia Inventor(s): Gunther, Wolfgang; (Planegg, DE), Kolb, Hans Jochen; (Munchen, DE) Correspondence: Jenkins & Wilson, PA; 3100 Tower Blvd; Suite 1400; Durham; NC; 27707; US Patent Application Number: 20030232433 Date filed: April 10, 2003 Abstract: The present invention relates to the use of a composition containing stem cells as well as CD6 depleted stem cells for the induction of a tolerance to allogenic transplants and/or for the treatment of blood, immune, and cancer diseases for timestaggered application wherein first the stem cells are applied followed by application of the CD6 depleted stem cells. Furthermore, the present invention relates to a compound preparation containing stem cells and CD6 depleted stem cells. Excerpt(s): The present invention relates to the use of a composition containing stem cells as well as CD6 depleted stem cells for the induction of tolerance to allogenic transplants and/or for the treatment of blood, immune, and cancer diseases for timestaggered application wherein first the stem cells are applied followed by application of the CD6 depleted stem cells. Furthermore, the present invention relates to a compound preparation containing stem cells and CD6 depleted stem cells. The transplantation of hematopoietic stem cells and bone marrow belongs to the prior art. This technique includes first a destruction of immunocompetent cells of the recipient by a pretreatment such as by means of chemotherapy or radiotherapy to an extent sufficient to enable growth of the donor cells including stem cells and immunocompetent cells. Generally, stem cells transplantation is used in the case of diseases accompanied by a functional loss of the bone marrow for example in the frame of the therapy of acute leucemia but also for other blood and immune diseases as well as for cancer diseases. This range of diseases to be treated is due to the fact that these are all diseases based on a malfunction in hematopoiesis. Thus, stem cells may be used for non-malignant blood disorders (such as severe aplastic anemia (SAA), aplastic anemia, sickle cell anemia, thalassemia), immune system disorders (multiple sclerosis (MS), rheumatic diseases (CP), scleroderma) as well as for malignant blood disorders (acute and chronic leucemias of myeloid and lymphatic origin). For this purpose, preparations containing stem cells such as bone marrow and blood leucocytes are usually obtained from the donor and administered to the recipient intravenously. A stem cell transplantation of this type can induce tolerance to organs such as heart, lung etc. as well as to blood stem cells of the stem cells donor (1). A disadvantage of this type of stem cell transplantation is, however, that on the one hand the patient transplant may be rejected and on the other hand immunocompetent cells of the transplant may attack and injure cells of the recipient in the course of a graft-versus-host (GVH) disease wherein T cells of the transplant recognize cells of the recipient as non-self. In contrast to the transplantation of solid organs, the immunosuppressive treatment may be discontinued after months or years in the case of a stem cell transplantation if no rejection or GVH reaction occurs. A mutual tolerance is assumed. To prevent or decrease, respectively, the graft-versus-host reaction, immunocompetent cells, particularly T lymphocytes are frequently removed from the transplant. This, however, quite often results in transplant rejection (2), and in the case of the treatment of leucemia recurrences of the disease increasingly occur. The recurrences in the case of leucemia treatment as well as transplant rejection presumably occur due to a lack of donor T cells in the transplant which would be able to eliminate the T cells remaining after pretreatment of the recipient (3). Such complications do
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indeed bear a rather high risk even in the case of HLA identity (identity of tissue features) between donor and recipient and a very high risk for HLA differences. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Tissue filler Inventor(s): Kanemaru, shin-ichi; (Osaka, JP), Kojima, Hisayoshi; (Kyoto, JP), Nakamura, Tatsuo; (Kyoto, JP), Shimizu, Yasuhiko; (Kyoto, JP) Correspondence: Frishauf, Holtz, Goodman & Chick, PC; 767 Third Avenue; 25th Floor; New York; NY; 10017-2023; US Patent Application Number: 20040028659 Date filed: March 14, 2003 Abstract: Disclosed are a tissue filler and tissue reconstruction method using the same that enables missing or reduced tissue of a body to recover to a normal state thereof, and the tissue filler comprised by mixing mesenchymal stem cells into a hydrochloric acid solution of atherocollagen. Excerpt(s): The present invention relates to a filler for missing or reduced tissue, and to a tissue reconstruction method using said tissue filler. There are many patients suffering from disfunction of their organs caused by missing or reduced (atrophied) tissue, an example of which is the larynx. The larynx is an important organ involved in the respiration, phonation and swallowing. In particular, deformation of the vocal cords brought about by lesions occurring thereon caused by cancer and other diseases, as well as their treatment and so forth, can cause phonation and swallowing disorders. These sequelae may be quite serious even after the primary disease has been completely treated. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Use of human neural stem cells secreting GDNF for treatment of parkinson's and other neurodegenerative diseases Inventor(s): Svendsen, Clive N.; (Madison, WI) Correspondence: Quarles & Brady Llp; 411 E. Wisconsin Avenue, Suite 2040; Milwaukee; WI; 53202-4497; US Patent Application Number: 20030228295 Date filed: April 25, 2003 Abstract: A method of treating brain disorders involving loss of cells that respond to GDNF is disclosed. In one embodiment, the invention comprises the steps of (a) transducing human neural stem cells with glial-derived neurotrophic factor (GDNF), wherein the GDNF gene is under control of an inducible promoter system, and (b) transplanting the transduced cells into the brain of a patient. Excerpt(s): This application claims priority to U.S. provisional application 60/375,587, filed Apr. 25, 2002, incorporated by reference herein. The degeneration of specific groups of cells in the human brain underlies many devastating diseases such as Parkinson's Disease (PD), Alzheimer's Disease, Huntington's Disease (HD), amyotrophic lateral sclerosis (ALS) and many others. It is also a prime concern for the military due to
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the prevalence of neurotoxic chemical weapons and war related head injury. PD affects one of every 100 people over 60 or approximately 1.5 million Americans, and costs the US an estimated 25 billion dollars a year. Treatment consists mainly of administering a dopamine precursor L-DOPA. This is very effective in the early stages of the disorder, but later leads to severe side effects and eventually no longer works. Newer agents are being produced to enhance dopamine efficiency, and alternative neurosurgical approaches are also being developed. Here, specific brain regions are either lesioned or stimulated which often results in dramatic acute clinical benefit (The Deep-Brain Stimulation for Parkinson's Disease Study Group, 2001). However, there can also be changes in executive function (Jahanshahi, et al., Brain 123(Pt. 6):1142-1154, 2000) and the long-term prognosis for these patients in the face of ongoing neuronal degeneration is not yet known. Transplantation of dopamine neurons derived from fetal tissues has also shown great promise in PD. Here, new dopamine neurons integrate into the putamen of patients and provide a new source of dopamine--which in some cases leads to clinical improvement (Dunnett and Bjorklund, Nature 399:A32-A39, 1999). Transplantation actually replaces the neurons lost during the course of the disease, but as they are placed ectopically in the putamen they may not be optimal for clinical recovery. The latest study on a large group of patients which included sham operations has shown that although younger patients respond to the transplants, the effects were less dramatic in older patients and, in some cases, there were side-effects including dyskinesias, even in the absence of L-DOPA (Freed, et al., N. Engl. J. Med. 344:710-719, 2001). However, there is some discussion as to why these side-effects were seen in this study, which used a very different protocol to the many that preceded it (Isacson, et al., Nat. Neurosci. 4:553, 2001). While drugs, neurosurgical methods and transplantation represent real opportunities to improve the quality of life for PD patients, there are other alternatives. The most attractive prospect would be to prevent the loss of dopamine neurons, or to encourage existing cells to put out new processes. In this way the disease is being treated, rather than the symptoms. It is very possible that neuotrophic factors may provide a way of achieving this in the near future. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
Keeping Current In order to stay informed about patents and patent applications dealing with stem cells, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “stem cells” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on stem cells. You can also use this procedure to view pending patent applications concerning stem cells. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.
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CHAPTER 7. BOOKS ON STEM CELLS Overview This chapter provides bibliographic book references relating to stem cells. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on stem cells include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.
Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “stem cells” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on stem cells: •
Aging, Osteoporosis, and Dental Implants Source: Chicago, IL: Quintessence Publishing Co, Inc. 2002. 260 p. Contact: Available from Quintessence Publishing Co, Inc. 551 Kimberly Drive, Carol Stream, IL 60188-9981. (800) 621-0387 or (630) 682-3223. Fax (630) 682-3288. E-mail:
[email protected]. Website: www.quintpub.com. PRICE: $78.06 plus shipping and handling. ISBN: 0867154071. Summary: The book contains the proceedings of a symposium on Aging, Osteoporosis and Dental Implants, that was held at the University of Toronto (Canada) in November 2000. The proceedings attempt to reconcile the current clinical understanding of aging, with or without osteoporosis (abnormal loss of bone density), with overall dental patient management strategies, placing particular emphasis on the induction and maintenance of the osseointegrated (an induced healing process where alloplastic materials are maintained in bone) response (necessary for dental implants). The text includes 19
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chapters in four sections: biologic and bioengineering considerations for prescribing prosthetic implants, the oral surgical experience, the prosthodontic experience, and biologic perspectives related to osseointegration in the elderly. Topics include mesenchymal stem cells, the concept of bone quality in osteoporosis, mechanical factors and osseointegration (the influence of implant design), choosing a prosthesis for total hip replacement, host determinants and outcome criteria for osseointegration surgery, compromised alveolar bone quality in edentulous (without teeth) jaws, compromised jawbone quantity, surgical site development, strategies for bone regeneration and osseointegration in completely edentulous patients, epidemiological considerations with oral implants for elderly patients, the significance of tooth loss in the elderly patients, the advent of osseointegration and its impact on prosthodontic management, mandibular implant-retained overdentures (load transfer, tissue reaction, oral function), implant prosthodontic treatment outcomes in elderly patients, regulation of biomineralization, the effects of postmenopausal osteoporosis on the mandible (lower jaw), and cigarette smoking and osseointegration. Each chapter concludes with a list of references. The text is illustrated with black and white and full color photographs, charts and figures. A subject index concludes the volume.
Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “stem cells” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “stem cells” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “stem cells” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •
100 Questions & Answers About Bone Marrow and Stem Cell Transplantation by Gracy Ledingham, Ewa, Md. Carrier; ISBN: 0763712736; http://www.amazon.com/exec/obidos/ASIN/0763712736/icongroupinterna
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21st Century Complete Guide to Stem Cell Research: Federal Government Information from HHS, FDA, NIH, and the White House, Bioethics and Legal Implications, Legislation and Research Programs, Future of Medicine and Genetics, Human Case Studies, Inside the Cell by U.S. Government; ISBN: 1592481132; http://www.amazon.com/exec/obidos/ASIN/1592481132/icongroupinterna
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A Clinical Guide to Stem Cell and Bone Marrow Transplantation by Terry Wikle Shapiro, et al; ISBN: 076370217X; http://www.amazon.com/exec/obidos/ASIN/076370217X/icongroupinterna
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Adoption of an Opinion on Ethical Aspects of Human Stem Cell Research and Use by Anne McLaren (Editor), Goran Hermeren (Editor); ISBN: 0756719429; http://www.amazon.com/exec/obidos/ASIN/0756719429/icongroupinterna
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Adult Stem Cells by Kursad Turksen (Editor); ISBN: 1588291529; http://www.amazon.com/exec/obidos/ASIN/1588291529/icongroupinterna
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Advances in Allogeneic Hematopoietic Stem Cell Transplantation (CANCER TREATMENT AND RESEARCH Volume 101) by Richard K. Burt (Editor), Mary M.
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Brush (Editor); ISBN: 0792377141; http://www.amazon.com/exec/obidos/ASIN/0792377141/icongroupinterna •
Advances in Hematopoietic Stem Cell Transplantation and Molecular Therapy: Proceedings of the Symposium "Hematopoietic Steam Cell Transplantation and Gene Therapy (Recent Results in Cancer Research, 144) by R. Haas (Editor), et al; ISBN: 3540626263; http://www.amazon.com/exec/obidos/ASIN/3540626263/icongroupinterna
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Aplastic anemia : stem cell biology and advances in treatment : proceedings of the Third International Conference on Aplastic Anemia, held in Airlie, Virginia, June 2628, 1983; ISBN: 084510148X; http://www.amazon.com/exec/obidos/ASIN/084510148X/icongroupinterna
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Aplastic Anemia: Stem Cell Biology and Advances in Treatment: Proceedings of the Third International Conference on Aplastic Anemia by International Conference on Aplastic Anemia, et al; ISBN: 0471834394; http://www.amazon.com/exec/obidos/ASIN/0471834394/icongroupinterna
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Autologous Stem Cell Transplantation: Biological and Clinical Results in Malignancies (Advances in Blood Disorders) by Angelo Carella (Editor); ISBN: 3718659336; http://www.amazon.com/exec/obidos/ASIN/3718659336/icongroupinterna
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Autologous Stem Cell Transplants: A Handbook for Patients by Susan K. Stewart; ISBN: 0964735210; http://www.amazon.com/exec/obidos/ASIN/0964735210/icongroupinterna
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Biology of Hematopoiesis and Stem Cell Gene Transfer by G. Stamatoyannopoulos (Editor); ISBN: 189829836X; http://www.amazon.com/exec/obidos/ASIN/189829836X/icongroupinterna
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Blood and Marrow Stem Cell Transplantation: Principles, Practice, and Nursing Insights (Jones and Bartlett Series in Oncology) by Debra, Rn Wujcik (Editor), et al; ISBN: 0763703567; http://www.amazon.com/exec/obidos/ASIN/0763703567/icongroupinterna
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Blood Stem Cell Transplantation by Josy Reiffers, et al; ISBN: 185317291X; http://www.amazon.com/exec/obidos/ASIN/185317291X/icongroupinterna
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Blood Stem Cell Transplants by Robert Peter Gale (Editor), et al; ISBN: 0521442109; http://www.amazon.com/exec/obidos/ASIN/0521442109/icongroupinterna
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Bone Marrow and Blood Stem Cell Transplants: A Guide For Patients by Susan Stewart; ISBN: 0964735237; http://www.amazon.com/exec/obidos/ASIN/0964735237/icongroupinterna
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Bone Marrow Transplantation and Peripheral Blood Stem Cell Transplantation by Barry Leonard (Editor); ISBN: 0788130056; http://www.amazon.com/exec/obidos/ASIN/0788130056/icongroupinterna
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Bone marrow transplantation and peripheral blood stem cell transplantation (SuDoc HE 20.3166:B 64/994) by U.S. Dept of Health and Human Services; ISBN: B00010NWP4; http://www.amazon.com/exec/obidos/ASIN/B00010NWP4/icongroupinterna
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Brain Stem Cells by J. A. Miyan (Editor), et al; ISBN: 185996222X; http://www.amazon.com/exec/obidos/ASIN/185996222X/icongroupinterna
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Cell lineage, stem cells, and cell determination : proceedings of the International Workshop on Cell Lineage, Stem Cells, and Cell Determination, held in Seillac,
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France, 20-24 May, 1979; ISBN: 0720406730; http://www.amazon.com/exec/obidos/ASIN/0720406730/icongroupinterna •
Cell Therapy : Stem Cell Transplantation, Gene Therapy, and Cellular Immunotherapy by George Morstyn (Editor), et al; ISBN: 0521473152; http://www.amazon.com/exec/obidos/ASIN/0521473152/icongroupinterna
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Cellular and molecular biology of hemopoietic stem cell differentiation : proceedings of a symposium held at Honey Harbor, Ontario, Canada, September 20-24, 1981; ISBN: 084510215X; http://www.amazon.com/exec/obidos/ASIN/084510215X/icongroupinterna
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Cellular and Molecular Biology of Hemopoietic Stem Cell Differentiation: Proceedings of a Symposium Held at Honey Harbor, Ontario, Canada, September by Symposium on Cellular and Molecular Biology of Hemopoietic Stem Cell d, et al; ISBN: 0471833940; http://www.amazon.com/exec/obidos/ASIN/0471833940/icongroupinterna
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Characteristics and Potentials of Blood Stem Cells by Theodor M. Fliedner (Editor), Dieter Hoelzer (Editor); ISBN: 188085421X; http://www.amazon.com/exec/obidos/ASIN/188085421X/icongroupinterna
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Clinical Bone Marrow and Blood Stem Cell Transplantation by Kerry Atkinson (Editor); ISBN: 0521622883; http://www.amazon.com/exec/obidos/ASIN/0521622883/icongroupinterna
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Cloning and Stem Cell Research by Anthony McCarthy; ISBN: 1860822118; http://www.amazon.com/exec/obidos/ASIN/1860822118/icongroupinterna
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Cloning of human tumor stem cells; ISBN: 0845100483; http://www.amazon.com/exec/obidos/ASIN/0845100483/icongroupinterna
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Cord Blood Characteristics: Role in Stem Cell Transplantation by Shara, PhD Cohen (Editor), et al; ISBN: 1853177946; http://www.amazon.com/exec/obidos/ASIN/1853177946/icongroupinterna
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Crafting a Cloning Policy: From Dolly to Stem Cells by Andrea L. Bonnicksen; ISBN: 087840371X; http://www.amazon.com/exec/obidos/ASIN/087840371X/icongroupinterna
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Differentiation of Embryonic Stem Cells by Paul Wassarman (Author); ISBN: 0121822680; http://www.amazon.com/exec/obidos/ASIN/0121822680/icongroupinterna
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Embryo Factory: The Stem Cell Wars by Richard A. Humphrey, Loren J. Humphrey; ISBN: 193212408X; http://www.amazon.com/exec/obidos/ASIN/193212408X/icongroupinterna
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Embryonal Stem Cells: Introducing Planned Changes into the Animal Germline (Modern Genetics, Vol. 1) by Martin L. Hooper; ISBN: 9992161442; http://www.amazon.com/exec/obidos/ASIN/9992161442/icongroupinterna
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Embryonic Stem Cells As a Developmental Model in Vitro (Cells Tissues Organs, Volume 165, Number 3-4, 1999) by A. M. Wobus (Editor), K.R. Boheler (Editor); ISBN: 3805569750; http://www.amazon.com/exec/obidos/ASIN/3805569750/icongroupinterna
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Embryonic Stem Cells for Medicine : A Scientific American article [DOWNLOAD: PDF] by Roger A. Pedersen (Author); ISBN: B00006BNPP; http://www.amazon.com/exec/obidos/ASIN/B00006BNPP/icongroupinterna
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249
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Embryonic Stem Cells: Methods and Protocols by Kursad Turksen (Editor); ISBN: 0896038815; http://www.amazon.com/exec/obidos/ASIN/0896038815/icongroupinterna
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Ethical issues in human stem cell research (SuDoc PREX 1.19:B 52/ST 4/V.1-3) by U.S. Postal Service; ISBN: B0001125I8; http://www.amazon.com/exec/obidos/ASIN/B0001125I8/icongroupinterna
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Forschung Mit Humanen Stammzellen /Research With Human Embryonic Stem Cells Standpunkte/Positions by Deutsche Forschungsgemeinschaft, Deutsche Forschungsgemeinschaft (Editor); ISBN: 3527272194; http://www.amazon.com/exec/obidos/ASIN/3527272194/icongroupinterna
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Gene Technology: Stem Cell and Leukemia Research (NATO Asi Series. Series H, Cell Biology, Vol 94) by A. R. Zander (Editor), et al; ISBN: 3540607439; http://www.amazon.com/exec/obidos/ASIN/3540607439/icongroupinterna
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God and the Embryo: Religious Voices on Stem Cells and Cloning by Brent Waters (Editor), Ronald Cole-Turner (Editor); ISBN: 087840998X; http://www.amazon.com/exec/obidos/ASIN/087840998X/icongroupinterna
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Growth Factors and Stem Cells (Molecular Biology) by Antony Burgess, Nicos Nicola; ISBN: 0121437507; http://www.amazon.com/exec/obidos/ASIN/0121437507/icongroupinterna
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Health Journeys: A Meditation to Help with Bone Marrow & Stem Cell Transplantation by Belleruth Naparstek; ISBN: 1881405524; http://www.amazon.com/exec/obidos/ASIN/1881405524/icongroupinterna
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Hematopoietic stem cell and its growth factor (SuDoc D 15.13:88-41) by S. M. Fu; ISBN: B00010ALGM; http://www.amazon.com/exec/obidos/ASIN/B00010ALGM/icongroupinterna
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Hematopoietic Stem Cell Physiology (Progress in Clinical and Biological Research, Vol 184) by Eugene P. Cronkite (Editor), et al; ISBN: 0471843954; http://www.amazon.com/exec/obidos/ASIN/0471843954/icongroupinterna
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Hematopoietic Stem Cell Protocols by Christopher A. Klug (Editor), Craig T. Jordan (Editor); ISBN: 0896038122; http://www.amazon.com/exec/obidos/ASIN/0896038122/icongroupinterna
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Hematopoietic Stem Cell Therapy by Edward D. Ball (Editor), et al; ISBN: 0443076227; http://www.amazon.com/exec/obidos/ASIN/0443076227/icongroupinterna
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Hematopoietic Stem Cell Transplantation by Anthony D. Ho (Editor), et al; ISBN: 0824702735; http://www.amazon.com/exec/obidos/ASIN/0824702735/icongroupinterna
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Hematopoietic Stem Cell Transplantation (Pathology and Laboratory Medicine) by James E. Talmadge (Editor), Stewart Sell (Editor); ISBN: 0896034267; http://www.amazon.com/exec/obidos/ASIN/0896034267/icongroupinterna
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Hematopoietic Stem Cells; ISBN: 354054531X; http://www.amazon.com/exec/obidos/ASIN/354054531X/icongroupinterna
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Hematopoietic Stem Cells by Thomas A. Bock (Editor), et al; ISBN: 1880854236; http://www.amazon.com/exec/obidos/ASIN/1880854236/icongroupinterna
250
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Hematopoietic Stem Cells (Hematology, Vol 2) by David W. Golde (Editor); ISBN: 0824772245; http://www.amazon.com/exec/obidos/ASIN/0824772245/icongroupinterna
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Hematopoietic Stem Cells 2000: Basic and Clinical Sciences/3rd International Conference (Annals of the New York Academy of Sciences, V. 938) by International Conference and Workshop on Hematopoietic Stem Cells 2000, Donald Orlic; ISBN: 1573312959; http://www.amazon.com/exec/obidos/ASIN/1573312959/icongroupinterna
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Hematopoietic Stem Cells 2000: Basic and Clinical Sciences: Third International Conference, June 2001 (Annals of the New York Academy of Sciences, V. 938) by International Conference and Workshop on Hematopoietic Stem Cells 2000, et al; ISBN: 1573312967; http://www.amazon.com/exec/obidos/ASIN/1573312967/icongroupinterna
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Hematopoietic Stem Cells 2002: Genetics and Function Fourth International Symposium (Annals of the New York Academy of Sciences, Vol 996) by International Conference and Workshop on Hematopoietic Stem Cells 2002, et al; ISBN: 1573314668; http://www.amazon.com/exec/obidos/ASIN/1573314668/icongroupinterna
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Hematopoietic Stem Cells: Animal Models and Human Transplantation (Current Topics in Microbiology and Immunology, Vol 177) by C. Muller-Sieberg, et al; ISBN: 038754531X; http://www.amazon.com/exec/obidos/ASIN/038754531X/icongroupinterna
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Hematopoietic Stem Cells: Biology and Therapeutic Applications by Daniel J. Levitt, Roland Mertelsmann (Editor); ISBN: 0824793056; http://www.amazon.com/exec/obidos/ASIN/0824793056/icongroupinterna
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Hematopoietic Stem Cells: Biology and Transplantation (Annals of the New York Academy of Sciences, Vol 872) by Donald Orlic (Editor), et al; ISBN: 157331188X; http://www.amazon.com/exec/obidos/ASIN/157331188X/icongroupinterna
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Hematopoietic Stem Cells: The Mulhouse Manual by Eckart Wunder, et al; ISBN: 1880854171; http://www.amazon.com/exec/obidos/ASIN/1880854171/icongroupinterna
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Hematopoietic Stem Cells: Their Assay, Ontogeny, Isolation and Molecular Functions (Medical Intelligence Unit) by Suzanne M. Watt; ISBN: 1570590257; http://www.amazon.com/exec/obidos/ASIN/1570590257/icongroupinterna
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Hepatic Stem Cells and the Origin of Hepatocellular Carcinoma (Medical Intelligence Unit) by Stewart Sell, Ilic Zoran; ISBN: 0412123819; http://www.amazon.com/exec/obidos/ASIN/0412123819/icongroupinterna
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High Dose Cancer Therapy: Pharmacology, Hematopoietins, Stem Cells by James O. Armitage MD; ISBN: 0683002546; http://www.amazon.com/exec/obidos/ASIN/0683002546/icongroupinterna
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Human Embryonic Stem Cells by Arlene Chiu (Editor), Mahendra S. Rao (Editor); ISBN: 1588293114; http://www.amazon.com/exec/obidos/ASIN/1588293114/icongroupinterna
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Human Embryonic Stem Cells: An Introduction to the Science and Therapeutic Potential by Ann A. Kiessling, Scott. C. Anderson; ISBN: 076372341X; http://www.amazon.com/exec/obidos/ASIN/076372341X/icongroupinterna
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251
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Isolation, Characterization and Utilization of Cns Stem Cells by F. Gage (Editor), Yves Christen (Editor); ISBN: 3540616969; http://www.amazon.com/exec/obidos/ASIN/3540616969/icongroupinterna
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Liver-Stem Cells (Medical Intelligence Unit Series) by Stewart Sell, Zoran Ilic; ISBN: 0412134918; http://www.amazon.com/exec/obidos/ASIN/0412134918/icongroupinterna
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Marrow and Stem Cell Processing for Transplantation by Larry C., Md Lasky, Phyllis I., MD Warkentin (Editor); ISBN: 1563950421; http://www.amazon.com/exec/obidos/ASIN/1563950421/icongroupinterna
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Mathematical Modeling of Cell Proliferation: Stem Cell Regulation in Hemopoiesis. Vol 1: Model Description, Irradiation, Erythropoietic Stimulation by H.-Erich Wichmann, Markus Loeffler (Editor); ISBN: 0849355036; http://www.amazon.com/exec/obidos/ASIN/0849355036/icongroupinterna
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Mathematical Modeling of Cell Proliferation: Stem Cell Regulation in Hemopoiesis: Erythropoietic Suppression, Combined Stresses, Drug Effects by H. Erich Wichmann (Editor); ISBN: 0849355044; http://www.amazon.com/exec/obidos/ASIN/0849355044/icongroupinterna
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My Detour on Life's Highway: The Story of a Stem Cell Transplant Survivor by Rosemary Champagne; ISBN: 0965031578; http://www.amazon.com/exec/obidos/ASIN/0965031578/icongroupinterna
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Neural Stem Cells for Brain and Spinal Cord Repair (Contemporary Neuroscience) by Tanja Zigova (Editor), et al; ISBN: 1588290034; http://www.amazon.com/exec/obidos/ASIN/1588290034/icongroupinterna
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Neural Stem Cells: Development and Transplantation by Jane E. Bottenstein (Editor); ISBN: 140207588X; http://www.amazon.com/exec/obidos/ASIN/140207588X/icongroupinterna
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Neuroepithelial Stem Cells and Progenitors (Developmental Neuroscience, 1-2) by S.W. Levinson (Editor), R.S. Nowakowski (Editor); ISBN: 3805569769; http://www.amazon.com/exec/obidos/ASIN/3805569769/icongroupinterna
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NIH human embryonic stem cell registry (SuDoc HE 20.3002:2002003629) by U.S. Dept of Health and Human Services; ISBN: B000115JAY; http://www.amazon.com/exec/obidos/ASIN/B000115JAY/icongroupinterna
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Opportunities and advancements in stem cell research : hearing before the Subcommittee on Criminal Justice, Drug Policy, and Human Resources of the Committee on Government Reform, House of Representatives, One Hundred Seventh Congress, first session, July 17, 2001 (SuDoc Y 4.G 74/7:ST 4); ISBN: 0160683246; http://www.amazon.com/exec/obidos/ASIN/0160683246/icongroupinterna
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Opportunities in Stem Cell Technology [DOWNLOAD: PDF] by Kalorama Information (Author); ISBN: B000063U6E; http://www.amazon.com/exec/obidos/ASIN/B000063U6E/icongroupinterna
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Peripheral Blood Stem Cell Autografts by E.W. Wunder, P.R. Henon (Editor); ISBN: 0387526129; http://www.amazon.com/exec/obidos/ASIN/0387526129/icongroupinterna
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Peripheral Blood Stem Cell Autografts; ISBN: 3540526129; http://www.amazon.com/exec/obidos/ASIN/3540526129/icongroupinterna
252
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Peripheral Blood Stem Cell Transplantation: Recommendations for Nursing Education & Practice by Wendy Holmes, et al; ISBN: 1890504033; http://www.amazon.com/exec/obidos/ASIN/1890504033/icongroupinterna
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Peripheral Blood Stem Cells by Douglas M. Smith (Editor), et al; ISBN: 1563950227; http://www.amazon.com/exec/obidos/ASIN/1563950227/icongroupinterna
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Production and Use of Embryonic Stem Cells; ISBN: 1860820956; http://www.amazon.com/exec/obidos/ASIN/1860820956/icongroupinterna
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Progress in Gene Therapy: Pioneering Stem Cell/Gene Therapy Trials; ISBN: 9067643947; http://www.amazon.com/exec/obidos/ASIN/9067643947/icongroupinterna
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Regeneration: Stem Cells and Beyond (Current Topics in Microbiology and Immunology, 280) by E. Heber-Katz (Editor); ISBN: 3540022384; http://www.amazon.com/exec/obidos/ASIN/3540022384/icongroupinterna
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SALMON CLONING OF HUMAN TUMOR STEM CELLS by SE SALMON; ISBN: 047156625X; http://www.amazon.com/exec/obidos/ASIN/047156625X/icongroupinterna
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Somatic Stem Cells and Their Plasticity by Albrecht M. Muller (Editor), Kelly M. McNagny (Editor); ISBN: 3805574061; http://www.amazon.com/exec/obidos/ASIN/3805574061/icongroupinterna
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Status of the Implementation of the Federal Stem Cell Research Policy: Hearing Before a Subcommittee of the Committee on Appropriations, United States by United States; ISBN: 0160697328; http://www.amazon.com/exec/obidos/ASIN/0160697328/icongroupinterna
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Stem Cell and Liver Regeneration by K. Okita (Editor); ISBN: 4431401997; http://www.amazon.com/exec/obidos/ASIN/4431401997/icongroupinterna
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Stem Cell Biology (Cold Spring Harbor Monograph Series, 40) by Daniel R. Marshak (Editor), et al; ISBN: 0879696737; http://www.amazon.com/exec/obidos/ASIN/0879696737/icongroupinterna
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Stem Cell Biology and Gene Therapy by Peter J. Quesenberry (Editor), et al; ISBN: 0471146560; http://www.amazon.com/exec/obidos/ASIN/0471146560/icongroupinterna
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Stem Cell Factor Induced Signal Transduction (Comprehensive Summaries of Uppsala Dissertations from the Faculty of mediciNe, 1142) by Johan Lennartsson; ISBN: 9155452914; http://www.amazon.com/exec/obidos/ASIN/9155452914/icongroupinterna
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Stem Cell Kinetics: Theory, Experiment, and Discovery by MD. PhD., James L. Sherley; ISBN: 0849312019; http://www.amazon.com/exec/obidos/ASIN/0849312019/icongroupinterna
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Stem Cell Proliferation and Differentiation: A Multitype Branching Process Model by C.a. Macken, Et Al; ISBN: 3540501835; http://www.amazon.com/exec/obidos/ASIN/3540501835/icongroupinterna
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Stem Cell Research by Jennifer Viegas; ISBN: 0823936694; http://www.amazon.com/exec/obidos/ASIN/0823936694/icongroupinterna
Books
253
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Stem Cell Research (Biomedical Ethics Reviews, 2004) by James M. Humber (Editor), Robert F. Almeder (Editor); ISBN: 1588294013; http://www.amazon.com/exec/obidos/ASIN/1588294013/icongroupinterna
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Stem cell research : hearing of the Committee on Health, Education, Labor, and Pensions, United States Senate, One Hundred Seventh Congress, first session on examining the scientific and ethical implications of stem cell research and its potential to improve human health, September 5, 2001 (SuDoc Y 4.L 11/4:S.HRG.107127); ISBN: 0160683963; http://www.amazon.com/exec/obidos/ASIN/0160683963/icongroupinterna
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Stem Cell Research: Medical Applications and Ethical Controversy by Joseph Panno; ISBN: 0816049491; http://www.amazon.com/exec/obidos/ASIN/0816049491/icongroupinterna
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Stem Cell Research: New Frontiers in Science and Ethics by Nancy E. Snow (Editor); ISBN: 0268017786; http://www.amazon.com/exec/obidos/ASIN/0268017786/icongroupinterna
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Stem Cell Therapeutics [DOWNLOAD: PDF] by MedPanel Inc. (Author); ISBN: B00005RBN6; http://www.amazon.com/exec/obidos/ASIN/B00005RBN6/icongroupinterna
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Stem Cell Transplantation and Tissue Engineering by A. Haverich (Editor), H. Graf (Editor); ISBN: 3540414959; http://www.amazon.com/exec/obidos/ASIN/3540414959/icongroupinterna
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Stem Cell Transplantation for Autoimmune Disease by Richard K. Burt; ISBN: 1587060310; http://www.amazon.com/exec/obidos/ASIN/1587060310/icongroupinterna
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Stem Cell Transplantation for Hematologic Disorders by Robert J., Md. Soiffer (Editor); ISBN: 1588291804; http://www.amazon.com/exec/obidos/ASIN/1588291804/icongroupinterna
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Stem Cell Transplantation: A Clinical Trial Textbook by Patricia Corcoran Buchsel (Editor), Pamela M. Kapustay (Editor); ISBN: 1890504157; http://www.amazon.com/exec/obidos/ASIN/1890504157/icongroupinterna
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Stem Cells by C. Potten (Author); ISBN: 0125634552; http://www.amazon.com/exec/obidos/ASIN/0125634552/icongroupinterna
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Stem Cells (Science on the Edge) by Jenny E. Tesar, Keith Elliot Greenberg; ISBN: 1567117872; http://www.amazon.com/exec/obidos/ASIN/1567117872/icongroupinterna
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Stem cells 2001 : hearings before a subcommittee of the Committee on Appropriations, United States Senate, One Hundred Seventh Congress, first session : special hearings, July 18, 2001, Washington DC, August 1, 2001, Washington DC, October 31, 2001, Washington DC (SuDoc Y 4.AP 6/2:S.HRG.107-499); ISBN: 0160685532; http://www.amazon.com/exec/obidos/ASIN/0160685532/icongroupinterna
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Stem Cells and Cell Signalling in Skeletel Myogenesis by D. A. Sassoon (Editor); ISBN: 0444506632; http://www.amazon.com/exec/obidos/ASIN/0444506632/icongroupinterna
254
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Stem Cells and Cloning by David A. Prentice (Author), Michael A. Palladino (Author); ISBN: 0805348646; http://www.amazon.com/exec/obidos/ASIN/0805348646/icongroupinterna
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Stem Cells and CNS Development (Contemporary Neuroscience) by Mahendra S. Rao (Editor); ISBN: 0896038866; http://www.amazon.com/exec/obidos/ASIN/0896038866/icongroupinterna
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Stem Cells and The Future Of Regenerative Medicine by Committee on Biological, et al; ISBN: 0309076307; http://www.amazon.com/exec/obidos/ASIN/0309076307/icongroupinterna
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Stem Cells and Tissue Homeostasis by B. I. Lord (Author), et al; ISBN: 0521217997; http://www.amazon.com/exec/obidos/ASIN/0521217997/icongroupinterna
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Stem Cells from Cord Blood, in Utero Stem Cells Development and Transplantation Inclusive Gene Therapy by Wolfgang Holgreve (Editor), et al; ISBN: 3540677011; http://www.amazon.com/exec/obidos/ASIN/3540677011/icongroupinterna
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Stem Cells Handbook by Stewart Sell (Editor), Humana Press; ISBN: 1588291138; http://www.amazon.com/exec/obidos/ASIN/1588291138/icongroupinterna
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Stem Cells in the Nervous System: Functional and Clinical Implications by F. Gage (Editor); ISBN: 3540205586; http://www.amazon.com/exec/obidos/ASIN/3540205586/icongroupinterna
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Stem cells of renewing cell populations : proceedings of a symposium held in October 1975 at McGill University, Montreal, in tribute to C. P. Leblond on the occasion of his sixty-fifth birthday; ISBN: 0121550508; http://www.amazon.com/exec/obidos/ASIN/0121550508/icongroupinterna
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Stem Cells: A Cellular Fountain of Youth by Mark P. Mattson (Editor), Gary Van Zant (Editor); ISBN: 0444507310; http://www.amazon.com/exec/obidos/ASIN/0444507310/icongroupinterna
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Study on the Patenting of Inventions Related to Human Stem Cell Research in Europe by Geertrui Van Overwalle; ISBN: 0756730481; http://www.amazon.com/exec/obidos/ASIN/0756730481/icongroupinterna
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Teratocarcinoma Stem Cells by Lee M. Silver (Editor); ISBN: 0879691603; http://www.amazon.com/exec/obidos/ASIN/0879691603/icongroupinterna
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Teratocarcinomas & Embryonic Stem Cell: Prac Approach by R. J. Robertson (Editor); ISBN: 1852210044; http://www.amazon.com/exec/obidos/ASIN/1852210044/icongroupinterna
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Teratocarcinomas and Embryonic Stem Cells: A Practical Approach (Practical Approach Series) by E.J. Robertson, R. J. Robertson (Editor); ISBN: 1852210052; http://www.amazon.com/exec/obidos/ASIN/1852210052/icongroupinterna
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The BMT Data Book: A Manual for Bone Marrow and Blood Stem Cell Transplantation by Kerry Atkinson (Author); ISBN: 0521556155; http://www.amazon.com/exec/obidos/ASIN/0521556155/icongroupinterna
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The dangers of cloning and the promise of regenerative medicine : hearing before the Committee on Health, Education, Labor, and Pensions, United States Senate, One Hundred Seventh Congress, second session, on examining cloning research, focusing on the clarification of how stem cell research, or therapeutic cloning, differs from human reproductive cloning, and the ethical and public-policy issues related to both, and related issues of S. 1853 to ban human cloning while protecting stem cell rese;
Books
255
ISBN: 0160685796; http://www.amazon.com/exec/obidos/ASIN/0160685796/icongroupinterna •
The Human Embryonic Stem Cell Debate: Science, Ethics, and Public Policy (Basic Bioethics) by Suzanne Holland (Editor), et al; ISBN: 0262582082; http://www.amazon.com/exec/obidos/ASIN/0262582082/icongroupinterna
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The Stem Cell Controversy: Debating the Issues by Michael Ruse (Editor), et al; ISBN: 1591020301; http://www.amazon.com/exec/obidos/ASIN/1591020301/icongroupinterna
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The Testis: From Stem Cell to Sperm Function by Erwin Goldberg (Editor), Ky.) North American Testis Workshop 1999 Louisville; ISBN: 0387950249; http://www.amazon.com/exec/obidos/ASIN/0387950249/icongroupinterna
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Tissue Engineering, Stem Cells, and Gene Therapies (Advances in Experimental Medicine and Biology, 534) by International Symposium on Biomedical Science and Technology 2002 Ant, Y. Murat Elcin (Editor); ISBN: 0306477882; http://www.amazon.com/exec/obidos/ASIN/0306477882/icongroupinterna
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Transfusion and Hematopoietic Stem Cells: Proceedings of the 6th Hokkaido Symposium on Transfusional Medicine by Sadayoshi Sekiguchi; ISBN: 0865429111; http://www.amazon.com/exec/obidos/ASIN/0865429111/icongroupinterna
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Understanding Bone Marrow and Stem Cell Transplants; ISBN: 1901276147; http://www.amazon.com/exec/obidos/ASIN/1901276147/icongroupinterna
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What the Church Teaches: Stem Cell Research by Our Sunday Visitor; ISBN: 1931709157; http://www.amazon.com/exec/obidos/ASIN/1931709157/icongroupinterna
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Whose View of Life? : Embryos, Cloning, and Stem Cells by Jane Maienschein (Author); ISBN: 0674011708; http://www.amazon.com/exec/obidos/ASIN/0674011708/icongroupinterna
Chapters on Stem Cells In order to find chapters that specifically relate to stem cells, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and stem cells using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type “stem cells” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on stem cells: •
New Horizons in the Treatment of Autoimmune Diseases: Immunoablation and Stem Cell Transplantation Source: in Coggins, C.H.; Hancock, E.W.; Levitt, L.J., eds. Annual Review of Medicine, Volume 51, 2000. Palo Alto, CA: Annual Reviews, Inc. 2000. p. 115-134. Contact: Available from Annual Reviews. 4139 El Camino Way, P.O. Box 10139, Palo Alto, CA 94303-0139. (650) 493-4400. E-mail:
[email protected]. Website: www.AnnualReviews.org.
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Summary: This chapter provides health professionals with information on the treatment of autoimmune diseases (ADs) with immunosuppression followed by allogeneic or even autologous hemolymphopoietic stem cells (HSCs). The current treatment for severe, relapsing, or refractory AD cases is still not satisfactory. The concept of using intense immunosuppression followed by stem cell transplantation to treat AD is based on encouraging results in experimental animals and from serendipitous cases of patients with both ADs and malignancies who were allotransplanted for the latter. However, rare unexpected relapses despite donor immune engraftment have been reported following HSC transplantation for AD. Autologous transplantation is a more feasible procedure with lower toxicity than allogenic transplantation. The article analyzes the experimental basis for stem cell transplantation in AD and highlights clinical results of HSC transplants in patients with rheumatoid arthritis, juvenile chronic arthritis, systemic lupus erythematous, and systemic sclerosis. The author concludes that although results are encouraging, remissions rather than cures have been obtained. 3 figures and 111 references. (AA-M).
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CHAPTER 8. PERIODICALS AND NEWS ON STEM CELLS Overview In this chapter, we suggest a number of news sources and present various periodicals that cover stem cells.
News Services and Press Releases One of the simplest ways of tracking press releases on stem cells is to search the news wires. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “stem cells” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. The search results are shown by order of relevance. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to stem cells. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “stem cells” (or synonyms). The following was recently listed in this archive for stem cells: •
Stem cell cloning revives ethics debate Source: Reuters Health eLine Date: February 12, 2004
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Scientists clone first human blastocyst and derive stem cell line Source: Reuters Industry Breifing Date: February 12, 2004
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Bone marrow stem cells tied to pulmonary fibrosis Source: Reuters Industry Breifing Date: January 30, 2004
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Stem cells curb osteoarthritis in goats Source: Reuters Health eLine Date: January 28, 2004
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Once-daily tobramycin best for febrile neutropenic children receiving stem cells Source: Reuters Industry Breifing Date: December 19, 2003
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Germ stem cell-derived sperm cells capable of fertilizing oocytes Source: Reuters Industry Breifing Date: December 10, 2003
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Anormed shares up 23 pct on stem cell therapy news Source: Reuters Industry Breifing Date: December 08, 2003
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EU to fund stem cell research despite ethics split Source: Reuters Health eLine Date: December 03, 2003
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Bid set to revive UN ban on stem cell research Source: Reuters Health eLine Date: December 03, 2003
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Stem cells prepped from white blood cells Source: Reuters Health eLine Date: November 27, 2003
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EU ministers fail to agree stem cell funding rules Source: Reuters Health eLine Date: November 26, 2003
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British firm plans human stem cell trial - magazine Source: Reuters Industry Breifing Date: November 26, 2003
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U.N. sets back U.S. bid for global stem cell ban Source: Reuters Health eLine Date: November 07, 2003
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Canada house backs embryonic stem cell research Source: Reuters Health eLine Date: October 29, 2003
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Actor Reeve: states will lead stem cell research Source: Reuters Health eLine Date: October 28, 2003
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UK scientists to identify best stem cells for treating heart failure Source: Reuters Industry Breifing Date: October 16, 2003
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Stem cells repair heart attack damage Source: Reuters Health eLine Date: October 13, 2003
Periodicals and News
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Unfertilized eggs could be new stem cell source Source: Reuters Health eLine Date: September 24, 2003
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Stem cells may eliminate need for heart transplant Source: Reuters Health eLine Date: September 01, 2003
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Still hope for stem cells in Parkinson's disease Source: Reuters Health eLine Date: August 22, 2003
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Scientists create Britain's first stem cell line Source: Reuters Health eLine Date: August 13, 2003
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Michigan teen gets stem cell transplant to heart Source: Reuters Health eLine Date: March 05, 2003
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Human pluripotent stem cells isolated from peripheral blood monocytes Source: Reuters Industry Breifing Date: February 28, 2003
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Scientists to study stem cell therapy in heart attack patients Source: Reuters Industry Breifing Date: February 24, 2003
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Heart attack victims to get stem cell trial Source: Reuters Health eLine Date: February 24, 2003
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Adult stem cells used to promote organ transplant tolerance in rats Source: Reuters Industry Breifing Date: February 19, 2003
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Adult stem cells may help organ transplant: study Source: Reuters Health eLine Date: February 19, 2003
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Ailing stem cell firm ReNeuron receives approach Source: Reuters Industry Breifing Date: February 17, 2003
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Scientists gene-engineer first human stem cells Source: Reuters Health eLine Date: February 10, 2003
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Muscle stem cells may treat heart attack damage Source: Reuters Health eLine Date: February 07, 2003
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Actor Reeve says stem cell research inevitable Source: Reuters Health eLine Date: January 29, 2003
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More evidence stem cells can make new brain cells Source: Reuters Health eLine Date: January 21, 2003
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UK stem cell firm ReNeuron hit by pain drug flop Source: Reuters Industry Breifing Date: January 20, 2003
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Hope of insulin-producing stem cells delayed Source: Reuters Health eLine Date: January 16, 2003
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First UK stem cell line established Source: Reuters Industry Breifing Date: August 12, 2003
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Spain approves stem cell research, with conditions Source: Reuters Health eLine Date: July 25, 2003
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Stem cells may solve infertility problems - expert Source: Reuters Health eLine Date: July 24, 2003
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Stem cell loss may promote artery disease Source: Reuters Health eLine Date: July 16, 2003
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Stem cells offer hope for muscular dystrophy Source: Reuters Health eLine Date: July 11, 2003
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EU sets rules for embryo use in stem cell research Source: Reuters Health eLine Date: July 09, 2003
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EU to adopt stem cell research rules this week Source: Reuters Health eLine Date: July 07, 2003
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Benefits of high-dose chemo/stem cell therapy for high-risk breast cancer still unclear Source: Reuters Industry Breifing Date: July 02, 2003
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Geron, Celera complete stem cell collaboration Source: Reuters Industry Breifing Date: July 01, 2003
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Official says stem cells produced "neurons" Source: Reuters Health eLine Date: June 30, 2003
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Teen's heart doing better after stem cell therapy Source: Reuters Health eLine Date: June 12, 2003
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Geron stock jumps on patent for stem cell method Source: Reuters Industry Breifing Date: June 10, 2003
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Second course of chemotherapy/stem cell support effective in germ cell cancer relapse Source: Reuters Industry Breifing Date: May 23, 2003
Periodicals and News
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Fetal stem cells treat diabetes in mice Source: Reuters Health eLine Date: May 23, 2003
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U.S. Senators accuse NIH of "politicizing" stem cell research Source: Reuters Industry Breifing Date: May 22, 2003
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Senators accuse NIH over stem cell research Source: Reuters Health eLine Date: May 22, 2003
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The NIH Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “stem cells” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “stem cells” (or synonyms). If you know the name of a company that is relevant to stem cells, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/.
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BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “stem cells” (or synonyms).
Newsletter Articles Use the Combined Health Information Database, and limit your search criteria to “newsletter articles.” Again, you will need to use the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter Article.” Type “stem cells” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months. The following is a typical result when searching for newsletter articles on stem cells: •
Stem Cells: Medicine's New Frontier Source: Mayo Clinic Health Letter. 18(11): 1-3. November 2000. Contact: Available from Mayo Clinic Health Letter, 200 First Street SW, Rochester, MN 55905. (800) 333-9037 or (303) 604-1465. Email:
[email protected]. Summary: This newsletter article provides people with information on the use of stem cells in the treatment of various diseases and conditions. A stem cell produces cells that perform specific functions in the body and it self replicates. The body contains many types of stem cells, which are known as adult stem cells. The most powerful stem cells, embryonic stem cells, are found in the very early stages of development. Two years ago, researchers in the United States announced that they had discovered how to stop human embryonic stem cells from becoming specialized and how to keep them at their maximum potential to differentiate into any cell in the body. In addition, researchers discovered that some adult stem cells can turn into one of several different tissues. Currently, the most common use for stem cells is in bone marrow transplants. The use of peripheral blood stem cells instead of bone marrow makes transplants safer. Another stem cell discovery related to bone marrow was the isolation of mesenchymal stem cells. These cells appear to enhance standard bone marrow transplantation. The article includes other examples of the use of stem cells and highlights future areas of stem cell research. 1 figure.
Academic Periodicals covering Stem Cells Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to stem cells. In addition to these sources, you can search for articles covering stem cells that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.”
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If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”
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CHAPTER 9. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.
U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for stem cells. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a non-profit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI Advice for the Patient can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP). Below, we have compiled a list of medications associated with stem cells. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The
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following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to stem cells: Colony Stimulating Factors •
Systemic - U.S. Brands: Leukine; Neupogen http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202628.html
Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.
Mosby’s Drug Consult Mosby’s Drug Consult database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/. PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee.
Researching Orphan Drugs Although the list of orphan drugs is revised on a daily basis, you can quickly research orphan drugs that might be applicable to stem cells by using the database managed by the National Organization for Rare Disorders, Inc. (NORD), at http://www.rarediseases.org/. Scroll down the page, and on the left toolbar, click on “Orphan Drug Designation Database.” On this page (http://www.rarediseases.org/search/noddsearch.html), type “stem cells” (or synonyms) into the search box, and click “Submit Query.” When you receive your results, note that not all of the drugs may be relevant, as some may have been withdrawn from orphan status. Write down or print out the name of each drug and the relevant contact information. From there, visit the Pharmacopeia Web site and type the name of each orphan
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drug into the search box at http://www.nlm.nih.gov/medlineplus/druginformation.html. You may need to contact the sponsor or NORD for further information. NORD conducts “early access programs for investigational new drugs (IND) under the Food and Drug Administration’s (FDA’s) approval ‘Treatment INDs’ programs which allow for a limited number of individuals to receive investigational drugs before FDA marketing approval.” If the orphan product about which you are seeking information is approved for marketing, information on side effects can be found on the product’s label. If the product is not approved, you may need to contact the sponsor. The following is a list of orphan drugs currently listed in the NORD Orphan Drug Designation Database for stem cells: •
cells produced using the AastromReplicelle System http://www.rarediseases.org/nord/search/nodd_full?code=1263
•
Recombinant Human Thrombopoietin http://www.rarediseases.org/nord/search/nodd_full?code=849
•
Pegylated Recombinant Human Megakarocyte Growth & (trade name: MEGAGEN) http://www.rarediseases.org/nord/search/nodd_full?code=853
If you have any questions about a medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.
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APPENDICES
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APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.
NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute11: •
Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm
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National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/
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National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html
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National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25
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National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm
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National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
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National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375
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National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/
11
These publications are typically written by one or more of the various NIH Institutes.
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•
National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm
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National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/
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National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm
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National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm
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National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/
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National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/
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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm
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National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html
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National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm
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National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm
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National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm
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National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html
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National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm
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Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp
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National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/
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National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp
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Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html
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Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm
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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.12 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:13 •
Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html
•
HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html
•
NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html
•
Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/
•
Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html
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Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html
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Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/
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Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html
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Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html
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Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html
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MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html
12
Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 13 See http://www.nlm.nih.gov/databases/databases.html.
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•
Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html
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Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html
The NLM Gateway14 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.15 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “stem cells” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total
Items Found 113887 497 747 138 364 115633
HSTAT16 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.17 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.18 Simply search by “stem cells” (or synonyms) at the following Web site: http://text.nlm.nih.gov.
14
Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.
15
The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 16 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 17 18
The HSTAT URL is http://hstat.nlm.nih.gov/.
Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.
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Coffee Break: Tutorials for Biologists19 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.20 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.21 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.
Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •
CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.
•
Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
The Genome Project and Stem Cells In the following section, we will discuss databases and references which relate to the Genome Project and stem cells. Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).22 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. 19 Adapted 20
from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.
The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 21 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process. 22 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.
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To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “stem cells” (or synonyms) into the search box, and click “Submit Search.” If too many results appear, you can narrow the search by adding the word “clinical.” Each report will have additional links to related research and databases. In particular, the option “Database Links” will search across technical databases that offer an abundance of information. The following is an example of the results you can obtain from the OMIM for stem cells: •
Hematopoietic Stem Cell Kinetics, Control of Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?300129
•
Stem Cell Growth Factor Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?604713 Genes and Disease (NCBI - Map)
The Genes and Disease database is produced by the National Center for Biotechnology Information of the National Library of Medicine at the National Institutes of Health. This Web site categorizes each disorder by system of the body. Go to http://www.ncbi.nlm.nih.gov/disease/, and browse the system pages to have a full view of important conditions linked to human genes. Since this site is regularly updated, you may wish to revisit it from time to time. The following systems and associated disorders are addressed: •
Cancer: Uncontrolled cell division. Examples: Breast and ovarian cancer, Burkitt lymphoma, chronic myeloid leukemia, colon cancer, lung cancer, malignant melanoma, multiple endocrine neoplasia, neurofibromatosis, p53 tumor suppressor, pancreatic cancer, prostate cancer, Ras oncogene, RB: retinoblastoma, von Hippel-Lindau syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Cancer.html
•
Immune System: Fights invaders. Examples: Asthma, autoimmune polyglandular syndrome, Crohn’s disease, DiGeorge syndrome, familial Mediterranean fever, immunodeficiency with Hyper-IgM, severe combined immunodeficiency. Web site: http://www.ncbi.nlm.nih.gov/disease/Immune.html
•
Metabolism: Food and energy. Examples: Adreno-leukodystrophy, atherosclerosis, Best disease, Gaucher disease, glucose galactose malabsorption, gyrate atrophy, juvenile-onset diabetes, obesity, paroxysmal nocturnal hemoglobinuria, phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html
•
Muscle and Bone: Movement and growth. Examples: Duchenne muscular dystrophy, Ellis-van Creveld syndrome, Marfan syndrome, myotonic dystrophy, spinal muscular atrophy. Web site: http://www.ncbi.nlm.nih.gov/disease/Muscle.html
•
Nervous System: Mind and body. Examples: Alzheimer disease, amyotrophic lateral sclerosis, Angelman syndrome, Charcot-Marie-Tooth disease, epilepsy, essential tremor, fragile X syndrome, Friedreich’s ataxia, Huntington disease, Niemann-Pick disease, Parkinson disease,
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Prader-Willi syndrome, Rett syndrome, spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html •
Signals: Cellular messages. Examples: Ataxia telangiectasia, Cockayne syndrome, glaucoma, male-patterned baldness, SRY: sex determination, tuberous sclerosis, Waardenburg syndrome, Werner syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Signals.html
•
Transporters: Pumps and channels. Examples: Cystic fibrosis, deafness, diastrophic dysplasia, Hemophilia A, long-QT syndrome, Menkes syndrome, Pendred syndrome, polycystic kidney disease, sickle cell anemia, Wilson’s disease, Zellweger syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Transporters.html Entrez
Entrez is a search and retrieval system that integrates several linked databases at the National Center for Biotechnology Information (NCBI). These databases include nucleotide sequences, protein sequences, macromolecular structures, whole genomes, and MEDLINE through PubMed. Entrez provides access to the following databases: •
3D Domains: Domains from Entrez Structure, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo
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Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books
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Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome
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NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/
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Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide
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OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
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PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset
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ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo
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Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein
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PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed
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Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure
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Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy
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To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=genome, and then select the database that you would like to search. The databases available are listed in the drop box next to “Search.” Enter “stem cells” (or synonyms) into the search box and click “Go.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database23 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html. The Genome Database24 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “stem cells” (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word “and” or “or” (using “or” might be useful when using synonyms).
23
Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 24 Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html - mission.
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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on stem cells can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.
Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to stem cells. Due to space limitations, these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly. The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below. Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages” which list links to available materials relevant to stem cells. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following when searched for “stem cells”:
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Guides on stem cells Stem Cells and Stem Cell Transplantation http://www.nlm.nih.gov/medlineplus/stemcellsandstemcelltransplantation.html
•
Other guides Bone Marrow Transplantation http://www.nlm.nih.gov/medlineplus/bonemarrowtransplantation.html Lymphoma http://www.nlm.nih.gov/medlineplus/lymphoma.html
Within the health topic page dedicated to stem cells, the following was listed: •
General/Overviews ABCs of Blood Stem Cell Donation and Transplantation Source: National Marrow Donor Program http://www.marrow.org/DONOR/abcs_blood_stem_cell_donation_transplantatio n.html Blood and Marrow Stem Cell Transplantation Source: Leukemia & Lymphoma Society http://www.leukemia-lymphoma.org/all_mat_toc.adp?item_id=2443 Umbilical Cord Blood Stem Cell Transplantation, Basic Version Source: National Marrow Donor Program http://www.marrow.org/MEDICAL/cord_blood_transplantation_basic.html Understanding Autologous Bone Marrow and Stem Cell Transplantation: Here's What You Should Know Source: International Myeloma Foundation http://myeloma.org/myeloma/kb_index.jsp?type=detail&id=37
•
Treatment Diseases Treatable by Stem Cell Transplantation Source: National Marrow Donor Program http://www.marrow.org/MEDICAL/diseases_treatable_by_stem_cell_transplants. html
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Specific Conditions/Aspects Banking Your Newborn's Cord Blood Source: Nemours Foundation http://kidshealth.org/parent/pregnancy_newborn/pregnancy/cord_blood.html Commercialization of Stem Cell “Banking” May Be Premature, Cautions ASPS Report Source: American Society of Plastic Surgeons http://www.plasticsurgery.org/news_room/press_releases/Commercialization-ofStem-Cell-Banking-May-Be-Premature-Cautions-ASPS-Report.cfm
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Cord Blood FAQs Source: National Marrow Donor Program http://www.marrow.org/FAQS/cord_blood_faqs.html Delayed Complications After a Blood Stem Cell Transplant Source: National Marrow Donor Program http://www.marrow.org/MEDICAL/delayed_complications_basic.html Evaluating Your Health Before Transplant Source: National Marrow Donor Program http://www.marrow.org/PATIENT/evaluating_health.html Fetal Cell Therapy Benefits Some Parkinson's Patients Source: National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov/news_and_events/freedfinal.htm?type=archived Graft-Versus-Host Disease Source: National Marrow Donor Program http://www.marrow.org/MEDICAL/graft_vs_host_disease.html Patient Resources http://www.marrow.org/PATIENT/MAZE/maze_glossary.pdf PBSC (Peripheral Blood Stem Cell) Donation Frequently Asked Questions Source: National Marrow Donor Program http://www.marrow.org/FAQS/pbsc_faqs.html Problems in the Post-Transplant Period Source: American Cancer Society http://www.cancer.org/docroot/ETO/content/ETO_1_4X_What_Are_Some_Of_T he_Problems_In_The_Post-Transplant_Period.asp?sitearea=ETO Stem Cell Therapy May Offer Hope to Spinal Cord Injured Patients Source: American Association of Neurological Surgeons http://www.neurosurgery.org/health/news/detail.asp?PressID=73 Stem Cell Transplant Coverage Information Source: National Marrow Donor Program http://www.marrow.org/PATIENT/transplant_coverage.html Transplants of Sibling Stem Cells Show Promise for Immune Disorder Source: National Institute of Allergy and Infectious Diseases http://www.nih.gov/news/pr/mar2001/niaid-21.htm •
Children Stem-Cell Transplants with Dramatic Results for JRA Source: Arthritis Foundation http://www.arthritis.org/resources/news/news_jraandstemcells.asp
•
From the National Institutes of Health Bone Marrow Transplantation and Peripheral Blood Stem Cell Transplantation: Questions and Answers Source: National Cancer Institute http://cis.nci.nih.gov/fact/7_41.htm
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Stem Cell Basics Source: National Institutes of Health http://stemcells.nih.gov/infoCenter/stemCellBasics.asp Stem Cells: Scientific Progress and Future Research Directions http://stemcells.nih.gov/stemcell/scireport.asp •
Journals/Newsletters Blood & Marrow Transplant Newsletter Source: BMT InfoNet http://www.bmtnews.org/newsletters/
•
Latest News Cloned Stem Cells Restore Dead Heart Tissue in Mice Source: 02/09/2004, United Press International http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_15955 .html More News on Stem Cells and Stem Cell Transplantation http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/alphanews_s.html#St emCellsandStemCellTransplantation Research Tries to Plant New Heart Cells Source: 02/03/2004, New York Times Syndicate http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_15888 .html Stem Cells Harvested from Embryos Source: 02/11/2004, New York Times Syndicate http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_16034 .html
•
Organizations National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov/ National Marrow Donor Program http://www.marrow.org/
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Research Craniofacial Research: Scientists Report New Lead in Craniofacial Development Source: National Institute of Dental and Craniofacial Research http://www.nidcr.nih.gov/news/inside_scoop_craniofacialResearch.asp Donor Stem Cell Grafts Restore Corneal Surface Source: American Academy of Ophthalmology http://www.medem.com/medlb/article_detaillb.cfm?article_ID=ZZZYIQLAJ3D&s ub_cat=2 Embryonic Stem Cells Research at the University of Wisconsin-Madison Source: University of Wisconsin http://www.news.wisc.edu/packages/stemcells/index.html
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Experimental Treatment Shows Promise against Kidney Cancer Source: American Cancer Society http://www.cancer.org/docroot/nws/content/nws_1_1x_experimental_treatment _shows_promise_against_kidney_cancer.asp Immunoglobulin in Patients with Stem-Cell Transplants Source: American College of Physicians http://www.annals.org/cgi/content/full/139/1/I-45 New Stem Cell Research Questions and Answers Source: Juvenile Diabetes Research Foundation International http://www.jdrf.org/index.cfm?fuseaction=home.viewPage&page_id=65A091ECDE4F-4696-8C3E40493A4101E8 NIGMS Center Grants to Explore Stem Cell Biology Source: National Institute of General Medical Sciences http://www.nih.gov/news/pr/sep2003/nigms-29.htm Preventing Fungal Infections in Patients with Stem-Cell Transplants Source: American College of Physicians http://www.annals.org/cgi/content/full/138/9/I-37 Scientists Discover Unique Source of Postnatal Stem Cells Source: National Institute of Dental and Craniofacial Research http://www.nih.gov/news/pr/apr2003/nidcr-21.htm Scientists Report Important New Data in Adult Stem Cell Debate Source: National Institute of Dental and Craniofacial Research http://www.nidcr.nih.gov/news/03272003.asp Stem Cell Research and Applications Monitoring the Frontiers of Biomedical Research http://www.aaas.org/spp/sfrl/projects/stem/report.pdf Under the Microscope: Looking at Stem Cell Research Source: National Academy of Sciences http://www4.nationalacademies.org/onpi/webextra.nsf/44bf87db309563a0852566 f2006d63bb/b7ea37ed3bcd3c5c85256ac20076452b?OpenDocument •
Statistics African American Facts & Figures Source: National Marrow Donor Program http://www.marrow.org/NMDP/aa_facts_figures.html American Indian/Alaska Native Facts & Figures Source: National Marrow Donor Program http://www.marrow.org/NMDP/aian_facts_figures.html Asian & Pacific Islander Facts & Figures Source: National Marrow Donor Program http://www.marrow.org/NMDP/api_facts_figures.html Facts and Figures Source: National Marrow Donor Program http://www.marrow.org/NMDP/facts_figures.html
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Hispanic Facts & Figures Source: National Marrow Donor Program http://www.marrow.org/NMDP/hispanic_facts_figures.html Understanding Survival Curves Source: National Marrow Donor Program http://www.marrow.org/MEDICAL/understanding_survival_outcomes.html You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The National Guideline Clearinghouse™ The National Guideline Clearinghouse™ offers hundreds of evidence-based clinical practice guidelines published in the United States and other countries. You can search this site located at http://www.guideline.gov/ by using the keyword “stem cells” (or synonyms). The following was recently posted: •
Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients Source: American Society for Blood and Marrow Transplantation - Professional Association; 2000 October 20; 126 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2573&nbr=1799&a mp;string=stem+AND+cells
•
Optimal therapy for patients diagnosed with multiple myeloma and the role of highdose chemotherapy and stem cell support Source: Practice Guidelines Initiative - State/Local Government Agency [Non-U.S.]; 2000 December 22 (revised online 2002 Apr); Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=3212&nbr=2438&a mp;string=stem+AND+cells
•
The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of multiple myeloma: an evidence-based review Source: American Society for Blood and Marrow Transplantation - Professional Association; 2003 January; 34 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3859&nbr=3070&a mp;string=stem+AND+cells
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Healthfinder™ Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database: •
NIH Stem Cell Information Summary: This web page presents links to news reports and releases related to research involving human pluripotent stem cells and include guidelines that detail procedures to help ensure that NIH-funded Source: National Institutes of Health, U.S. Department of Health and Human Services http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=5398 The NIH Search Utility
The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to stem cells. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats
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Family Village: http://www.familyvillage.wisc.edu/specific.htm
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Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/
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Med Help International: http://www.medhelp.org/HealthTopics/A.html
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Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/
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Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/
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WebMDHealth: http://my.webmd.com/health_topics
Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to stem cells. By consulting all of associations listed in
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this chapter, you will have nearly exhausted all sources for patient associations concerned with stem cells. The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about stem cells. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “stem cells” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “stem cells”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “stem cells” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “stem cells” (or a synonym) into the search box, and click “Submit Query.”
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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.
Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.25
Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.
Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of
25
Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.
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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)26: •
Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/
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Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)
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Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm
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California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html
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California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html
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California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html
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California: Gateway Health Library (Sutter Gould Medical Foundation)
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California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/
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California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp
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California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html
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California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/
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California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/
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California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/
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California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html
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California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/
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Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/
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Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/
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Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/
26
Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.
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Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml
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Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm
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Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html
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Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm
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Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp
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Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/
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Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm
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Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html
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Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/
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Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm
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Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/
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Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/
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Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/
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Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm
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Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html
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Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm
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Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/
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Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/
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Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10
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Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/
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Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html
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Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp
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Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp
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Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/
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Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html
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Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm
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Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp
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Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/
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Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html
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Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/
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Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm
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Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/
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Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html
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Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm
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Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330
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Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)
•
National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html
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National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/
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National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/
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Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm
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New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/
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New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm
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New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm
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New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/
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New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html
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New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/
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New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html
•
New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/
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Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm
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Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp
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Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/
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Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/
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Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml
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Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html
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Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html
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Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml
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Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp
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Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm
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Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/
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South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp
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Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/
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Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/
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Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72
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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •
ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html
•
MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp
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Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/
•
Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html
•
On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/
•
Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp
•
Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm
Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a).
Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •
Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical
•
MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html
•
Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/
•
Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine
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STEM CELLS DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 1-phosphate: A drug that halts cell suicide in human white blood cells. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Ablation: The removal of an organ by surgery. [NIH] Accelerated phase: Refers to chronic myelogenous leukemia that is progressing. The number of immature, abnormal white blood cells in the bone marrow and blood is higher than in the chronic phase, but not as high as in the blast phase. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Accommodation: Adjustment, especially that of the eye for various distances. [EU] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acinus: The berrylike ending of a tiny airway in the lung, where the alveoli (air sacs) are located. [NIH] Actin: Essential component of the cell skeleton. [NIH] Acute leukemia: A rapidly progressing cancer of the blood-forming tissue (bone marrow). [NIH]
Acute lymphoblastic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphocytic leukemia. [NIH] Acute lymphocytic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphoblastic leukemia. [NIH] Acute myelogenous leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute nonlymphocytic leukemia. [NIH] Acute myeloid leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myelogenous leukemia or acute nonlymphocytic leukemia. [NIH] Acute nonlymphocytic leukemia: A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute myelogenous leukemia. [NIH]
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Acyl: Chemical signal used by bacteria to communicate. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenosine Deaminase: An enzyme that catalyzes the hydrolysis of adenosine to inosine with the elimination of ammonia. Since there are wide tissue and species variations in the enzyme, it has been used as a tool in the study of human and animal genetics and in medical diagnosis. EC 3.5.4.4. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adhesions: Pathological processes consisting of the union of the opposing surfaces of a wound. [NIH] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [NIH] Adipose Tissue: Connective tissue composed of fat cells lodged in the meshes of areolar tissue. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adverse Effect: An unwanted side effect of treatment. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agammaglobulinemia: An immunologic deficiency state characterized by an extremely low level of generally all classes of gamma-globulin in the blood. [NIH] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis.
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[NIH]
Agarose: A polysaccharide complex, free of nitrogen and prepared from agar-agar which is produced by certain seaweeds (red algae). It dissolves in warm water to form a viscid solution. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Air Sacs: Thin-walled sacs or spaces which function as a part of the respiratory system in birds, fishes, insects, and mammals. [NIH] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Aldehyde Dehydrogenase: An enzyme that oxidizes an aldehyde in the presence of NAD+ and water to an acid and NADH. EC 1.2.1.3. Before 1978, it was classified as EC 1.1.1.70. [NIH]
Alginates: Salts of alginic acid that are extracted from marine kelp and used to make dental impressions and as absorbent material for surgical dressings. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alkaline: Having the reactions of an alkali. [EU] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allogeneic: Taken from different individuals of the same species. [NIH] Allograft: An organ or tissue transplant between two humans. [NIH] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha Cell: A type of cell in the pancreas (in areas called the islets of Langerhans). Alpha cells make and release a hormone called glucagon, which raises the level of glucose (sugar) in the blood. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Alveoli: Tiny air sacs at the end of the bronchioles in the lungs. [NIH] Ameliorated: A changeable condition which prevents the consequence of a failure or
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accident from becoming as bad as it otherwise would. [NIH] Amifostine: A phosphorothioate proposed as a radiation-protective agent. It causes splenic vasodilation and may block autonomic ganglia. [NIH] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino-terminal: The end of a protein or polypeptide chain that contains a free amino group (-NH2). [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Ampulla: A sac-like enlargement of a canal or duct. [NIH] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anaplastic: A term used to describe cancer cells that divide rapidly and bear little or no resemblance to normal cells. [NIH] Anaplastic large cell lymphoma: A rare agressive form of lymphoma (cancer that begins in cells of the lymphatic system) that is usually of T-cell origin. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anemia, Aplastic: A form of anemia in which the bone marrow fails to produce adequate numbers of peripheral blood elements. [NIH] Anemia, Sickle Cell: A disease characterized by chronic hemolytic anemia, episodic painful crises, and pathologic involvement of many organs. It is the clinical expression of homozygosity for hemoglobin S. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve
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function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] Angiogenesis inhibitor: A substance that may prevent the formation of blood vessels. In anticancer therapy, an angiogenesis inhibitor prevents the growth of blood vessels from surrounding tissue to a solid tumor. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]
Anoikis: Apoptosis triggered by loss of contact with the extracellular matrix. [NIH] Anomalies: Birth defects; abnormalities. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Anterior Cruciate Ligament: A strong ligament of the knee that originates from the posteromedial portion of the lateral condyle of the femur, passes anteriorly and inferiorly between the condyles, and attaches to the depression in front of the intercondylar eminence of the tibia. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]
Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Antibody therapy: Treatment with an antibody, a substance that can directly kill specific tumor cells or stimulate the immune system to kill tumor cells. [NIH] Antibody-Dependent Cell Cytotoxicity: The phenomenon of antibody-mediated target cell destruction by non-sensitized effector cells. The identity of the target cell varies, but it must possess surface IgG whose Fc portion is intact. The effector cell is a "killer" cell possessing Fc receptors. It may be a lymphocyte lacking conventional B- or T-cell markers, or a monocyte, macrophage, or polynuclear leukocyte, depending on the identity of the target cell. The reaction is complement-independent. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood
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thinner. [NIH] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Antigen-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. [NIH] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antineoplastic Agents: Substances that inhibit or prevent the proliferation of neoplasms. [NIH]
Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiproliferative: Counteracting a process of proliferation. [EU] Antithymocyte globulin: A protein used to reduce the risk of or to treat graft-versus-host disease. [NIH] Antiviral: Destroying viruses or suppressing their replication. [EU] Aorta: The main trunk of the systemic arteries. [NIH] Apheresis: Components plateletpheresis. [NIH]
being
separated
out,
as
leukapheresis,
plasmapheresis,
Aplastic anemia: A condition in which the bone marrow is unable to produce blood cells. [NIH]
Apomixis: A type of reproduction in which the sexual organs, or related structures, take part, but in which no fertilization occurs so that the resulting seed is of a vegetative nature. [NIH]
Aponeurosis: Tendinous expansion consisting of a fibrous or membranous sheath which serves as a fascia to enclose or bind a group of muscles. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Applicability: A list of the commodities to which the candidate method can be applied as
Dictionary 301
presented or with minor modifications. [NIH] Approximate: Approximal [EU] Aqueous: Having to do with water. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arrhythmia: Any variation from the normal rhythm or rate of the heart beat. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriolosclerosis: Sclerosis and thickening of the walls of the smaller arteries (arterioles). Hyaline arteriolosclerosis, in which there is homogeneous pink hyaline thickening of the arteriolar walls, is associated with benign nephrosclerosis. Hyperplastic arteriolosclerosis, in which there is a concentric thickening with progressive narrowing of the lumina may be associated with malignant hypertension, nephrosclerosis, and scleroderma. [EU] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Articular: Of or pertaining to a joint. [EU] Ascites: Accumulation or retention of free fluid within the peritoneal cavity. [NIH] Ascorbic Acid: A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. [NIH] Aseptic: Free from infection or septic material; sterile. [EU] Aspirate: Fluid withdrawn from a lump, often a cyst, or a nipple. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atrial: Pertaining to an atrium. [EU]
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Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Attenuated: Strain with weakened or reduced virulence. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autologous bone marrow transplantation: A procedure in which bone marrow is removed from a person, stored, and then given back to the person after intensive treatment. [NIH] Autologous lymphocytes: A person's white blood cells. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and disease. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autonomic Nervous System: The enteric, parasympathetic, and sympathetic nervous systems taken together. Generally speaking, the autonomic nervous system regulates the internal environment during both peaceful activity and physical or emotional stress. Autonomic activity is controlled and integrated by the central nervous system, especially the hypothalamus and the solitary nucleus, which receive information relayed from visceral afferents; these and related central and sensory structures are sometimes (but not here) considered to be part of the autonomic nervous system itself. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Axotomy: Transection or severing of an axon. This type of denervation is used often in experimental studies on neuronal physiology and neuronal death or survival, toward an understanding of nervous system disease. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Bacteriuria: The presence of bacteria in the urine with or without consequent urinary tract infection. Since bacteriuria is a clinical entity, the term does not preclude the use of urine/microbiology for technical discussions on the isolation and segregation of bacteria in the urine. [NIH] Barbiturate: A drug with sedative and hypnotic effects. Barbiturates have been used as
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sedatives and anesthetics, and they have been used to treat the convulsions associated with epilepsy. [NIH] Basal cells: Small, round cells found in the lower part (or base) of the epidermis, the outer layer of the skin. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]
Beta-Galactosidase: A group of enzymes that catalyzes the hydrolysis of terminal, nonreducing beta-D-galactose residues in beta-galactosides. Deficiency of beta-Galactosidase A1 may cause gangliodisosis GM1. EC 3.2.1.23. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Bile Canaliculi: Minute intercellular channels that occur between liver cells and carry bile towards interlobar bile ducts. Also called bile capillaries. [NIH] Bile Ducts: Tubes that carry bile from the liver to the gallbladder for storage and to the small intestine for use in digestion. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Bioartificial Organs: Artificial organs that are composites of biomaterials and cells. The biomaterial can act as a membrane (container) as in bioartificial liver or a scaffold as in bioartificial skin. [NIH] Bioassay: Determination of the relative effective strength of a substance (as a vitamin,
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hormone, or drug) by comparing its effect on a test organism with that of a standard preparation. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Bioengineering: The application of engineering principles to the solution of biological problems, for example, remote-handling devices, life-support systems, controls, and displays. [NIH] Biological Assay: A method of measuring the effects of a biologically active substance using an intermediate in vivo or in vitro tissue or cell model under controlled conditions. It includes virulence studies in animal fetuses in utero, mouse convulsion bioassay of insulin, quantitation of tumor-initiator systems in mouse skin, calculation of potentiating effects of a hormonal factor in an isolated strip of contracting stomach muscle, etc. [NIH] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological Sciences: All of the divisions of the natural sciences dealing with the various aspects of the phenomena of life and vital processes. The concept includes anatomy and physiology, biochemistry and biophysics, and the biology of animals, plants, and microorganisms. It should be differentiated from biology, one of its subdivisions, concerned specifically with the origin and life processes of living organisms. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biophysics: The science of physical phenomena and processes in living organisms. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Bioreactors: Tools or devices for generating products using the synthetic or chemical conversion capacity of a biological system. They can be classical fermentors, cell culture perfusion systems, or enzyme bioreactors. For production of proteins or enzymes, recombinant microorganisms such as bacteria, mammalian cells, or insect or plant cells are usually chosen. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Biotin: Hexahydro-2-oxo-1H-thieno(3,4-d)imidazole-4-pentanoic acid. Growth factor present in minute amounts in every living cell. It occurs mainly bound to proteins or polypeptides and is abundant in liver, kidney, pancreas, yeast, and milk.The biotin content of cancerous tissue is higher than that of normal tissue. [NIH] Bladder: The organ that stores urine. [NIH] Blast phase: The phase of chronic myelogenous leukemia in which the number of immature, abnormal white blood cells in the bone marrow and blood is extremely high. Also called blast crisis. [NIH]
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Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Blastomeres: The undifferentiated cells formed by cleavage of the fertilized ovum. This includes cells in the cleavage, morula, and blastula stages of the embryo. [NIH] Blasts: Immature blood cells. [NIH] Bleomycin: A complex of related glycopeptide antibiotics from Streptomyces verticillus consisting of bleomycin A2 and B2. It inhibits DNA metabolism and is used as an antineoplastic, especially for solid tumors. [NIH] Blister: Visible accumulations of fluid within or beneath the epidermis. [NIH] Blood Cell Count: A count of the number of leukocytes and erythrocytes per unit volume in a sample of venous blood. A complete blood count (CBC) also includes measurement of the hemoglobin, hematocrit, and erythrocyte indices. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]
Body Fluids: Liquid components of living organisms. [NIH] Bone Density: The amount of mineral per square centimeter of bone. This is the definition used in clinical practice. Actual bone density would be expressed in grams per milliliter. It is most frequently measured by photon absorptiometry or x-ray computed tomography. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone Marrow Cells: Cells contained in the bone marrow including fat cells, stromal cells, megakaryocytes, and the immediate precursors of most blood cells. [NIH] Bone Marrow Transplantation: The transference of bone marrow from one human or animal to another. [NIH] Bone metastases: Cancer that has spread from the original (primary) tumor to the bone. [NIH]
Bone Morphogenetic Proteins: Bone-growth regulatory factors that are members of the transforming growth factor-beta superfamily of proteins. They are synthesized as large precursor molecules which are cleaved by proteolytic enzymes. The active form can consist of a dimer of two identical proteins or a heterodimer of two related bone morphogenetic proteins. [NIH]
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Bone Regeneration: Renewal or repair of lost bone tissue. It excludes bony callus formed after bone fracture but not yet replaced by hard bone. [NIH] Bone Resorption: Bone loss due to osteoclastic activity. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Brain Hypoxia: Lack of oxygen leading to unconsciousness. [NIH] Brain Infarction: The formation of an area of necrosis in the brain, including the cerebral hemispheres (cerebral infarction), thalami, basal ganglia, brain stem (brain stem infarctions), or cerebellum secondary to an insufficiency of arterial or venous blood flow. [NIH] Brain Injuries: Acute and chronic injuries to the brain, including the cerebral hemispheres, cerebellum, and brain stem. Clinical manifestations depend on the nature of injury. Diffuse trauma to the brain is frequently associated with diffuse axonal injury or coma, posttraumatic. Localized injuries may be associated with neurobehavioral manifestations; hemiparesis, or other focal neurologic deficits. [NIH] Brain Ischemia: Localized reduction of blood flow to brain tissue due to arterial obtruction or systemic hypoperfusion. This frequently occurs in conjuction with brain hypoxia. Prolonged ischemia is associated with brain infarction. [NIH] Brain metastases: Cancer that has spread from the original (primary) tumor to the brain. [NIH]
Brain Stem: The part of the brain that connects the cerebral hemispheres with the spinal cord. It consists of the mesencephalon, pons, and medulla oblongata. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]
Breakdown: A physical, metal, or nervous collapse. [NIH] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH] Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Burns: Injuries to tissues caused by contact with heat, steam, chemicals (burns, chemical), electricity (burns, electric), or the like. [NIH] Burns, Electric: Burns produced by contact with electric current or from a sudden discharge of electricity. [NIH] Butyric Acid: A four carbon acid, CH3CH2CH2COOH, with an unpleasant odor that occurs in butter and animal fat as the glycerol ester. [NIH] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH]
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Calcification: Deposits of calcium in the tissues of the breast. Calcification in the breast can be seen on a mammogram, but cannot be detected by touch. There are two types of breast calcification, macrocalcification and microcalcification. Macrocalcifications are large deposits and are usually not related to cancer. Microcalcifications are specks of calcium that may be found in an area of rapidly dividing cells. Many microcalcifications clustered together may be a sign of cancer. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Callus: A callosity or hard, thick skin; the bone-like reparative substance that is formed round the edges and fragments of broken bone. [NIH] Canonical: A particular nucleotide sequence in which each position represents the base more often found when many actual sequences of a given class of genetic elements are compared. [NIH] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carboplatin: An organoplatinum compound that possesses antineoplastic activity. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]
Cardiac: Having to do with the heart. [NIH] Cardiogenic: Originating in the heart; caused by abnormal function of the heart. [EU] Cardiomyoplasty: A surgical procedure that involves detaching one end of a back muscle and attaching it to the heart. An electric stimulator causes the muscle to contract to pump blood from the heart. [NIH] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Cardiovascular System: The heart and the blood vessels by which blood is pumped and
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circulated through the body. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Cataracts: In medicine, an opacity of the crystalline lens of the eye obstructing partially or totally its transmission of light. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Communication: Any of several ways in which living cells of an organism communicate with one another, whether by direct contact between cells or by means of chemical signals carried by neurotransmitter substances, hormones, and cyclic AMP. [NIH] Cell Count: A count of the number of cells of a specific kind, usually measured per unit volume of sample. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell Fusion: Fusion of somatic cells in vitro or in vivo, which results in somatic cell hybridization. [NIH] Cell Lineage: The developmental history of cells as traced from the first division of the original cell or cells in the embryo. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell Movement: The movement of cells from one location to another. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell
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division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Size: The physical dimensions of a cell. It refers mainly to changes in dimensions correlated with physiological or pathological changes in cells. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cell Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [NIH] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Ceramide: A type of fat produced in the body. It may cause some types of cells to die, and is being studied in cancer treatment. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebellum: Part of the metencephalon that lies in the posterior cranial fossa behind the brain stem. It is concerned with the coordination of movement. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral hemispheres: The two halves of the cerebrum, the part of the brain that controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. The right hemisphere controls muscle movement on the left side of the body, and the left hemisphere controls muscle movement on the right side of the body. [NIH] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chemokines: Class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. They can be divided into at least three structural branches: C (chemokines, C), CC (chemokines, CC), and CXC (chemokines, CXC), according to variations in a shared cysteine motif. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotaxis: The movement of cells or organisms toward or away from a substance in response to its concentration gradient. [NIH]
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Chemotherapy: Treatment with anticancer drugs. [NIH] Chimeras: Organism that contains a mixture of genetically different cells. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chondrogenesis: The formation of cartilage. This process is directed by chondrocytes which continually divide and lay down matrix during development. It is sometimes a precursor to osteogenesis. [NIH] Chondroitin sulfate: The major glycosaminoglycan (a type of sugar molecule) in cartilage. [NIH]
Chorion: The outermost extraembryonic membrane. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Choroid Plexus: A villous structure of tangled masses of blood vessels contained within the third, lateral, and fourth ventricles of the brain. It regulates part of the production and composition of cerebrospinal fluid. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic granulocytic leukemia: A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myelogenous leukemia or chronic myeloid leukemia. [NIH] Chronic leukemia: A slowly progressing cancer of the blood-forming tissues. [NIH] Chronic lymphocytic leukemia: A slowly progressing disease in which too many white blood cells (called lymphocytes) are found in the body. [NIH] Chronic myelogenous leukemia: CML. A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myeloid leukemia or chronic granulocytic leukemia. [NIH] Chronic phase: Refers to the early stages of chronic myelogenous leukemia or chronic lymphocytic leukemia. The number of mature and immature abnormal white blood cells in the bone marrow and blood is higher than normal, but lower than in the accelerated or blast phase. [NIH] Chronic phase chronic myelogenous leukemia: A phase of chronic myelogenous leukemia that may last from several months to several years. Although there may be no symptoms of leukemia, there are too many white blood cells. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Cicatrix: The formation of new tissue in the process of wound healing. [NIH] Cilium: A hairlike appendage of the surface of a cell. It aids in cellular locomotion and
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creates currents in surrounding fluids. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Citrus: Any tree or shrub of the Rue family or the fruit of these plants. [NIH] C-kit receptor: A protein on the surface of some cells that binds to stem cell factor (a substance that causes certain types of cells to grow). Altered forms of this receptor may be associated with some types of cancer. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]
Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [NIH]
Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Coculture: The culturing of normal cells or tissues with infected or latently infected cells or tissues of the same kind (From Dorland, 28th ed, entry for cocultivation). It also includes culturing of normal cells or tissues with other normal cells or tissues. [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Colchicine: A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. Its primary therapeutic use is in the treatment of gout, but it has been used also in the therapy of familial Mediterranean fever (periodic disease). [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Colloidal: Of the nature of a colloid. [EU] Colony-Stimulating Factors: Glycoproteins found in a subfraction of normal mammalian
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plasma and urine. They stimulate the proliferation of bone marrow cells in agar cultures and the formation of colonies of granulocytes and/or macrophages. The factors include interleukin-3 (IL-3), granulocyte colony-stimulating factor (G-CSF), macrophage colonystimulating factor (M-CSF), and granulocyte-macrophage colony-stimulating factor (GMCSF). [NIH] Combination chemotherapy: Treatment using more than one anticancer drug. [NIH] Common Bile Duct: The largest biliary duct. It is formed by the junction of the cystic duct and the hepatic duct. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complete remission: The disappearance of all signs of cancer. Also called a complete response. [NIH] Complete response: The disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH]
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Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Conduction: The transfer of sound waves, heat, nervous impulses, or electricity. [EU] Cone: One of the special retinal receptor elements which are presumed to be primarily concerned with perception of light and color stimuli when the eye is adapted to light. [NIH] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Connexins: A group of homologous proteins which form the intermembrane channels of gap junctions. The connexins are the products of an identified gene family which has both highly conserved and highly divergent regions. The variety contributes to the wide range of functional properties of gap junctions. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Consolidation: The healing process of a bone fracture. [NIH] Constriction: The act of constricting. [NIH] Consumption: Pulmonary tuberculosis. [NIH] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Continuum: An area over which the vegetation or animal population is of constantly changing composition so that homogeneous, separate communities cannot be distinguished. [NIH]
Contraception: Use of agents, devices, methods, or procedures which diminish the likelihood of or prevent conception. [NIH] Contractility: Capacity for becoming short in response to a suitable stimulus. [EU] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Contralateral: Having to do with the opposite side of the body. [NIH] Convulsion: A violent involuntary contraction or series of contractions of the voluntary muscles. [EU] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Corneal Diseases: Diseases of the cornea. [NIH] Corneum: The superficial layer of the epidermis containing keratinized cells. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments,
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etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Corpus: The body of the uterus. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Cranial Nerves: Twelve pairs of nerves that carry general afferent, visceral afferent, special afferent, somatic efferent, and autonomic efferent fibers. [NIH] Craniotomy: An operation in which an opening is made in the skull. [NIH] Criterion: A standard by which something may be judged. [EU] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Cryofixation: Fixation of a tissue by localized cooling at very low temperature. [NIH] Cryopreservation: Preservation of cells, tissues, organs, or embryos by freezing. In histological preparations, cryopreservation or cryofixation is used to maintain the existing form, structure, and chemical composition of all the constituent elements of the specimens. [NIH]
Cues: Signals for an action; that specific portion of a perceptual field or pattern of stimuli to which a subject has learned to respond. [NIH] Culture Media: Any liquid or solid preparation made specifically for the growth, storage, or transport of microorganisms or other types of cells. The variety of media that exist allow for the culturing of specific microorganisms and cell types, such as differential media, selective media, test media, and defined media. Solid media consist of liquid media that have been solidified with an agent such as agar or gelatin. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclin: Molecule that regulates the cell cycle. [NIH] Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect,
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alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] Cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. [NIH] Cyst: A sac or capsule filled with fluid. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]
Cystitis: Inflammation of the urinary bladder. [EU] Cytidine: A pyrimidine nucleoside that is composed of the base cytosine linked to the fivecarbon sugar D-ribose. [NIH] Cytogenetics: A branch of genetics which deals with the cytological and molecular behavior of genes and chromosomes during cell division. [NIH] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Databases, Bibliographic: Extensive collections, reputedly complete, of references and citations to books, articles, publications, etc., generally on a single subject or specialized subject area. Databases can operate through automated files, libraries, or computer disks. The concept should be differentiated from factual databases which is used for collections of data and facts apart from bibliographic references to them. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Decidua: The epithelial lining of the endometrium that is formed before the fertilized ovum reaches the uterus. The fertilized ovum embeds in the decidua. If the ovum is not fertilized, the decidua is shed during menstruation. [NIH] Defense Mechanisms: Unconscious process used by an individual or a group of individuals in order to cope with impulses, feelings or ideas which are not acceptable at their conscious level; various types include reaction formation, projection and self reversal. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial
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relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Demyelinating Diseases: Diseases characterized by loss or dysfunction of myelin in the central or peripheral nervous system. [NIH] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dendritic cell: A special type of antigen-presenting cell (APC) that activates T lymphocytes. [NIH]
Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dental Hygienists: Persons trained in an accredited school or dental college and licensed by the state in which they reside to provide dental prophylaxis under the direction of a licensed dentist. [NIH] Dental implant: A small metal pin placed inside the jawbone to mimic the root of a tooth. Dental implants can be used to help anchor a false tooth or teeth, or a crown or bridge. [NIH] Dentate Gyrus: Gray matter situated above the gyrus hippocampi. It is composed of three layers. The molecular layer is continuous with the hippocampus in the hippocampal fissure. The granular layer consists of closely arranged spherical or oval neurons, called granule cells, whose axons pass through the polymorphic layer ending on the dendrites of pyramidal cells in the hippocampus. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Dermal: Pertaining to or coming from the skin. [NIH] Detoxification: Treatment designed to free an addict from his drug habit. [EU] Dexamethasone: (11 beta,16 alpha)-9-Fluoro-11,17,21-trihydroxy-16-methylpregna-1,4diene-3,20-dione. An anti-inflammatory glucocorticoid used either in the free alcohol or esterified form in treatment of conditions that respond generally to cortisone. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, hypothalamus, epithalamus, and subthalamus are derived. [NIH] Diffuse Axonal Injury: A relatively common sequela of blunt head injury, characterized by a global disruption of axons throughout the brain. Associated clinical features may include neurobehavioral manifestations; persistent vegetative state; dementia; and other disorders. [NIH]
Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can
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use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dilatation: The act of dilating. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dilution: A diluted or attenuated medicine; in homeopathy, the diffusion of a given quantity of a medicinal agent in ten or one hundred times the same quantity of water. [NIH] Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer. [NIH] Dimethyl: A volatile metabolite of the amino acid methionine. [NIH] Diphtheria: A localized infection of mucous membranes or skin caused by toxigenic strains of Corynebacterium diphtheriae. It is characterized by the presence of a pseudomembrane at the site of infection. Diphtheria toxin, produced by C. diphtheriae, can cause myocarditis, polyneuritis, and other systemic toxic effects. [NIH] Diphtheria Toxin: A 60 kD single chain protein elaborated by Corynebacterium diphtheriae that causes the sign and symptoms of diphtheria; it can be broken into two unequal fragments, the smaller (A fragment) inhibits protein synthesis and is the lethal moiety that needs the larger (B fragment) for entry into cells. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Disease-Free Survival: Period after successful treatment in which there is no appearance of the symptoms or effects of the disease. [NIH] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dorsum: A plate of bone which forms the posterior boundary of the sella turcica. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity
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of another drug. [NIH] Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from drug tolerance which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dura mater: The outermost, toughest, and most fibrous of the three membranes (meninges) covering the brain and spinal cord; called also pachymeninx. [EU] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dyskinesia: Impairment of the power of voluntary movement, resulting in fragmentary or incomplete movements. [EU] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dyspnea: Difficult or labored breathing. [NIH] Dystrophic: Pertaining to toxic habitats low in nutrients. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Ectoderm: The outer of the three germ layers of the embryo. [NIH] Ectopic: Pertaining to or characterized by ectopia. [EU] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Electrocardiogram: Measurement of electrical activity during heartbeats. [NIH] Electrolytes: Substances that break up into ions (electrically charged particles) when they are dissolved in body fluids or water. Some examples are sodium, potassium, chloride, and calcium. Electrolytes are primarily responsible for the movement of nutrients into cells, and the movement of wastes out of cells. [NIH] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH]
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Electrophysiological: Pertaining to electrophysiology, that is a branch of physiology that is concerned with the electric phenomena associated with living bodies and involved in their functional activity. [EU] Electroporation: A technique in which electric pulses of intensity in kilovolts per centimeter and of microsecond-to-millisecond duration cause a temporary loss of the semipermeability of cell membranes, thus leading to ion leakage, escape of metabolites, and increased uptake by cells of drugs, molecular probes, and DNA. Some applications of electroporation include introduction of plasmids or foreign DNA into living cells for transfection, fusion of cells to prepare hybridomas, and insertion of proteins into cell membranes. [NIH] Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryogenesis: The process of embryo or embryoid formation, whether by sexual (zygotic) or asexual means. In asexual embryogenesis embryoids arise directly from the explant or on intermediary callus tissue. In some cases they arise from individual cells (somatic cell embryoge). [NIH] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH]
Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endocrinology: A subspecialty of internal medicine concerned with the metabolism, physiology, and disorders of the endocrine system. [NIH] Endoderm: The inner of the three germ layers of the embryo. [NIH] Endometrial: Having to do with the endometrium (the layer of tissue that lines the uterus). [NIH]
Endometriosis: A condition in which tissue more or less perfectly resembling the uterine mucous membrane (the endometrium) and containing typical endometrial granular and stromal elements occurs aberrantly in various locations in the pelvic cavity. [NIH] Endometrium: The layer of tissue that lines the uterus. [NIH] Endoscope: A thin, lighted tube used to look at tissues inside the body. [NIH] Endoscopic: A technique where a lateral-view endoscope is passed orally to the duodenum for visualization of the ampulla of Vater. [NIH] Endostatin: A drug that is being studied for its ability to prevent the growth of new blood vessels into a solid tumor. Endostatin belongs to the family of drugs called angiogenesis
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inhibitors. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxins: Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Enteric Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Entorhinal Cortex: Cortex where the signals are combined with those from other sensory systems. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]
Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] Enzyme-Linked Immunosorbent Assay: An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme-antibody-antigen reaction is proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed. [NIH] Eosinophil: A polymorphonuclear leucocyte with large eosinophilic granules in its cytoplasm, which plays a role in hypersensitivity reactions. [NIH] Eosinophilic: A condition found primarily in grinding workers caused by a reaction of the
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pulmonary tissue, in particular the eosinophilic cells, to dust that has entered the lung. [NIH] Ependymal: It lines the cavities of the brain's ventricles and the spinal cord and slowly divides to create a stem cell. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermal Growth Factor: A 6 kD polypeptide growth factor initially discovered in mouse submaxillary glands. Human epidermal growth factor was originally isolated from urine based on its ability to inhibit gastric secretion and called urogastrone. epidermal growth factor exerts a wide variety of biological effects including the promotion of proliferation and differentiation of mesenchymal and epithelial cells. [NIH] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epidermolysis Bullosa: Group of genetically determined disorders characterized by the blistering of skin and mucosae. There are four major forms: acquired, simple, junctional, and dystrophic. Each of the latter three has several varieties. [NIH] Epidermolysis Bullosa Simplex: Form of epidermolysis bullosa characterized by autosomal dominant inheritance and by serous bullae that heal without scarring. [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]
Erectile: The inability to get or maintain an erection for satisfactory sexual intercourse. Also called impotence. [NIH] Erythrocyte Indices: Quantification of size and cell hemoglobin content or concentration of the erythrocyte, usually derived from erythrocyte count, blood hemoglobin concentration, and hematocrit. Includes the mean cell volume (MCV), mean cell hemoglobin (MCH), and mean cell hemoglobin concentration (MCHC). Use also for cell diameter and thickness. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythroid Progenitor Cells: Committed, erythroid stem cells derived from myeloid stem cells. The progenitor cells develop in two phases: erythroid burst-forming units (BFU-E)
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followed by erythroid colony-forming units (CFU-E). BFU-E differentiate into CFU-E on stimulation by erythropoietin, and then further differentiate into erythroblasts when stimulated by other factors. [NIH] Erythropoietin: Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. [NIH] Esophageal: Having to do with the esophagus, the muscular tube through which food passes from the throat to the stomach. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]
Essential Tremor: A rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction and relaxation of opposing groups of muscles. [NIH] Esterification: The process of converting an acid into an alkyl or aryl derivative. Most frequently the process consists of the reaction of an acid with an alcohol in the presence of a trace of mineral acid as catalyst or the reaction of an acyl chloride with an alcohol. Esterification can also be accomplished by enzymatic processes. [NIH] Estrogens: A class of sex hormones associated with the development and maintenance of secondary female sex characteristics and control of the cyclical changes in the reproductive cycle. They are also required for pregnancy maintenance and have an anabolic effect on protein metabolism and water retention. [NIH] Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Etoposide: A semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exons: Coding regions of messenger RNA included in the genetic transcript which survive the processing of RNA in cell nuclei to become part of a spliced messenger of structural RNA in the cytoplasm. They include joining and diversity exons of immunoglobulin genes. [NIH]
Expiration: The act of breathing out, or expelling air from the lungs. [EU]
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Expiratory: The volume of air which leaves the breathing organs in each expiration. [NIH] Extensive-stage small cell lung cancer: Cancer that has spread outside the lung to other tissues in the chest or to other parts of the body. [NIH] External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extrapyramidal: Outside of the pyramidal tracts. [EU] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]
Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Febrile: Pertaining to or characterized by fever. [EU] Femoral: Pertaining to the femur, or to the thigh. [EU] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [NIH] Fermentation: An enzyme-induced chemical change in organic compounds that takes place in the absence of oxygen. The change usually results in the production of ethanol or lactic acid, and the production of energy. [NIH] Fetal Blood: Blood of the fetus. Exchange of nutrients and waste between the fetal and maternal blood occurs via the placenta. The cord blood is blood contained in the umbilical vessels at the time of delivery. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibroblast Growth Factor: Peptide isolated from the pituitary gland and from the brain. It is a potent mitogen which stimulates growth of a variety of mesodermal cells including chondrocytes, granulosa, and endothelial cells. The peptide may be active in wound healing
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and animal limb regeneration. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibroid: A benign smooth muscle tumor, usually in the uterus or gastrointestinal tract. Also called leiomyoma. [NIH] Fibronectin: An adhesive glycoprotein. One form circulates in plasma, acting as an opsonin; another is a cell-surface protein which mediates cellular adhesive interactions. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Filgrastim: A colony-stimulating factor that stimulates the production of neutrophils (a type of white blood cell). It is a cytokine that belongs to the family of drugs called hematopoietic (blood-forming) agents. Also called granulocyte colony-stimulating factor (G-CSF). [NIH] Filler: An inactive substance used to make a product bigger or easier to handle. For example, fillers are often used to make pills or capsules because the amount of active drug is too small to be handled conveniently. [NIH] Fissure: Any cleft or groove, normal or otherwise; especially a deep fold in the cerebral cortex which involves the entire thickness of the brain wall. [EU] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Flexor: Muscles which flex a joint. [NIH] Flow Cytometry: Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. [NIH] Fludarabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]
Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH]
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Fluorescent Dyes: Dyes that emit light when exposed to light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags. They are used as markers in biochemistry and immunology. [NIH] Foam Cells: Lipid-laden macrophages originating from monocytes or from smooth muscle cells. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Follicles: Shafts through which hair grows. [NIH] Follicular large cell lymphoma: A rare type of non- Hodgkin's lymphoma (cancer of the lymphatic system) with large cells that look cleaved (split) or non-cleaved under the microscope. It is an indolent (slow-growing) type of lymphoma. [NIH] Foramen: A natural hole of perforation, especially one in a bone. [NIH] Fossa: A cavity, depression, or pit. [NIH] Fovea: The central part of the macula that provides the sharpest vision. [NIH] Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites, including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [NIH] Galactosides: Glycosides formed by the reaction of the hydroxyl group on the anomeric carbon atom of galactose with an alcohol to form an acetal. They include both alpha- and beta-galactosides. [NIH] Galanin: A neurotransmitter. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous capsule enclosing a clear mucinous fluid. [EU] Gap Junctions: Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of proteins which form the junctions. [NIH]
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Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastric: Having to do with the stomach. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]
Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gastrula: The embryo in the early stage following the blastula, characterized by morphogenetic cell movements, cell differentiation, and the formation of the three germ layers. [NIH] Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as a protein food adjuvant, plasma substitute, hemostatic, suspending agent in pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [NIH] Gels: Colloids with a solid continuous phase and liquid as the dispersed phase; gels may be unstable when, due to temperature or other cause, the solid phase liquifies; the resulting colloid is called a sol. [NIH] Gemtuzumab ozogamicin: A type of monoclonal antibody used in cancer detection or therapy. Monoclonal antibodies are laboratory-produced substances that can locate and bind to cancer cells. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]
Gene Conversion: The asymmetrical segregation of genes during replication which leads to the production of non-reciprocal recombinant strands and the apparent conversion of one allele into another. Thus, e.g., the meiotic products of an Aa individual may be AAAa or aaaA instead of AAaa, i.e., the A allele has been converted into the a allele or vice versa. [NIH]
Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Silencing: Interruption or suppression of the expression of a gene at transcriptional or translational levels. [NIH] Gene Targeting: The integration of exogenous DNA into the genome of an organism at sites where its expression can be suitably controlled. This integration occurs as a result of homologous recombination. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU]
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Genomics: The systematic study of the complete DNA sequences (genome) of organisms. [NIH]
Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ cell tumors: Tumors that begin in the cells that give rise to sperm or eggs. They can occur virtually anywhere in the body and can be either benign or malignant. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Germ Layers: The three layers of cells comprising the early embryo. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Gestational: Psychosis attributable to or occurring during pregnancy. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glial Fibrillary Acidic Protein: An intermediate filament protein found only in glial cells or cells of glial origin. MW 51,000. [NIH] Gliosis: The production of a dense fibrous network of neuroglia; includes astrocytosis, which is a proliferation of astrocytes in the area of a degenerative lesion. [NIH] Globus Pallidus: The representation of the phylogenetically oldest part of the corpus striatum called the paleostriatum. It forms the smaller, more medial part of the lentiform nucleus. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]
Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]
Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosaminoglycan: A type of long, unbranched polysaccharide molecule. Glycosaminoglycans are major structural components of cartilage and are also found in the cornea of the eye. [NIH] Goats: Any of numerous agile, hollow-horned ruminants of the genus Capra, closely related to the sheep. [NIH]
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Gonad: A sex organ, such as an ovary or a testicle, which produces the gametes in most multicellular animals. [NIH] Gonadal: Pertaining to a gonad. [EU] Gonadotropin: The water-soluble follicle stimulating substance, by some believed to originate in chorionic tissue, obtained from the serum of pregnant mares. It is used to supplement the action of estrogens. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]
Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Graft-versus-host disease: GVHD. A reaction of donated bone marrow or peripheral stem cells against a person's tissue. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Granule: A small pill made from sucrose. [EU] Granulocyte Colony-Stimulating Factor: A glycoprotein of MW 25 kDa containing internal disulfide bonds. It induces the survival, proliferation, and differentiation of neutrophilic granulocyte precursor cells and functionally activates mature blood neutrophils. Among the family of colony-stimulating factors, G-CSF is the most potent inducer of terminal differentiation to granulocytes and macrophages of leukemic myeloid cell lines. [NIH] Granulocyte-Macrophage Colony-Stimulating Factor: An acidic glycoprotein of MW 23 kDa with internal disulfide bonds. The protein is produced in response to a number of inflammatory mediators by mesenchymal cells present in the hemopoietic environment and at peripheral sites of inflammation. GM-CSF is able to stimulate the production of neutrophilic granulocytes, macrophages, and mixed granulocyte-macrophage colonies from bone marrow cells and can stimulate the formation of eosinophil colonies from fetal liver progenitor cells. GM-CSF can also stimulate some functional activities in mature granulocytes and macrophages. [NIH] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH]
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Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Habitat: An area considered in terms of its environment, particularly as this determines the type and quality of the vegetation the area can carry. [NIH] Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] Haemopoietic: Haematopoietic; pertaining to or effecting the formation of blood cells. [EU] Hair follicles: Shafts or openings on the surface of the skin through which hair grows. [NIH] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heartbeat: One complete contraction of the heart. [NIH] Hematocrit: Measurement of the volume of packed red cells in a blood specimen by centrifugation. The procedure is performed using a tube with graduated markings or with automated blood cell counters. It is used as an indicator of erythrocyte status in disease. For example, anemia shows a low hematocrit, polycythemia, high values. [NIH] Hematologic malignancies: Cancers of the blood or bone marrow, including leukemia and lymphoma. Also called hematologic cancers. [NIH] Hematology: A subspecialty of internal medicine concerned with morphology, physiology, and pathology of the blood and blood-forming tissues. [NIH] Hematopoiesis: The development and formation of various types of blood cells. [NIH] Hematopoietic growth factors: A group of proteins that cause blood cells to grow and mature. [NIH] Hematopoietic Stem Cell Mobilization: The release of stem cells from the bone marrow into the peripheral blood circulation for the purpose of leukapheresis, prior to stem cell transplantion. Hematopoietic growth factors or chemotherapeutic agents often are used to stimulate the mobilization. [NIH] Hematopoietic Stem Cell Transplantation: The transference of stem cells from one animal or human to another (allogeneic), or within the same individual (autologous). The source for the stem cells may be the bone marrow or peripheral blood. Stem cell transplantation has been used as an alternative to autologous bone marrow transplantation in the treatment of a variety of neoplasms. [NIH] Hematopoietic Stem Cells: Progenitor cells from which all blood cells derive. [NIH] Hematopoietic tissue: Tissue in which new blood cells are formed. [NIH] Hemiparesis: The weakness or paralysis affecting one side of the body. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels
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of 9 percent or more. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemolysis: The destruction of erythrocytes by many different causal agents such as antibodies, bacteria, chemicals, temperature, and changes in tonicity. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]
Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatocyte: A liver cell. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Heterochromatin: The portion of chromosome material that remains condensed and is transcriptionally inactive during interphase. [NIH] Heterodimer: Zippered pair of nonidentical proteins. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]
Heterogenic: Derived from a different source or species. Also called heterogenous. [NIH] Heterogenous: Derived from a different source or species. Also called heterogenic. [NIH] Heterotrophic: Pertaining to organisms that are consumers and dependent on other organisms for their source of energy (food). [NIH] Hippocampus: A curved elevation of gray matter extending the entire length of the floor of the temporal horn of the lateral ventricle (Dorland, 28th ed). The hippocampus, subiculum, and dentate gyrus constitute the hippocampal formation. Sometimes authors include the entorhinal cortex in the hippocampal formation. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Homeobox: Distinctive sequence of DNA bases. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homodimer: Protein-binding "activation domains" always combine with identical proteins. [NIH]
Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU]
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Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Horny layer: The superficial layer of the epidermis containing keratinized cells. [NIH] Horseradish Peroxidase: An enzyme isolated from horseradish which is able to act as an antigen. It is frequently used as a histochemical tracer for light and electron microscopy. Its antigenicity has permitted its use as a combined antigen and marker in experimental immunology. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Human Development: Continuous sequential changes which occur in the physiological and psychological functions during the individual's life. [NIH] Human growth hormone: A protein hormone, secreted by the anterior lobe of the pituitary, which promotes growth of the whole body by stimulating protein synthesis. The human gene has already been cloned and successfully expressed in bacteria. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hybridomas: Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure or "monoclonal" antibodies or T-cell products, identical to those produced by the immunologically competent parent, and continually grow and divide as the neoplastic parent. [NIH] Hydrochloric Acid: A strong corrosive acid that is commonly used as a laboratory reagent. It is formed by dissolving hydrogen chloride in water. Gastric acid is the hydrochloric acid component of gastric juice. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrolases: Any member of the class of enzymes that catalyze the cleavage of the substrate and the addition of water to the resulting molecules, e.g., esterases, glycosidases (glycoside hydrolases), lipases, nucleotidases, peptidases (peptide hydrolases), and phosphatases (phosphoric monoester hydrolases). EC 3. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic
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acid can result in impaired hydroxyproline formation. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hypnotic: A drug that acts to induce sleep. [EU] Hypopigmentation: A condition caused by a deficiency in melanin formation or a loss of pre-existing melanin or melanocytes. It can be complete or partial and may result from trauma, inflammation, and certain infections. [NIH] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Hypoxanthine: A purine and a reaction intermediate in the metabolism of adenosine and in the formation of nucleic acids by the salvage pathway. [NIH] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Ileum: The lower end of the small intestine. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immortal: Stage when the mother cell and its descendants will multiply indefinitely. [NIH] Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]
Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]
effects
of
foreign
Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] Immunocompromised: Having a weakened immune system caused by certain diseases or treatments. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunodiffusion: Technique involving the diffusion of antigen or antibody through a semisolid medium, usually agar or agarose gel, with the result being a precipitin reaction. [NIH]
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Immunoelectrophoresis: A technique that combines protein electrophoresis and double immunodiffusion. In this procedure proteins are first separated by gel electrophoresis (usually agarose), then made visible by immunodiffusion of specific antibodies. A distinct elliptical precipitin arc results for each protein detectable by the antisera. [NIH] Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunogen: A substance that is capable of causing antibody formation. [NIH] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incubated: Grown in the laboratory under controlled conditions. (For instance, white blood cells can be grown in special conditions so that they attack specific cancer cells when returned to the body.) [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Incubation period: The period of time likely to elapse between exposure to the agent of the disease and the onset of clinical symptoms. [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Indolent: A type of cancer that grows slowly. [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a
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specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]
Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Initiator: A chemically reactive substance which may cause cell changes if ingested, inhaled or absorbed into the body; the substance may thus initiate a carcinogenic process. [NIH] Inlay: In dentistry, a filling first made to correspond with the form of a dental cavity and then cemented into the cavity. [NIH] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insertional: A technique in which foreign DNA is cloned into a restriction site which occupies a position within the coding sequence of a gene in the cloning vector molecule. Insertion interrupts the gene's sequence such that its original function is no longer expressed. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Insulin-like: Muscular growth factor. [NIH] Integrins:
A
family
of
transmembrane
glycoproteins
consisting
of
noncovalent
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heterodimers. They interact with a wide variety of ligands including extracellular matrix glycoproteins, complement, and other cells, while their intracellular domains interact with the cytoskeleton. The integrins consist of at least three identified families: the cytoadhesin receptors, the leukocyte adhesion receptors, and the very-late-antigen receptors. Each family contains a common beta-subunit combined with one or more distinct alpha-subunits. These receptors participate in cell-matrix and cell-cell adhesion in many physiologically important processes, including embryological development, hemostasis, thrombosis, wound healing, immune and nonimmune defense mechanisms, and oncogenic transformation. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Interleukin-3: A multilineage cell growth factor secreted by lymphocytes, epithelial cells, and astrocytes which stimulates clonal proliferation and differentiation of various types of blood and tissue cells. Also called multi-CSF, it is considered one of the hematopoietic colony stimulating factors. [NIH] Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [NIH] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] Interneurons: Most generally any neurons which are not motor or sensory. Interneurons may also refer to neurons whose axons remain within a particular brain region as contrasted with projection neurons which have axons projecting to other brain regions. [NIH] Interphase: The interval between two successive cell divisions during which the chromosomes are not individually distinguishable and DNA replication occurs. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intracellular: Inside a cell. [NIH] Intraocular: Within the eye. [EU] Intravascular: Within a vessel or vessels. [EU] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU]
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Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]
Involuntary: Reaction occurring without intention or volition. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Irritants: Drugs that act locally on cutaneous or mucosal surfaces to produce inflammation; those that cause redness due to hyperemia are rubefacients; those that raise blisters are vesicants and those that penetrate sebaceous glands and cause abscesses are pustulants; tear gases and mustard gases are also irritants. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Islet: Cell producing insulin in pancreas. [NIH] Jejunum: That portion of the small intestine which extends from the duodenum to the ileum; called also intestinum jejunum. [EU] Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Karyotype: The characteristic chromosome complement of an individual, race, or species as defined by their number, size, shape, etc. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Keloid: A sharply elevated, irregularly shaped, progressively enlarging scar resulting from formation of excessive amounts of collagen in the dermis during connective tissue repair. It is differentiated from a hypertrophic scar (cicatrix, hypertrophic) in that the former does not spread to surrounding tissues. [NIH] Keratin: A class of fibrous proteins or scleroproteins important both as structural proteins and as keys to the study of protein conformation. The family represents the principal constituent of epidermis, hair, nails, horny tissues, and the organic matrix of tooth enamel.
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Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms an alpha-helix, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. [NIH] Keratinocytes: Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Pelvis: The flattened, funnel-shaped expansion connecting the ureter to the kidney calices. [NIH] Killer Cells: Lymphocyte-like effector cells which mediate antibody-dependent cell cytotoxicity. They kill antibody-coated target cells which they bind with their Fc receptors. [NIH]
Kinetic: Pertaining to or producing motion. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Laminin: Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Larynx: An irregularly shaped, musculocartilaginous tubular structure, lined with mucous membrane, located at the top of the trachea and below the root of the tongue and the hyoid bone. It is the essential sphincter guarding the entrance into the trachea and functioning secondarily as the organ of voice. [NIH] Lateral Ventricles: Cavity in each of the cerebral hemispheres derived from the cavity of the embryonic neural tube. They are separated from each other by the septum pellucidum, and each communicates with the third ventricle by the foramen of Monro, through which also the choroid plexuses of the lateral ventricles become continuous with that of the third ventricle. [NIH] Laxative: An agent that acts to promote evacuation of the bowel; a cathartic or purgative. [EU]
Leiomyoma: A benign tumor derived from smooth muscle tissue, also known as a fibroid tumor. They rarely occur outside of the uterus and the gastrointestinal tract but can occur in the skin and subcutaneous tissues, probably arising from the smooth muscle of small blood vessels in these tissues. [NIH] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Lentivirus: A genus of the family Retroviridae consisting of non-oncogenic retroviruses that produce multi-organ diseases characterized by long incubation periods and persistent infection. Lentiviruses are unique in that they contain open reading frames (ORFs) between the pol and env genes and in the 3' env region. Five serogroups are recognized, reflecting the mammalian hosts with which they are associated. HIV-1 is the type species. [NIH]
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Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]
Leukaemia: An acute or chronic disease of unknown cause in man and other warm-blooded animals that involves the blood-forming organs, is characterized by an abnormal increase in the number of leucocytes in the tissues of the body with or without a corresponding increase of those in the circulating blood, and is classified according of the type leucocyte most prominently involved. [EU] Leukapheresis: The preparation of leukocyte concentrates with the return of red cells and leukocyte-poor plasma to the donor. [NIH] Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Levo: It is an experimental treatment for heroin addiction that was developed by German scientists around 1948 as an analgesic. Like methadone, it binds with opioid receptors, but it is longer acting. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]
Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Liposomal: A drug preparation that contains the active drug in very tiny fat particles. This fat-encapsulated drug is absorbed better, and its distribution to the tumor site is improved. [NIH]
Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver metastases: Cancer that has spread from the original (primary) tumor to the liver. [NIH]
Lobe: A portion of an organ such as the liver, lung, breast, or brain. [NIH] Loc: A brain region associated with object recognition. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to
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humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Lucida: An instrument, invented by Wollaton, consisting essentially of a prism or a mirror through which an object can be viewed so as to appear on a plane surface seen in direct view and on which the outline of the object may be traced. [NIH] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]
Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphoblastic: One of the most aggressive types of non-Hodgkin lymphoma. [NIH] Lymphoblasts: Interferon produced predominantly by leucocyte cells. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphocyte Subsets: A classification of lymphocytes based on structurally or functionally different populations of cells. [NIH] Lymphocytic: Referring to lymphocytes, a type of white blood cell. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphokine: A soluble protein produced by some types of white blood cell that stimulates other white blood cells to kill foreign invaders. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysosomal Storage Diseases: Inborn errors of metabolism characterized by defects in specific lysosomal hydrolases and resulting in intracellular accumulation of unmetabolized substrates. [NIH] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU] Macaca: A genus of the subfamily Cercopithecinae, family Cercopithecidae, consisting of 16 species inhabiting forests of Africa, Asia, and the islands of Borneo, Philippines, and Celebes. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Macula: A stain, spot, or thickening. Often used alone to refer to the macula retinae. [EU] Macula Lutea: An oval area in the retina, 3 to 5 mm in diameter, usually located temporal to the superior pole of the eye and slightly below the level of the optic disk. [NIH] Macular Degeneration: Degenerative changes in the macula lutea of the retina. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy
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based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Maintenance therapy: Treatment that is given to help a primary (original) treatment keep working. Maintenance therapy is often given to help keep cancer in remission. [NIH] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malformation: A morphologic developmental process. [EU]
defect
resulting
from
an
intrinsically
abnormal
Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]
Mammary: Pertaining to the mamma, or breast. [EU] Mammogram: An x-ray of the breast. [NIH] Mandible: The largest and strongest bone of the face constituting the lower jaw. It supports the lower teeth. [NIH] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medicament: A medicinal substance or agent. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Medullary: Pertaining to the marrow or to any medulla; resembling marrow. [EU] Megakaryocytes: Very large bone marrow cells which release mature blood platelets. [NIH] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanoblasts: Cell originating from the neural crest that differentiates into a melanocyte. [NIH]
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Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Melphalan: An alkylating nitrogen mustard that is used as an antineoplastic in the form of the levo isomer - melphalan, the racemic mixture - merphalan, and the dextro isomer medphalan; toxic to bone marrow, but little vesicant action; potential carcinogen. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Meniscus: A fibro-cartilage within a joint, especially of the knee. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mercury: A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Mesoderm: The middle germ layer of the embryo. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] Methylcellulose: Methylester of cellulose. Methylcellulose is used as an emulsifying and suspending agent in cosmetics, pharmaceutics and the chemical industry. It is used therapeutically as a bulk laxative. [NIH] Methyltransferase: A drug-metabolizing enzyme. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH]
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Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microcalcifications: Tiny deposits of calcium in the breast that cannot be felt but can be detected on a mammogram. A cluster of these very small specks of calcium may indicate that cancer is present. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Micro-organism: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Milliliter: A measure of volume for a liquid. A milliliter is approximately 950-times smaller than a quart and 30-times smaller than a fluid ounce. A milliliter of liquid and a cubic centimeter (cc) of liquid are the same. [NIH] Mineralization: The action of mineralizing; the state of being mineralized. [EU] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitotic: Cell resulting from mitosis. [NIH] Mitoxantrone: An anthracenedione-derived antineoplastic agent. [NIH] Mobility: Capability of movement, of being moved, or of flowing freely. [EU] Mobilization: The process of making a fixed part or stored substance mobile, as by separating a part from surrounding structures to make it accessible for an operative procedure or by causing release into the circulation for body use of a substance stored in the body. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]
Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular Probes: A group of atoms or molecules attached to other molecules or cellular structures and used in studying the properties of these molecules and structures. Radioactive DNA or RNA sequences are used in molecular genetics to detect the presence of a complementary sequence by molecular hybridization. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the
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same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocyte: A type of white blood cell. [NIH] Mononuclear: A cell with one nucleus. [NIH] Morphogenesis: The development of the form of an organ, part of the body, or organism. [NIH]
Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Morula: The early embryo at the developmental stage in which the blastomeres, resulting from repeated mitotic divisions of the fertilized ovum, form a compact mass. [NIH] Mosaicism: The occurrence in an individual of two or more cell populations of different chromosomal constitutions, derived from a single zygote, as opposed to chimerism in which the different cell populations are derived from more than one zygote. [NIH] Motility: The ability to move spontaneously. [EU] Motor Neurons: Neurons which activate muscle cells. [NIH] Movement Disorders: Syndromes which feature dyskinesias as a cardinal manifestation of the disease process. Included in this category are degenerative, hereditary, post-infectious, medication-induced, post-inflammatory, and post-traumatic conditions. [NIH] Mucinous: Containing or resembling mucin, the main compound in mucus. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. [NIH] Multiple Myeloma: A malignant tumor of plasma cells usually arising in the bone marrow; characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria, and anemia. [NIH] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH]
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Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Mustard Gas: Severe irritant and vesicant of skin, eyes, and lungs. It may cause blindness and lethal lung edema and was formerly used as a war gas. The substance has been proposed as a cytostatic and for treatment of psoriasis. It has been listed as a known carcinogen in the Fourth Annual Report on Carcinogens (NTP-85-002, 1985) (Merck, 11th ed). [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Mycophenolate mofetil: A drug that is being studied for its effectiveness in preventing graft-versus-host disease and autoimmune disorders. [NIH] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myelin Sheath: The lipid-rich sheath investing many axons in both the central and peripheral nervous systems. The myelin sheath is an electrical insulator and allows faster and more energetically efficient conduction of impulses. The sheath is formed by the cell membranes of glial cells (Schwann cells in the peripheral and oligodendroglia in the central nervous system). Deterioration of the sheath in demyelinating diseases is a serious clinical problem. [NIH] Myelodysplasia: Abnormal bone marrow cells that may lead to myelogenous leukemia. [NIH]
Myelodysplastic syndrome: Disease in which the bone marrow does not function normally. Also called preleukemia or smoldering leukemia. [NIH] Myelogenous: Produced by, or originating in, the bone marrow. [NIH] Myeloid Cells: Cells which include the monocytes and the granulocytes. [NIH] Myeloid Progenitor Cells: One of the two stem cells derived from hematopoietic stem cells the other being the lymphoid progenitor cell. Derived from these myeloid progenitor cells are the erythroid progenitor cells and the myeloid cells (monocytes and granulocytes). [NIH] Myeloma: Cancer that arises in plasma cells, a type of white blood cell. [NIH] Myeloproliferative Disorders: Disorders in which one or more stimuli cause proliferation of hemopoietically active tissue or of tissue which has embryonic hemopoietic potential. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocarditis: Inflammation of the myocardium; inflammation of the muscular walls of the heart. [EU] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myopathy: Any disease of a muscle. [EU]
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Myopia: That error of refraction in which rays of light entering the eye parallel to the optic axis are brought to a focus in front of the retina, as a result of the eyeball being too long from front to back (axial m.) or of an increased strength in refractive power of the media of the eye (index m.). Called also nearsightedness, because the near point is less distant than it is in emmetropia with an equal amplitude of accommodation. [EU] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Naive: Used to describe an individual who has never taken a certain drug or class of drugs (e. g., AZT-naive, antiretroviral-naive), or to refer to an undifferentiated immune system cell. [NIH] Natural killer cells: NK cells. A type of white blood cell that contains granules with enzymes that can kill tumor cells or microbial cells. Also called large granular lymphocytes (LGL). [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Nearsightedness: The common term for myopia. [NIH] Nebramycin: A complex of antibiotic substances produced by Streptomyces tenebrarius. [NIH]
Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Neostriatum: The phylogenetically newer part of the corpus striatum consisting of the caudate nucleus and putamen. It is often called simply the striatum. [NIH] Nephropathy: Disease of the kidneys. [EU] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nerve Growth Factor: Nerve growth factor is the first of a series of neurotrophic factors that were found to influence the growth and differentiation of sympathetic and sensory neurons. It is comprised of alpha, beta, and gamma subunits. The beta subunit is responsible for its growth stimulating activity. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Nervous System Diseases: Diseases of the central and peripheral nervous system. This includes disorders of the brain, spinal cord, cranial nerves, peripheral nerves, nerve roots, autonomic nervous system, neuromuscular junction, and muscle. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers
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or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neural Crest: A strip of specialized ectoderm flanking each side of the embryonal neural plate, which after the closure of the neural tube, forms a column of isolated cells along the dorsal aspect of the neural tube. Most of the cranial and all of the spinal sensory ganglion cells arise by differentiation of neural crest cells. [NIH] Neurites: In tissue culture, hairlike projections of neurons stimulated by growth factors and other molecules. These projections may go on to form a branched tree of dendrites or a single axon or they may be reabsorbed at a later stage of development. "Neurite" may refer to any filamentous or pointed outgrowth of an embryonal or tissue-culture neural cell. [NIH] Neurobehavioral Manifestations: Signs and symptoms of higher cortical dysfunction caused by organic conditions. These include certain behavioral alterations and impairments of skills involved in the acquisition, processing, and utilization of knowledge or information. [NIH]
Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neurodegenerative Diseases: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures. [NIH] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neurogenic: Loss of bladder control caused by damage to the nerves controlling the bladder. [NIH] Neuroglia: The non-neuronal cells of the nervous system. They are divided into macroglia (astrocytes, oligodendroglia, and schwann cells) and microglia. They not only provide physical support, but also respond to injury, regulate the ionic and chemical composition of the extracellular milieu, participate in the blood-brain and blood-retina barriers, form the myelin insulation of nervous pathways, guide neuronal migration during development, and exchange metabolites with neurons. Neuroglia have high-affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitters, but their role in signaling (as in many other functions) is unclear. [NIH] Neurologic: Having to do with nerves or the nervous system. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuromuscular Junction: The synapse between a neuron and a muscle. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as neurotransmitters and some functioning as hormones. [NIH] Neurosurgery: A surgical specialty concerned with the treatment of diseases and disorders of the brain, spinal cord, and peripheral and sympathetic nervous system. [NIH] Neurotoxic: Poisonous or destructive to nerve tissue. [EU]
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Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [NIH]
Neurotransmitters: Endogenous signaling molecules that alter the behavior of neurons or effector cells. Neurotransmitter is used here in its most general sense, including not only messengers that act directly to regulate ion channels, but also those that act through second messenger systems, and those that act at a distance from their site of release. Included are neuromodulators, neuroregulators, neuromediators, and neurohumors, whether or not acting at synapses. [NIH] Neurotrophins: A nerve growth factor. [NIH] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutropenia: An abnormal decrease in the number of neutrophils, a type of white blood cell. [NIH] Neutrophil: A type of white blood cell. [NIH] Niche: The ultimate unit of the habitat, i. e. the specific spot occupied by an individual organism; by extension, the more or less specialized relationships existing between an organism, individual or synusia(e), and its environment. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]
Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclear Fusion: Thermonuclear reaction in which the nuclei of an element of low atomic weight unite under extremely high temperature and pressure to form a nucleus of a heavier atom. [NIH] Nuclear Matrix: The fibrogranular network of residual structural elements within which are immersed both chromatin and ribonucleoproteins. It extends throughout the nuclear interior from the nucleolus to the nuclear pore complexes along the nuclear periphery. [NIH] Nuclear Pore: An opening through the nuclear envelope formed by the nuclear pore complex which transports nuclear proteins or RNA into or out of the cell nucleus and which, under some conditions, acts as an ion channel. [NIH]
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Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleolus: A small dense body (sub organelle) within the nucleus of eukaryotic cells, visible by phase contrast and interference microscopy in live cells throughout interphase. Contains RNA and protein and is the site of synthesis of ribosomal RNA. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Ointments: Semisolid preparations used topically for protective emollient effects or as a vehicle for local administration of medications. Ointment bases are various mixtures of fats, waxes, animal and plant oils and solid and liquid hydrocarbons. [NIH] Oligodendroglia: A class of neuroglial (macroglial) cells in the central nervous system. Oligodendroglia may be called interfascicular, perivascular, or perineuronal satellite cells according to their location. The most important recognized function of these cells is the formation of the insulating myelin sheaths of axons in the central nervous system. [NIH] Oligodendroglial: A cell that lays down myelin. [NIH] Oligodendroglioma: A rare, slow-growing tumor that begins in brain cells called oligodendrocytes, which provide support and nourishment for cells that transmit nerve impulses. Also called oligodendroglial tumor. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] Oncology: The study of cancer. [NIH] Oncolysis: The destruction of or disposal by absorption of any neoplastic cells. [NIH] Oncolytic: Pertaining to, characterized by, or causing oncolysis (= the lysis or destruction of tumour cells). [EU] Oocytes: Female germ cells in stages between the prophase of the first maturation division and the completion of the second maturation division. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Open Reading Frames: Reading frames where successive nucleotide triplets can be read as codons specifying amino acids and where the sequence of these triplets is not interrupted by stop codons. [NIH] Ophthalmology: A surgical specialty concerned with the structure and function of the eye and the medical and surgical treatment of its defects and diseases. [NIH] Opportunistic Infections: An infection caused by an organism which becomes pathogenic under certain conditions, e.g., during immunosuppression. [NIH] Opsin: A protein formed, together with retinene, by the chemical breakdown of meta-
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rhodopsin. [NIH] Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organ Transplantation: Transference of an organ between individuals of the same species or between individuals of different species. [NIH] Organoids: An organization of cells into an organ-like structure. Organoids can be generated in culture. They are also found in certain neoplasms. [NIH] Orofacial: Of or relating to the mouth and face. [EU] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] Osseointegration: The growth action of bone tissue, as it assimilates surgically implanted devices or prostheses to be used as either replacement parts (e.g., hip) or as anchors (e.g., endosseous dental implants). [NIH] Ossification: The formation of bone or of a bony substance; the conversion of fibrous tissue or of cartilage into bone or a bony substance. [EU] Osteoarthritis: A progressive, degenerative joint disease, the most common form of arthritis, especially in older persons. The disease is thought to result not from the aging process but from biochemical changes and biomechanical stresses affecting articular cartilage. In the foreign literature it is often called osteoarthrosis deformans. [NIH] Osteoblasts: Bone-forming cells which secrete an extracellular matrix. Hydroxyapatite crystals are then deposited into the matrix to form bone. [NIH] Osteoclasts: A large multinuclear cell associated with the absorption and removal of bone. An odontoclast, also called cementoclast, is cytomorphologically the same as an osteoclast and is involved in cementum resorption. [NIH] Osteogenesis: The histogenesis of bone including ossification. It occurs continuously but particularly in the embryo and child and during fracture repair. [NIH] Osteopetrosis: Excessive formation of dense trabecular bone leading to pathological fractures, osteitis, splenomegaly with infarct, anemia, and extramedullary hemopoiesis. [NIH]
Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overexpress: An excess of a particular protein on the surface of a cell. [NIH] Ovulation: The discharge of a secondary oocyte from a ruptured graafian follicle. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH]
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Ovum Implantation: Endometrial implantation of the blastocyst. [NIH] Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]
Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Oxides: Binary compounds of oxygen containing the anion O(2-). The anion combines with metals to form alkaline oxides and non-metals to form acidic oxides. [NIH] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Pacemaker: An object or substance that influences the rate at which a certain phenomenon occurs; often used alone to indicate the natural cardiac pacemaker or an artificial cardiac pacemaker. In biochemistry, a substance whose rate of reaction sets the pace for a series of interrelated reactions. [EU] Paclitaxel: Antineoplastic agent isolated from the bark of the Pacific yew tree, Taxus brevifolia. Paclitaxel stabilizes microtubules in their polymerized form and thus mimics the action of the proto-oncogene proteins c-mos. [NIH] Palate: The structure that forms the roof of the mouth. It consists of the anterior hard palate and the posterior soft palate. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatectomy: Surgery to remove the pancreas. In a total pancreatectomy, a portion of the stomach, the duodenum, common bile duct, gallbladder, spleen, and nearby lymph nodes also are removed. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Pancreatic Ducts: Ducts that collect pancreatic juice from the pancreas and supply it to the duodenum. [NIH] Pancreatic Juice: The fluid containing digestive enzymes secreted by the pancreas in response to food in the duodenum. [NIH] Pancreatic Polypeptide: A 36-amino acid polypeptide with physiological regulatory functions. It is secreted by pancreatic tissue. Plasma pancreatic polypeptide increases after ingestion of food, with age, and in disease states. A lack of pancreatic polypeptide in the islets of Langerhans has been associated with the obese syndrome in rats and mice. [NIH] Pancytopenia: Deficiency of all three cell elements of the blood, erythrocytes, leukocytes and platelets. [NIH] Papillomavirus: A genus of Papovaviridae causing proliferation of the epithelium, which may lead to malignancy. A wide range of animals are infected including humans,
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chimpanzees, cattle, rabbits, dogs, and horses. [NIH] Paraffin: A mixture of solid hydrocarbons obtained from petroleum. It has a wide range of uses including as a stiffening agent in ointments, as a lubricant, and as a topical antiinflammatory. It is also commonly used as an embedding material in histology. [NIH] Parathyroid: 1. Situated beside the thyroid gland. 2. One of the parathyroid glands. 3. A sterile preparation of the water-soluble principle(s) of the parathyroid glands, ad-ministered parenterally as an antihypocalcaemic, especially in the treatment of acute hypoparathyroidism with tetany. [EU] Parathyroid Glands: Two small paired endocrine glands in the region of the thyroid gland. They secrete parathyroid hormone and are concerned with the metabolism of calcium and phosphorus. [NIH] Parathyroid hormone: A substance made by the parathyroid gland that helps the body store and use calcium. Also called parathormone, parathyrin, or PTH. [NIH] Parenchyma: The essential elements of an organ; used in anatomical nomenclature as a general term to designate the functional elements of an organ, as distinguished from its framework, or stroma. [EU] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Parthenogenesis: A specialized type of apomixis in which an organism develops from an unfertilized female gamete. [NIH] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] Particle: A tiny mass of material. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]
Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Patient Selection: Criteria and standards used for the determination of the appropriateness of the inclusion of patients with specific conditions in proposed treatment plans and the criteria used for the inclusion of subjects in various clinical trials and other research protocols. [NIH] Pelvic: Pertaining to the pelvis. [EU] Penicillin: An antibiotic drug used to treat infection. [NIH] Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third compartment below, the corpus spongiosum, houses the urethra. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH]
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Peptide Fragments: Partial proteins formed by partial hydrolysis of complete proteins. [NIH] Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [NIH] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]
Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Periodontal Ligament: Fibrous connective tissue surrounding the root of a tooth that separates it from and attaches it to the alveolar bone. [NIH] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Nerves: The nerves outside of the brain and spinal cord, including the autonomic, cranial, and spinal nerves. Peripheral nerves contain non-neuronal cells and connective tissue as well as axons. The connective tissue layers include, from the outside to the inside, the epineurium, the perineurium, and the endoneurium. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peripheral stem cell transplantation: A method of replacing blood-forming cells destroyed by cancer treatment. Immature blood cells (stem cells) in the circulating blood that are similar to those in the bone marrow are given after treatment to help the bone marrow recover and continue producing healthy blood cells. Transplantation may be autologous (an individual's own blood cells saved earlier), allogeneic (blood cells donated by someone else), or syngeneic (blood cells donated by an identical twin). Also called peripheral stem cell support. [NIH] Peripheral stem cells: Immature cells found circulating in the bloodstream. New blood cells develop from peripheral stem cells. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneal Cavity: The space enclosed by the peritoneum. It is divided into two portions, the greater sac and the lesser sac or omental bursa, which lies behind the stomach. The two sacs are connected by the foramen of Winslow, or epiploic foramen. [NIH] Perivascular: Situated around a vessel. [EU] Petroleum: Naturally occurring complex liquid hydrocarbons which, after distillation, yield combustible fuels, petrochemicals, and lubricants. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative
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logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Phallic: Pertaining to the phallus, or penis. [EU] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phonation: The process of producing vocal sounds by means of vocal cords vibrating in an expiratory blast of air. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Photoreceptor: Receptor capable of being activated by light stimuli, as a rod or cone cell of the eye. [NIH] Phylogeny: The relationships of groups of organisms as reflected by their evolutionary history. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]
Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Piebaldism: Autosomal dominant, congenital disorder characterized by localized hypomelanosis of the skin and hair. The most familiar feature is a white forelock presenting in 80 to 90 percent of the patients. The underlying defect is possibly related to the differentiation and migration of melanoblasts, as well as to defective development of the neural crest (neurocristopathy). Piebaldism may be closely related to Waardenburg's syndrome. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH]
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Planarians: Nonparasitic free-living flatworms of the class Turbellaria. The most common genera are Dugesia, formerly Planaria, which lives in water, and Bipalium, which lives on land. Geoplana occurs in South America and California. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasmapheresis: Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. [NIH] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [NIH] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelet Transfusion: The transfer of blood platelets from a donor to a recipient or reinfusion to the donor. [NIH] Platelet-Derived Growth Factor: Mitogenic peptide growth hormone carried in the alphagranules of platelets. It is released when platelets adhere to traumatized tissues. Connective tissue cells near the traumatized region respond by initiating the process of replication. [NIH] Plateletpheresis: The preparation of platelet concentrates with the return of red cells and platelet-poor plasma to the donor. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Podophyllotoxin: The main active constituent of the resin from the roots of may apple or mandrake (Podophyllum peltatum and P. emodi). It is a potent spindle poison, toxic if taken internally, and has been used as a cathartic. It is very irritating to skin and mucous membranes, has keratolytic actions, has been used to treat warts and keratoses, and may have antineoplastic properties, as do some of its congeners and derivatives. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working
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kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-traumatic: Occurring as a result of or after injury. [EU] Potentiate: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiating: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practicability: A non-standard characteristic of an analytical procedure. It is dependent on the scope of the method and is determined by requirements such as sample throughout and costs. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precipitation: The act or process of precipitating. [EU] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which
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another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Pre-cursor: Any other radionuclide produced for radio-labeling of another substance prior to administration. [NIH] Preleukemia: Conditions in which the abnormalities in the peripheral blood or bone marrow represent the early manifestations of acute leukemia, but in which the changes are not of sufficient magnitude or specificity to permit a diagnosis of acute leukemia by the usual clinical criteria. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Presumptive: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Prickle: Several layers of the epidermis where the individual cells are connected by cell bridges. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Progeny: The offspring produced in any generation. [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Proportional: Being in proportion : corresponding in size, degree, or intensity, having the same or a constant ratio; of, relating to, or used in determining proportions. [EU] Prosencephalon: The part of the brain developed from the most rostral of the three primary vesicles of the embryonic neural tube and consisting of the diencephalon and telencephalon. [NIH]
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Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Prosthesis: An artificial replacement of a part of the body. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] Proteoglycan: A molecule that contains both protein and glycosaminoglycans, which are a type of polysaccharide. Proteoglycans are found in cartilage and other connective tissues. [NIH]
Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Prothrombin: A plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions. Deficiency of prothrombin leads to hypoprothrombinemia. [NIH]
Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proto-Oncogene Proteins: Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity. [NIH] Proto-Oncogene Proteins c-mos: Cellular proteins encoded by the c-mos genes. They function in the cell cycle to maintain maturation promoting factor in the active state and have protein-serine/threonine kinase activity. Oncogenic transformation can take place when c-mos proteins are expressed at the wrong time. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH]
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Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]
Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Fibrosis: Chronic inflammation and progressive fibrosis of the pulmonary alveolar walls, with steadily progressive dyspnea, resulting finally in death from oxygen lack or right heart failure. [NIH] Pupil: The aperture in the iris through which light passes. [NIH] Purifying: Respiratory equipment whose function is to remove contaminants from otherwise wholesome air. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Putamen: The largest and most lateral of the basal ganglia lying between the lateral medullary lamina of the globus pallidus and the external capsule. It is part of the neostriatum and forms part of the lentiform nucleus along with the globus pallidus. [NIH] Pyramidal Cells: Projection neurons in the cerebral cortex and the hippocampus. Pyramidal cells have a pyramid-shaped soma with the apex and an apical dendrite pointed toward the pial surface and other dendrites and an axon emerging from the base. The axons may have local collaterals but also project outside their cortical region. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Quiescent: Marked by a state of inactivity or repose. [EU] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radioimmunotherapy: Radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (immunotoxins) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire. Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (radiotherapy). [NIH]
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Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Reactivation: The restoration of activity to something that has been inactivated. [EU] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Receptors, Serotonin: Cell-surface proteins that bind serotonin and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombinant Proteins: Proteins prepared by recombinant DNA technology. [NIH] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Reconstitution: 1. A type of regeneration in which a new organ forms by the rearrangement of tissues rather than from new formation at an injured surface. 2. The restoration to original form of a substance previously altered for preservation and storage, as the restoration to a liquid state of blood serum or plasma that has been dried and stored. [EU] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reflex: An involuntary movement or exercise of function in a part, excited in response to a stimulus applied to the periphery and transmitted to the brain or spinal cord. [NIH]
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Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractive Power: The ability of an object, such as the eye, to bend light as light passes through it. [NIH] Refractory: Not readily yielding to treatment. [EU] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal capsule: The fibrous connective tissue that surrounds each kidney. [NIH] Renal cell cancer: Cancer that develops in the lining of the renal tubules, which filter the blood and produce urine. [NIH] Renal pelvis: The area at the center of the kidney. Urine collects here and is funneled into the ureter, the tube that connects the kidney to the bladder. [NIH] Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing reperfusion injury. [NIH] Reperfusion Injury: Functional, metabolic, or structural changes, including necrosis, in ischemic tissues thought to result from reperfusion to ischemic areas of the tissue. The most common instance is myocardial reperfusion injury. [NIH] Repopulation: The replacement of functional cells, usually by proliferation, following or during irradiation. [NIH] Reproductive cells: Egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes. [NIH] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respiratory distress syndrome: A lung disease that occurs primarily in premature infants; the newborn must struggle for each breath and blueing of its skin reflects the baby's inability to get enough oxygen. [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The
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outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retrospective: Looking back at events that have already taken place. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Retrovirus: A member of a group of RNA viruses, the RNA of which is copied during viral replication into DNA by reverse transcriptase. The viral DNA is then able to be integrated into the host chromosomal DNA. [NIH] Reversion: A return to the original condition, e. g. the reappearance of the normal or wild type in previously mutated cells, tissues, or organisms. [NIH] Rheumatic Diseases: Disorders of connective tissue, especially the joints and related structures, characterized by inflammation, degeneration, or metabolic derangement. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Ribonucleoproteins: Proteins conjugated with ribonucleic acids (RNA) or specific RNA. Many viruses are ribonucleoproteins. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rituximab: A type of monoclonal antibody used in cancer detection or therapy. Monoclonal antibodies are laboratory-produced substances that can locate and bind to cancer cells. [NIH] Rod: A reception for vision, located in the retina. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid
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or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Satellite: Applied to a vein which closely accompanies an artery for some distance; in cytogenetics, a chromosomal agent separated by a secondary constriction from the main body of the chromosome. [NIH] Sclera: The tough white outer coat of the eyeball, covering approximately the posterior fivesixths of its surface, and continuous anteriorly with the cornea and posteriorly with the external sheath of the optic nerve. [EU] Scleroderma: A chronic disorder marked by hardening and thickening of the skin. Scleroderma can be localized or it can affect the entire body (systemic). [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Sebaceous: Gland that secretes sebum. [NIH] Sebaceous gland: Gland that secretes sebum. [NIH] Secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary cancer. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sediment: A precipitate, especially one that is formed spontaneously. [EU] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Senescence: The bodily and mental state associated with advancing age. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Septum: A dividing wall or partition; a general term for such a structure. The term is often used alone to refer to the septal area or to the septum pellucidum. [EU]
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Septum Pellucidum: A triangular double membrane separating the anterior horns of the lateral ventricles of the brain. It is situated in the median plane and bounded by the corpus callosum and the body and columns of the fornix. [NIH] Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]
Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH]
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Skin graft: Skin that is moved from one part of the body to another. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small cell lung cancer: A type of lung cancer in which the cells appear small and round when viewed under the microscope. Also called oat cell lung cancer. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smoldering leukemia: Disease in which the bone marrow does not function normally. Also called preleukemia or myelodysplastic syndrome. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]
Smooth Muscle Tumor: A tumor composed of smooth muscle tissue, as opposed to leiomyoma, a tumor derived from smooth muscle. [NIH] Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatic cells: All the body cells except the reproductive (germ) cells. [NIH] Somatic mutations: Alterations in DNA that occur after conception. Somatic mutations can occur in any of the cells of the body except the germ cells (sperm and egg) and therefore are not passed on to children. These alterations can (but do not always) cause cancer or other diseases. [NIH] Somatostatin: A polypeptide hormone produced in the hypothalamus, and other tissues and organs. It inhibits the release of human growth hormone, and also modulates important physiological functions of the kidney, pancreas, and gastrointestinal tract. Somatostatin receptors are widely expressed throughout the body. Somatostatin also acts as a neurotransmitter in the central and peripheral nervous systems. [NIH] Sound wave: An alteration of properties of an elastic medium, such as pressure, particle displacement, or density, that propagates through the medium, or a superposition of such alterations. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by
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refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spermatocyte: An early stage in the development of a spermatozoon. [NIH] Spermatogenesis: Process of formation and development of spermatozoa, including spermatocytogenesis and spermiogenesis. [NIH] Spermatozoa: Mature male germ cells that develop in the seminiferous tubules of the testes. Each consists of a head, a body, and a tail that provides propulsion. The head consists mainly of chromatin. [NIH] Spermatozoon: The mature male germ cell. [NIH] Spheroplasts: Cells, usually bacteria or yeast, which have partially lost their cell wall, lost their characteristic shape and become round. [NIH] Sphincter: A ringlike band of muscle fibres that constricts a passage or closes a natural orifice; called also musculus sphincter. [EU] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spinal Cord Injuries: Penetrating and non-penetrating injuries to the spinal cord resulting from traumatic external forces (e.g., wounds, gunshot; whiplash injuries; etc.). [NIH] Spinal Nerves: The 31 paired peripheral nerves formed by the union of the dorsal and ventral spinal roots from each spinal cord segment. The spinal nerve plexuses and the spinal roots are also included. [NIH] Spinous: Like a spine or thorn in shape; having spines. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Splenomegaly: Enlargement of the spleen. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Spotting: A slight discharge of blood via the vagina, especially as a side-effect of oral contraceptives. [EU] Squamous: Scaly, or platelike. [EU] Squamous Epithelium: Tissue in an organ such as the esophagus. Consists of layers of flat, scaly cells. [NIH] Stabilization: The creation of a stable state. [EU] Stem Cell Factor: Hematopoietic growth factor and the ligand of the c-kit receptor CD117 (proto-oncogene protein C-kit). It is expressed during embryogenesis and provides a key signal in multiple aspects of mast-cell differentiation and function. [NIH] Stem cell transplantation: A method of replacing immature blood-forming cells that were destroyed by cancer treatment. The stem cells are given to the person after treatment to help the bone marrow recover and continue producing healthy blood cells. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Sterile: Unable to produce children. [NIH]
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Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Sterilization: The destroying of all forms of life, especially microorganisms, by heat, chemical, or other means. [NIH] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Striatum: A higher brain's domain thus called because of its stripes. [NIH] Stringency: Experimental conditions (e. g. temperature, salt concentration) used during the hybridization of nucleic acids. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stroma: The middle, thickest layer of tissue in the cornea. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stromal Cells: Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subiculum: A region of the hippocampus that projects to other areas of the brain. [NIH] Submaxillary: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]
Substrate: A substance upon which an enzyme acts. [EU] Sudden death: Cardiac arrest caused by an irregular heartbeat. The term "death" is
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somewhat misleading, because some patients survive. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synapses: Specialized junctions at which a neuron communicates with a target cell. At classical synapses, a neuron's presynaptic terminal releases a chemical transmitter stored in synaptic vesicles which diffuses across a narrow synaptic cleft and activates receptors on the postsynaptic membrane of the target cell. The target may be a dendrite, cell body, or axon of another neuron, or a specialized region of a muscle or secretory cell. Neurons may also communicate through direct electrical connections which are sometimes called electrical synapses; these are not included here but rather in gap junctions. [NIH] Synapsis: The pairing between homologous chromosomes of maternal and paternal origin during the prophase of meiosis, leading to the formation of gametes. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synaptic Vesicles: Membrane-bound compartments which contain transmitter molecules. Synaptic vesicles are concentrated at presynaptic terminals. They actively sequester transmitter molecules from the cytoplasm. In at least some synapses, transmitter release occurs by fusion of these vesicles with the presynaptic membrane, followed by exocytosis of their contents. [NIH] Synaptophysin: A 38-kDa integral membrane glycoprotein of the presynaptic vesicles in neuron and neuroendocrine cells. It is expressed by a variety of normal and neoplastic neuroendocrine cells and is therefore used as an immunocytochemical marker for neuroendocrine differentiation in various tumors. In Alzheimer disease and other dementing disorders there is an important synapse loss due in part to a decrease of synaptophysin in the presynaptic vesicles. [NIH] Systemic: Affecting the entire body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH]
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Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] T cell: One type of white blood cell that attacks virus-infected cells, foreign cells, and cancer cells. T cells also produce a number of substances that regulate the immune response. [NIH] Tacrolimus: A macrolide isolated from the culture broth of a strain of Streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro. [NIH] Taurine: 2-Aminoethanesulfonic acid. A conditionally essential nutrient, important during mammalian development. It is present in milk but is isolated mostly from ox bile and strongly conjugates bile acids. [NIH] Tear Gases: Gases that irritate the eyes, throat, or skin. Severe lacrimation develops upon irritation of the eyes. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Telencephalon: Paired anteriolateral evaginations of the prosencephalon plus the lamina terminalis. The cerebral hemispheres are derived from it. Many authors consider cerebrum a synonymous term to telencephalon, though a minority include diencephalon as part of the cerebrum (Anthoney, 1994). [NIH] Telomerase: Essential ribonucleoprotein reverse transcriptase that adds telomeric DNA to the ends of eukaryotic chromosomes. Telomerase appears to be repressed in normal human somatic tissues but reactivated in cancer, and thus may be necessary for malignant transformation. EC 2.7.7.-. [NIH] Telomere: A terminal section of a chromosome which has a specialized structure and which is involved in chromosomal replication and stability. Its length is believed to be a few hundred base pairs. [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Teratogenesis: Production of monstrous growths or fetuses. [NIH] Terminalis: A groove on the lateral surface of the right atrium. [NIH] Testicular: Pertaining to a testis. [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetany: 1. Hyperexcitability of nerves and muscles due to decrease in concentration of extracellular ionized calcium, which may be associated with such conditions as parathyroid hypofunction, vitamin D deficiency, and alkalosis or result from ingestion of alkaline salts; it is characterized by carpopedal spasm, muscular twitching and cramps, laryngospasm with inspiratory stridor, hyperreflexia and choreiform movements. 2. Tetanus. [EU] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH]
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Thalassemia: A group of hereditary hemolytic anemias in which there is decreased synthesis of one or more hemoglobin polypeptide chains. There are several genetic types with clinical pictures ranging from barely detectable hematologic abnormality to severe and fatal anemia. [NIH] Thalidomide: A pharmaceutical agent originally introduced as a non-barbiturate hypnotic, but withdrawn from the market because of its known tetratogenic effects. It has been reintroduced and used for a number of immunological and inflammatory disorders. Thalidomide displays immunosuppresive and anti-angiogenic activity. It inhibits release of tumor necrosis factor alpha from monocytes, and modulates other cytokine action. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [NIH] Thioguanine: An antineoplastic compound which also has antimetabolite action. The drug is used in the therapy of acute leukemia. [NIH] Thiotepa: A very toxic alkylating antineoplastic agent also used as an insect sterilant. It causes skin, gastrointestinal, CNS, and bone marrow damage. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), thiotepa may reasonably be anticipated to be a carcinogen (Merck Index, 11th ed). [NIH] Third Ventricle: A narrow cleft inferior to the corpus callosum, within the diencephalon, between the paired thalami. Its floor is formed by the hypothalamus, its anterior wall by the lamina terminalis, and its roof by ependyma. It communicates with the fourth ventricle by the cerebral aqueduct, and with the lateral ventricles by the interventricular foramina. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thrombocytopenia: A decrease in the number of blood platelets. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]
Thrombopoietin: A humoral factor that controls blood platelet production through stimulation of megakaryocyte populations. Bone marrow megakaryocytes increase in both size and number in response to exposure to thrombopoietin. [NIH] Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]
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Thymidine Kinase: An enzyme that catalyzes the conversion of ATP and thymidine to ADP and thymidine 5'-phosphate. Deoxyuridine can also act as an acceptor and dGTP as a donor. (From Enzyme Nomenclature, 1992) EC 2.7.1.21. [NIH] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [NIH] Tissue Extracts: Preparations made from animal tissues or organs; they usually contain many components, any one of which may be pharmacologically or physiologically active; extracts may contain specific, but uncharacterized factors or proteins with specific actions. [NIH]
Tissue Therapy: Historically, tissue transplantation, especially of refrigerated tissue (after Filatov). It was theorized that nonspecific substances, capable of initiating restorative processes, formed in tissues when refrigerated. Cell therapy (after Niehans) refers to implantation of tissue by injection. Originally this involved fresh cells but later frozen or lyophilized cells. [NIH] Tissue Transplantation: Transference of tissue within an individual, between individuals of the same species, or between individuals of different species. [NIH] Tobramycin: An aminoglycoside, broad-spectrum antibiotic produced by Streptomyces tenebrarius. It is effective against gram-negative bacteria, especially the Pseudomonas species. It is a 10% component of the antibiotic complex, nebramycin, produced by the same species. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tonicity: The normal state of muscular tension. [NIH] Tooth Loss: The failure to retain teeth as a result of disease or injury. [NIH] Topical: On the surface of the body. [NIH] Topotecan: An antineoplastic agent used to treat ovarian cancer. It works by inhibiting DNA topoisomerase. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Total pancreatectomy: Surgery to remove the entire pancreas. [NIH] Total-body irradiation: Radiation therapy to the entire body. Usually followed by bone marrow or peripheral stem cell transplantation. [NIH]
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Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transforming Growth Factor beta: A factor synthesized in a wide variety of tissues. It acts synergistically with TGF-alpha in inducing phenotypic transformation and can also act as a negative autocrine growth factor. TGF-beta has a potential role in embryonal development, cellular differentiation, hormone secretion, and immune function. TGF-beta is found mostly as homodimer forms of separate gene products TGF-beta1, TGF-beta2 or TGF-beta3. Heterodimers composed of TGF-beta1 and 2 (TGF-beta1.2) or of TGF-beta2 and 3 (TGFbeta2.3) have been isolated. The TGF-beta proteins are synthesized as precursor proteins. [NIH]
Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Transgenes: Genes that are introduced into an organism using gene transfer techniques. [NIH]
Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Transplantation Tolerance: An induced state of non-reactivity to grafted tissue from a donor organism that would ordinarily trigger a cell-mediated or humoral immune response.
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[NIH]
Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Treatment Outcome: Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, practicability, etc., of these interventions in individual cases or series. [NIH]
Trophic: Of or pertaining to nutrition. [EU] Trophoblast: The outer layer of cells of the blastocyst which works its way into the endometrium during ovum implantation and grows rapidly, later combining with mesoderm. [NIH] Tropism: Directed movements and orientations found in plants, such as the turning of the sunflower to face the sun. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Tubulin: A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from sperm flagella, cilia, and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to colchicine, vincristine, and vinblastine. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Tumor Stem Cells: Colony-forming cells which give rise to neoplasms. [NIH] Tumor suppressor gene: Genes in the body that can suppress or block the development of cancer. [NIH] Tumorigenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH]
Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Umbilical Arteries: Either of a pair of arteries originating from the internal iliac artery and passing through the umbilical cord to carry blood from the fetus to the placenta. [NIH] Umbilical Cord: The flexible structure, giving passage to the umbilical arteries and vein,
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which connects the embryo or fetus to the placenta. [NIH] Umbilical cord blood: Blood from the placenta (afterbirth) that contains high concentrations of stem cells needed to produce new blood cells. [NIH] Unconditioned: An inborn reflex common to all members of a species. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Unresectable: Unable to be surgically removed. [NIH] Ureter: One of a pair of thick-walled tubes that transports urine from the kidney pelvis to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]
Urinalysis: Examination of urine by chemical, physical, or microscopic means. Routine urinalysis usually includes performing chemical screening tests, determining specific gravity, observing any unusual color or odor, screening for bacteriuria, and examining the sediment microscopically. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urology: A surgical specialty concerned with the study, diagnosis, and treatment of diseases of the urinary tract in both sexes and the genital tract in the male. It includes the specialty of andrology which addresses both male genital diseases and male infertility. [NIH] Urothelium: The epithelial lining of the urinary tract. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Venous blood: Blood that has given up its oxygen to the tissues and carries carbon dioxide back for gas exchange. [NIH] Ventral: 1. Pertaining to the belly or to any venter. 2. Denoting a position more toward the belly surface than some other object of reference; same as anterior in human anatomy. [EU]
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Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Ventricular Dysfunction: A condition in which the ventricles of the heart exhibit a decreased functionality. [NIH] Ventricular Remodeling: The geometric and structural changes that the ventricle undergoes, usually following myocardial infarction. It comprises expansion of the infarct and dilatation of the healthy ventricle segments. While most prevalent in the left ventricle, it can also occur in the right ventricle. [NIH] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Vinblastine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. [NIH] Vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] Vitelline Membrane: The plasma membrane of the egg. [NIH] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Vocal cord: The vocal folds of the larynx. [NIH]
Dictionary 375
Vulgaris: An affection of the skin, especially of the face, the back and the chest, due to chronic inflammation of the sebaceous glands and the hair follicles. [NIH] War: Hostile conflict between organized groups of people. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]
Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Wounds, Gunshot: Disruption of structural continuity of the body as a result of the discharge of firearms. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Yolk Sac: An embryonic membrane formed from endoderm and mesoderm. In reptiles and birds it incorporates the yolk into the digestive tract for nourishing the embryo. In placental mammals its nutritional function is vestigial; however, it is the source of most of the intestinal mucosa and the site of formation of the germ cells. It is sometimes called the vitelline sac, which should not be confused with the vitelline membrane of the egg. [NIH] Zygote: The fertilized ovum. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]
377
INDEX 1 1-phosphate, 232, 295 A Abdomen, 295, 306, 321, 335, 338, 350, 352, 365, 366, 374 Abdominal, 174, 295, 296, 350, 352 Aberrant, 59, 230, 295 Ablation, 56, 184, 295 Accelerated phase, 161, 295 Acceptor, 295, 338, 350, 370 Accommodation, 295, 345 Acetylcholine, 295, 310, 347 Acinus, 237, 295 Actin, 15, 35, 295 Acute leukemia, 148, 159, 295, 356, 369 Acute lymphoblastic leukemia, 150, 159, 295 Acute lymphocytic leukemia, 295 Acute myelogenous leukemia, 111, 112, 295 Acute myeloid leukemia, 46, 143, 145, 152, 153, 159, 295 Acute nonlymphocytic leukemia, 295 Acyl, 296, 322 Adaptability, 296, 308, 309 Adaptation, 296, 354 Adenine, 296, 358 Adenosine, 70, 190, 296, 332, 353 Adenosine Deaminase, 190, 296 Adenovirus, 92, 296 Adhesions, 174, 296 Adipocytes, 36, 48, 49, 167, 168, 223, 296, 313 Adipose Tissue, 17, 296 Adrenergic, 296, 317, 321, 367 Adverse Effect, 296, 363 Affinity, 296, 297, 301, 346 Agammaglobulinemia, 31, 296 Agar, 193, 296, 297, 312, 314, 332 Agarose, 188, 297, 332, 333 Agonist, 214, 219, 297, 317 Air Sacs, 295, 297 Airway, 56, 295, 297 Albumin, 197, 297, 354 Aldehyde Dehydrogenase, 225, 297 Alginates, 86, 297 Algorithms, 297, 304 Alkaline, 297, 298, 307, 350, 368
Alleles, 23, 66, 297 Allograft, 21, 35, 297 Alopecia, 297, 315 Alpha Cell, 205, 297 Alpha Particles, 297, 358 Alternative medicine, 261, 297 Alveoli, 295, 297 Ameliorated, 26, 297 Amifostine, 158, 298 Amino Acid Sequence, 169, 198, 298, 299, 326 Amino Acids, 196, 203, 298, 326, 346, 348, 351, 352, 355, 357, 361, 363, 371 Amino-terminal, 46, 298 Ammonia, 296, 298 Amplification, 9, 19, 26, 54, 186, 298 Ampulla, 298, 319 Anaesthesia, 298, 334 Anal, 298, 324 Analog, 182, 298 Analogous, 31, 215, 222, 230, 298, 371 Anaphylatoxins, 298, 312 Anaplastic, 144, 298 Anaplastic large cell lymphoma, 144, 298 Anatomical, 20, 298, 302, 333, 351, 362 Anemia, 68, 141, 162, 202, 218, 221, 242, 247, 277, 298, 325, 329, 343, 349, 369 Anemia, Aplastic, 203, 218, 298 Anemia, Sickle Cell, 242, 298 Anesthesia, 297, 298 Aneurysm, 52, 299, 373 Angiogenesis, 112, 213, 240, 299, 319 Angiogenesis inhibitor, 240, 299, 320 Animal model, 6, 7, 11, 16, 27, 35, 40, 45, 46, 58, 61, 66, 101, 203, 204, 215, 222, 299 Anions, 297, 299, 336 Annealing, 299, 355 Anoikis, 97, 299 Anomalies, 48, 299 Antagonism, 125, 299 Anterior Cruciate Ligament, 231, 299 Antibacterial, 299, 365 Antibiotic, 21, 299, 306, 345, 351, 365, 370 Antibody therapy, 139, 141, 145, 152, 153, 299 Antibody-Dependent Cell Cytotoxicity, 299, 337 Anticoagulant, 299, 357
378
Stem Cells
Antigen-Antibody Complex, 300, 312 Antigen-presenting cell, 300, 316 Anti-inflammatory, 300, 316, 327, 351 Antimetabolite, 300, 369 Antineoplastic, 177, 300, 305, 307, 314, 341, 342, 350, 354, 369, 370 Antineoplastic Agents, 177, 300 Antioxidant, 49, 300, 301, 350 Antiproliferative, 174, 300 Antithymocyte globulin, 140, 300 Antiviral, 300, 335, 352 Aorta, 300, 374 Apheresis, 23, 98, 149, 300 Aplastic anemia, 6, 162, 242, 247, 300 Apomixis, 300, 351 Aponeurosis, 300, 325 Applicability, 15, 55, 188, 300 Approximate, 185, 301 Aqueous, 301, 303, 315, 319, 337 Arginine, 298, 301, 347 Arrhythmia, 241, 301 Arterial, 301, 306, 332, 357, 368 Arteries, 300, 301, 305, 314, 341, 344, 372 Arterioles, 237, 301, 305, 307 Arteriolosclerosis, 301 Arteriosclerosis, 104, 301 Articular, 188, 301, 349 Ascites, 175, 301 Ascorbic Acid, 197, 301, 332 Aseptic, 301, 349, 366 Aspirate, 216, 301 Assay, 11, 27, 29, 38, 39, 53, 99, 135, 225, 250, 301, 332 Astrocytes, 12, 35, 72, 78, 86, 116, 178, 207, 301, 327, 335, 346 Ataxia, 276, 277, 301, 368 Atrial, 168, 301 Atrium, 168, 301, 302, 368, 374 Atrophy, 276, 277, 302, 346 Attenuated, 302, 317 Atypical, 44, 142, 147, 152, 302 Autoimmune disease, 196, 211, 219, 256, 302, 343 Autoimmunity, 212, 302 Autologous bone marrow transplantation, 51, 153, 194, 302, 329 Autologous lymphocytes, 173, 302 Autonomic, 295, 298, 302, 314, 345, 347, 352, 367 Autonomic Nervous System, 302, 345, 352, 367
Axons, 203, 207, 302, 316, 335, 344, 348, 349, 352, 358 Axotomy, 207, 302 B Bacteriophage, 302, 371 Bacterium, 45, 302, 330 Bacteriuria, 302, 373 Barbiturate, 302, 369 Basal cells, 7, 14, 59, 303 Basal Ganglia, 301, 303, 306, 325, 358 Basal Ganglia Diseases, 301, 303 Base, 182, 296, 303, 307, 315, 316, 326, 336, 358, 368 Basement Membrane, 48, 303, 323, 337 Basophils, 94, 303, 328, 338 Benign, 59, 174, 191, 225, 301, 303, 324, 325, 327, 337, 345, 359 Beta-Galactosidase, 18, 303 Bile, 29, 237, 303, 325, 331, 338, 366, 368 Bile Acids, 303, 366, 368 Bile Acids and Salts, 303 Bile Canaliculi, 237, 303 Bile Ducts, 29, 237, 303 Biliary, 88, 107, 236, 303, 312 Bilirubin, 297, 303 Bioartificial Organs, 235, 236, 237, 303 Bioassay, 46, 303, 304 Biochemical, 29, 45, 78, 80, 85, 86, 104, 116, 229, 297, 300, 304, 324, 349, 363 Bioengineering, 246, 272, 304 Biological Assay, 29, 304 Biological response modifier, 304, 335 Biological Sciences, 86, 125, 195, 204, 304 Biological therapy, 143, 304, 328 Biophysics, 116, 304 Biopsy, 176, 220, 304, 352 Bioreactors, 112, 304 Biosynthesis, 177, 304, 363 Biotechnology, 39, 61, 69, 85, 86, 125, 203, 261, 273, 275, 276, 277, 278, 304 Biotin, 197, 304 Bladder, 4, 44, 304, 315, 343, 346, 357, 360, 373 Blast phase, 295, 304, 310 Blastocyst, 53, 108, 257, 305, 313, 350, 353, 372 Blastomeres, 305, 343 Blasts, 106, 305 Bleomycin, 10, 305 Blister, 58, 305 Blood Cell Count, 149, 305, 329 Blood Coagulation, 305, 307, 369
Index 379
Blood Platelets, 305, 340, 354, 363, 369 Blood pressure, 305, 307, 332, 343 Blot, 185, 305 Body Fluids, 305, 306, 318, 372 Bone Density, 245, 305 Bone Marrow Cells, 18, 19, 25, 28, 52, 60, 177, 190, 225, 305, 312, 328, 340, 344 Bone metastases, 146, 305 Bone Morphogenetic Proteins, 169, 192, 305 Bone Regeneration, 83, 246, 306 Bone Resorption, 191, 306 Bowel, 298, 306, 317, 335, 337 Bowel Movement, 306, 317 Brachytherapy, 306, 335, 336, 358, 375 Bradykinin, 306, 347, 354 Brain Hypoxia, 306, 368 Brain Infarction, 306 Brain Injuries, 207, 306 Brain Ischemia, 206, 306 Brain metastases, 146, 306 Brain Stem, 247, 306, 309 Branch, 291, 306, 315, 319, 339, 351, 364, 369 Breakdown, 306, 316, 326, 348 Breeding, 27, 215, 306 Broad-spectrum, 306, 370 Buccal, 306, 339 Burns, 109, 167, 175, 197, 306 Burns, Electric, 306 Butyric Acid, 202, 306 Bypass, 226, 306 C Calcification, 17, 301, 307 Calcium, 20, 70, 182, 188, 195, 307, 312, 318, 342, 351, 357, 363, 368 Callus, 306, 307, 319 Canonical, 35, 222, 307 Capillary, 240, 306, 307, 374 Capsules, 307, 324, 326 Carbohydrate, 58, 61, 307, 327, 355 Carbon Dioxide, 307, 324, 353, 360, 373 Carboplatin, 129, 155, 307 Carcinogen, 307, 341, 344, 369 Carcinogenesis, 104, 223, 307 Carcinogenic, 307, 334, 348, 356, 366, 372 Carcinoma, 59, 86, 135, 150, 174, 210, 250, 307 Cardiac, 25, 27, 30, 36, 40, 45, 70, 95, 123, 169, 180, 208, 241, 307, 321, 344, 350, 366 Cardiogenic, 75, 209, 307 Cardiomyoplasty, 76, 307
Cardiovascular, 27, 30, 75, 76, 79, 89, 92, 104, 129, 130, 180, 307, 363 Cardiovascular disease, 27, 129, 130, 307 Cardiovascular System, 30, 79, 307 Carotene, 308, 361 Carrier Proteins, 308, 354 Caspase, 43, 308 Cataracts, 5, 308 Catecholamine, 308, 317 Caudal, 308, 316, 332, 355 Causal, 308, 330 Cause of Death, 221, 308 Cell Adhesion, 213, 308, 335 Cell Communication, 13, 308 Cell Count, 149, 239, 308 Cell Cycle, 7, 10, 43, 44, 54, 69, 179, 212, 308, 314, 322, 357 Cell Death, 3, 174, 177, 183, 191, 200, 207, 230, 240, 300, 308, 322, 345 Cell Fusion, 80, 206, 227, 308 Cell Lineage, 21, 30, 43, 44, 57, 172, 176, 184, 189, 203, 214, 222, 223, 232, 233, 247, 308 Cell membrane, 219, 308, 316, 319, 325, 344, 353 Cell Movement, 186, 308, 326 Cell proliferation, 18, 23, 36, 43, 49, 53, 62, 174, 186, 200, 203, 234, 301, 308, 363 Cell Respiration, 309, 360 Cell Size, 309, 324 Cell Survival, 22, 23, 34, 44, 62, 207, 309, 328 Cellulose, 309, 341, 354 Ceramide, 43, 309 Cerebellar, 9, 301, 309, 359 Cerebellum, 9, 306, 309, 359 Cerebral, 9, 58, 186, 301, 303, 306, 309, 321, 322, 324, 337, 358, 368, 369 Cerebral hemispheres, 303, 306, 309, 337, 368 Cerebrospinal, 9, 309, 310 Cerebrospinal fluid, 9, 309, 310 Cerebrovascular, 195, 303, 307, 309, 368 Cerebrum, 309, 368, 372 Character, 14, 56, 227, 309, 315 Chemokines, 20, 204, 309 Chemotactic Factors, 309, 312 Chemotaxis, 12, 105, 309 Chimeras, 213, 310 Cholesterol, 303, 310, 314, 366 Cholinergic, 66, 107, 310 Chondrogenesis, 192, 310
380
Stem Cells
Chondroitin sulfate, 186, 310 Chorion, 235, 310 Choroid, 310, 337, 360 Choroid Plexus, 310, 337 Chromatin, 136, 229, 300, 310, 347, 365 Chromosomal, 182, 298, 310, 343, 354, 361, 362, 368 Chromosome, 19, 46, 101, 142, 150, 161, 191, 204, 310, 330, 336, 338, 362, 368 Chronic Disease, 206, 310, 338 Chronic granulocytic leukemia, 310 Chronic leukemia, 148, 310 Chronic lymphocytic leukemia, 139, 151, 158, 159, 310 Chronic myelogenous leukemia, 142, 143, 150, 161, 295, 304, 310 Chronic phase, 105, 142, 161, 295, 310 Chronic phase chronic myelogenous leukemia, 142, 161, 310 Chronic renal, 310, 355 Cicatrix, 310, 336 Cilium, 12, 310 CIS, 34, 64, 281, 311, 361 Citrus, 301, 311 C-kit receptor, 311, 365 Clinical Medicine, 88, 96, 311, 356 Clinical trial, 5, 7, 51, 139, 156, 163, 174, 222, 273, 311, 315, 351, 357, 359 Clone, 17, 20, 185, 189, 257, 311 Coagulation, 305, 311, 330, 354, 369 Coculture, 77, 80, 311 Coenzyme, 301, 311 Cofactor, 311, 357, 369 Colchicine, 311, 372 Collagen, 18, 59, 188, 241, 303, 311, 324, 326, 336, 354, 356 Colloidal, 297, 311 Colony-Stimulating Factors, 311, 328 Combination chemotherapy, 140, 141, 143, 144, 145, 146, 158, 159, 161, 162, 312 Common Bile Duct, 312, 350 Complement, 34, 298, 299, 312, 326, 335, 336, 340, 354 Complementary and alternative medicine, 121, 133, 312 Complementary medicine, 121, 312 Complete remission, 153, 312, 360 Complete response, 312 Computational Biology, 273, 275, 312 Conception, 220, 313, 323, 364, 366 Concomitant, 34, 313 Conduction, 168, 241, 313, 344
Cone, 313, 353 Congestive heart failure, 52, 313 Conjunctiva, 197, 313 Connective Tissue Cells, 167, 313 Connexins, 313, 325 Consciousness, 313, 316 Consolidation, 188, 313 Constriction, 313, 336, 362 Consumption, 85, 313, 350 Contamination, 23, 313 Continuum, 10, 313 Contraception, 219, 313 Contractility, 241, 313 Contraindications, ii, 313 Contralateral, 117, 313, 359 Convulsion, 304, 313 Coordination, 309, 313, 343 Cornea, 15, 103, 175, 178, 197, 313, 327, 362, 366 Corneal Diseases, 84, 313 Corneum, 313, 321 Coronary, 15, 307, 313, 314, 341, 344 Coronary heart disease, 307, 314 Coronary Thrombosis, 314, 341, 344 Corpus, 314, 327, 345, 351, 356, 363, 369 Cortex, 9, 58, 186, 301, 314, 320, 322, 324, 356, 358, 359 Cortical, 58, 93, 314, 322, 346, 358, 362, 368 Cortisol, 297, 314 Cortisone, 314, 316 Cranial, 90, 207, 309, 314, 345, 346, 349, 352 Cranial Nerves, 314, 345 Craniotomy, 90, 314 Criterion, 16, 121, 314 Crossing-over, 314, 359 Cryofixation, 314 Cryopreservation, 4, 314 Cues, 13, 16, 37, 65, 178, 179, 314 Culture Media, 172, 193, 296, 314 Curative, 26, 314, 369 Cutaneous, 97, 159, 167, 236, 314, 336, 339 Cyclic, 77, 195, 308, 314, 329, 347 Cyclin, 116, 314 Cyclophosphamide, 63, 78, 100, 123, 146, 149, 150, 225, 314 Cyclosporine, 143, 148, 151, 153, 154, 156, 159, 315 Cyst, 301, 315 Cysteine, 204, 309, 315 Cystine, 315 Cystitis, 44, 315
Index 381
Cytidine, 216, 315 Cytogenetics, 315, 362 Cytokine, 10, 21, 42, 136, 183, 221, 222, 315, 324, 369 Cytoplasm, 300, 303, 308, 315, 320, 322, 328, 361, 367 Cytosine, 315 Cytoskeleton, 315, 335, 342 Cytotoxic, 19, 36, 100, 194, 211, 222, 284, 315, 358, 359, 363 Cytotoxicity, 112, 222, 315 D Databases, Bibliographic, 273, 315 De novo, 141, 315 Decidua, 315, 353 Defense Mechanisms, 315, 335 Degenerative, 37, 49, 50, 53, 102, 128, 207, 315, 327, 330, 339, 343, 349 Deletion, 300, 315 Dementia, 206, 207, 315, 316 Demyelinating Diseases, 316, 344 Denaturation, 207, 316, 355 Dendrites, 207, 236, 316, 346, 358 Dendritic, 66, 79, 97, 176, 196, 222, 235, 236, 316, 341 Dendritic cell, 66, 79, 97, 176, 196, 222, 235, 236, 316 Density, 47, 305, 316, 324, 348, 364 Dental Hygienists, 4, 316 Dental implant, 245, 316, 349 Dentate Gyrus, 11, 19, 316, 330 Depolarization, 316, 363 Dermal, 32, 167, 316 Detoxification, 104, 316 Dexamethasone, 197, 316 Diabetes Mellitus, 17, 40, 218, 316, 327, 329 Diagnostic procedure, 165, 261, 316 Diastolic, 316, 332 Diencephalon, 316, 332, 356, 368, 369 Diffuse Axonal Injury, 306, 316 Diffusion, 316, 317, 332 Digestion, 185, 205, 303, 306, 316, 335, 338, 366 Digestive system, 163, 316, 343 Digestive tract, 317, 364, 375 Dihydrotestosterone, 317, 359 Dilatation, 299, 317, 356, 373, 374 Dilation, 52, 306, 317, 373 Dilution, 38, 317 Dimerization, 60, 317 Dimethyl, 102, 317
Diphtheria, 112, 317 Diphtheria Toxin, 112, 317 Diploid, 228, 229, 317, 354 Direct, iii, 4, 7, 13, 27, 33, 36, 39, 48, 50, 63, 80, 81, 83, 93, 125, 178, 180, 182, 183, 227, 238, 240, 265, 308, 311, 317, 339, 359, 367 Discrimination, 112, 317 Disease-Free Survival, 153, 317 Distal, 59, 168, 317, 357 Dopamine, 113, 244, 317, 353 Dorsal, 317, 346, 355, 365 Dorsum, 317, 325 Drive, ii, vi, 12, 36, 115, 245, 317 Drug Interactions, 266, 317 Drug Resistance, 137, 182, 225, 318 Drug Tolerance, 318, 370 Duct, 40, 174, 237, 298, 312, 318, 322, 361 Duodenum, 303, 318, 319, 336, 350, 366 Dura mater, 220, 318 Dyes, 303, 318, 325 Dyskinesia, 318 Dysplasia, 277, 318 Dyspnea, 318, 358 Dystrophic, 318, 321 Dystrophy, 260, 276, 318 E Ectoderm, 5, 170, 235, 318, 346 Ectopic, 8, 14, 20, 43, 62, 174, 318 Effector, 4, 54, 192, 199, 295, 299, 312, 318, 337, 347 Effector cell, 4, 199, 299, 318, 337, 347 Efficacy, 51, 58, 174, 223, 318, 372 Elasticity, 301, 318 Elastin, 311, 318 Electrocardiogram, 149, 318 Electrolytes, 303, 318 Electrons, 300, 303, 318, 336, 350, 358, 359 Electrophysiological, 20, 82, 181, 319 Electroporation, 88, 182, 195, 319 Embolus, 319, 334 Embryogenesis, 46, 57, 228, 229, 319, 365 Emulsion, 319, 324 Encapsulated, 86, 203, 319, 338 Endemic, 319, 365 Endocrine System, 319, 346 Endocrinology, 41, 125, 175, 205, 319 Endoderm, 33, 41, 80, 170, 208, 319, 375 Endometrial, 319, 350 Endometriosis, 174, 319 Endometrium, 315, 319, 372 Endoscope, 319
382
Stem Cells
Endoscopic, 188, 319 Endostatin, 240, 319 Endothelial cell, 49, 52, 98, 167, 183, 213, 218, 240, 320, 323, 369 Endothelium, 37, 68, 240, 320, 347 Endothelium, Lymphatic, 320 Endothelium, Vascular, 320 Endothelium-derived, 320, 347 Endotoxins, 312, 320 End-stage renal, 310, 320, 355 Enhancer, 5, 15, 46, 218, 320 Enteric Nervous System, 99, 320 Entorhinal Cortex, 320, 330 Environmental Exposure, 320, 348 Environmental Health, 272, 274, 320 Enzymatic, 307, 308, 312, 320, 322, 355, 361 Enzyme Inhibitors, 320, 354 Enzyme-Linked Immunosorbent Assay, 166, 320 Eosinophil, 194, 320, 328 Eosinophilic, 320 Ependymal, 7, 321 Epidemic, 321, 365 Epidemiological, 246, 321 Epidermal, 7, 45, 58, 63, 110, 179, 321, 337, 341 Epidermal Growth Factor, 179, 321 Epidermis, 7, 13, 32, 45, 108, 169, 171, 303, 305, 313, 321, 331, 336, 337, 356 Epidermolysis Bullosa, 58, 321 Epidermolysis Bullosa Simplex, 58, 321 Epigastric, 321, 350 Epinephrine, 296, 317, 321, 347, 372 Epithelial Cells, 28, 29, 51, 175, 321, 335, 337 Epithelium, 16, 28, 44, 51, 80, 175, 197, 200, 225, 303, 320, 321, 336, 350 Epitope, 61, 321 Erectile, 321, 351 Erythrocyte Indices, 305, 321 Erythrocytes, 189, 193, 224, 234, 298, 305, 321, 330, 350, 359 Erythroid Progenitor Cells, 321, 344 Erythropoietin, 194, 202, 239, 322 Esophageal, 102, 322 Esophagus, 317, 322, 365, 366 Essential Tremor, 276, 322 Esterification, 167, 322 Estrogens, 125, 322, 328 Ethanol, 322, 323 Etoposide, 78, 123, 322 Eukaryotic Cells, 195, 322, 333, 348
Evoke, 322, 366 Excitation, 322, 324 Excitatory, 207, 322, 327 Exhaustion, 43, 299, 322 Exocrine, 29, 205, 322, 350 Exogenous, 183, 322, 326 Exons, 185, 322 Expiration, 322, 323, 360 Expiratory, 323, 353 Extensive-stage small cell lung cancer, 142, 323 External-beam radiation, 323, 336, 358, 375 Extracellular Matrix, 14, 33, 45, 167, 170, 186, 238, 299, 313, 323, 324, 335, 349 Extracellular Space, 323 Extrapyramidal, 317, 323 Eye Infections, 296, 323 F Family Planning, 273, 323 Fat, 9, 48, 74, 223, 296, 303, 305, 306, 308, 309, 314, 319, 323, 338, 343, 361, 364 Fatigue, 323, 329 Fatty acids, 297, 323 Febrile, 195, 258, 323 Femoral, 8, 98, 323 Femur, 299, 323 Fermentation, 238, 323 Fetal Blood, 187, 323 Fetus, 26, 322, 323, 353, 356, 372, 373 Fibrin, 52, 188, 197, 241, 305, 323, 369 Fibrinogen, 323, 354, 369 Fibroblast Growth Factor, 19, 62, 94, 179, 192, 194, 323 Fibroblasts, 167, 172, 174, 229, 241, 313, 324, 335 Fibroid, 180, 324, 337 Fibronectin, 45, 190, 324 Fibrosis, 277, 324, 358, 362 Filgrastim, 118, 148, 149, 159, 160, 161, 324 Filler, 243, 324 Fissure, 316, 324 Fixation, 188, 223, 314, 324 Flexor, 231, 324 Flow Cytometry, 6, 12, 14, 26, 28, 30, 45, 324 Fludarabine, 140, 149, 150, 151, 156, 158, 159, 324 Fluorescence, 221, 324, 325 Fluorescent Dyes, 324, 325 Foam Cells, 33, 325 Folate, 177, 325
Index 383
Fold, 183, 221, 324, 325 Folic Acid, 325 Follicles, 13, 32, 325 Follicular large cell lymphoma, 160, 325 Foramen, 325, 337, 352 Fossa, 309, 325 Fovea, 324, 325 Fungi, 196, 224, 323, 325, 341, 342, 375 G Galactosides, 303, 325 Galanin, 87, 325 Gallbladder, 295, 303, 317, 325, 350 Gamma Rays, 325, 358, 359 Ganglia, 225, 295, 298, 303, 320, 325, 345, 352, 367 Ganglion, 168, 325, 346, 349 Gap Junctions, 13, 313, 325, 367 Gas, 298, 307, 316, 326, 331, 344, 347, 373 Gastric, 87, 321, 326, 331 Gastrin, 326, 331 Gastrointestinal, 32, 306, 321, 322, 324, 326, 337, 363, 364, 366, 369, 372 Gastrointestinal tract, 32, 322, 324, 326, 337, 363, 364, 372 Gastrula, 209, 228, 326 Gelatin, 314, 326, 327, 369 Gels, 59, 188, 326 Gemtuzumab ozogamicin, 145, 326 Gene Conversion, 184, 185, 326 Gene Expression, 11, 12, 15, 16, 18, 19, 24, 27, 33, 40, 42, 45, 49, 62, 64, 99, 117, 118, 130, 136, 170, 177, 189, 195, 215, 216, 277, 326 Gene Silencing, 67, 326 Gene Targeting, 102, 128, 129, 182, 185, 326 Genetic Code, 326, 348 Genetic Engineering, 304, 311, 326 Genetic testing, 326, 355 Genetics, 13, 29, 129, 169, 185, 246, 248, 250, 296, 315, 326, 342 Genital, 326, 373 Genomics, 19, 87, 327 Genotype, 6, 90, 185, 327, 353 Germ cell tumors, 88, 327 Germ Cells, 54, 186, 238, 327, 340, 348, 349, 364, 365, 368, 375 Germ Layers, 170, 225, 318, 319, 326, 327 Gestation, 57, 171, 327, 352, 353 Gestational, 43, 327 Gland, 95, 229, 314, 327, 339, 350, 351, 353, 357, 362, 366, 370
Glial Fibrillary Acidic Protein, 12, 327 Gliosis, 35, 327 Globus Pallidus, 303, 327, 358 Glucocorticoid, 316, 327 Glucose, 85, 89, 205, 276, 297, 301, 309, 316, 327, 329, 334, 362 Glucose Intolerance, 316, 327 Glutamate, 207, 327 Glutathione Peroxidase, 327, 362 Glycerol, 306, 327, 353 Glycine, 303, 327, 363 Glycoprotein, 71, 202, 322, 323, 324, 327, 328, 337, 367, 369, 372 Glycosaminoglycan, 310, 327 Goats, 258, 327 Gonad, 328 Gonadal, 216, 328, 366 Gonadotropin, 219, 328 Governing Board, 328, 355 Gp120, 328, 352 Grade, 140, 141, 142, 145, 158, 160, 328 Graft Rejection, 23, 328, 333 Grafting, 7, 18, 328, 333 Graft-versus-host disease, 23, 91, 99, 140, 151, 300, 328, 344 Gram-negative, 328, 370 Granule, 9, 316, 328, 361 Granulocyte Colony-Stimulating Factor, 63, 85, 87, 94, 106, 221, 239, 312, 324, 328 Granulocyte-Macrophage ColonyStimulating Factor, 112, 312, 328 Granulocytes, 189, 312, 328, 338, 344, 363, 375 Growth factors, 11, 17, 42, 44, 49, 50, 58, 90, 105, 167, 178, 192, 193, 194, 207, 236, 238, 328, 346 Guanylate Cyclase, 329, 347 H Habitat, 329, 347 Habitual, 309, 329 Haemopoietic, 99, 329 Hair follicles, 13, 329, 375 Half-Life, 206, 329 Heart attack, 258, 259, 307, 329 Heart failure, 52, 76, 180, 258, 329, 358 Heartbeat, 168, 329, 366 Hematocrit, 305, 321, 329 Hematologic malignancies, 148, 156, 329 Hematopoietic growth factors, 49, 194, 329 Hematopoietic Stem Cell Mobilization, 63, 106, 148, 329
384
Stem Cells
Hematopoietic Stem Cell Transplantation, 4, 84, 128, 156, 246, 247, 249, 284, 329 Hematopoietic tissue, 19, 20, 51, 200, 201, 305, 329 Hemiparesis, 306, 329 Hemoglobin, 298, 305, 321, 329, 330, 369 Hemoglobinuria, 276, 330 Hemolysis, 224, 330 Hemolytic, 298, 330, 369 Hemorrhage, 330, 366 Hemostasis, 330, 335, 363 Hepatic, 25, 29, 60, 65, 107, 111, 205, 235, 236, 250, 297, 312, 330 Hepatitis, 224, 330 Hepatocyte, 25, 88, 205, 236, 330 Hereditary, 330, 343, 346, 361, 369 Heredity, 326, 330 Heterochromatin, 64, 330 Heterodimer, 192, 305, 330 Heterogeneity, 11, 66, 230, 296, 330 Heterogenic, 330 Heterogenous, 218, 330 Heterotrophic, 325, 330 Hippocampus, 19, 316, 330, 358, 366 Histology, 330, 351 Homeobox, 39, 55, 330 Homeostasis, 3, 7, 28, 32, 33, 56, 210, 223, 230, 254, 330 Homodimer, 192, 330, 371 Homogeneous, 206, 234, 301, 313, 330 Homologous, 167, 182, 184, 185, 212, 297, 313, 314, 326, 330, 362, 367 Hormonal, 59, 302, 304, 331 Hormone, 5, 32, 65, 117, 205, 217, 219, 238, 297, 304, 314, 321, 322, 326, 331, 334, 354, 356, 361, 363, 364, 368, 370, 371 Horny layer, 321, 331 Horseradish Peroxidase, 320, 331 Human Development, 217, 272, 331 Human growth hormone, 217, 331, 364 Humoral, 31, 42, 328, 331, 369, 371 Humour, 331 Hybrid, 31, 34, 65, 184, 311, 331 Hybridization, 29, 47, 185, 308, 331, 342, 366 Hybridomas, 319, 331, 335 Hydrochloric Acid, 243, 331 Hydrogen, 295, 303, 307, 316, 327, 331, 338, 343, 347, 348, 350, 352, 357 Hydrolases, 331, 339 Hydrolysis, 296, 303, 331, 352, 353, 355, 357
Hydroxylysine, 311, 331 Hydroxyproline, 311, 331 Hyperplasia, 56, 332 Hypersensitivity, 34, 320, 332, 361 Hypertension, 15, 301, 307, 332 Hypertrophy, 52, 59, 95, 332 Hypnotic, 302, 332, 369 Hypopigmentation, 50, 332 Hypothalamus, 302, 316, 332, 353, 364, 369 Hypoxanthine, 182, 332 I Id, 119, 131, 280, 283, 284, 285, 290, 292, 332 Ileum, 332, 336 Imidazole, 304, 332 Immortal, 117, 238, 332 Immune function, 31, 51, 332, 371 Immunity, 16, 43, 121, 173, 204, 205, 332 Immunization, 332, 333 Immunoassay, 320, 332 Immunocompromised, 225, 332 Immunodeficiency, 16, 31, 66, 69, 99, 171, 190, 195, 203, 276, 332 Immunodiffusion, 296, 332, 333 Immunoelectrophoresis, 296, 333 Immunofluorescence, 32, 333 Immunogen, 215, 333 Immunoglobulin, 31, 106, 283, 299, 322, 333, 343 Immunohistochemistry, 7, 10, 13, 32, 46, 333 Immunologic, 91, 296, 309, 332, 333, 359 Immunosuppressive, 93, 242, 314, 327, 333, 368 Immunosuppressive therapy, 333 Immunotherapy, 23, 82, 151, 222, 240, 248, 304, 333 Impairment, 43, 241, 301, 318, 323, 333, 341 Implant radiation, 333, 335, 336, 358, 375 In situ, 5, 9, 22, 32, 54, 118, 188, 213, 333 In Situ Hybridization, 32, 54, 118, 333 In vivo, 3, 6, 7, 8, 11, 15, 17, 18, 20, 21, 22, 24, 25, 28, 29, 30, 31, 32, 37, 39, 41, 42, 43, 45, 47, 49, 50, 51, 52, 53, 58, 59, 60, 62, 65, 66, 67, 69, 72, 90, 101, 106, 109, 126, 127, 166, 167, 171, 178, 179, 188, 194, 195, 201, 203, 204, 208, 209, 215, 217, 219, 227, 230, 304, 308, 333, 368 Incision, 333, 336 Incubated, 176, 333 Incubation, 19, 225, 333, 337
Index 385
Incubation period, 333, 337 Indicative, 13, 246, 333, 351, 373 Indolent, 325, 333 Infarction, 45, 180, 240, 306, 334, 360 Infection, 18, 24, 51, 67, 94, 170, 172, 173, 174, 195, 203, 211, 301, 302, 304, 309, 317, 323, 332, 334, 337, 339, 348, 351, 361, 366, 375 Infertility, 260, 334, 373 Infusion, 21, 23, 93, 94, 155, 162, 334, 371 Ingestion, 334, 350, 368 Initiation, 28, 334, 371 Initiator, 304, 334 Inlay, 334, 360 Inotropic, 317, 334 Insertional, 169, 334 Insight, 53, 334 Insulator, 334, 343, 344 Insulin, 17, 33, 39, 63, 64, 89, 192, 197, 202, 205, 260, 304, 334, 336 Insulin-dependent diabetes mellitus, 334 Insulin-like, 192, 334 Integrins, 33, 45, 334 Interferon, 142, 143, 151, 335, 339 Interferon-alpha, 335 Interleukin-2, 151, 335 Interleukin-3, 94, 166, 312, 335 Interleukin-6, 90, 335 Internal Medicine, 17, 56, 118, 319, 329, 335 Internal radiation, 335, 336, 358, 375 Interneurons, 53, 335 Interphase, 330, 335, 348 Interstitial, 44, 306, 323, 335, 336, 375 Intestinal, 17, 28, 225, 308, 335, 340, 375 Intestine, 17, 28, 303, 306, 335, 337 Intracellular, 12, 47, 334, 335, 339, 347, 359, 362, 363 Intraocular, 5, 335 Intravascular, 35, 335 Intravenous, 93, 334, 335 Intrinsic, 8, 16, 19, 22, 38, 42, 44, 57, 65, 66, 207, 296, 303, 335 Invasive, 24, 35, 63, 174, 235, 332, 336, 339 Involuntary, 303, 313, 322, 336, 344, 359 Ion Channels, 301, 336, 346, 347 Ionizing, 297, 320, 336, 359 Ions, 303, 318, 331, 336, 357 Iris, 313, 336, 358 Irradiation, 10, 29, 100, 101, 143, 150, 151, 152, 156, 158, 162, 171, 224, 251, 336, 360, 375
Irritants, 44, 336 Ischemia, 93, 302, 306, 336, 360 Islet, 33, 39, 40, 211, 218, 336 J Jejunum, 18, 336 Joint, 236, 301, 324, 336, 341, 349, 367 K Karyotype, 170, 336 Kb, 185, 272, 280, 336 Keloid, 174, 336 Keratin, 96, 336, 337 Keratinocytes, 13, 16, 32, 45, 63, 97, 108, 337 Kidney Disease, 163, 272, 277, 337 Kidney Pelvis, 337, 373 Killer Cells, 43, 176, 337 Kinetic, 44, 87, 336, 337 L Labile, 312, 337 Laminin, 48, 303, 337 Large Intestine, 317, 335, 337, 359, 364 Larynx, 243, 337, 371, 374 Lateral Ventricles, 11, 337, 363, 369 Laxative, 296, 337, 341 Leiomyoma, 324, 337, 364 Lens, 5, 308, 337, 374 Lentivirus, 89, 337 Lesion, 327, 338 Lethal, 29, 53, 169, 174, 192, 317, 338, 344 Leucocyte, 320, 338, 339 Leukaemia, 101, 338 Leukapheresis, 98, 160, 300, 329, 338 Leukocytes, 193, 224, 303, 305, 309, 328, 335, 338, 350, 372 Levo, 338, 341 Library Services, 290, 338 Life cycle, 325, 338 Ligament, 55, 169, 191, 299, 338, 357 Ligands, 31, 81, 166, 198, 240, 335, 338 Linkage, 19, 338 Lipid, 49, 301, 325, 327, 334, 338, 343, 344, 350 Lipid Peroxidation, 338, 350 Liposomal, 195, 338 Liver metastases, 146, 338 Lobe, 331, 338 Loc, 210, 338 Localization, 20, 188, 195, 333, 338 Localized, 64, 143, 306, 314, 317, 319, 324, 334, 337, 338, 353, 354, 362 Locomotion, 310, 338, 354 Lucida, 337, 339
386
Stem Cells
Lupus, 4, 256, 339, 367 Lymph, 238, 239, 320, 331, 339, 350, 366 Lymph node, 238, 339, 350 Lymphatic, 242, 298, 320, 325, 334, 339, 341, 364, 365, 370 Lymphatic system, 298, 325, 339, 364, 365, 370 Lymphoblastic, 150, 159, 339 Lymphoblasts, 295, 339 Lymphocyte, 16, 36, 65, 86, 162, 173, 176, 194, 222, 299, 300, 337, 339, 340 Lymphocyte Subsets, 86, 339 Lymphocytic, 16, 139, 149, 151, 158, 160, 166, 339 Lymphokine, 222, 339 Lysosomal Storage Diseases, 26, 339 Lytic, 192, 219, 339 M Macaca, 136, 339 Macrophage, 33, 66, 68, 194, 299, 312, 328, 339 Macula, 325, 339 Macula Lutea, 339 Macular Degeneration, 9, 339 Magnetic Resonance Imaging, 46, 91, 339 Maintenance therapy, 154, 340 Major Histocompatibility Complex, 211, 226, 340 Malabsorption, 276, 340 Malformation, 43, 340 Malignancy, 340, 350 Malignant, 117, 174, 193, 219, 229, 242, 276, 300, 301, 327, 340, 343, 345, 359, 368 Malignant tumor, 219, 340, 343 Malnutrition, 297, 302, 340, 344 Mammary, 95, 135, 229, 340 Mammogram, 307, 340, 342 Mandible, 246, 340, 360 Manifest, 176, 340 Medial, 208, 301, 327, 340 Mediate, 32, 42, 64, 201, 317, 337, 340 Mediator, 233, 335, 340, 363 Medicament, 217, 340 MEDLINE, 273, 275, 277, 340 Medullary, 340, 358 Megakaryocytes, 78, 194, 239, 305, 340, 369 Meiosis, 340, 367 Melanin, 332, 336, 340, 353, 372 Melanoblasts, 340, 353 Melanocytes, 332, 341 Melanoma, 108, 152, 162, 276, 341
Melphalan, 129, 140, 341 Memory, 173, 207, 315, 341 Meninges, 220, 309, 318, 341 Meniscus, 169, 341 Menopause, 341, 355 Mental Disorders, 164, 341, 357 Mercury, 324, 341 Mesoderm, 39, 170, 208, 235, 341, 372, 375 Metabolite, 317, 341, 356 Metastasis, 222, 341 Metastatic, 117, 140, 150, 154, 157, 171, 341, 362 Methionine, 317, 341 Methylcellulose, 193, 341 Methyltransferase, 66, 101, 341 MI, 73, 158, 180, 193, 293, 341 Microbe, 341, 371 Microbiology, 12, 24, 250, 252, 296, 302, 342 Microcalcifications, 307, 342 Microorganism, 311, 342, 351, 374 Micro-organism, 224, 342 Microscopy, 7, 13, 32, 60, 303, 331, 342, 348 Microtubules, 342, 350 Migration, 3, 24, 33, 35, 36, 45, 48, 110, 178, 186, 202, 208, 232, 342, 346, 353 Milliliter, 305, 342 Mineralization, 77, 342 Mitochondrial Swelling, 342, 345 Mitosis, 196, 300, 342 Mitotic, 43, 54, 180, 218, 322, 342, 343, 374 Mitoxantrone, 62, 342 Mobility, 34, 342 Mobilization, 12, 63, 91, 93, 101, 106, 217, 329, 342 Modeling, 45, 251, 342 Modification, 45, 55, 202, 212, 215, 326, 342, 358 Modulator, 196, 342 Molecular Probes, 319, 342 Monitor, 343, 347 Monoclonal antibodies, 29, 54, 139, 141, 145, 146, 152, 153, 160, 171, 173, 206, 326, 343, 361 Monocyte, 166, 299, 343 Mononuclear, 94, 221, 343, 372 Morphogenesis, 33, 343 Morphological, 65, 207, 234, 319, 341, 343 Morphology, 28, 162, 189, 329, 343 Morula, 238, 305, 343 Mosaicism, 68, 343 Motility, 25, 343, 363
Index 387
Motor Neurons, 116, 207, 227, 343 Movement Disorders, 343, 368 Mucinous, 325, 343 Mucosa, 339, 343, 366, 375 Mucositis, 343, 369 Multiple Myeloma, 85, 117, 152, 154, 155, 156, 157, 161, 162, 284, 343 Multiple sclerosis, 242, 343 Muscle Fibers, 48, 343, 344 Muscular Atrophy, 276, 344 Muscular Dystrophies, 318, 344 Mustard Gas, 336, 344 Mutagenesis, 34, 185, 223, 344 Mutagens, 344 Mycophenolate mofetil, 143, 154, 156, 159, 344 Mydriatic, 317, 344 Myelin, 53, 110, 203, 234, 235, 316, 343, 344, 346, 348 Myelin Sheath, 234, 235, 344, 348 Myelodysplasia, 195, 344 Myelodysplastic syndrome, 141, 148, 153, 154, 231, 344, 364 Myelogenous, 131, 142, 150, 153, 161, 344 Myeloid Cells, 21, 33, 201, 344 Myeloid Progenitor Cells, 211, 344 Myeloma, 123, 152, 154, 155, 157, 161, 189, 280, 344 Myeloproliferative Disorders, 132, 148, 156, 231, 344 Myocardial infarction, 46, 52, 122, 180, 314, 341, 344, 374 Myocarditis, 317, 344 Myocardium, 46, 52, 70, 74, 76, 121, 136, 180, 241, 341, 344 Myopathy, 168, 344 Myopia, 98, 345, 360 Myotonic Dystrophy, 276, 345 N Naive, 173, 345 Natural killer cells, 43, 100, 196, 345 Nearsightedness, 345 Nebramycin, 345, 370 Necrosis, 207, 300, 306, 334, 341, 344, 345, 360 Neonatal, 7, 9, 16, 25, 179, 181, 187, 345 Neoplasia, 56, 276, 345 Neoplasm, 147, 152, 154, 156, 161, 171, 345, 372 Neoplastic, 34, 56, 191, 197, 331, 339, 345, 348, 367 Neostriatum, 345, 358
Nephropathy, 337, 345 Nerve, 57, 66, 168, 169, 178, 206, 217, 220, 235, 296, 298, 301, 302, 316, 320, 325, 340, 343, 345, 346, 347, 348, 349, 355, 362, 365, 366, 371 Nerve Growth Factor, 66, 207, 345, 347 Nervous System, 9, 22, 57, 63, 82, 100, 102, 128, 178, 179, 203, 207, 227, 232, 234, 254, 276, 295, 302, 309, 325, 340, 343, 344, 345, 346, 347, 348, 349, 352, 363, 367 Nervous System Diseases, 207, 345 Networks, 45, 207, 227, 345 Neural Crest, 50, 55, 57, 64, 65, 88, 110, 340, 346, 353 Neurites, 186, 206, 346 Neurobehavioral Manifestations, 306, 316, 346 Neuroblastoma, 117, 143, 144, 157, 346 Neurodegenerative Diseases, 106, 207, 243, 303, 346 Neuroendocrine, 56, 218, 346, 367 Neurogenic, 11, 227, 346 Neuroglia, 327, 346 Neurologic, 306, 346 Neuromuscular, 206, 295, 345, 346 Neuromuscular Junction, 206, 295, 345, 346 Neuronal, 3, 7, 9, 43, 70, 92, 102, 124, 128, 179, 186, 206, 227, 235, 238, 244, 302, 346, 352 Neurons, 3, 7, 9, 11, 19, 35, 38, 57, 64, 66, 69, 78, 80, 88, 89, 107, 113, 116, 178, 179, 186, 203, 209, 220, 227, 232, 244, 260, 316, 322, 325, 335, 343, 345, 346, 347, 358, 367 Neuropeptide, 50, 346 Neurosurgery, 70, 113, 281, 346 Neurotoxic, 244, 346 Neurotoxicity, 207, 347 Neurotransmitters, 346, 347 Neurotrophins, 207, 347 Neutrons, 297, 336, 347, 358 Neutropenia, 21, 194, 347 Neutrophil, 194, 196, 347 Niche, 14, 59, 62, 67, 83, 105, 121, 347 Nitric Oxide, 200, 347 Nitrogen, 199, 297, 314, 324, 341, 347, 372 Norepinephrine, 296, 317, 347 Nuclear Fusion, 80, 347 Nuclear Matrix, 229, 347 Nuclear Pore, 347
388
Stem Cells
Nuclei, 82, 212, 213, 228, 297, 318, 322, 326, 340, 342, 347, 348, 349, 357 Nucleic acid, 188, 195, 198, 218, 230, 315, 326, 331, 332, 333, 344, 347, 348, 358, 366 Nucleic Acid Hybridization, 331, 348 Nucleolus, 347, 348, 361 O Ocular, 14, 103, 197, 348 Ointments, 348, 351 Oligodendroglia, 179, 344, 346, 348 Oligodendroglial, 348 Oligodendroglioma, 117, 348 Oncogene, 42, 77, 102, 116, 230, 276, 348, 365 Oncogenic, 335, 337, 348, 357 Oncolysis, 348 Oncolytic, 24, 348 Oocytes, 82, 212, 213, 258, 348 Opacity, 308, 316, 348 Open Reading Frames, 337, 348 Ophthalmology, 14, 83, 111, 282, 324, 348 Opportunistic Infections, 284, 348 Opsin, 348, 361 Optic Nerve, 349, 360, 362 Organ Culture, 18, 349, 370 Organ Transplantation, 81, 94, 124, 349 Organoids, 17, 349 Orofacial, 48, 349 Osmotic, 297, 342, 349 Osseointegration, 246, 349 Ossification, 349 Osteoarthritis, 258, 349 Osteoblasts, 167, 168, 191, 192, 194, 349 Osteoclasts, 191, 192, 194, 239, 349 Osteogenesis, 92, 310, 349 Osteopetrosis, 218, 349 Osteoporosis, 17, 245, 349 Ovary, 174, 328, 349, 366 Overexpress, 46, 349 Ovulation, 349 Ovum, 186, 305, 315, 327, 338, 343, 349, 350, 356, 372, 375 Ovum Implantation, 350, 372 Oxidation, 295, 300, 315, 327, 338, 350 Oxidative Stress, 48, 66, 85, 350 Oxides, 76, 350 Oxygen Consumption, 350, 360 P Pacemaker, 168, 350 Paclitaxel, 129, 155, 350 Palate, 48, 350 Palliative, 350, 369
Pancreas, 29, 40, 96, 169, 178, 205, 218, 295, 297, 304, 317, 334, 336, 350, 364, 370, 372 Pancreatectomy, 40, 350 Pancreatic, 29, 33, 39, 40, 65, 88, 107, 109, 205, 218, 235, 276, 350 Pancreatic cancer, 276, 350 Pancreatic Ducts, 29, 350 Pancreatic Juice, 350 Pancreatic Polypeptide, 205, 350 Pancytopenia, 21, 162, 350 Papillomavirus, 68, 350 Paraffin, 176, 351 Parathyroid, 202, 351, 368 Parathyroid Glands, 351 Parathyroid hormone, 202, 351 Parenchyma, 29, 351 Paroxysmal, 79, 276, 351 Parthenogenesis, 228, 351 Partial remission, 351, 360 Particle, 351, 364, 371 Patch, 52, 58, 351 Pathogen, 333, 351 Pathogenesis, 26, 46, 351 Pathologic, 27, 49, 298, 300, 304, 314, 332, 351, 360, 373 Pathologic Processes, 300, 351 Pathologies, 35, 351 Patient Selection, 4, 351 Pelvic, 319, 351, 357 Penicillin, 299, 351 Penis, 4, 351, 353 Peptide, 135, 174, 195, 196, 211, 219, 236, 323, 331, 337, 351, 352, 354, 355, 357 Peptide Fragments, 211, 352 Peptide T, 236, 352 Percutaneous, 27, 352 Perfusion, 304, 352 Pericardium, 352, 367 Perinatal, 24, 352 Periodontal Ligament, 55, 352 Peripheral Nerves, 57, 206, 345, 352, 365 Peripheral Nervous System, 57, 207, 316, 344, 345, 346, 352, 364, 366 Peripheral stem cells, 144, 146, 148, 154, 159, 160, 177, 328, 352 Peritoneal, 301, 352 Peritoneal Cavity, 301, 352 Perivascular, 105, 348, 352 Petroleum, 351, 352 PH, 82, 83, 125, 305, 352 Phallic, 324, 353
Index 389
Pharmaceutical Preparations, 173, 209, 210, 309, 322, 326, 353 Pharmacologic, 299, 329, 353, 371 Phenylalanine, 353, 372 Phonation, 243, 353 Phospholipases, 353, 363 Phospholipids, 323, 353 Phosphorus, 307, 351, 353 Photoreceptor, 9, 353 Phylogeny, 17, 353 Physiologic, 49, 176, 223, 297, 304, 329, 353, 359, 360 Physiology, 81, 100, 103, 116, 117, 125, 128, 249, 296, 302, 304, 319, 329, 353 Piebaldism, 50, 353 Pigment, 50, 303, 341, 353 Pituitary Gland, 323, 353 Placenta, 4, 222, 231, 233, 235, 323, 353, 356, 372, 373 Planarians, 54, 354 Plants, 304, 306, 307, 311, 327, 343, 347, 354, 361, 371, 372 Plasma cells, 299, 343, 344, 354 Plasma protein, 224, 297, 320, 354, 357 Plasmapheresis, 300, 354 Plasmid, 185, 354, 373 Plasticity, 7, 10, 18, 21, 25, 27, 36, 37, 47, 52, 53, 54, 57, 73, 74, 87, 102, 105, 237, 252, 354 Platelet Activation, 354, 363 Platelet Aggregation, 298, 347, 354 Platelet Transfusion, 162, 354 Platelet-Derived Growth Factor, 192, 354 Plateletpheresis, 300, 354 Platelets, 148, 189, 193, 217, 224, 239, 347, 350, 354, 369 Podophyllotoxin, 322, 354 Polycystic, 277, 354 Polymerase, 106, 355 Polymerase Chain Reaction, 106, 355 Polymers, 18, 188, 355, 357 Polymorphic, 222, 316, 355 Polypeptide, 208, 233, 298, 311, 321, 323, 331, 350, 355, 357, 364, 369, 375 Polysaccharide, 297, 300, 309, 327, 355, 357 Posterior, 208, 298, 301, 309, 310, 317, 336, 350, 355, 362 Postmenopausal, 246, 349, 355 Postnatal, 24, 57, 67, 105, 186, 283, 355, 365 Postsynaptic, 355, 363, 367 Post-traumatic, 306, 343, 355 Potentiate, 194, 355
Potentiating, 194, 304, 355 Potentiation, 355, 363 Practicability, 355, 372 Practice Guidelines, 274, 284, 355 Precipitation, 182, 195, 355 Preclinical, 61, 355 Pre-cursor, 29, 356 Preleukemia, 344, 356, 364 Prenatal, 319, 356 Presumptive, 33, 208, 356 Presynaptic, 356, 367 Prevalence, 51, 180, 244, 356 Prickle, 337, 356 Probe, 23, 185, 356 Prodrug, 192, 356 Progesterone, 356, 366 Progression, 33, 34, 299, 356 Projection, 57, 315, 335, 347, 349, 356, 358, 359 Proline, 311, 331, 356 Promoter, 15, 34, 35, 55, 68, 96, 192, 218, 243, 356 Prone, 191, 356 Prophase, 348, 356, 367 Prophylaxis, 316, 356 Proportional, 320, 356 Prosencephalon, 316, 356, 368 Prostate, 59, 117, 276, 357, 372 Prosthesis, 188, 246, 357 Protein C, 44, 169, 297, 298, 302, 336, 357 Protein Conformation, 298, 336, 357 Protein S, 277, 304, 317, 326, 331, 357, 361 Proteinuria, 343, 357 Proteoglycan, 108, 116, 357 Proteolytic, 106, 305, 312, 323, 357 Prothrombin, 357, 369 Protocol, 7, 22, 176, 244, 357 Protons, 297, 331, 336, 357, 358 Proto-Oncogene Proteins, 350, 357 Proto-Oncogene Proteins c-mos, 350, 357 Proximal, 17, 44, 59, 236, 317, 356, 357 Psychiatry, 89, 117, 324, 357 Public Policy, 255, 273, 357 Publishing, 4, 62, 245, 358 Pulmonary, 56, 195, 258, 305, 313, 321, 358, 374 Pulmonary Artery, 305, 358, 374 Pulmonary Fibrosis, 258, 358 Pupil, 313, 317, 344, 358 Purifying, 15, 358 Purines, 358, 363 Putamen, 244, 303, 345, 358
390
Stem Cells
Pyramidal Cells, 316, 358 Q Quality of Life, 244, 358 Quiescent, 20, 48, 56, 59, 60, 84, 171, 195, 229, 358 R Race, 336, 341, 342, 358 Radioactive, 152, 329, 331, 333, 335, 336, 342, 343, 347, 348, 358, 359, 372, 375 Radioimmunotherapy, 358, 359 Radiolabeled, 152, 153, 336, 358, 359, 375 Radiological, 352, 359 Radiotherapy, 117, 203, 242, 306, 336, 358, 359, 375 Randomized, 158, 159, 160, 318, 359 Reactivation, 199, 211, 359 Reactive Oxygen Species, 48, 359 Reagent, 216, 232, 331, 359 Receptor, 12, 19, 20, 42, 49, 50, 59, 62, 66, 81, 90, 102, 105, 110, 135, 166, 175, 198, 211, 219, 226, 236, 296, 300, 311, 313, 317, 328, 352, 353, 359, 363 Receptors, Serotonin, 359, 363 Recombinant, 7, 19, 20, 52, 92, 94, 107, 118, 162, 174, 185, 203, 267, 304, 326, 359, 373 Recombinant Proteins, 174, 359 Recombination, 182, 184, 185, 191, 212, 215, 326, 359 Reconstitution, 23, 24, 27, 31, 32, 44, 51, 108, 124, 166, 187, 359 Rectum, 306, 317, 326, 337, 357, 359 Recurrence, 173, 359 Red blood cells, 72, 148, 189, 217, 234, 239, 321, 330, 359, 362 Red Nucleus, 301, 359 Reductase, 177, 359 Refer, 1, 187, 222, 306, 312, 324, 325, 335, 338, 339, 345, 346, 347, 358, 359, 362 Reflex, 359, 373 Refraction, 345, 360, 365 Refractive Power, 345, 360 Refractory, 19, 23, 25, 117, 141, 151, 152, 154, 158, 160, 161, 256, 360 Regimen, 4, 93, 109, 118, 144, 195, 225, 318, 360 Relapse, 117, 154, 155, 260, 360 Remission, 72, 101, 143, 159, 340, 359, 360 Renal capsule, 59, 360 Renal cell cancer, 150, 154, 360 Renal pelvis, 44, 360 Reperfusion, 46, 360 Reperfusion Injury, 360
Repopulation, 23, 26, 29, 98, 171, 360 Reproductive cells, 327, 360 Resorption, 349, 360 Respiration, 243, 307, 343, 360 Respiratory distress syndrome, 10, 360 Restoration, 31, 130, 359, 360, 375 Retina, 9, 310, 337, 339, 345, 346, 349, 360, 361, 374 Retinal, 9, 80, 313, 349, 361 Retinoblastoma, 276, 361 Retinoid, 228, 361 Retinol, 361 Retrospective, 117, 361 Retroviral vector, 13, 18, 31, 37, 196, 361 Retrovirus, 45, 64, 361 Reversion, 68, 361 Rheumatic Diseases, 242, 361 Rheumatism, 361 Rheumatoid, 256, 361 Rheumatoid arthritis, 256, 361 Ribonucleoproteins, 347, 361 Ribose, 296, 315, 361 Ribosome, 361, 371 Risk factor, 106, 361 Rituximab, 145, 146, 153, 160, 361 Rod, 202, 302, 353, 361 S Salivary, 317, 350, 361, 366 Salivary glands, 317, 361 Saponins, 361, 366 Satellite, 48, 348, 362 Sclera, 175, 310, 313, 362 Scleroderma, 242, 301, 362 Sclerosis, 130, 243, 256, 276, 301, 343, 362 Screening, 15, 27, 39, 47, 125, 192, 229, 234, 235, 238, 311, 362, 373 Sebaceous, 336, 362, 375 Sebaceous gland, 336, 362, 375 Secondary tumor, 341, 362 Secretion, 81, 193, 237, 238, 321, 331, 334, 362, 371 Secretory, 18, 56, 179, 362, 367 Sediment, 362, 373 Segregation, 302, 326, 359, 362 Seizures, 351, 362 Selenium, 197, 362 Semen, 357, 362 Semisynthetic, 322, 362 Senescence, 38, 73, 109, 238, 362 Senile, 349, 362 Septum, 337, 362, 363 Septum Pellucidum, 337, 362, 363
Index 391
Sequence Homology, 352, 363 Sequencing, 25, 355, 363 Serine, 174, 177, 357, 363 Serotonin, 118, 359, 363, 372 Serous, 320, 321, 363 Serum, 19, 67, 197, 198, 216, 297, 298, 312, 328, 359, 363, 372 Sex Determination, 277, 363 Shock, 363, 372 Side effect, 51, 148, 155, 158, 161, 209, 220, 244, 265, 267, 296, 304, 314, 363, 371 Signal Transduction, 14, 22, 47, 177, 252, 363 Signs and Symptoms, 360, 363 Skeletal, 25, 36, 39, 48, 76, 122, 191, 197, 241, 343, 344, 363 Skeleton, 295, 323, 336, 363, 364 Skin graft, 36, 167, 364 Skull, 314, 364, 368 Small cell lung cancer, 141, 142, 364 Small intestine, 17, 28, 303, 318, 331, 332, 335, 336, 364 Smoldering leukemia, 344, 364 Smooth muscle, 15, 30, 52, 104, 225, 298, 313, 324, 325, 337, 364, 366 Smooth Muscle Tumor, 324, 364 Social Environment, 358, 364 Soft tissue, 305, 363, 364 Solid tumor, 299, 305, 319, 364 Soma, 210, 358, 364 Somatic cells, 14, 27, 54, 63, 191, 229, 308, 340, 342, 364 Somatic mutations, 34, 364 Somatostatin, 205, 364 Sound wave, 313, 364 Specialist, 286, 317, 364 Specificity, 34, 64, 296, 356, 364 Spectrum, 35, 364 Sperm, 109, 210, 255, 258, 310, 327, 360, 364, 365, 372 Spermatocyte, 54, 365 Spermatogenesis, 13, 54, 223, 365 Spermatozoa, 362, 365 Spermatozoon, 186, 365 Spheroplasts, 215, 365 Sphincter, 337, 365 Spinal Cord Injuries, 217, 365 Spinal Nerves, 352, 365 Spinous, 321, 337, 365 Spleen, 100, 339, 350, 365 Splenomegaly, 349, 365 Sporadic, 34, 346, 361, 365
Spotting, 49, 50, 365 Squamous, 16, 225, 365 Squamous Epithelium, 16, 225, 365 Stabilization, 128, 365 Stem Cell Factor, 49, 59, 136, 162, 166, 194, 214, 233, 252, 311, 365 Sterile, 301, 351, 365 Sterility, 99, 219, 315, 334, 366 Sterilization, 28, 219, 366 Steroid, 211, 303, 314, 361, 366 Stimulus, 56, 313, 317, 318, 322, 336, 359, 366, 369 Stomach, 295, 304, 317, 322, 326, 331, 350, 352, 364, 365, 366 Strand, 184, 355, 366 Stress, 49, 64, 302, 308, 314, 350, 361, 366 Striatum, 35, 186, 327, 345, 366 Stringency, 188, 366 Stroke, 90, 117, 164, 272, 281, 282, 307, 366 Stroma, 20, 80, 84, 183, 233, 336, 351, 366 Stromal Cells, 31, 36, 49, 53, 65, 95, 181, 193, 305, 366 Subacute, 334, 366 Subclinical, 334, 362, 366 Subcutaneous, 296, 337, 366 Subiculum, 330, 366 Submaxillary, 321, 366 Subspecies, 364, 366 Substance P, 341, 356, 359, 362, 366 Substrate, 197, 213, 220, 225, 320, 331, 366 Sudden death, 180, 366 Suppression, 44, 59, 66, 126, 251, 326, 367 Suppressive, 29, 367 Sympathetic Nervous System, 302, 346, 367 Sympathomimetic, 317, 321, 347, 367 Symphysis, 357, 367 Symptomatic, 58, 89, 367 Synapses, 207, 347, 367 Synapsis, 367 Synaptic, 7, 130, 207, 363, 367 Synaptic Vesicles, 367 Synaptophysin, 7, 367 Systemic, 4, 192, 256, 266, 300, 305, 306, 317, 321, 334, 336, 358, 362, 367, 375 Systemic lupus erythematosus, 4, 367 Systolic, 332, 368 T T cell, 23, 24, 36, 43, 94, 196, 199, 211, 221, 222, 223, 242, 335, 368 Tacrolimus, 148, 150, 159, 368 Taurine, 10, 303, 368
392
Stem Cells
Tear Gases, 336, 368 Telangiectasia, 277, 368 Telencephalon, 124, 178, 303, 356, 368 Telomerase, 6, 97, 190, 191, 368 Telomere, 6, 22, 103, 191, 368 Temporal, 21, 30, 233, 330, 339, 368 Teratogenesis, 223, 368 Terminalis, 368, 369 Testicular, 5, 146, 210, 368 Testis, 13, 67, 68, 174, 255, 368 Testosterone, 359, 368 Tetany, 351, 368 Thalamic, 301, 368 Thalamic Diseases, 301, 368 Thalassemia, 242, 369 Thalidomide, 155, 369 Therapeutics, 41, 107, 187, 199, 253, 266, 369 Thermal, 175, 194, 347, 355, 369 Thigh, 323, 369 Thioguanine, 182, 369 Thiotepa, 155, 369 Third Ventricle, 332, 337, 369 Threonine, 174, 352, 357, 363, 369 Threshold, 58, 332, 369 Thrombin, 52, 323, 354, 357, 369 Thrombocytes, 354, 369 Thrombocytopenia, 21, 369 Thrombomodulin, 357, 369 Thrombopoietin, 68, 194, 214, 239, 267, 369 Thrombosis, 104, 335, 357, 366, 369 Thrombus, 314, 334, 354, 369 Thymidine, 7, 13, 192, 369, 370 Thymidine Kinase, 192, 370 Thymus, 24, 43, 132, 211, 332, 339, 370 Thyroid, 351, 370, 372 Thyroid Gland, 351, 370 Thyroxine, 297, 353, 370 Tissue Culture, 45, 48, 212, 216, 346, 370 Tissue Extracts, 169, 370 Tissue Therapy, 130, 370 Tissue Transplantation, 197, 370 Tobramycin, 258, 370 Tolerance, 35, 182, 200, 211, 242, 259, 296, 327, 370 Tomography, 305, 370 Tonicity, 330, 370 Tooth Loss, 246, 370 Topical, 58, 322, 351, 370 Topotecan, 118, 155, 370 Torsion, 334, 370
Total pancreatectomy, 350, 370 Total-body irradiation, 143, 150, 151, 153, 154, 156, 159, 162, 370 Toxic, iv, 177, 225, 233, 234, 315, 317, 318, 320, 332, 341, 354, 362, 369, 371 Toxicity, 85, 100, 237, 256, 317, 341, 371 Toxicology, 104, 122, 274, 371 Toxins, 236, 300, 320, 334, 343, 358, 371 Trachea, 337, 370, 371 Transcriptase, 361, 368, 371 Transcription Factors, 27, 33, 39, 43, 49, 55, 68, 371 Transduction, 6, 17, 20, 24, 31, 45, 47, 69, 70, 91, 121, 137, 179, 190, 363, 371 Transfection, 32, 34, 76, 182, 185, 195, 304, 319, 371 Transforming Growth Factor beta, 41, 192, 371 Transfusion, 21, 181, 255, 371 Transgenes, 17, 24, 52, 89, 178, 196, 371 Translation, 7, 27, 51, 72, 371 Translational, 27, 182, 326, 371 Translocation, 20, 62, 64, 195, 371 Transmitter, 295, 301, 317, 336, 340, 346, 347, 367, 371 Transplantation Tolerance, 36, 371 Trauma, 175, 303, 306, 332, 345, 368, 372 Treatment Outcome, 246, 372 Trophic, 50, 372 Trophoblast, 222, 235, 305, 372 Tropism, 66, 372 Tryptophan, 311, 363, 372 Tuberculosis, 313, 339, 372 Tuberous Sclerosis, 277, 372 Tubulin, 79, 342, 372 Tumor marker, 176, 372 Tumor Necrosis Factor, 369, 372 Tumor Stem Cells, 248, 372 Tumor suppressor gene, 34, 372 Tumorigenic, 178, 230, 372 Tumour, 325, 348, 372 Tyrosine, 31, 42, 49, 166, 198, 317, 372 U Umbilical Arteries, 372 Umbilical Cord, 4, 25, 72, 90, 93, 102, 203, 216, 224, 280, 372 Umbilical cord blood, 25, 72, 90, 93, 102, 111, 203, 216, 373 Unconditioned, 231, 373 Unconscious, 315, 332, 373 Unresectable, 143, 373 Ureter, 44, 337, 360, 373
Index 393
Urethra, 4, 44, 351, 357, 373 Urinalysis, 149, 373 Urinary, 44, 146, 152, 302, 315, 373 Urinary tract, 44, 302, 373 Urine, 44, 66, 302, 304, 312, 321, 330, 357, 360, 373 Urology, 4, 373 Urothelium, 44, 373 Uterus, 314, 315, 319, 324, 337, 356, 373 V Vaccine, 157, 223, 240, 357, 373 Vagina, 365, 373 Vascular, 27, 30, 92, 104, 112, 174, 213, 237, 240, 310, 320, 334, 347, 353, 369, 370, 373 Vasodilation, 298, 373 Vasodilator, 306, 317, 373 Vector, 25, 60, 61, 81, 189, 196, 203, 204, 218, 334, 371, 373 Vein, 96, 127, 149, 216, 237, 299, 335, 347, 362, 372, 373 Venous, 46, 98, 305, 306, 357, 373 Venous blood, 305, 306, 373 Ventral, 228, 332, 365, 373 Ventricle, 12, 330, 337, 358, 368, 369, 374 Ventricular, 52, 168, 180, 187, 374 Ventricular Dysfunction, 180, 374 Ventricular Remodeling, 52, 374 Venules, 237, 305, 307, 320, 374 Vertebrae, 365, 374 Veterinary Medicine, 116, 117, 273, 374 Vinblastine, 372, 374 Vincristine, 372, 374
Viral, 18, 24, 38, 51, 94, 124, 190, 192, 195, 219, 224, 348, 361, 371, 372, 374 Viral vector, 18, 94, 124, 192, 196, 374 Virulence, 302, 304, 371, 374 Viscera, 364, 374 Visceral, 80, 302, 314, 374 Viscosity, 194, 374 Vitelline Membrane, 374, 375 Vitreous Body, 360, 374 Vivo, 6, 7, 11, 18, 21, 22, 24, 26, 30, 31, 37, 39, 46, 47, 50, 51, 55, 58, 59, 60, 80, 83, 84, 91, 98, 101, 125, 126, 167, 171, 179, 180, 183, 196, 201, 202, 204, 208, 214, 219, 230, 374 Vocal cord, 243, 353, 374 Vulgaris, 132, 375 W War, 244, 344, 375 Wound Healing, 32, 45, 169, 240, 310, 323, 335, 375 Wounds, Gunshot, 365, 375 X Xenograft, 61, 299, 375 X-ray, 101, 140, 142, 147, 149, 154, 156, 159, 160, 162, 305, 324, 325, 336, 340, 347, 358, 359, 375 X-ray therapy, 336, 375 Y Yeasts, 325, 353, 375 Yolk Sac, 30, 171, 375 Z Zygote, 313, 343, 375 Zymogen, 357, 375
394
Stem Cells
Index 395
396
Stem Cells
