Bladder Cancer - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

BLADDER CANCER A

3-in-1

Medical

Reference

A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers TO INTERNET REFERENCES

BLADDER CANCER A BIBLIOGRAPHY AND DICTIONARY FOR PHYSICIANS, PATIENTS, AND GENOME RESEARCHERS

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. 7404 Trade Street San Diego, CA 92121 USA Copyright ©2007 by ICON Group International, Inc. Copyright ©2007 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., 1960Bladder Cancer: A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers/ James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-11372-4 1. Bladder Cancer-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.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International, Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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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 bladder cancer. 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 Chaired Professor of Management Science 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. 7404 Trade Street San Diego, CA 92121 USA Fax: 858-635-9414 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON BLADDER CANCER .................................................................................... 3 Overview........................................................................................................................................ 3 Genetics Home Reference ............................................................................................................... 3 What Is Bladder Cancer? ............................................................................................................... 3 How Common Is Bladder Cancer?................................................................................................. 4 What Genes Are Related to Bladder Cancer? ................................................................................ 4 How Do People Inherit Bladder Cancer? ....................................................................................... 4 Where Can I Find Additional Information about Bladder Cancer?............................................... 4 References....................................................................................................................................... 6 What Is the Official Name of the FGFR3 Gene?............................................................................ 7 What Is the Normal Function of the FGFR3 Gene? ...................................................................... 7 What Conditions Are Related to the FGFR3 Gene? ...................................................................... 8 Where Is the FGFR3 Gene Located? .............................................................................................. 9 References..................................................................................................................................... 10 What Is the Official Name of the HRAS Gene? ........................................................................... 11 What Is the Normal Function of the HRAS Gene? ..................................................................... 11 What Conditions Are Related to the HRAS Gene? ..................................................................... 12 Where Is the HRAS Gene Located? ............................................................................................. 12 References..................................................................................................................................... 13 What Is the Official Name of the RB1 Gene?............................................................................... 13 What Is the Normal Function of the RB1 Gene? ......................................................................... 14 What Conditions Are Related to the RB1 Gene? ......................................................................... 14 Where Is the RB1 Gene Located? ................................................................................................. 14 References..................................................................................................................................... 15 What Is the Official Name of the TP53 Gene? ............................................................................. 16 What Is the Normal Function of the TP53 Gene? ....................................................................... 16 What Conditions Are Related to the TP53 Gene? ....................................................................... 16 Where Is the TP53 Gene Located? ............................................................................................... 17 References..................................................................................................................................... 18 Federally Funded Research on Bladder Cancer............................................................................ 19 The National Library of Medicine: PubMed ................................................................................ 82 CHAPTER 2. ALTERNATIVE MEDICINE AND BLADDER CANCER.................................................. 127 Overview.................................................................................................................................... 127 National Center for Complementary and Alternative Medicine................................................ 127 Additional Web Resources ......................................................................................................... 149 General References ..................................................................................................................... 150 CHAPTER 3. DISSERTATIONS ON BLADDER CANCER.................................................................... 151 Overview.................................................................................................................................... 151 Dissertations on Bladder Cancer................................................................................................ 151 Keeping Current ........................................................................................................................ 152 CHAPTER 4. PATENTS ON BLADDER CANCER .............................................................................. 153 Overview.................................................................................................................................... 153 Patent Applications on Bladder Cancer ..................................................................................... 153 Keeping Current ........................................................................................................................ 162 CHAPTER 5. BOOKS ON BLADDER CANCER .................................................................................. 163 Overview.................................................................................................................................... 163 Book Summaries: Online Booksellers......................................................................................... 163 The National Library of Medicine Book Index ........................................................................... 165 APPENDIX A. HELP ME UNDERSTAND GENETICS ....................................................................... 167 Overview.................................................................................................................................... 167

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The Basics: Genes and How They Work..................................................................................... 167 Genetic Mutations and Health................................................................................................... 178 Inheriting Genetic Conditions ................................................................................................... 184 Genetic Consultation ................................................................................................................. 192 Genetic Testing .......................................................................................................................... 194 Gene Therapy ............................................................................................................................. 200 The Human Genome Project and Genomic Research................................................................. 203 APPENDIX B. PHYSICIAN RESOURCES ........................................................................................... 206 Overview.................................................................................................................................... 206 NIH Guidelines.......................................................................................................................... 206 NIH Databases........................................................................................................................... 207 Other Commercial Databases..................................................................................................... 210 The Genome Project and Bladder Cancer................................................................................... 210 APPENDIX C. PATIENT RESOURCES .............................................................................................. 214 Overview.................................................................................................................................... 214 Patient Guideline Sources.......................................................................................................... 214 Finding Associations.................................................................................................................. 218 Resources for Patients and Families........................................................................................... 219 ONLINE GLOSSARIES................................................................................................................ 221 Online Dictionary Directories ................................................................................................... 225 BLADDER CANCER DICTIONARY......................................................................................... 226 INDEX .............................................................................................................................................. 295

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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 bladder cancer 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 bladder cancer, 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 bladder cancer, from the essentials to the most advanced areas of research. Special attention has been paid to present the genetic basis and pattern of inheritance of bladder cancer. 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 bladder cancer. 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 bladder cancer, 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. We hope these resources will prove useful to the widest possible audience seeking information on bladder cancer. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/.

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CHAPTER 1. STUDIES ON BLADDER CANCER Overview In this chapter, we will show you how to locate peer-reviewed references and studies on bladder cancer. For those interested in basic information about bladder cancer, we begin with a condition summary published by the National Library of Medicine.

Genetics Home Reference Genetics Home Reference (GHR) is the National Library of Medicine’s Web site for consumer information about genetic conditions and the genes or chromosomes responsible for those conditions. Here you can find a condition summary on bladder cancer that describes the major features of the condition, provides information about the condition’s genetic basis, and explains its pattern of inheritance. In addition, a summary of the gene or chromosome related to bladder cancer is provided.2 The Genetics Home Reference has recently published the following summary for bladder cancer:

What Is Bladder Cancer?3 Bladder cancer is a disease in which abnormal cells multiply without control in the bladder. The bladder is a hollow, muscular organ that stores urine; it is located in the lower abdomen. The most common type of bladder cancer begins in cells lining the inside of the bladder and is called transitional cell carcinoma (TCC). Bladder cancer may cause blood in the urine, pain during urination, frequent urination, or feeling the need to urinate without results. These signs and symptoms are not specific to bladder cancer, and are also caused by noncancerous conditions. 2 3

This section has been adapted from the National Library of Medicine: http://ghr.nlm.nih.gov/.

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/condition=bladdercancer.

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How Common Is Bladder Cancer? In the United States, bladder cancer is the fourth most common type of cancer in men and the ninth most common cancer in women. More than 47,000 men and 16,000 women are diagnosed with bladder cancer each year.

What Genes Are Related to Bladder Cancer? The FGFR3 (ghr.nlm.nih.gov/gene=fgfr3), HRAS (ghr.nlm.nih.gov/gene=hras), RB1 (ghr.nlm.nih.gov/gene=rb1), and TP53 (ghr.nlm.nih.gov/gene=tp53) genes are associated with bladder cancer. As with most cancers, the exact causes of bladder cancer are not known; however, many risk factors are associated with this disease. Chief among them are smoking and exposure to industrial chemicals. Mutations in the FGFR3 gene that arise in the bladder are another important risk factor for developing bladder cancer. Similar changes in other genes, such as RB1, HRAS and TP53, may also increase risk. Each of these genes plays a critical role in regulating the cycle of cell division, preventing cells from dividing too rapidly or in an uncontrolled way. Alterations in these genes may help explain why some bladder cancers grow and spread more rapidly than others. A family history of bladder cancer is a risk factor for the disease, although most genetic changes that are associated with bladder cancer develop in bladder tissue during a person’s lifetime, rather than being inherited from a parent. Some people, however, appear to inherit a reduced ability to break down certain chemicals, which makes them more sensitive to the cancer-causing effects of tobacco smoke and certain industrial chemicals.

How Do People Inherit Bladder Cancer? Bladder cancer is generally not inherited; tumors usually result from genetic mutations that occur in certain bladder cells during a person’s lifetime. These noninherited genetic changes are called somatic mutations.

Where Can I Find Additional Information about Bladder Cancer? You may find the following resources about bladder cancer helpful. These materials are written for the general public. NIH Publications - National Institutes of Health •

National Cancer Institute: Bladder Cancer Home Page: www.cancer.gov/cancerinfo/types/bladder/

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National Cancer Institute: What You Need To Know About Bladder Cancer: www.cancer.gov/cancerinfo/wyntk/bladder

Studies

MedlinePlus - Health Information •

Encyclopedia: Bladder Cancer: www.nlm.nih.gov/medlineplus/ency/article/000486.htm

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Health Topic: Bladder Cancer: www.nlm.nih.gov/medlineplus/bladdercancer.html Educational Resources - Information Pages

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American Urological Association: www.urologyhealth.org/adult/index.cfm?cat=03&topic=37

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M. D. Anderson Cancer Center: www.mdanderson.org/diseases/bladder/

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Mayo Clinic: www.mayoclinic.org/bladder-cancer/

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Merck Manual of Medical Information, Second Home Edition: www.merck.com/mmhe/sec11/ch151/ch151d.html

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National Comprehensive Cancer Network: www.nccn.org/patients/patient_gls/_english/_bladder/contents.asp

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NetWellness: www.netwellness.org/healthtopics/urinarycancer/

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New York Online Access to Health (NOAH): www.noah-health.org/en/cancer/types/bladder/

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Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: www.hopkinskimmelcancercenter.org/cancertypes/bladder-cancer.cfm?cancerid=20

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Stanford Comprehensive Cancer Center: cancer.stanford.edu/urologic/bladder/ Patient Support - for Patients and Families

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American Cancer Society: www.cancer.org/docroot/cri/cri_2_3x.asp?dt=44

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American Foundation for Urologic Disease: www.afud.org

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National Coalition for Cancer Survivorship: www.canceradvocacy.org

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Resource list from the University of Kansas Medical Center: www.kumc.edu/gec/support/cancer.html

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Professional Resources You may also be interested in these resources, which are designed for healthcare professionals and researchers. •

ClinicalTrials.gov - Linking patients to medical research: clinicaltrials.gov/search/condition=%22bladder+cancer%22?recruiting=false

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PubMed - Recent literature: ghr.nlm.nih.gov/condition=bladdercancer/show/PubMed;jsessionid=E0697F5D771063 885F893895BAE4AEA6

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OMIM - Genetic disorder catalog: www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=109800

References These sources were used to develop the Genetics Home Reference condition summary on bladder cancer. •

American Cancer Society: What Are the Key Statistics for Bladder Cancer?

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Bryan RT, Hussain SA, James ND, Jankowski JA, Wallace DM. Molecular pathways in bladder cancer: part 1. BJU Int. 2005 Mar;95(4):485-90. Review. No abstract available. PubMed citation

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Bryan RT, Hussain SA, James ND, Jankowski JA, Wallace DM. Molecular pathways in bladder cancer: part 2. BJU Int. 2005 Mar;95(4):491-6. Review. No abstract available. PubMed citation

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Buscarini M, Quek ML, Gill P, Xia G, Quinn DI, Stein JP. Molecular prognostic factors in bladder cancer. BJU Int. 2005 Apr;95(6):739-42. Review. No abstract available. PubMed citation

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Dinney CP, McConkey DJ, Millikan RE, Wu X, Bar-Eli M, Adam L, Kamat AM, SiefkerRadtke AO, Tuziak T, Sabichi AL, Grossman HB, Benedict WF, Czerniak B. Focus on bladder cancer. Cancer Cell. 2004 Aug;6(2):111-6. Review. No abstract available. PubMed citation

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Lindgren D, Liedberg F, Andersson A, Chebil G, Gudjonsson S, Borg A, Mansson W, Fioretos T, Hoglund M. Molecular characterization of early-stage bladder carcinomas by expression profiles, FGFR3 mutation status, and loss of 9q. Oncogene. 2006 Apr 27;25(18):2685-96. PubMed citation

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Mhawech-Fauceglia P, Cheney RT, Schwaller J. Genetic alterations in urothelial bladder carcinoma: an updated review. Cancer. 2006 Mar 15;106(6):1205-16. Review. PubMed citation

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Oxford G, Theodorescu D. The role of Ras superfamily proteins in bladder cancer progression. J Urol. 2003 Nov;170(5):1987-93. Review. PubMed citation

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Smith ND, Rubenstein JN, Eggener SE, Kozlowski JM. The p53 tumor suppressor gene and nuclear protein: basic science review and relevance in the management of bladder cancer. J Urol. 2003 Apr;169(4):1219-28. Review. PubMed citation

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Syrigos KN, Karapanagiotou E, Harrington KJ. The clinical significance of molecular markers to bladder cancer. Hybrid Hybridomics. 2004 Dec;23(6):335-42. Review. PubMed citation

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van Rhijn BW, van Tilborg AA, Lurkin I, Bonaventure J, de Vries A, Thiery JP, van der Kwast TH, Zwarthoff EC, Radvanyi F. Novel fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer previously identified in non-lethal skeletal disorders. Eur J Hum Genet. 2002 Dec;10(12):819-24. PubMed citation

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Wolff EM, Liang G, Jones PA. Mechanisms of Disease: genetic and epigenetic alterations that drive bladder cancer. Nat Clin Pract Urol. 2005 Oct;2(10):502-10. Review. PubMed citation

A summary of the genes related to bladder cancer is provided below:

What Is the Official Name of the FGFR3 Gene?4 The official name of this gene is “fibroblast growth factor receptor 3 (achondroplasia, thanatophoric dwarfism).” FGFR3 is the gene‘s official symbol. The FGFR3 gene is also known by other names, listed below.

What Is the Normal Function of the FGFR3 Gene? The FGFR3 gene provides instructions for making a protein called fibroblast growth factor receptor 3. This protein is part of a family of fibroblast growth factor receptors that share similar structures and functions. These proteins play a role in several important cellular processes, including regulation of cell growth and division, determination of cell type, formation of blood vessels, wound healing, and embryo development. The FGFR3 protein spans the cell membrane, so that one end of the protein remains inside the cell and the other end projects from the outer surface of the cell. This positioning of the protein allows it to interact with specific growth factors outside the cell and to receive signals that control growth and development. When these growth factors attach to the FGFR3 protein, the protein triggers a cascade of chemical reactions inside the cell that instructs the cell to undergo certain changes, such as maturing to take on specialized functions. The FGFR3 protein is involved in the development and maintenance of bone and brain tissue. Researchers believe that this receptor regulates bone growth by limiting the formation of bone from cartilage (a process called ossification), particularly in the long bones.

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Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=fgfr3;jsessionid=E0697F5D771063885F893895BAE4AEA6.

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What Conditions Are Related to the FGFR3 Gene? Achondroplasia - Caused by Mutations in the FGFR3 Gene Two mutations in the FGFR3 gene cause more than 99 percent of cases of achondroplasia. Both mutations lead to the same change in building blocks (amino acids) that make up the fibroblast growth factor receptor 3 protein. Specifically, the amino acid glycine is replaced with the amino acid arginine at protein position 380 (written as Gly380Arg or G380R). Researchers believe that this genetic change causes the receptor to be overly active, which leads to the disturbances in bone growth seen with this disorder. Crouzonodermoskeletal Syndrome - Caused by Mutations in the FGFR3 Gene Two mutations in the FGFR3 gene cause more than 99 percent of cases of achondroplasia. Both mutations lead to the same change in building blocks (amino acids) that make up the fibroblast growth factor receptor 3 protein. Specifically, the amino acid glycine is replaced with the amino acid arginine at protein position 380 (written as Gly380Arg or G380R). Researchers believe that this genetic change causes the receptor to be overly active, which leads to the disturbances in bone growth seen with this disorder. Hypochondroplasia - Caused by Mutations in the FGFR3 Gene A single FGFR3 mutation has been identified in people with Crouzonodermoskeletal syndrome. This genetic change replaces the amino acid alanine with the amino acid glutamic acid at position 391 of the fibroblast growth factor receptor 3 protein (written as Ala391Glu or A391E). Researchers have not determined how this mutation leads to the signs and symptoms of this disorder, but the altered receptor appears to disrupt the normal growth of skull bones and affect skin pigmentation. Muenke Syndrome - Caused by Mutations in the FGFR3 Gene Several mutations in the FGFR3 gene have been identified in people with hypochondroplasia. Many cases are caused by one of two specific FGFR3 mutations, both of which lead to the same change in amino acids in the fibroblast growth factor receptor 3 protein. Specifically, the amino acid asparagine is replaced with the amino acid lysine at protein position 540 (written as Asn540Lys or N540K). Other FGFR3 mutations probably cause a small number of cases of hypochondroplasia. Although the effects of these mutations have not been explained, they probably cause the receptor to be mildly overactivated, which leads to the disturbances in bone growth seen with this disorder. SADDAN - Caused by Mutations in the FGFR3 Gene A single mutation in the FGFR3 gene has been shown to cause Muenke syndrome. This change substitutes the amino acid arginine for the amino acid proline at position 250 in the fibroblast growth factor receptor 3 protein (written as Pro250Arg or P250R). This mutation results in the production of a receptor that is overly active, which allows the bones of the skull to fuse before they should.

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Thanatophoric Dysplasia - Caused by Mutations in the FGFR3 Gene One mutation in the FGFR3 gene has been identified in people with SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans). This genetic change substitutes the amino acid methionine for the amino acid lysine at position 650 of the fibroblast growth factor receptor 3 protein (written as Lys650Met or K650M). Researchers believe that this mutation strongly overactivates the FGFR3 protein, which leads to severe problems with bone growth. It remains uncertain how the mutation disrupts brain development or causes acanthosis nigricans (a skin disorder characterized by thick, dark, velvety skin). Bladder Cancer - Associated with the FGFR3 Gene At least 10 mutations in the FGFR3 gene have been identified in people with thanatophoric dysplasia type I. Most of these mutations change a single amino acid in the fibroblast growth factor receptor 3 protein. The most common mutation substitutes the amino acid cysteine for the amino acid arginine at protein position 248 (written as Arg248Cys or R248C). Other mutations cause the protein to be longer than normal. Other Disorders - Caused by Mutations in the FGFR3 Gene Some gene mutations are acquired during a person’s lifetime and are present only in certain cells. These changes, which are called somatic mutations, are not inherited. Somatic mutations in the FGFR3 gene are associated with some cases of bladder cancer. These mutations overactivate the fibroblast growth factor receptor 3 protein, which likely directs bladder cells to grow and divide in the absence of signals from outside the cell. This uncontrolled cell division leads to the formation of a bladder tumor. Other Cancers - Associated with the FGFR3 Gene Mutations in the FGFR3 gene also cause platyspondylic lethal skeletal dysplasia, San Diego type. This skeletal disorder is characterized by severe problems with bone growth similar to thanatophoric dysplasia. Most mutations that cause this disorder change single amino acids in the FGFR3 protein. The altered protein is improperly folded and cannot be transported to the cell membrane. Instead, it accumulates within cartilage cells (chondrocytes) and forms clumps called inclusion bodies. The absence of normal FGFR3 signaling and the formation of inclusion bodies probably disrupt the normal development of bones, leading to the skeletal abnormalities characteristic of platyspondylic lethal skeletal dysplasia, San Diego type.

Where Is the FGFR3 Gene Located? Cytogenetic Location: 4p16.3 Molecular Location on chromosome 4: base pairs 1,765,420 to 1,780,395

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The FGFR3 gene is located on the short (p) arm of chromosome 4 at position 16.3. More precisely, the FGFR3 gene is located from base pair 1,765,420 to base pair 1,780,395 on chromosome 4.

References These sources were used to develop the Genetics Home Reference gene summary on the FGFR3 gene. •

Brodie SG, Kitoh H, Lachman RS, Nolasco LM, Mekikian PB, Wilcox WR. Platyspondylic lethal skeletal dysplasia, San Diego type, is caused by FGFR3 mutations. Am J Med Genet. 1999 Jun 11;84(5):476-80. PubMed citation

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Cappellen D, De Oliveira C, Ricol D, de Medina S, Bourdin J, Sastre-Garau X, Chopin D, Thiery JP, Radvanyi F. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat Genet. 1999 Sep;23(1):18-20. No abstract available. PubMed citation

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Chen L, Deng CX. Roles of FGF signaling in skeletal development and human genetic diseases. Front Biosci. 2005 May 1;10:1961-76. PubMed citation

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Cohen MM Jr. Some chondrodysplasias with short limbs: molecular perspectives. Am J Med Genet. 2002 Oct 15;112(3):304-13. Review. PubMed citation

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Coumoul X, Deng CX. Roles of FGF receptors in mammalian development and congenital diseases. Birth Defects Res C Embryo Today. 2003 Nov;69(4):286-304. Review. PubMed citation

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Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev. 2005 Apr;16(2):139-49. Epub 2005 Feb 1. PubMed citation

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Horton WA, Lunstrum GP. Fibroblast growth factor receptor 3 mutations in achondroplasia and related forms of dwarfism. Rev Endocr Metab Disord. 2002 Dec;3(4):381-5. Review. No abstract available. PubMed citation

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Kimura T, Suzuki H, Ohashi T, Asano K, Kiyota H, Eto Y. The incidence of thanatophoric dysplasia mutations in FGFR3 gene is higher in low-grade or superficial bladder carcinomas. Cancer. 2001 Nov 15;92(10):2555-61. Erratum in: Cancer 2002 Apr 1;94(7):2117. PubMed citation

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L’Hote CG, Knowles MA. Cell responses to FGFR3 signalling: growth, differentiation and apoptosis. Exp Cell Res. 2005 Apr 1;304(2):417-31. Epub 2004 Dec 16. Review. PubMed citation

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Lievens PM, Liboi E. The thanatophoric dysplasia type II mutation hampers complete maturation of fibroblast growth factor receptor 3 (FGFR3), which activates signal transducer and activator of transcription 1 (STAT1) from the endoplasmic reticulum. J Biol Chem. 2003 May 9;278(19):17344-9. Epub 2003 Mar 06. PubMed citation

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Vajo Z, Francomano CA, Wilkin DJ. The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans. Endocr Rev. 2000 Feb;21(1):23-39. Review. PubMed citation

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van Rhijn BW, van Tilborg AA, Lurkin I, Bonaventure J, de Vries A, Thiery JP, van der Kwast TH, Zwarthoff EC, Radvanyi F. Novel fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer previously identified in non-lethal skeletal disorders. Eur J Hum Genet. 2002 Dec;10(12):819-24. PubMed citation

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Wilkie AO. Bad bones, absent smell, selfish testes: the pleiotropic consequences of human FGF receptor mutations. Cytokine Growth Factor Rev. 2005 Apr;16(2):187-203. Epub 2005 Apr 1. PubMed citation

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Zieger K, Dyrskjot L, Wiuf C, Jensen JL, Andersen CL, Jensen KM, Orntoft TF. Role of activating fibroblast growth factor receptor 3 mutations in the development of bladder tumors. Clin Cancer Res. 2005 Nov 1;11(21):7709-19. PubMed citation

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What Is the Official Name of the HRAS Gene?5 The official name of this gene is “v-Ha-ras Harvey rat sarcoma viral oncogene homolog.” HRAS is the gene‘s official symbol. The HRAS gene is also known by other names, listed below.

What Is the Normal Function of the HRAS Gene? The HRAS gene provides instructions for making a protein that is involved in cell division. In a process called signal transduction, the protein relays signals from outside the cell to the cell nucleus and instructs the cell to grow or divide. The HRAS protein is a GTPase, which means it converts a molecule called GTP into another molecule called GDP. The protein acts like a switch; to transmit signals, the HRAS protein must be turned on (activated) by binding to GTP. The HRAS protein is turned off (inactivated) when it converts GTP to GDP. When the protein is bound to GDP, it does not relay signals to the cell nucleus. HRAS is a member of a class of genes called oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous. HRAS is in the Ras family, which also includes two other oncogenes: KRAS2 and NRAS. The protein products of these three genes are GTPases. These proteins play important roles in cell division, cell specialization (the 5

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=hras.

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process by which cells mature to carry out specific functions), and controlled cell death (apoptosis).

What Conditions Are Related to the HRAS Gene? Costello Syndrome - Caused by Mutations in the HRAS Gene At least five inherited mutations in the HRAS gene have been identified in people with Costello syndrome. Each of these mutations changes a single protein building block (amino acid) in a critical region of the HRAS protein. The most common mutation replaces the amino acid glycine with the amino acid serine at position 12 (written as Gly12Ser or G12S). Bladder Cancer - Associated with the HRAS Gene At least five inherited mutations in the HRAS gene have been identified in people with Costello syndrome. Each of these mutations changes a single protein building block (amino acid) in a critical region of the HRAS protein. The most common mutation replaces the amino acid glycine with the amino acid serine at position 12 (written as Gly12Ser or G12S). Other Cancers - Associated with the HRAS Gene Some gene mutations are acquired during a person’s lifetime and are present only in certain cells. These changes are called somatic mutations and are not inherited. Somatic mutations in the HRAS gene in bladder cells have been associated with bladder cancer. One specific mutation has been identified in a significant percentage of bladder tumors; this mutation substitutes one protein building block (amino acid) for another amino acid in the HRAS protein. Specifically, the mutation replaces the amino acid glycine with the amino acid valine at position 12 (written as Gly12Val or G12V). The altered HRAS protein is permanently activated within the cell. This overactive protein directs the cell to grow and divide in the absence of outside signals, leading to uncontrolled cell division and the formation of a tumor. Mutations in the HRAS gene also have been associated with the progression of bladder cancer and an increased risk of tumor recurrence after treatment.

Where Is the HRAS Gene Located? Cytogenetic Location: 11p15.5 Molecular Location on chromosome 11: base pairs 522,241 to 525,549

Studies

13

The HRAS gene is located on the short (p) arm of chromosome 11 at position 15.5. More precisely, the HRAS gene is located from base pair 522,241 to base pair 525,549 on chromosome 11.

References These sources were used to develop the Genetics Home Reference gene summary on the HRAS gene. •

Adjei AA. Blocking oncogenic Ras signaling for cancer therapy. J Natl Cancer Inst. 2001 Jul 18;93(14):1062-74. Review. PubMed citation

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Aoki Y, Niihori T, Kawame H, Kurosawa K, Ohashi H, Tanaka Y, Filocamo M, Kato K, Suzuki Y, Kure S, Matsubara Y. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005 Oct;37(10):1038-40. Epub 2005 Sep 18. PubMed citation

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Colicelli J. Human RAS superfamily proteins and related GTPases. Sci STKE. 2004 Sep 7;2004(250):RE13. Review. PubMed citation

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Gripp KW, Lin AE, Stabley DL, Nicholson L, Scott CI Jr, Doyle D, Aoki Y, Matsubara Y, Zackai EH, Lapunzina P, Gonzalez-Meneses A, Holbrook J, Agresta CA, Gonzalez IL, Sol-Church K. HRAS mutation analysis in Costello syndrome: Genotype and phenotype correlation. Am J Med Genet A. 2005 Dec 2; [Epub ahead of print]. PubMed citation

•

Oxford G, Theodorescu D. The role of Ras superfamily proteins in bladder cancer progression. J Urol. 2003 Nov;170(5):1987-93. Review. PubMed citation

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Wolff EM, Liang G, Jones PA. Mechanisms of Disease: genetic and epigenetic alterations that drive bladder cancer. Nat Clin Pract Urol. 2005 Oct;2(10):502-10. Review. PubMed citation

What Is the Official Name of the RB1 Gene?6 The official name of this gene is “retinoblastoma 1 (including osteosarcoma).”

6

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=rb1;jsessionid=E0697F5D771063885F893895BAE4AEA6.

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Bladder Cancer

RB1 is the gene‘s official symbol. The RB1 gene is also known by other names, listed below.

What Is the Normal Function of the RB1 Gene? The RB1 gene belongs to a class of genes known as tumor suppressors. Like other tumor suppressor genes, RB1 regulates the cycle of cell division by keeping cells from growing and dividing too rapidly or in an uncontrolled way. The RB1 protein is located in the nucleus of cells throughout the body. This protein stops certain other proteins from triggering the process by which DNA makes a copy of itself (DNA replication). The RB1 protein may also play a role in the process by which cells mature to carry out special functions (differentiation), cell survival, and programmed cell death (apoptosis).

What Conditions Are Related to the RB1 Gene? Retinoblastoma - Increased Risk from Variations of the RB1 Gene More than 360 mutations in the RB1 gene have been identified in people with retinoblastoma, a rare type of eye cancer that usually affects young children. Most of these RB1 mutations prevent the gene from producing any functional protein. Without the RB1 protein, cells are unable to effectively regulate cell division and may divide uncontrollably to form a tumor. Bladder Cancer - Associated with the RB1 Gene More than 360 mutations in the RB1 gene have been identified in people with retinoblastoma, a rare type of eye cancer that usually affects young children. Most of these RB1 mutations prevent the gene from producing any functional protein. Without the RB1 protein, cells are unable to effectively regulate cell division and may divide uncontrollably to form a tumor. Other Cancers - Associated with the RB1 Gene Some gene mutations are acquired during a person’s lifetime and are present only in certain cells. These changes are called somatic mutations and are not inherited. Somatic mutations that inactivate the RB1 gene have been reported in some cases of bladder cancer. Mutations in RB1 are thought to contribute to the development of bladder cancer, and can help predict whether tumors will grow rapidly and spread to other tissues.

Where Is the RB1 Gene Located? Cytogenetic Location: 13q14.2 Molecular Location on chromosome 13: base pairs 47,775,911 to 47,954,022

Studies

15

The RB1 gene is located on the long (q) arm of chromosome 13 at position 14.2. More precisely, the RB1 gene is located from base pair 47,775,911 to base pair 47,954,022 on chromosome 13.

References These sources were used to develop the Genetics Home Reference gene summary on the RB1 gene. •

Classon M, Harlow E. The retinoblastoma tumour suppressor in development and cancer. Nat Rev Cancer. 2002 Dec;2(12):910-7. Review. PubMed citation

•

de Andrade AF, da Hora Barbosa R, Vargas FR, Ferman S, Eisenberg AL, Fernandes L, Bonvicino CR. A molecular study of first and second RB1 mutational hits in retinoblastoma patients. Cancer Genet Cytogenet. 2006 May;167(1):43-6. PubMed citation

•

Gene Review: Retinoblastoma

•

Goodrich DW. The retinoblastoma tumor-suppressor gene, the exception that proves the rule. Oncogene. 2006 Aug 28;25(38):5233-43. Review. PubMed citation

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Herwig S, Strauss M. The retinoblastoma protein: a master regulator of cell cycle, differentiation and apoptosis. Eur J Biochem. 1997 Jun 15;246(3):581-601. Review. PubMed citation

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Korabiowska M, Ruschenburg I, Betke H, Stachura J, Schlott T, Cardo CC, Brinck U. Downregulation of the retinoblastoma gene expression in the progression of malignant melanoma. Pathobiology. 2001;69(5):274-80. PubMed citation

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Liu H, Dibling B, Spike B, Dirlam A, Macleod K. New roles for the RB tumor suppressor protein. Curr Opin Genet Dev. 2004 Feb;14(1):55-64. Review. PubMed citation

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Lohmann DR, Gallie BL. Retinoblastoma: revisiting the model prototype of inherited cancer. Am J Med Genet C Semin Med Genet. 2004 Aug 15;129(1):23-8. Review. PubMed citation

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Richter S, Vandezande K, Chen N, Zhang K, Sutherland J, Anderson J, Han L, Panton R, Branco P, Gallie B. Sensitive and efficient detection of RB1 gene mutations enhances care for families with retinoblastoma. Am J Hum Genet. 2003 Feb;72(2):253-69. Epub 2002 Dec 18. PubMed citation

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•

Sampieri K, Hadjistilianou T, Mari F, Speciale C, Mencarelli MA, Cetta F, Manoukian S, Peissel B, Giachino D, Pasini B, Acquaviva A, Caporossi A, Frezzotti R, Renieri A, Bruttini M. Mutational screening of the RB1 gene in Italian patients with retinoblastoma reveals 11 novel mutations. J Hum Genet. 2006;51(3):209-16. Epub 2006 Feb 4. PubMed citation

•

Wolff EM, Liang G, Jones PA. Mechanisms of Disease: genetic and epigenetic alterations that drive bladder cancer. Nat Clin Pract Urol. 2005 Oct;2(10):502-10. Review. PubMed citation

What Is the Official Name of the TP53 Gene?7 The official name of this gene is “tumor protein p53 (Li-Fraumeni syndrome).” TP53 is the gene‘s official symbol. The TP53 gene is also known by other names, listed below.

What Is the Normal Function of the TP53 Gene? The TP53 gene provides instructions for making a protein called tumor protein p53. TP53 is a tumor suppressor gene, which means that it regulates cell division by keeping cells from growing and dividing too fast or in an uncontrolled way. Tumor protein p53 is located in the nucleus of cells throughout the body and can bind directly to DNA. When the DNA in a cell becomes damaged by agents such as toxic chemicals or ultraviolet (UV) rays from sunlight, this protein plays a critical role in determining whether the DNA will be repaired or the cell will undergo programmed cell death (apoptosis). If the DNA can be repaired, tumor protein p53 activates other genes to fix the damage. If the DNA cannot be repaired, tumor protein p53 prevents the cell from dividing and signals it to undergo apoptosis. This process prevents cells with mutated or damaged DNA from dividing, which helps prevent the development of tumors. Because tumor protein p53 is essential for regulating cell division, it has been nicknamed the “guardian of the genome.”

What Conditions Are Related to the TP53 Gene? Bladder Cancer - Associated with the TP53 Gene Some gene mutations are acquired during a person’s lifetime and are present only in certain cells. These changes are called somatic mutations and are not inherited. Somatic mutations in the TP53 gene have been found in some cases of bladder cancer. Most of these mutations replace one amino acid (a building block of proteins) with another amino acid in tumor protein p53. The altered protein cannot bind to DNA correctly, which prevents the protein from effectively regulating cell growth and division. As a result, DNA damage accumulates 7

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=tp53.

Studies

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in cells and they divide in an uncontrolled way, leading to a cancerous tumor. Mutations in the TP53 gene may also help predict whether bladder cancer will progress and spread to nearby tissues and whether the disease will recur after treatment. Breast Cancer - Associated with the TP53 Gene Some gene mutations are acquired during a person’s lifetime and are present only in certain cells. These changes are called somatic mutations and are not inherited. Somatic mutations in the TP53 gene have been found in some cases of bladder cancer. Most of these mutations replace one amino acid (a building block of proteins) with another amino acid in tumor protein p53. The altered protein cannot bind to DNA correctly, which prevents the protein from effectively regulating cell growth and division. As a result, DNA damage accumulates in cells and they divide in an uncontrolled way, leading to a cancerous tumor. Mutations in the TP53 gene may also help predict whether bladder cancer will progress and spread to nearby tissues and whether the disease will recur after treatment. Li-Fraumeni Syndrome - Associated with the TP53 Gene Some gene mutations are acquired during a person’s lifetime and are present only in certain body cells. These changes are called somatic mutations and are not inherited. Somatic mutations in the TP53 gene have been found in approximately 20 percent to 40 percent of breast cancer cases. Many of these mutations replace one amino acid (a building block of proteins) with another amino acid in tumor protein p53. These mutations lead to the production of a nonfunctional version of this protein that builds up in cells and cannot regulate cell growth and division. In some breast cancer cases, one copy of the TP53 gene is lost, leaving cells with only the mutated copy of this gene. With no functional tumor protein p53, DNA damage accumulates and cells divide in an uncontrolled way, leading to a cancerous tumor. Mutations in the TP53 gene are associated with larger tumors and more advanced disease than breast cancers without TP53 mutations. Recurring tumors are also more likely to have mutations in the TP53 gene. Other Cancers - Associated with the TP53 Gene More than 55 different inherited mutations in the TP53 gene have been found in individuals with Li-Fraumeni syndrome. Many of these changes involve the substitution of one amino acid for another amino acid in the part of tumor protein p53 that binds to DNA. Other types of mutations include deletions of small amounts of DNA within the gene. Mutations in the TP53 gene lead to a version of tumor protein p53 that cannot regulate cell growth and division. The altered protein is unable to signal cells with mutated or damaged DNA to undergo apoptosis. As a result, such cells continue to divide and can form tumors.

Where Is the TP53 Gene Located? Cytogenetic Location: 17p13.1 Molecular Location on chromosome 17: base pairs 7,512,463 to 7,531,641

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The TP53 gene is located on the short (p) arm of chromosome 17 at position 13.1. More precisely, the TP53 gene is located from base pair 7,512,463 to base pair 7,531,641 on chromosome 17.

References These sources were used to develop the Genetics Home Reference gene summary on the TP53 gene. •

Borresen-Dale AL. TP53 and breast cancer. Hum Mutat. 2003 Mar;21(3):292-300. Review. PubMed citation

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Gene Review for Li-Fraumeni Syndrome

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Lacroix M, Toillon RA, Leclercq G. p53 and breast cancer, an update. Endocr Relat Cancer. 2006 Jun;13(2):293-325. Review. PubMed citation

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Lane DP. Exploiting the p53 pathway for the diagnosis and therapy of human cancer. Cold Spring Harb Symp Quant Biol. 2005;70:489-97. Review. PubMed citation

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Lorenzo Romero JG, Salinas Sanchez AS, Gimenez Bachs JM, Sanchez Sanchez F, Escribano Martinez J, Hernandez Millan IR, Segura Martin M, Virseda Rodriguez JA. p53 Gene mutations in superficial bladder cancer. Urol Int. 2004;73(3):212-8. PubMed citation

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Mills AA. p53: link to the past, bridge to the future. Genes Dev. 2005 Sep 15;19(18):20919. Review. No abstract available. PubMed citation

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Olivier M, Goldgar DE, Sodha N, Ohgaki H, Kleihues P, Hainaut P, Eeles RA. LiFraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res. 2003 Oct 15;63(20):6643-50. PubMed citation

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Sengupta S, Harris CC. p53: traffic cop at the crossroads of DNA repair and recombination. Nat Rev Mol Cell Biol. 2005 Jan;6(1):44-55. Review. PubMed citation

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Smith ND, Rubenstein JN, Eggener SE, Kozlowski JM. The p53 tumor suppressor gene and nuclear protein: basic science review and relevance in the management of bladder cancer. J Urol. 2003 Apr;169(4):1219-28. Review. PubMed citation

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Soussi T, Beroud C. Significance of TP53 mutations in human cancer: a critical analysis of mutations at CpG dinucleotides. Hum Mutat. 2003 Mar;21(3):192-200. Review. PubMed citation

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Soussi T, Lozano G. p53 mutation heterogeneity in cancer. Biochem Biophys Res Commun. 2005 Jun 10;331(3):834-42. Review. PubMed citation

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Varley J. TP53, hChk2, and the Li-Fraumeni syndrome. Methods Mol Biol. 2003;222:11729. Review. PubMed citation

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Varley JM. Germline TP53 mutations and Li-Fraumeni syndrome. Hum Mutat. 2003 Mar;21(3):313-20. Review. Erratum in: Hum Mutat. 2003 May;21(5):551. PubMed citation

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Vousden KH, Lu X. Live or let die: the cell‘s response to p53. Nat Rev Cancer. 2002 Aug;2(8):594-604. Review. No abstract available. PubMed citation

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Vousden KH, Prives C. P53 and prognosis: new insights and further complexity. Cell. 2005 Jan 14;120(1):7-10. Review. PubMed citation

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Zamzami N, Kroemer G. p53 in apoptosis control: an introduction. Biochem Biophys Res Commun. 2005 Jun 10;331(3):685-7. Review. No abstract available. PubMed citation

Federally Funded Research on Bladder Cancer The U.S. Government supports a variety of research studies relating to bladder cancer. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.8 CRISP (Computerized Retrieval of Information on Scientific Projects) CRISP is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at 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 bladder cancer. 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 bladder cancer. The following is typical of the type of information found when searching the CRISP database for bladder cancer: •

Project Title: 2006 AUA/SBUR SUMMER “UROTHELIAL BIOLOGY & BLADDER CANCER”

RESEARCH

CONFERENCE

Principal Investigator & Institution: Bjorling, Dale E.; Professor and Chair; American Urological Association Po Box 815 Wilmette, Il 60091 Timing: Fiscal Year 2006; Project Start 30-SEP-2006; Project End 29-SEP-2007 Summary: (provided by applicant): The 2006 American Urological Association Foundation/Society for Basic Urologic Research (AUA Foundation/SBUR) Summer Research Conference (SRC) is entitled “Urothelial Biology & Bladder Cancer.” This conference is in its 13th year and has a long history of enriching young investigators’ 8

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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careers and networks. The goal of this meeting is to bring together new investigators and outstanding successful senior researchers in a small, informal meeting to allow maximum interactions. The 13-year-old meeting already has earned a name as a progressive and unique opportunity for both juniors and seniors in the field of urology research, and this year’s SRC stands out among its predecessors. Faculty members come from a varied list of specialties, including pathology, dermatology, biomedical engineering and microbiology, as well as leaders in urologic research. The meeting is exceptional in that it brings together attendees from different research communities, including urothelial biology, benign urologic diseases, and bladder cancer biology. Sessions are planned in Development and Wound Healing, Cellular Signaling, and New Models. Talks range from “Uroplakins” and “Cellular Signaling in Bladder Cancer” to “Reactive Stroma: Lessons from Prostate Diseases“ and “Virus Transmitted Gene Expression.” In addition to the traditional lectures, faculty members and the SRC program committee will engage junior investigator attendees in one-on-one and small group discussion. The most important occasion for networking will take place at the Mentoring Dinner and Discussion on the first night of the conference. The focus of the meeting, urothelial biology, is consistent with the mission of the National Institute of Diabetes & Digestive & Kidney Diseases, especially in the development and future success of new urologic research investigators. The 2006 American Urological Association /Society for Basic Urologic Research Summer Research Conference, entitled “Urothelial Biology & Bladder Cancer,” brings together new investigators and outstanding successful senior researchers in a small, informal meeting to allow maximum interactions and opportunity for advancement of urologic research. The focus of the meeting is consistent with the mission of the National Institute of Diabetes & Digestive & Kidney Diseases, especially in the development and future success of new urologic research investigators. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANALYSIS OF SOMATIC MUTATIONS IN CANCER OF THE KIDNEY Principal Investigator & Institution: Hunt, Jay D.; Associate Professor; Biochemistry and Molecular Biology; Louisiana State Univ Hsc New Orleans New Orleans, La 70112 Timing: Fiscal Year 2004; Project Start 30-SEP-2004; Project End 31-AUG-2006 Summary: (provided by applicant): Obesity, hypertension, and heavy cigarette smoking are suspected risk factors for kidney cancer, although the actual mechanisms by which these factors exert their action remain to be elucidated. Because the type of p53 gene mutation has provided clues as to etiology for several cancers (e.g., in bladder cancer and renal pelvic carcinoma it has been established that G:C->A:T transitions in p53 result from tobacco smoke carcinogens), and because we have access to DNA from 1,141 newly diagnosed renal cell carcinoma cases in the INCO Central Europe Health Study (CEHS), this NCI R03 project will evaluate whether there is a relationship between p53 gene mutation characteristics and certain selected risk factor characteristics in renal cell carcinoma. The results will help elucidate potential etiologic pathways for kidney cancer that will be pursued in subsequent studies. The CEHS is a hospital-based case-control study of environmental and genetic risk factors for kidney cancers at six centers across Central and Eastern Europe. Funded intramurally by NCI Division of Cancer Epidemiology and Genetics and IARC, the CEHS used an extensive in-person questionnaire to assess general lifestyle, medical and drug use history, family history, use of tobacco products, exposure to environmental tobacco smoke, residential history, alcohol and dietary information, and a detailed occupational history in the 1,141 cases

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and in 1,157 age-matched controls. Blood samples were collected on all 2,300 participants for genotyping of specific single nucleotide polymorphisms in genes encoding enzymes that are in well characterized metabolic pathways for a variety of environmental and occupational carcinogens, as well as for genes involved in DNA repair, immune function, and cell cycle control. Tumor tissue was collected and DNA was extracted at the NCI. Aim 1 is to determine the frequency, spectrum and specificity of p53 gene mutations from the DNA of each CEHS kidney cancer case. Exons 4-9 will be evaluated for mutations using denaturing high-performance liquid chromatography, which will be followed by sequencing to determine the exact nature of the mutation. Aim 2, in collaboration with Environmental Cancer Epidemiology Unit at IARC, is to use the p53 gene mutation data together with the lifestyle and occupational data on the cases to test specific etiologic hypotheses: (A) Is there a correlation between tobacco smoke exposure and p53 gene mutation spectrum? Do the kidney cancer patients with the highest levels of tobacco smoke exposure have a higher prevalence of p53 gene mutation and gene mutation spectrums that resemble the patterns associated with exposure to tobacco in bladder cancer and renal pelvic carcinoma patients? These analyses will be stratified by (i) never smokers versus ever smokers, (ii) duration and (iii) intensity of exposure. (B) Is there a correlation between other suspected risk factors, hypertension and obesity, and p53 gene mutation prevalence and spectrum? (C) Is there a correlation between survival and p53 gene mutation prevalence and spectrum? Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTI MALIGNANCIES

TUMOR

THERAPIES

FOR

GENIOTURINARY

Principal Investigator & Institution: Nanus, David M.; Associate Professor; Medicine; Weill Medical College of Cornell Univ 1300 York Avenue New York, Ny 10021 Timing: Fiscal Year 2004; Project Start 14-SEP-2000; Project End 31-AUG-2005 Summary: Research Plan: The objectives of this proposal are to develop a Genitourinary Oncology Program at NYPH for the treatment of patients with urological tumors involving the activation of state of the art clinical trials, performing laboratory-based studies which will increase our understanding of these diseases leading to improved therapies, and to instruct beginning clinicians in the methodologies of patient-oriented research. The specific aims are 1) to conduct clinical and translational trials for patients with renal cancer, including the study of biologic therapies with liposomal tretinoin plus interferon, and monocloncal antibodies (mAb); 2) To conduct clinical and translational trials for patients with prostate cancer, including the study of mAb muJ591 which recognizes prostate specific membrane antigen (PSMA), and the effects of liposomal tretinoin on biochemical (PSA) relapse; 3) To conduct clinical trials for patients with bladder cancer including chemotherapy for patients with metastatic disease or who are at high-risk for relapse (adjuvant); and 4): To mentor medical oncology fellows and junior faculty in clinical and translational trial design and conduct. This award will allow Dr. Nanus protected time to successfully complete these aims. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ARSENIC AND HEALTH IN BANGLADESH Principal Investigator & Institution: Christiani, David C.; Professor; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2004

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Summary: (Taken from application) Exposure to arsenic has been associated with the induction of cancer in humans. It is widely accepted that arsenic can cause nonmelanoma skin cancers (in particular, squamous-cell carcinoma). In addition, arsenic may be an important cause of bladder, lung, lung, and other internal cancers. We propose to study biomarkers of exposure, skin lesions, skin and bladder cancer, and heritable susceptibility in two populations: one in Taiwan, where remediation efforts have resulted in a reduction in arsenic exposure to ranges of one to three-hold in most US communities; and a second population in Bangladesh, an area recently described with extremely high exposures from drinking-water contamination. We propose a population-based approach, incorporating markers of exposure (drinking-water arsenic, toenail arsenic), susceptibility (genetic polymorphisms in metabolizing genes), and outcome (squamous-cell carcinoma of the skin, bladder, cancer, non-malignant skin lesions) in order to test several hypotheses important to advancing our understanding of the human-health consequence of arsenic exposure. We will conduct a repeat-measures study, designed to evaluate biologic markers including toenail concentrations, methylated arsenic compounds in the urine, and genetic traits. We will also conduct two case-control studies of skin and bladder cancer: one an extension of our ongoing work in Taiwan and the other in Bangladesh. These studies are designed to fill important research gaps in our understanding of arsenic and human health. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ARSENIC EXPOSURE AND BLADDER CANCER IN MICHIGAN Principal Investigator & Institution: Nriagu, Jerome; Professor; Environmental Health Sciences; University of Michigan at Ann Arbor 3003 South State Street, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2004; Project Start 01-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): The objective of this proposal is to explore the factors that have contributed to the observed geographic co-clustering in bladder cancer mortality and arsenic concentrations in drinking water in Michigan. The focus will be on the spatial and spatio-temporal patterns of arsenic exposure and how these may relate to the incidence of bladder cancer in those areas of Michigan with elevated levels of arsenic in their drinking water. Reported arsenic concentrations in well waters in the study area range from 1 to 1310 mg/I, with most common levels being 5-50 mg/L. The project being proposed will consist of three components: (1) Construction of exposure scenarios with time dimension that will involve development of the novel space-time information system (STIS) model to be validated using a combination of space-and-timedependent concentrations of arsenic measured in the study, supplementary historical information on arsenic levels in water supplies, hydrogeochemistry of the area, and selfreported residence information and water drinking habits; (2) Biomonitoring of arsenic exposure to be based on analysis of toenails (known to indicate average exposure over a relatively long time) for arsenic and a number of confounding trace elements such as selenium, zinc, copper and antimony; (3) A population-based, case-control bladder cancer study which will be used as an outcome measure for exposure to arsenic in drinking water. Bladder cancer cases (700) and controls (700, matched to cases by sex, race, and +/- 5-year age groups) will be recruited from long-term residents of the 11 counties (Genesee, Huron, lngham, Jackson, Lapeer, Livingston, Oakland, Sanilac, Shiawassee, Tuscola and Washtenaw) with elevated levels of arsenic in their groundwater. Structured personal interviews will be administered to obtain information on lifetime residential history, current and past water consumption patterns, life-style risk factors (including cigarette smoking and alcohol use), medical history, occupational

Studies

23

history, family history of cancer, and dietary habits. The study is designed to shed some light on the dose-response relations for exposure of the U.S. population to arsenic concentrations in the 5-100 mg/L range where no information currently exists. Current efforts by the U.S. Environmental Protection Agency to reduce the maximum contaminant level for arsenic in our drinking water have been bedeviled by contradictory and unvalidated predictions of the risks of chronic exposure to low levels (< 100 mg/L) of arsenic in water. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ARSENIC MODE OF ACTION IN CANCER--MODELS OF EPIGENIC MECHANISM Principal Investigator & Institution: Kelsey, Karl T.; Professor; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2004 Summary: Arsenic poses unique problems for environmental health scientists in that it is recognized as a human carcinogenic but is not carcinogenic in animal models. Furthermore, arsenical compounds do not induce gene mutations, although they do potentiate the genotoxic effects of other mutagens and are associated with chromosomal abnormalities. These properties indicate that arsenic has a mode of action different from other well-characterized environmental carcinogens whose actions are mediated by DNA damage. One hypothesis is that arsenic acts through epigenetic mechanisms; arsenic may produce reversible cell alterations that influence the expression of genes involved in growth and differentiation. The purpose of this proposal is to investigate the effects of arsenic exposure in the context of an ongoing population based case control study of bladder cancer. We hypothesize that DNA methylation of genes in the causal pathway for disease will occur with a higher frequency in cases with bladder cancer who are also exposed to high levels of arsenicals. Thus, we propose to investigate methylation and mutation of genes in the causal pathway for the genesis of bladder cancer, with special attention to their association with exposure to arsenic. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: BIOMARKERS FOR DETECTION OF BLADDER CANCER Principal Investigator & Institution: Ribeiro-Filho, Leopoldo A.; University of Sao Paulo Caixa Postal 11.273-9 Sao Paulo, Timing: Fiscal Year 2004; Project Start 20-SEP-2002; Project End 30-JUN-2007 Summary: (provided by applicant) The main goal of this project is to investigate the whether inactivation of E-cadherin, Beta and gamma-catenins can be used as biomarkers for bladder cancer initiation / progression or metastasis. Also investigate the molecular mechanisms of inactivation of E-cadherin, Beta and gamma-catenins in bladder cancer through mutation / CpG methylation pathways. We will also investigate the functional role of the E-cadherin, Beta, and gamma catenins genes in bladder cancer. Specific Hypotheses: We hypothesize that inactivation of E-cadherin, Beta, and gamma catenins is associated with stage and grades of bladder cancer. The mechanisms of inactivation of the E-cadherin, Beta, and gamma catenins gene are through mutation/hypermethylation pathways. Transfection of E-cadherin, Beta and gamma catenins genes will suppress growth of bladder cancer cells. To test these hypotheses, we will pursue the following specific aims. Specific Aim # 1. To analyze gene and protein expression of E-cadherin, Beta, and gamma catenins in different stages and grades of bladder cancer. This specific aim is based on the hypothesis that inactivation

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of E-cadherin, Beta, and gamma catenins genes can be detected in early stages of bladder cancer and that the frequency of loss of these genes increases with progression of the cancer process. Under this specific aim, we will determine the gene and protein expression of E-cadherin, Beta, and gamma catenins in normal and different stages and grades of bladder cancer. RNA expression will be analyzed by RT-PCR (for screening) and northern blot (for quantification). Protein expression will be analyzed by immunohistochemistry (for localization) and western blotting (for quantification). Specific Aim # 2. To investigate the mechanisms of inactivation of E-cadherin, Beta, and gamma catenins genes in bladder cancer. This specific aim is based on the hypothesis that mutation / hypermethylation pathways are involved in inactivation of E-cadherin, Beta, and gamma catenins genes in bladder cancer. Under this specific aim, we will first determine the mutation and CpG methylation of E-cadherin, Beta, and gamma catenins genes in different stages and grades of bladder cancer. CpG methylation will be analyzed by sodium bisulfite methylation techniques and confirm by direct DNA sequencing. Specific Aim # 3. To investigate the functional role of E-cadherin, Beta, and gamma catenins genes in bladder carcinogenesis. Under this specific aim, we will test the hypothesis that transfection of the E-cadherin, Beta, and gamma catenins genes in dominant-negative bladder cancer cells can suppress in vitro growth. Under this specific aim, we will transfect these genes and assess their in vitro growth and in vitro invasion assays. Accomplishment of these experiments will provide us with better biomarkers for detection of bladder cancer Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOMARKERS FOR PROSTATE AND BLADDER CANCER Principal Investigator & Institution: Liu, Alvin Y.; Urology; University of Washington Office of Sponsored Programs Seattle, Wa 98105 Timing: Fiscal Year 2004; Project Start 22-SEP-2004; Project End 31-AUG-2009 Summary: (provided by applicant): A strategy based on mass spectrometry proteomics is used to discover biomarkers for prostate and bladder cancer. The markers targeted are proteins secreted by the cancer cells and/or cancer-associated cells. Tumor tissue specimens are obtained from surgically resected organs after pathology. The specimens are digested by collagenase into single cells in a serum-free media. The digestion media, termed COL, is made cell-free by centrifugation, and it contains proteins made by the cells. A matched non-cancer specimen is processed similarly for comparative analysis. Differentially expressed protein species in the cancer and non-cancer COL pairs are screened by a method termed glycopeptide capture followed by tandem mass spectrometry for identification. Since virtually all secreted proteins are posttranslationally modified by the addition of carbohydrate groups this method selectively analyzes these proteins. Quantification is achieved by isotopic labeling of the peptides, i.e. light isotopes for cancer and heavy isotopes for non-cancer. Candidate markers will be validated by Western blotting of the COL samples and immunohistochemistry if specific antibodies are available, or by in situ nucleic acid probe hybridization. This marker discovery process is illustrated by TIMP1, found in our initial experiments. The feasibility of proteomic analysis of urine samples to detect markers will be done. Preliminary experiments have generated a human urinary proteome of 239 protein species. Urine samples will be obtained from cancer patients and age-matched volunteers. The goal is to develop an assay for cancer associated protein markers that can be detected in voided urine for the diagnosis of prostate and bladder cancer. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIOMARKERS OF CARCINOGENESIS Principal Investigator & Institution: Smith, Martyn T.; Professor; University of California Berkeley 2150 Shattuck Avenue, Room 313 Berkeley, Ca 947045940 Timing: Fiscal Year 2004 Summary: Carcinogenesis is known to involve multiple steps of somatic mutation. During the last two decades various biomarkers have been developed to detect early chromosomal and mutational effects of carcinogenic exposure in humans. Although these biomarkers have been shown to be associated with a wide range of carcinogenic exposures, they are not truly biomarkers of early effect as they are not on the causal pathway of environmentally-induced cancers. These biomarkers should be better predictors of increased cancer risk than those currently available. Specific chromosome rearrangements and altered gene methylation are known to be key factors in the development of leukemia, lymphoma, lung and bladder cancer. We plan to develop novel quantitative real time PCR methods for a number of leukemia/lymphoma-related translocations (e.g. 1 (12;21) and t(14;18)) and methylation-specific PCR methods that allow us to examine the methylation status of various cancer-related genes (e.g.p16/INK4a and p14/ARF. We will then make an initial test of the association of some of these markers with non-Hodgkins lymphoma and examine their prevalence in the general population, including newborns. There is currently considerable debate about the presence of translocations in human blood, especially in newborns. In addition, we will perform in vitro cell culture studies with these new markers to examine the nature of the chromosomal damage and aberrant gene methylation produced in critical target cells by the Superfund chemicals, arsenic and benzene. We also plan to use the real-time PCR methods to backtrack leukemia to birth in newborn blood samples from childhood leukemia cases collected under Project 2. This will determine if the translocations or inversions present in the blood of leukemia cases were present at birth and open up new avenues for potentially predicting childhood leukemia. Finally, we will apply the methylation specific-PCR methods to specific genes in leukemia marrow samples collected under Project 2 and in lung and bladder tumors from arsenic endemic areas collected under Project 3, to determine if chemical-specific gene methylation patterns exist in the tumors. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BLADDER CANCER AND URINARY SCHISTOSOMIASIS IN GHANA Principal Investigator & Institution: Shiff, Clive J.; Molecular Microbiology and Immunology; Johns Hopkins University W400 Wyman Park Building Baltimore, Md 212182680 Timing: Fiscal Year 2004; Project Start 01-SEP-2003; Project End 31-AUG-2006 Summary: (provided by applicant): Bladder cancer in Africa is frequently associated with infection by the urinary trematode parasite, Schistosoma haematobium and has been the subject of several hospital-based studies. In fact, a recent review of the topic was unable only to quote any data on the epidemiology and associated risk factor analysis for bladder cancer in Africa. There is a need to establish the role of this condition in endemic areas, and to determine the nature and frequency of various risk factors so that public health authorities can formulate effective control strategies. Recent research has suggested that chronic inflammation due to chronic and repeated insults from microorganisms may increase oxidative stress damage in tissue resulting in genetic changes that set the stage for malignant transformation of tissue. Urinary

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schistosomiasis is a persistent infection of young people that becomes chronic as they age, providing a nidus in the urothelium, which may attract bacteria, viruses and other inflammation stimulants. These, in their plethora may be the source of the repeated insults that contribute to tissue hyperplasia. However, in order to establish the true public health importance of bladder cancer, it is necessary to collect epidemiological data from an endemic area. This can be done in Ghana where S. haematobium is prevalent. Using appropriate sampling procedures, within the limitation of a small grant, sufficient infected individuals can be examined with noninvasive techniques which will provide data on the prevalence and intensity of infection as well as on the existence of biomarkers of cancer and co-infections detected by urine examination. Ultrasound examination will provide evidence for lesions of the urothelium classified for magnitude. Finally where indicated, and with informed consent, invasive examination by collection of biopsy material may be necessary for verification of the nature of any lesion. Cytological examination of urine sediment and subsequent testing of tissue for proteomics analysis in later studies will provide information on the various insults occurring in the bladder and the extent of local inflammatory responses and their association with developing cancer. The study has the potential to be extended in order to consider the mechanism of genetic change and selection of oncogenes on an epidemiological basis, and to assess the frequencies with which these occur in people living in such endemic conditions. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BLADDER TUMOR TARGETING BY INTRAVESICAL PACLITAXEL Principal Investigator & Institution: Lu, Ze; Optimum Therapeutics, Llc 2287 Palmleaf Ct Columbus, Oh 432354215 Timing: Fiscal Year 2004; Project Start 01-AUG-2004; Project End 31-JUL-2006 Summary: (provided by applicant): Superficial bladder cancer is often managed by transurethral surgical resection, followed by intravesical chemotherapy. Mitomycin C (MMC) and doxorubicin are among the most commonly used drugs. Through a series of preclinical and clinical studies, our research group has established that the efficacy of intravesical MMC or doxorubicin therapy is limited by two factors, i.e., inadequate drug delivery to tumor cells and low chemosensitivity of the more rapidly proliferating tumors. We subsequently identified a method to enhance the delivery of MMC to superficial bladder tumors, and tested this method in an NCI-supported international phase Ill trial in 14 academic centers. The results confirm our hypothesis that maximizing the MMC delivery significantly improves the recurrence-free rate from 23% to 43%. This substantial improvement highlights the importance of drug delivery in this treatment modality and the need of finding an agent that is effective in the remaining majority of the patients. Paclitaxel has a number of properties, which render it a good candidate for intravesical therapy of superficial bladder cancer. Because of its high lipophilicity, paclitaxel (when dissolved in water) penetrates the bladder tissues more readily than MMC or doxorubicin. The strong binding of paclitaxel to macromolecules causes it to be retained in the bladder tissue at high concentrations. Further, paclitaxel is active against human bladder cancer, and shows a higher apoptotic effect in more rapidly proliferating tumors. Paclitaxel is also more active in p53-mutated tumors compared to MMC or doxorubicin. Clearly, development of paclitaxel for intravesical application would be promising. However, as shown by our group, the cremophor micelles in the FDA-approved paclitaxel formulation entraps the drug, and significantly reduces the paclitaxel partitioning into the bladder wall, thus ruling out the use of his formulation. To overcome this problem, we have developed two alternative

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formulations, which do not use cremophor, allow rapid drug release, show biological activity in human superficial data cancer cells, and enhanced paclitaxel penetration into bladder tissue. The purpose of this application is to develop these paclitaxel-loaded particles and to select one formulation for future clinical evaluation. The proposed studies will (1) develop rapid-release paclitaxel-loaded particles, (2) evaluate the targeting advantage of these particles, and (3) identify the treatment schedule to deliver an effective drug exposure. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BPDE SENSITIVITY AT 9P21 AND BLADDER CANCER RISK Principal Investigator & Institution: Gu, Jian; Epidemiology; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009 Timing: Fiscal Year 2004; Project Start 01-SEP-2004; Project End 31-AUG-2006 Summary: (provided by applicant): This proposed study will build upon the extensive epidemiologic database and specimen repository derived from an ongoing bladder cancer study entitled “Genetic Susceptibility to Bladder Cancer: A Molecular Epidemiologic Approach” (R01 CA74880, applicant: Xifeng Wu). This parent grant includes a multidisciplinary group of researchers using a molecular epidemiologic approach in a case-control study with the common goal of identifying inter-individual differences in susceptibility to tobacco-induced bladder carcinogenesis. Recent evidence has suggested that sensitivity to benzo[(]pyrene diol epoxide (BPDE), the metabolic product of benzo[(]pyrene (B[(]P), a constituent of tobacco smoke, is a constitutional phenomenon and is a risk factor for several tobacco-related cancers such as lung, head and neck, and bladder cancers. There is a need for further elucidation of the molecular targets of BPDE. Loss of chromosome 9p material is one of the most frequent genomic alterations in bladder cancer. In addition, alterations of 9p21 and p16 are frequently seen in the epithelial cells of chronic smokers. The specific aims of the proposed study are: 1). To determine whether BPDE-induced chromosome aberrations on 9p21 are more common in the cultured peripheral blood lymphocyte (PBLs) of 200 bladder cancer patients than those of 200 controls matched to the cases on sex, age ( 5 years) and ethnicity. Our working hypothesis is that 9p21 BPDE sensitivity may reflect inherited genetic susceptibility of a specific locus to carcinogens in tobacco smoking, that chromosome 9p21 may be the molecular target of carcinogens contained in tobacco smoke, and that individuals with such aberrations are at an increased risk for bladder cancer. 2). To determine frequency of spontaneous 9p21 aberrations occur in cells in urine from 50 cases of bladder cancer patients and whether there is a correlation between level of 9p21 aberrations in lymphocytes and corresponding urine samples. Our working hypothesis is that aberrations in PBLs accurately reflect changes in the target tissue. 3). To assess the associations between the genetic marker and age, sex, cigarette smoking status, and nutrition status by integrating epidemiologic data with the molecular cytogenetic data. These data are being routinely collected in the parent grant. The proposed susceptibility marker may be useful as biomarkers to identify high-risk populations that could then be targeted for intensive smoking-cessation programs and could be enrolled into chemoprevention trials. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BRAIN CANCER ZEBRAFISH XENOTRANSPLANT MODEL FOR DRUG SCREENING Principal Investigator & Institution: Haldi, Maryann L.; Phylonix Pharmaceuticals, Inc. 100 Inman St, Ste 300 Cambridge, Ma 02139

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Timing: Fiscal Year 2006; Project Start 08-SEP-2006; Project End 31-AUG-2007 Summary: (provided by applicant): Metastatic brain tumors occur in approximately 1030% of adult cancers. Many forms of cancer can spread to the brain, the most common being lung cancer, breast cancer, melanoma, kidney cancer, bladder cancer, certain sarcomas, testicular and a number of others. The most commonly diagnosed primary malignant brain tumor of adults is glioblastoma multiforme (GBM). It represents about 30% of all primary brain tumors. The characteristic features of GBM are that they proliferate rapidly and invade adjacent tissue although rarely metastasize outside the brain. Complete surgical removal of GBM is not possible. The prognosis for survival of patients with glioblastoma remains at approximately 1 year, despite aggressive surgery, radio- and chemotherapy. The main obstacle to treatment of brain cancer is the blood brain barrier (BBS). Approximately 98% of all small-molecule drugs and nearly all largemolecule drugs cannot cross this barrier to effectively target brain cancer. In addition active efflux mechanisms exist in brain vessels to pump drugs out of the brain. There is no efficient in vivo model system for testing drug candidates for their ability to thwart the blood brain tumor barrier or the efficient drug efflux mechanisms that reduce the efficacy of chemotherapy for brain cancer. This SBIR aims to develop a zebrafish xenograft model for identifying potential drug candidates for brain cancer. This SBIR will assess embryogenesis, patterning, cancer cell proliferation, the ability of drugs to cross the BBB and their effects on brain tumors. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CALIFORNIA NEVADA ARSENIC AND LUNG CANCER STUDY Principal Investigator & Institution: Smith, Allan H.; Professor; Environmental Health Sciences (Ehs); University of California Berkeley 2150 Shattuck Avenue, Room 313 Berkeley, Ca 947045940 Timing: Fiscal Year 2004; Project Start 22-MAR-2002; Project End 31-DEC-2005 Summary: (provided by applicant): Millions of people are exposed to drinking water contaminated with arsenic, and extensive epidemiological evidence has demonstrated that these exposures can cause cancer. In fact, at high concentrations the levels of risk exceed those of any other known environmental carcinogen. At relatively low exposures such as those commonly found in the U.S., cancer risks from lifetime exposure could be above 1 in 1000 people, even at the newly proposed drinking water standard of 10 micrograms/L. In certain susceptible subpopulations, such as those who smoke or have poor diets, the risks may be even greater. Furthermore, our studies in Chile suggest particularly high risks for those drinking arsenic-contaminated water as children. Unfortunately, cancer risks at low exposures are uncertain since risk estimates to date involve extrapolation from high dose levels to lower exposures where the shape of the dose-response relationship is unknown. Such extrapolations are highly controversial. We therefore propose a population-based case-control study to assess the association of lung cancer with low to moderate levels of arsenic in drinking water. Current evidence indicates that lung cancer may be responsible for more deaths due to ingested arsenic than all other cancer sites combined, including bladder cancer. It is therefore particularly important to obtain a clear picture of the dose-response relationship for this cancer. The study area includes Kings County, California, and six counties in Nevada. These counties incorporate the largest population in the U.S. exposed to water supplies containing between 50 and 100 micrograms/L of arsenic. Most other water supplies in the study region contain less than 5 micrograms/L and thus provide a marked contrast in exposure. A total of 271 lung cancer cases diagnosed in the study area between 2002 and 2004 will be identified with rapid case ascertainment from local hospitals. Tumor

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biopsies will be archived for a potential subsequent study of DNA alterations. Random digit dialing and the rolls of the Health Care Financing Administration will be used to identify two controls for each case, frequency-matched by age and sex. Telephone interviews of all study subjects will be conducted to gather information on lifetime residential history and drinking water sources which will be used in conjunction with water arsenic measurements to construct exposure histories. A strength of the study is that exposure can be reliably ascertained retrospectively since it is largely dependent on residential history. Information on cigarette smoking will also be obtained and synergistic effects with arsenic assessed. Dietary information, medical history, and demographic data will be collected and analyzed for potential susceptibility factors. The proposed study has over 83 percent statistical power to detect a relative risk of 1.7, the risk predicted by linear extrapolation from high dose studies. The study has public health importance since finding the hypothesized relative risk would identify important health effects from low levels of exposure, whereas not finding increased risks would contribute to assurance about public health protection from the new drinking water standard. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CANCER CLUSTERING FOR RESIDENTIAL HISTORIES Principal Investigator & Institution: Jacquez, Geoffrey M.; (Acad) President; Biomedware 516 N State St Ann Arbor, Mi 481041236 Timing: Fiscal Year 2005; Project Start 01-JUL-2005; Project End 31-DEC-2005 Summary: (provided by applicant): This project will develop a new approach for evaluating clustering in case-control data that accounts for residential histories. At present, few if any methods exist for modeling and analyzing residential histories using data from epidemiologic case-control studies. Local, global and focused tests for residential histories will be developed based on sets of matrices of nearest neighbor relationships that reflect the changing space-time geometry of the residential addresses of cases and controls. Exposure traces that account for the latency between exposure and disease manifestation, and that use exposure windows of varying duration will be defined. Several of the methods so derived will be applied to evaluate clustering of residential histories in an ongoing case-control study of bladder cancer in south eastern Michigan. Because humans are mobile, these new methods are a significant advance over approaches that ignore residential histories and instead rely only on place of residence at time of diagnosis or death. The major innovation is the creation of methods for analyzing and modeling the residential histories of cases and controls to identify geographic excesses of cancer risk, both in the study population itself as well as in relation to putative hazards such as point-source releases of carcinogens. The techniques and software to be developed in this project will provide a more concise and accurate description of clustering of cancer cases that accounts for residential history, cancer latency, time of diagnosis, and the exposure windows during which causative exposures are hypothesized to have occurred. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHEMOPREVENTION OF CHEMICALLY-INDUCED BLADDER CANCERS Principal Investigator & Institution: Grubbs, Clinton J.; Professor; Surgery; University of Alabama at Birmingham 1530 3Rd Avenue South Birmingham, Al 35294 Timing: Fiscal Year 2004; Project Start 02-MAY-2002; Project End 30-APR-2006

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Summary: (provided by applicant): Numerous epidemiological studies have established a strong association between cigarette smoking and urinary %+%bold%+%bladder cancer.%?%. The overall goals of this proposal are to evaluate chemopreventive agents and surrogate markers for future clinical trials to prevent cancers in former smokers. The chemically induced urinary bladder cancer model that will be used will allow the correlation of changes in surrogate endpoints with the ability of the agent(s) to inhibit bladder carcinogenesis. The first specific aim will evaluate three classes of chemopreventive agents (lipoxygenase inhibitor, farnesyl transferase inhibitor (FTI), and COX-2 inhibitor) either alone or in combination for efficacy in the prevention of bladder cancers. The agents are esculetin, R115777, and celecoxib, respectively. The second specific aim will measure the expression of survivin in urinary bladder lesions and in urine of rats treated with the carcinogen OH-BBN and/or chemopreventive agents. The rationale for using survivin as a molecular marker/predictor in these studies is twofold. First, increased expression of survivin in cancer versus normal tissues is contributed by associated Ras and secondly, survivin provides a highly sensitive and specific marker of onset and progression of bladder cancer. This is particularly relevant for the chemopreventive experiments with the farnesyl transferase inhibitor R115777 and suggests that monitoring the modulation of survivin expression during this study may provide a molecular indicator of Ras-dependent transformation. The third specific aim will initially determine the effect of R115777 on gene expression profiles as assessed by Affymetrix gene chip analysis to establish new biomarkers that are involved in urinary bladder carcinogenesis and modulatable by chemopreventive agents. The hypothesis is that farnesyl transferase inhibitors will prevent chemically-induced urinary bladder cancers by modulating the expression of genes associated with apoptosis and cell cycle regulation pathways. Depending on the results in the FTI treated rats, additional profiles can be assessed in the celecoxib and esculetin treated animals. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHEMOPREVENTION CARCINOGENESIS

OF

MURINE

URINARY

BLADDER

Principal Investigator & Institution: Kamat, Ashish M.; Clinical Specialist; Urology; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 30-JUN-2006 Summary: (provided by applicant): The incidence of bladder cancer in the United States is increasing with 57,400 new cases projected for the year 2003. The majority of bladder tumors present as superficial papillary transitional cell carcinomas and recurrence rates approach 88% at 15 years. New approaches, including chemoprevention, are needed to reduce morbidity from this disease. Our study proposes to evaluate the hypothesis that two classes of agents - a cyclooxygenase-2 inhibitor and a quinolone antibiotic - either alone or in combination, have chemopreventive activity against superficial bladder cancer. Both these agents have been widely used with minimal toxicity, making them attractive for chemoprevention studies in humans. The first specific aim will study the in vitro effects of these agents on a panel of human bladder cancer cells with varying invasive and metastatic potential in order to obtain insights regarding activity against different grades of human bladder tumors. The second specific aim will evaluate the agents’ chemopreventive efficacy in vivo. For these studies, we will use the transgenic mouse model in which development of papillary tumors in the bladder is driven by the presence of mutant Ha-ras. The tumors in this model mimic the tumors seen in patients who are considered candidates for chemoprevention studies. We will use MRI to image and monitor the tumors within the bladder of the animals since this will provide a rapid

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method to assess the efficacy of the chemopreventive agents. The third specific aim will determine the effects of the chemopreventive agents on tissue pathology and will address the hypothesis that the agents will prevent or inhibit the growth of tumors by inhibiting cell proliferation, inducing apoptosis, or both. We believe that this application will meet the stated goals of the program announcement to evaluate new chemopreventive agents, test strategies to prevent cancer in persons/animals at increased genetic risk, and to develop innovative animal models to mimic the human cancer process in order to expedite research in cancer prevention. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHEMOPREVENTION OF SUPERFICIAL BLADDER CANCER Principal Investigator & Institution: Belldegrun, Arie S.; Associate Professor of Surgery; Urology; University of California Los Angeles Office of Research Administration Los Angeles, Ca 90024 Timing: Fiscal Year 2004; Project Start 07-AUG-2002; Project End 31-JUL-2008 Summary: The overall goals of this grant application are to 1) develop an effective chemoprevention strategy to reduce the risk of bladder cancer recurrence and to 2) investigate surrogate biomarkers that can serve as intermediate endpoints of the interventional efficacy of chemoprevention. Bladder cancer represents an important health problem in the United States and it currently ranks as the fourth most common cancer site in men and the eight most leading site in women. Since these tumors have a very high incidence of recurrence, the psychological and economic burden to the health care system of repeated diagnostic evaluations and therapy are substantial. Bladder cancer is an ideal model for studies of risk assessment early detection, chemoprevention and the development of intermediate biomarkers. Cigarette smoking represents the single most significant, preventable cause of bladder cancer and its carcinogenesis has a long latency period of close to twenty years following initial exposure, providing ample opportunities for intervention. Recently several potential surrogate end point markers have been developed for the detection of the clinically occult, premalignant phase of bladder cancer. These markers include the QFIA biomarker profile (DNA/M344/Actin Associated Protein) urinary basic fibroblast growth factor (bFGF) measurement, and Microsatellite Instability (MI) markers. Using the tumor recurrence rate as a primary end point and the biomarkers as secondary end points, we propose to perform a randomized, placebo-controlled, clinical trial using two promising chemoprevention agents targeting specific biochemical pathways on a cohort of high risk individuals who are former smokers with a grater than 30 pack year smoking history. Eligible subjects will have had a previous episode of low grade, low stage cancer of the bladder who are at high risk to develop disease recurrence, but for whom the standard of care would be observation. We will also construct tissue microarrays using specimens obtained during the evaluation of this clinical cohort to perform present and future translational high throughput studies to study the expression of markers associated with genetic susceptibility and tumor progression, and to identify potential therapeutic targets for cancer prevention. This grant application will involve a multi-disciplinary approached based on organization into program cores. An Administrative Core will perform the overall oversight for all aspects of the proposed work. A Clinical Core will run the clinical trial. The development and evaluation of the proposed biomarkers will be performed by the Biomarker and Nutritional Cores. All tissue samples will be collected and stored, and tissue arrays constructed by the Tissue Core. Finally, the Biostatistics Core will help design the clinical trial and evaluate the measured endpoints. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHEMOPREVENTION OF TOBACCO RELATED CANCER IN ANIMALS Principal Investigator & Institution: Pereira, Michael A.; Professor; Internal Medicine; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2004; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant): Our overall goal is to develop biomarkers for chemoprevention studies of cigarette smoke-related cancers that can be translated to clinical studies in former smokers. To obtain this aim, we propose: Specific Aim 1: Develop biomarkers for chemoprevention of lung cancer in former smokers using a mouse model for lung cancer and related biological and molecular alterations; and Specific Aim 2: Develop biomarkers for chemoprevention of bladder cancer in exsmokers using a rat model for urinary bladder cancer and associated biological and molecular alterations. Our hypothesis is that chemopreventive agents will decrease cancer incidence by modulating and reversing biological and molecular alterations in phenotypically normal tissue, precancerous tissues and tumors. Further, we hypothesize that the modulation of the biological and molecular alterations can be developed as biomarkers for chemoprevention in animal and clinical studies including studies in former smokers. To accomplish Aim 1, lung tumors will be induced in strain A mice by exposure to cigarette smoke, benzo(a)pyrene and 4-(Methyl nitrosamino)-1-(3- pyridyl)1-butanone (NNK) and to accomplish Aim 2, bladder tumors will be induced in F344 rats by N-butyl-N-hydroxybutyl)nitrosamine (OH-BBN). After exposure to the carcinogens including cigarette smoke has ceased the animals will be administered the chemo-preventive agents: budesonide and the farnesyl transferase inhibitor, R115777 in the lung studies and budesonide, ketoprofen and sulindac in the bladder study. Biological and molecular alterations of cell proliferation, apoptosis, methylation of genes (both hypomethylation of protooncogenes and hypermethylation of tumor suppressor genes) and alteration in mRNA and protein expression will be determined in phenotypically normal tissues, precancerous lesions and tumors at different times during the progression to cancer. The ability of the chemopreventive agents to modulate and reverse these biological and molecular alterations in tissue and lesions will be determined in parallel with the ability of the agents to prevent cancer. Thus, biological and molecular alterations that are modulated in parallel with the prevention of cancer by the chemopreventive agents will be indicated as biomarkers for chemoprevention studies including those in former smokers where the agents will similarly be administered after exposure to cigarette smoke had ceased. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CLIN.RELEVANCE OF CIRCULAT.TUMOR CELLS IN BLADDER CANCER Principal Investigator & Institution: Osman, Iman; Assistant Professor; Dermatology; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2004; Project Start 07-MAY-2003; Project End 30-APR-2006 Summary: (provided by applicant): The main objective of this proposal is to define the clinical relevance of detecting circulating tumor cells (CTC) in bladder cancer patients. The specific aims are: 1) To compare the detection rates of CTC for uroplakins (I-Ill), keratins (k19 and k20), and Epidermal Growth Factor Receptor (EGFR) in patients with superficial bladder cancer versus those with metastatic bladder cancer, and 2) To examine the relation between the expression of these molecular markers in primary and metastatic tissue deposits and their CTC detection rate. We propose to test blood

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samples from 50 bladder cancer patients with superficial tumors (expected to have low likelihood of micrometastases) and 50 with grossly metastatic disease (expected to have a high likelihood of micrometastases) using Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR). All patients will be sampled three times over a four week period to increase the positive CTC detection rate. The CTC RT-PCR will be then correlated with presence of disease at the time of the assay to define the most clinically informative marker(s) that provide the best sensitivity, specificity and overall predictive value for the presence of micrometastases. The tissue expression of the molecular markers will be assessed using immunohistochemistry as well as RT-PCR in specimens obtained from patients outlined in aim 1, and the results will then be correlated with the RT-PCR results for CTC. This analysis will help us to understand changes in the tissue expression of these markers during the progression of bladder cancer and how these changes are related to seeding of CTC in the blood. Our preliminary data clearly demonstrate the feasibility of conducting the proposed work as a collaborative effort between New York University School of Medicine and Memorial Sloan-Kettering Cancer Center. This cooperative work endows the study with the strong laboratory and clinical facilities that are necessary for the successful conduct of this type of translation research. We plan this project as a phase I pilot study, in response to the “Pilot and Feasibility Program in Urology” Program Announcement #02-013; we intend to generate sufficient data in order to pursue the development of CTC in a phase II prospective study that will examine the correlation between CTC detection and recurrence in patients with muscle invasive disease following surgical resection of the tumor. We foresee phase III marker development as a multi-institutional study with the goals of independently verifying and validating this correlation prior to considering an application to the FDA for integrating CTC detection as part of the standard of care management for bladder cancer patients. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COLLABORATIVE UROLOGICAL RESEARCH IN SPINAL CORD INJURY Principal Investigator & Institution: Chancellor, Michael B.; Professor; Urology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2004; Project Start 22-AUG-2001; Project End 30-JUN-2006 Summary: (provided by applicant): Urological complications are one of the most common and devastating health problems for SCI patients. Yet this important field has not received significant research attention. Especially lacking is collaboration among urologists, rehabilitation physicists and basic scientists. The Collaborative Urologic Research Program in SCI (CURP-SCI) at the University of Pittsburgh was organized in 1998 to build upon the strengths of the large number of laboratories interested in SCI neurophysiology, cellular biology, tissue mechanics and advanced therapeutics. The goal of the CURP-SCI is to foster collaborative, interdisciplinary research programs with the aim of developing a rational therapy for SCI urologic dysfunction. There are four Projects and three Cores in the Program: Project 1. Mechanisms of detrusor hyperreflexia development after SCI (William de Groat, Pharmacology); Project 2. Alterations in bladder mechanics in SCI (Michael Sacks, Biomechanics); Project 3. Biomarkers of bladder cancer in SCI individuals (Robert Getzenberg, Urology and Pittsburgh Cancer Institute); and Project 4. Novel intervention strategies for neurogenic bladder (Michael Chancellor, Urology). The Cores are: A. Administrative Core (Michael Chancellor); B. Patient and Tissue Banking Core (Rajiv Dhir); and C. SCI Animal Core (William de Groat). Although all four projects will have animal studies, there is also

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focus on clinical correlation and improvement of care for SCI patients. Project 4 (Dr. Chancellor) will bridge a study of intravesical vanilloids in animal models and concurrent clinical trial of intravesical resiniferatoxin (RTX) in neurogenic bladder patients. Projects 2 and 3 will also have direct clinical correlation with analysis of human bladder tissue and urine (Core B). The program is integrated with the regional SCI and MS programs that serve over 2.5 million people. Dr. John Horton, Department of Rehabilitation Medicine, is the Director of the SCI Clinical Program. Diane BorelloFrance, Ph.D., Department of Physical Therapy and Rehabilitation Medicine, will oversee and direct clinical outcome and data analysis. This Program builds on the commitment of the participants to SCI research and the synergistic and collaborative history of the laboratories. It takes advantage of the considerable resources of the university and will be carried out in the more than 25,000 s.f. of fully equipped laboratory and clinical space. This Program is important for the advancement of patient care and basic understanding of SCI and neurogenic bladder dysfunction. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COMPLEMENT INHIBITORS AND IMMUNOTHERAPY Principal Investigator & Institution: Tomlinson, Stephen; Professor; Microbiology and Immunology; Medical University of South Carolina Charleston, Sc 29425 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): Complement is a crucial component of the immune system that can be involved in an effector response to tumor cells, and can also enhance the induction phase of a humoral immune response. Nevertheless, immunotherapy using complement activating antibodies that are specific for tumor-associated antigens has met with only limited success. A significant factor in the resistance of tumor cells to antibody-mediated immunotherapy is the expression of complement inhibitory proteins that are often upregulated on the tumor cell surface. It is hypothesized that the downregulation of complement inhibitors expressed on tumor cells will significantly enhance tumor sensitivity to antibody-mediated immunotherapy and may also enhance the outcome of a normally ineffective humoral immune response. Although frequently upregulated on tumor cells, complement inhibitory proteins remain largely unexplored as targets for cancer therapy due to their widespread expression. For some cancers, intracavitary delivery of a therapeutic reagent to modulate complement inhibitor function may obviate a requirement for specialized targeting strategies. It is proposed to investigate a therapeutic strategy involving intravesical (bladder) delivery of small interfering RNAs (siRNAs) to downregulate complement inhibitory proteins on bladder tumor cells, together with intravenous administration of a complement activating mAb directed against a bladder cancer-associated antigen. Optimum siRNA sequences for downregulation of complement inhibitory proteins on a mouse bladder cancer cell line will be determined in vitro. Selected siRNA sequences will be used to determine optimum strategy for siRNA/gene delivery to tumor cells in an orthotopic syngeneic mouse model of bladder cancer. Naked siRNAs and adenoviral vector delivery of siRNA will be investigated. Finally, the effect of complement inhibitor downregulation on the immune response to bladder cancer in the absence and presence of intravenously administered mAb immunotherapy will be investigated in an orthotopic mouse model. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--MOLECULAR EPIDEMIOLOGY AND ECOGENETICS Principal Investigator & Institution: Spitz, Margaret R.; Professor and Chair; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009

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Timing: Fiscal Year 2004 Summary: The overall goal of this research core is to develop and validate genetic markers for cancer susceptibility. By incorporating molecular genetics and cytogenetics into population studies, the investigators hope to gain insights into the complex interactions between genetic and environmental determinants of cancer. Of particular interest are the low penetrance genes that may modulate one’s response to environmental exposures and contribute to the etiology of sporadic cancers. Specific aims include maintaining and expanding communication and scientific interaction among Core and other Center members, as well as non-Center members; strengthen current and promote future research activities in the area of genetic susceptibility to environmental disease; stimulate and facilitate intra- and inter-Core grant renewals and new investigators-initiated grant proposals; and serve in consultative and collaborative roles across research and facility cores to include concept development, study design, human tissue procurement and environmental data collection. Major areas of research focus in this Core encompass: 1) the assessment of phenotypic markers of DNA damage and repair as markers of susceptibility to carcinogenesis, 2) the evaluation of polymorphisms in select metabolic and DNA repair genes and DNA adducts in the etiology of lung, bladder, breast, and pancreatic cancers, and 3) the development of statistical models for cancer risk assessment by combining biomarkers and for genotypephenotype and surrogate-tissue marker correlation. Intra-Core 4 and inter-Core collaborative studies being conducted or completed include the following: 1) a casecontrol study of lung cancer examining cytogenetic and molecular determinants of tobacco carcinogenesis, 2) a study of genetic and environmental determinants, including phytoestrogen intake, of prostate cancer progression, 3) a genetic epidemiologic study of gliomas in relation to family history and genetic susceptibility markers, 4) a study of microsatellite instability and the risk of bilateral breast cancer, 5) a study of genetic polymorphisms, epidemiologic risk factors and differences in breast cancer survival among different ethnic groups, 6) a study of DNA adducts, P53 mutation spectrum, oxidative DNA damage and breast cancer risk among premenopausal women, 7) a study of molecular genetics of hereditary nonpolyposis colorectal cancer, 8) a study of modifier genes that influence age-associated risk of colorectal cancer, 9) two studies evaluating environmental and genetic determinants of advanced prostate cancer, 10) studies of second malignancies after treatment for hairy cell leukemia, acute myelocytic leukemia, 11) a study of cutaneous malignant melanoma and non-melanoma skin cancer, 12) a study of linkage and linkage disequilibrium, methods for traits, 13) a study of genetic susceptibility of bladder cancer, 14) a study of mutagen sensitivity and progression in Barrett’s esophagus, 15) a study of the genetic, hormonal and behavioral determinants of obesity, 16) a pilot study of breast and colorectal cancers among Egyptians and organochlorine pesticides exposures, and 17) a pilot study to examine associations of mutagen sensitivity, oxidative damage and DNA adducts in lung cancer. The stated long term goal of this Core is to develop a validated risk model for cancer, such as lung cancer, to take into account simultaneously the effects of numerous genetic and environmental factors and the nature of subgroups (women, never-smokers, young subjects, ethnic minorities, etc). Future plans include the use of funds from the Tobacco Settlement for the State of Texas to establish an archival laboratory for the long-term storage and tracking of biological specimens and a centralized genotyping core. It also plans to expand in the area of nutritional epidemiology, and in its molecular epidemiologic studies to include brain and lymphoid malignancies. Future plans also include the development of a genotyping chip, in collaboration with Genometrix, expansion of the CRED website and implementation of multivariate statistical analysis

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to the large database that will be generated by incorporating chip technologies into studies. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--TRANSLATIONAL PATHOLOGY Principal Investigator & Institution: Martin, Sue Ellen.; Associate Professor; University of California Los Angeles Office of Research Administration Los Angeles, Ca 90024 Timing: Fiscal Year 2004 Summary: The Translational Pathology Core Facility provides normal and tumor tissue specimens necessary for many of the laboratory-based, epidemiologic and clinical studies being conducted by Cancer Center investigators. Since the establishment of this facility four years ago, over 9,000 fresh, frozen, OCT or fixed tissue specimens have been provided to over 45 Cancer Center members located at the USC Health Sciences campus and Childrens Hospital Los Angeles (CHLA) to support their peer-reviewed, funded research. The facility is organized into three arms, each with distinct but related functions; one supplies fresh or frozen adult normal and tumor tissue specimens (supervised by Dr. Andy Sherrod, Department of Pathology), another provides pediatric normal and tumor tissue specimens (supervised by Dr. Timothy Triche, CHLA Department of Pathology), and the third provides population-based, fixed tissue specimens primarily for epidemiologic studies (supervised by Dr. Wendy Cozen, Department of Preventive Medicine). Although each arm operates somewhat independently due to the unique aspects of reach type of service, there is overall coordination under the direction of Dr. Sue Ellen Martin, Associate Professor of Pathology. The request process for tissue has a formal, multi-step protocol to ensure that all studies utilizing tissue are judged to be of sufficient scientific merit and have documented approval from the USC or CHLA Institutional Review Board (IRB). Patient identifying information is not released unless the investigator has IRB approval and a signed informed consent from the patient. Examples of past research supported by the Translational Pathology Core Facility includes studies examining the relationship between exogenous hormones and expression of breast cancer markers, DNA-repair mechanisms and hereditary non-polyposis colon cancer, the effectiveness of antiangiogenesis factors on tumor progression, tobacco smoke exposure and p53 expression in lung and bladder cancer, and the function of the BRCA1 protein. Current research supported by the Translational Pathology Core Facility includes identification of genetic markers that predict prostate cancer progression, characterization of the VEGF repertoire in a variety of tumors for targeting a novel and promising anti- angiogenesis factor, studies of genetic determinants of biologic behavior in neuroblastoma tumors, genetic predisposition to and therapeutic response to retinoblastoma; and gene translocation and microarray gene expression in pediatric sarcoma. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COSTS OF OCCUPATIONAL INJURY AND ILLNESS Principal Investigator & Institution: Leigh, J Paul.; Public Health Sciences; University of California Davis Office of Research - Sponsored Programs Davis, Ca 95618 Timing: Fiscal Year 2005; Project Start 01-JUN-2005; Project End 31-MAY-2010 Summary: We will estimate costs of occupational injury and illness using current data and improved methods. Costs will be estimated in the following categories: 1) economic categories of direct (medical, administrative) and indirect (lost earnings, fringe benefits, home production, employer costs); 2) demographic categories involving gender, race,

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ethnic, and age groups, as well as occupations, industries and states; 3) fatal diseases such as asthma, COPD, pneumoconiosis, bladder cancer, lung cancer, coronary heart disease, and renal disease; 4) non-fatal diseases such as dermatitis, carpal tunnel syndrome, hernia, and poisoning; 5) fatal injuries such as homicides and falls; 6) and non-fatal injuries such as amputations, burns, concussions, electric shock, fractures, sprains and strains. We will also conduct an extensive sensitivity analysis to determine how our estimates vary as key assumptions are altered. Fatal disease costs will be estimated by aggregating and cross-classifying data from government surveys, data sets, and reports. We will assign population-attributable risk percents (PAR%) based upon numerous studies that estimate the contribution of occupational exposures to the development of 19 fatal diseases. Indirect morbidity costs will be based on combining regression analyses of work-loss days, restricted activity days and bed days in the National Health Interview Survey with data on earnings (from the Bureau of Labor Statistics (BLS)) and home production. Indirect mortality Costs will use the Biddle model which includes medical cost data from the National Council on Compensation Insurance (NCCI) and a present value equation to estimate lost future earnings and home production. The BLS Annual Survey, adjusted for omissions of government workers and the self-employed as well as under-reporting, will be used to estimate nonfatal injuries and illnesses. Medical and indemnity data from the NCCI will be combined with wage replacement rates to estimate costs in Workers’ Compensation (WC) categories: medical only, temporary partial and total disability, permanent partial disability, and permanent total disability. The Biddle model will be used for fatal injuries. To forecast future costs we will combine our current cost estimates across occupations and industries with BLS 10-year projections for future employment in occupations and industries. An over-riding concern will be transparency. We will explain how estimates are derived and fully disclose all limitations. Another concern will be timeliness. The most recent study dates from 1992. But reported national injury rates have been fallen since 1992. Moreover, Workers’ Compensation costs fell from 1993 to 1998 but have risen since 1999. Current and comprehensive estimates are needed. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DE NOVO DNA METHYLATION IN BLADDER CANCER Principal Investigator & Institution: Jones, Peter A.; Director; Biochem and Molecular Biology; University of Southern California Department of Contracts and Grants Los Angeles, Ca 90033 Timing: Fiscal Year 2005; Project Start 01-MAR-2000; Project End 28-FEB-2010 Summary: (provided by applicant): Bladder cancer is common in the United States and is bnmkjrelatively understudied relative to its public health implications. This project seeks to understand how the epigenetic silencing of apoptotic genes by abnormal methylation of cytosine residues occurs as a function of age and carcinogenesis. We have discovered that we can use the quantitative MethyLight high throughput platform to detect DNA methylation changes in urine sediments, which gives us unique opportunities to study cancer evolution and progression in a longitudinal fashion using a noninvasive sampling technique. We wish to take advantage of the availability of urine sediments to translate our basic science discoveries into strategies which can assist in the identification of recurrent tumors. Since recurrence is a common feature of superficial bladder cancer, the achievements of these goals would have profound impact on the patient’s quality of life. To achieve these goals we will accomplish the following specific aims. First, we will complete the development of a marker panel of CpG islands located upstream and just downstream of the transcription start sites of

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apoptotic genes and verify that methylation observed in urine sediments corresponds with methylation in the primary tumors. Secondly, we will take advantage of the urine sediment system to ascertain how DNA methylation patterns evolve in the urinary bladder as a function of aging. Thirdly, we will conduct consecutive studies on patients who have been surgically treated for either superficial or invasive bladder cancer to determine whether the methylation patterns present at the time of initial surgical excision reappear in the urine sediments before the recurrent tumors can be detected by conventional means. Thus, the achievement of these three specific aims will allow us not only to understand the epigenetics of bladder cancer but also use these fundamental discoveries to better the lives of patients with this disease. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DISCOVERY OF GENOTOXIC BIOMARKERS IN URINE FOR CANCER Principal Investigator & Institution: Giese, Roger W.; Professor; Pharmaceutical Sciences; Northeastern University 360 Huntington Ave Boston, Ma 02115 Timing: Fiscal Year 2004; Project Start 30-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): This project seeks to develop a new methological procedure that has the potential for improving the quality of cancer epidemiological research. The new procedure involves the use of mass spectrometry (MS) to analyze DNA adducts inherent to or derived from urine. The “inherent DNA adducts” will be analyzed for two purposes: (1) as potential biomarkers for human exposure to carcinogens, and (2) as potential biomarkers for the presence and tissue location of cancer. This latter hypothesis is suggested by bringing together the following observations by others: (1) each tissue has a unique pattern of lipophilic, apparently endogenous DNA adducts (as detected by 32P-post-labeling/HPLC); (2) some tissue DNA is spilled into the blood (increasingly so in cancer), and (3) some of the free DNA in the blood ends up in the urine. The “derived DNA adducts” will be obtained by following a published method in which genotoxic chemicals are extracted from smoker’s urine and reacted in the presence of an S9 metabolic activation system with calf thymus DNA. Previous investigators have considered the genotoxic chemicals in smoker’s urine to be the same as the mutagens, which are present. Detection in this project of the three types of DNA adducts (inherentexogenous, inherent-endogenous and derived) will be accomplished by using a method that we have recently developed in which the adducts, after isolation, are labeled with an imidazole substituted mass tag followed by use of matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOFMS). Our new technique is very sensitive and measures the exact masses of a broad range of known and unknown DNA adducts simultaneously, unlike any prior analytical method for DNA adducts. Along with urine samples from control subjects and smokers, urine from patients with renal and bladder cancer will be tested. Urine is an attractive sample for epidemiological studies. The project initiates a collaboration between an analytical chemist and a molecular biologist. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DNA REPAIR AND BLADDER CANCER Principal Investigator & Institution: Andrew, Angeline Sanderson.; Assistant Professor; Community and Family Medicine; Dartmouth College Office of Sponsored Projects Hanover, Nh 03755 Timing: Fiscal Year 2004; Project Start 01-JUL-2003; Project End 30-JUN-2006

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Summary: (provided by applicant): Each year, 51,200 people in the United States are diagnosed with bladder cancer and 10,600 die of the disease. Exposure to environmental chemicals as well as genetic factors play a significant role in initiation of bladder cancer. Epidemiologic investigations have clearly shown an increased risk of bladder and other cancers associated with arsenic exposure, but the level at which it poses a measurable health risk has been the topic of considerable debate, and its precise mechanism of action remains unknown. Furthermore, a number of studies have reported an interaction between smoking, genetic polymorphisms and cancer risk. We will test the hypothesis that polymorphisms in the nucleotide excision repair pathway are associated with increased bladder cancer risk. We will address this hypothesis using exposure data and blood samples collected in a large population-based study of bladder cancer in the New Hampshire (850 cases, 1,365 controls). The specific aims of the project will be to 1) test the hypothesis that genetic variants in the nucleotide excision repair pathway genes (XPD, XPC, XPA, and ERCC1), are associated with increased risk of bladder cancer, and 2) determine whether environmental exposures (arsenic, smoking) and nucleotide excision repair polymorphisms interact to increase bladder cancer risk. This study presents a unique opportunity to clarify how genetic and environmental factors affect DNA repair and contribute to bladder cancer susceptibility. Through our study, we hope to contribute to both our mechanistic understanding of bladder cancer and to identify subgroups of the population that may be at greater risk of environmentallyinduced cancers. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DOSIMETRY OF RISK FOR LUNG AND BLADDER CANCER AMONG CIGA Principal Investigator & Institution: Djordjevic, Mirjana V.; Institute for Cancer Prevention 1 Dana Rd Valhalla, Ny 105951549 Timing: Fiscal Year 2004 Summary: During the past four decades the cigarette consumption in the U.S.A. gradually changed from high-nicotine, high-”tar” to low-nicotine, low- “tar” brands. Concurrently, there was also a gradual shift observed in the major types of cancer and sites within the lung in cigarette smokers. These changes went from predominance of squamous cell carcinoma, located primarily in the bronchi, to adenocarcinoma in the peripheral lung. It is our working hypothesis that the reduction of the smoke yields of U.S. cigarettes and especially that of the addicting nicotine (sales weighted average changed from 2.7 mg in 1955 to 0.85 mg in 1993) resulted in deeper inhalation of the smoke and thus greater exposure of the peripheral lung to cigarette smoke carcinogens. Increased exposure is also to be considered since more intense smoking of low-nicotine cigarettes leads to higher yields of nicotine and certain carcinogens. Four groups of white and African-American male and female smokers of low- (1.2) nicotine cigarettes will be studied to assess the relationship between their smoking habits and their actual exposure to nicotine, “airborne”, and “bloodborne” carcinogens. Currently, the exposure to nicotine and “tar” is assessed on the basis of FTC data. These are established with standard machine-smoking parameters which were developed in 1936. This method does not reflect the smoking habits of today’s cigarette smokers. This project together with the risk estimates established in Project 1 for the major types of lung cancer among smokers of cigarettes with low-, medium-, and high-nicotine content, will result, for the first time, in meaningful estimates of exposure to nicotine and to nicotinederived carcinogens for each of the three classes of cigarettes. The study will also clarify if the low-nicotine cigarette is indeed less “harmful” than the medium- and high-

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nicotine cigarette. This study has major public health implications. Lung cancer remains the leading cause of cancer death in the U.S.A, while the overall mortality rate from lung cancer continues to rise. Currently, cigarette smoking contributes to more than 90% of the lung cancer deaths in American men and to more than 75% in American women. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DRUG METABOLIZING ENZYMES-RISK FACTORS IN BLADDER CANCER Principal Investigator & Institution: Branch, Robert A.; Professor and Director; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2004; Project Start 01-JUL-1994; Project End 30-JUN-2007 Summary: This molecular epidemiology proposal is to continue applying knowledge of pharmacogenomic implications of gene expression of individual drug metabolizing enzymes to assess their role as risk markers for bladder cancer. We propose to use measures of whole body activity for drug metabolizing enzymes using the Pittsburgh cocktail that comprises CYP1A2 (caffeine), CYP2C19 (S-mephenytoin), CYP2D6 (debrisoquine), CYP2E1 (chlorzoxazone) and CYP3A4 (dapsone), as well as mRNA concentrations for each of these CYP enzymes in leukocytes and genotypic identification of known polymorphisms of CYP metabolizing enzymes to include CYP2D6 and CYP2E1. We will assess acetylation using a phenotypic trait measure (dapsone), supplemented by genotyping as well as GSTMI, and GSSTI using genotyping. Our initial work has provided evidence that high activity for CYPD6, low activity of CYP3A4, mutant alleles for acetylation and the null genotype for GSTMI are risk factors for bladder cancer, but to different extent for various forms of this cancer. We have also shown that high CYP2D6 activity is associated with mutations of the retinoblastoma (Rb) gene and low activity of CYP3A4 is independently associated with p53 mutations. Furthermore, different groups of risk factors relate to different mutational spectra of p53. We now propose to extend these observations. Our specific aim is to test the hypothesis that bladder cancer is comprised of a heterogeneous group of diseases in which different groups of associated risk factors relate to disease states that not only vary in etiology, but also in histopathological expression and natural history of the disease. This hypothesis will be evaluated in a case-control study of over 200 patients with incidence presentation of bladder cancer and over 200 controls matched for age, gender and ethnicity, in which environmental and constitutive variables will be related to the disease process. This study will involve a protocol that incorporates an exposure questionnaire, the Pittsburgh cocktail and blood sampling for mRNA quantitation and DNA genotyping. The disease process will be evaluated by clinical assessment and staging, identification of mutations of p53 and Rb genes, blinded histopathological review with grading and following the natural history for the disease. Collectively, these molecular epidemiology studies will improve our understanding of pathogenic mechanisms involved in different forms of bladder cancer and will expand our understanding of the regulation of the gene products that are responsible for drug metabolism in humans. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EFFECT OF G-CSFR EXPRESSION IN BLADDER CANCER Principal Investigator & Institution: Chakraborty, Arup; Medicine; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 770303498

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Timing: Fiscal Year 2004; Project Start 01-AUG-2004; Project End 31-JUL-2006 Summary: (provided by applicant): An increasing number of molecular markers are being identified that correlate with cancer metastasis or a poor prognosis. Typically these markers were examined based on the potential for a biologic activity that would act to enhance cancer cell growth and metastasis. There are also reports of various cytokine or growth factor receptors that are constitutively activated via autocrine or paracrine loops thus supporting cancer cell growth. While granulocyte colonystimulating factor (G-CSF) expression has been shown for a wide variety of cancer cell types, an increasing number of reports are being published regarding the aberrant expression of the G-CSF receptor (G-CSFR) by various non-hematopoietic human cancers and cancer cell lines. Our aim is to clearly demonstrate that G-CSF expression coupled with aberrant G-CSFR expression by transitional cell carcinoma (TCC) can be used as a predictor of more aggressive behavior. We will demonstrate the biological impact of G-CSF/G-CSFR expression in in vitro and also in vivo by using a murine TCC model. Thus the aberrant G-CSFR expression that is being demonstrated by an expanding variety of solid tumors may serve as both a marker of specific tumor cell capabilities impacting clinical outcome and as a mechanism for many of these tumorenhancing functions. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EPIDEMIOLOGY OF ARSENIC Principal Investigator & Institution: Karagas, Margaret R.; Professor; Dartmouth College Office of Sponsored Projects Hanover, Nh 03755 Timing: Fiscal Year 2004 Summary: Overall objectives of the proposed study are to quantify carcinogenesis risks due to arsenic exposure at levels commonly found in the US. This research project shares the goals of the program of the program project of furthering our understanding of the environmental and health effects of arsenic has been identified as a potent skin carcinogen in highly exposed in rural regions of the northeastern US. Arsenic has been identified as a potent skin carcinogen in highly exposed human populations, but it is uncertain whether these effects occur at low levels. We propose to extend our epidemiological case-control study of bladder and skin of bladder and skin cancers in a US population: (1) to further resolve the dose-response relationship between low to moderate levels of arsenic exposure and risk of bladder cancer, (2) to test the hypothesis that arsenic is related specifically to intraepidermal carcinomas (including Bowen’s disease) and multiple concomitant basal cell carcinomas (BCC) of the skin, and (3) to identify subgroups of individuals who may be at high risk of arsenic-associated cancers due to co-carcinogen exposure (e.g., low selenium). We will expand our investigations of individual biomarkers of arsenic exposure by testing the reliability of existing measures (drinking water, urine, and toenails) and exploring new molecular-genetic markers (i.e., based on cDNA arrays). New Hampshire is ideally suited to study the effects of low-dose arsenic exposure since it is one of the few regions of the country with a population-based surveillance system for non- melanoma skin cancer and over 20% of the private wells in the region contain levels of arsenic suspected of being carcinogenic. New Hampshire has unusually high bladder cancer mortality rates which are as yet unexplained, and there is accumulating evidence that these malignancies may result from arsenic ingestion. Thus, our study provides a unique opportunity to obtain results directly applicable to the US population and to help identify those at greater risk for arsenic-induced malignancies. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EPIGENETIC REGULATION BY POLY(ADP-RIBOSE) IN RESPONSE TO ARSENITE Principal Investigator & Institution: Jung, Mitchell C.; Assistant Professor; Biochemistry, Molec & Cell Biology; Georgetown University 37Th and O Sts Nw Washington, Dc 20057 Timing: Fiscal Year 2006; Project Start 25-SEP-2006; Project End 30-JUN-2008 Summary: (provided by applicant) Chronic arsenic exposure endangers millions of people with skin alterations, peripheral vascular disease, and cancer, including skin, lung, and bladder cancer by, in part, altering gene expression. Increasing evidence demonstrates that epigenetic mechanisms could regulate gene activation or silencing. Therefore, epigenetic regulation could be a part of the mechanisms for arsenic-induced toxicity. Poly(ADP-ribose) polymerase-1 (PARP-1) covalently modifies histones with poly(ADP-ribose), a negatively charged polymer. Poly(ADP-ribosyl)ation of nucleosomal histones alters chromatin structure and is thus thought to regulate chromatin template-dependent processes including gene transcription. Recently, PARP1 has been shown to regulate stress-induced gene transcription. The overall hypothesis is that chromatin-associated PARP-1 covalently modifies nucleosomal histones with poly(ADP-ribose), and poly(ADP-ribosyl)ated histone(s) epigenetically regulates gene transcription in response to arsenite. The specific aims are to (1) determine the level and patterns of poly(ADP-ribosyl)ated histones in response to arsenite exposure, (2) elucidate the cellular mechanism that can alter the level of pADPr-histones in response to arsenite, (3) determine poly(ADP-ribosyl)ated histone(s) at the chromatin promoters of arsenite-induced target genes, and (4) determine the impact of a PARP enzymatic inhibitor on other arsenite-induced epigenetic markings. The significance of the proposed studies is to offer new insights into the epigenetic mechanism(s) by which poly(ADP-ribosyl)ation of histone(s) may regulate and be regulated to achieve stress response gene transcription in response to arsenite exposure. This mechanism of poly(ADP-ribosyl)ation may be especially adapted to facilitate sudden bursts of efficient transcription activity and therefore is critical for the outcome of environmental exposure. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FULL POLARIZATION CHARACTERIZATION BY OCT Principal Investigator & Institution: Wang, Lihong; Professor and Director; Biomedical Engineering; Texas Engineering Experiment Station 3000 Tamu College Station, Tx 778433000 Timing: Fiscal Year 2004; Project Start 01-JUN-2003; Project End 31-MAY-2007 Summary: (provided by applicant): The long-term objective of the proposed research is to develop a novel, non-invasive tool for microscopic imaging of superficial lesions, including cancers and burns. The short-term goal is to apply the proposed technology in small-animal imaging. The proposed technique, Mueller-matrix optical coherence tomograph, (OCT), can image in real time the complete polarization properties of intact biological tissues for the first time at the microscopic scale (about 10 microns) in vivo. Optical polarization properties are sensitive indicators of physiological states such as the collagen content and abnormalities of biological tissues such as necrosis, and they can provide novel contrast mechanisms for imaging. Initially, this technology will likely have an impact on small-animal experimental studies because it can reduce the number of animals needed and the time required to conduct a study and can also improve the temporal correlation of a study. In addition to the immediate applications, this

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technology has the potential to detect various superficial human diseases--such as oral, skin, cervical, colon, and bladder cancers as well as skin burns--that can be accessed either directly or endoscopically as already demonstrated by conventional OCT. Mueller matrices can completely characterize the polarization properties of any material. The applicants’ group pioneered Mueller-matrix OCT and demonstrated that this new imaging modality reveals tissue structures that are not observable with conventional OCT. Striking polarization contrast has already been shown in burns by Mueller-matrix OCT. The specific aims of the proposed research are as follows, in which the animal experiments will have dual foci: the imaging of skin cancers (animal model 1) and the imaging of burns (animal model 2). Aim 1. Develop a free-space Mueller-matrix OCT system to image Mueller matrices of biological tissues with both depth and lateral resolutions in real time. Aim 2. Characterize the capability of the proposed system and understand the origin of OCT polarization contrast by imaging tissue samples ex vivo. Compare the Mueller-matrix images with the corresponding histological results from both conventional and polarization light microscopes and identify the relationships between the Mueller-matrix images and the histological structures. Aim 3. Further develop the free-space Mueller-matrix OCT system using fiber optics and construct a hand-held probe for in vivo applications. Compare the experimental results from the fiber-optic system with those from the original free-space system. Aim 4. Characterize the capability of the proposed hand-held probe by imaging skin cancers in vivo in a mouse model (animal model 1). Detect the location, size, and Mueller-matrix contrast of skin cancers in comparison with the histological results from both conventional and polarization light microscopes. Analyze and characterize the temporal progression of skin cancer in the animal model. Aim 5. Characterize the capability of the proposed hand-held probe by imaging skin burns in vivo in a mini-pig model (animal model 2). Detect the lateral extent, depth, and Mueller-matrix contrast of skin burns in comparison with the histological results from both conventional and polarization light microscopes. Analyze and characterize the temporal healing process of burns in the animal model. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENDER DIFFERENCES IN BLADDER CANCER RISK FACTORS Principal Investigator & Institution: Loffredo, Christopher A.; Assistant Professor; Oncology; Georgetown University 37Th and O Sts Nw Washington, Dc 20057 Timing: Fiscal Year 2006; Project Start 11-APR-2006; Project End 28-FEB-2011 Summary: (provided by applicant): Cancer of the urinary bladder affects 4 to 5 times more men than women worldwide. Cigarette smoking, occupational exposures and infection with Schistosoma haematobium are well-established risk factors for this malignancy. Furthermore, several genetic polymorphisms have been associated with increased bladder cancer risk. Important gaps in knowledge remain about synergistic effects between environmental factors, gene-environment interactions, and gender differences in bladder cancer risk factors. Egypt represents a unique setting for such research, as bladder cancer continues to be the most common malignancy in men in Egypt despite recent reductions in schistosomiasis, and the ratio of men to women remains consistently high; few women in Egypt smoke cigarettes (< 5%) compared to 50-70% of men; and in addition to the transitional cell type carcinoma that is predominantly observed world wide, squamous type carcinoma is very common in Egypt. We therefore propose to conduct a case-control study of bladder cancer in Egypt, with a sample size of 3,312 cases and 4 population-based controls per case. The Specific Aims of the study are as follows: 1) to evaluate environmental risk factors for bladder cancer, in men and women combined, including infections, and interactions among

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these factors; 2) to determine if associations between risk factors and bladder cancer are affected by gender; 3) to evaluate associations between bladder cancer risk (in men and women combined) and functional polymorphism in genes that mediate the oxidative stress response; 4) to evaluate interactions between environmental exposures and the candidate susceptibility genes, and to determine if gene-environment interactions exert differential effects on bladder cancer risk in men and women. Within these aims we will account for risk differences by histological type of bladder cancer (transitional vs. squamous). The results of this study will help establish the best preventive measures for bladder cancer in men and women, by appropriately directing the resources of the public health sector for effective cancer control. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENES & PROTEINS OF UROTHELIAL-ECM INTERACTION Principal Investigator & Institution: Hurst, Robert E.; Professor of Urology; Urology; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 731171213 Timing: Fiscal Year 2005; Project Start 01-APR-2005; Project End 31-MAR-2010 Summary: (provided by applicant): The urothelium lines the bladder and protects it from bacteria and toxic or carcinogenic substances in the urine by maintaining an impermeable barrier. Although this functions remarkably well, it fails in bladder cancer, interstitial cystitis, and possibly other diseases as well. Understanding how the urothelium grows and differentiates and carries out its function may provide important clues to the diagnosis and treatment of bladder diseases. Although urothelium can be cultured, most models fail to adequately model the interactions between the urothelium and the underlying stroma. Together the two form a complex and interacting system. This proposal describes studies to meet the requirements of a PAR to develop cellselective tools, specifically item (8) identification of cell specific markers to aid studies of epithelial-stromal interactions in normal and malignant tissues and secondarily item (5) discovery of biomarkers that indicate health or mass of individual cell types and item (1) discovery of genes selective to individual cell types. Novel methods for growth of urothelium as an artificial tissue in 3-dimensions and for bladder cancers as artificial tumors on both normal and cancer-modified matrix provides a basis for discovering the genes and proteins involved in defining normal and malignant urothelium. In a first discovery phase, microarrays and a novel proteomics approach with 2-D chromatography will be combined with innovative bioinformatics approaches to identify candidate genes and proteins. A public database of gene expression and protein levels will be constructed. Candidate genes/proteins will be validated sequentially, first by data mining and informatics to identify plausible mechanisms and to compare with other expression data, then biochemically by immunohistochemistry or quantitative PCR. A limited number of the most interesting genes will be investigated in greater depth in a second phase of hypothesis testing. Expression will be forced in cell lines not expressing a gene or knocked down in those that do. The “deliverables” will be sets of genes and proteins subjected to several levels of verification for their role in aiding studies of epithelial-stromal interactions in normal and malignant tissues. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC & ENVIRONMENTAL RISK FACTORS FOR BLADDER CANCER Principal Investigator & Institution: Pike, Malcolm C.; Professor of Epidemiology; Preventive Medicine; University of Southern California Department of Contracts and Grants Los Angeles, Ca 90033 Timing: Fiscal Year 2006; Project Start 01-JUL-2006; Project End 31-MAY-2010 Summary: (provided by applicant): Occupational exposure to arylamines used in the manufacturing of industrial dyes was the first known cause of human bladder cancer. These carcinogenic arylamines, specifically, 4-aminobiphenyl (4-ABP), betanaphthylamine, and benzidine, are also contained in tobacco smoke, and are the most likely causative agents responsible for the raised rates of bladder cancer in smokers. Oxidation of arylamines is recognized as a critical first step in turning these chemical species into their carcinogenic metabolites capable of causing DNA damage to urothelial cells. Hair dyes represent another substantial source of arylamines in humans, and we recently showed that sustained use of permanent hair dyes in women is a risk factor for bladder cancer, especially among those deficient in arylamine detoxifying enzymes. Subsequently, 4-ABP was detected in bottles of commercial hair dyes bought in a US store. Then, using hemoglobin adducts of 4-ABP as a biomarker of exposure, we showed that other, presumably diffuse, sources of 4-ABP exposure may be related to bladder cancer in nonsmokers. Thus, the latest evidence indicates arylamine exposure as the primary cause of bladder cancer in the United States. Ten years ago, we reported that a reason for the 3-fold increased risk of bladder cancer in US white versus Chinese men despite their comparable smoking habits may be the higher prevalence in the former population of individuals with deficient arylamine-detoxifying enzymes, which are under genetic control. We capitalized on this finding and launched a population-based case-control study involving both a Los Angeles and a Shanghai, China component to explore genetic factors that play a major role in determining bladder cancer risk in arylamine-exposed individuals. This already completed database consists of roughly 1300 cases of incident bladder cancer (750 cases in Los Angeles, 550 cases in Shanghai) and about an equal number of control subjects. Our initial goals were to investigate the roles of selected polymorphic, arylarnine-metabolizing genotypes/phenotypes in bladder cancer, and in the Los Angeles component, to use hemoglobin adducts as biomarkers of exposure to arylamines in examining nonsmoking-related bladder cancer. In this application, we aim for a more comprehensive understanding of the arylaminebladder cancer etiologic link through the following extensions on our Los Angeles/Shanghai database: (1) Completion of arylamine hemoglobin adduct measurements on Shanghai subjects in order to compare the respective effects of these adducts on risk between Los Angles and Shanghai study subjects; (2) Addition of genotypes involved in arylamine metabolism, in cellular response to oxidative stress and in DNA repair; and (3) Development of a Bayesian hierarchical statistical model to allow for an efficient, pathway-driven examination of multiple gene-arylamine interactions in bladder cancer. The ultimate goal of this research is to assess individual bladder cancer risk for the purpose of preventive interventions. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC MARKERS OF BLADDER CANCER PROGRESSION Principal Investigator & Institution: Waldman, Frederic M.; Professor; Pathology; University of California San Francisco 3333 California St., Ste. 315 San Francisco, Ca 941430962 Timing: Fiscal Year 2004; Project Start 05-JUL-2001; Project End 31-JAN-2006

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Summary: The goal is to identify and validate tumor markers, which predict the outcome of patients with bladder cancer. Analyses of tumor material will be done to define genetic and expression alterations in each tumor, to associate these alterations with the tumor stage, with other clinical characteristics of the tumor, and with the patient’s clinical course. High throughput analyses using genomic slide-based arrays comprised of human BAC genomic probes at 1 mb density, and gene expression arrays comprised of more than 7,000 human cDNA clones, will be applied to human bladder tumor samples. Tumor will be grouped by stage in order to identify correlated sets of genes for each group. These gene sets will then be used for testing of prognostic utility in separate sets of patient samples. The Specific Aims are: Aim 1. Genetic Alterations During Bladder Cancer Progression. We will test the hypothesis that pathways of tumor progression are genetically defined. DNA copy number and RNA expression alterations will be identified in groups of tumor according to stage of bladder tumor progression. A. Low Grade Superficial Disease (150 pTa tumors). B. High Grade Superficial Disease (100pT1 tumors and 50 pTis). C. Muscle Invasive Disease (150) tumors will be used to identify patterns of genetic alterations and expression changes according to stage. D. Stromal changes in superficial and invasive cancer: Tumor fibroblasts prepared by collaborators (Drs. Hayward) will be used to define altered gene expression patterns in the tumor stroma (compared to fibroblasts away from the tumor). Candidates genes identified in these studies will then be tested for association with tumor stage. Aim 2. Genetic Alterations as Predictors of Clinical Outcome. Candidate gene alterations identified in Aim 1 will be tested for association with clinical outcome. A. High risk superficial tumor. We will test the utility of candidate gene markers will be tested in separate patient groups for association with outcome after treatment with intravesicle BCG and Gemcitibine. A. High risk muscle invasive tumors. Molecular markers will be tested in patients with node positive tumors who receive no further treatment, and in separate patient groups, as markers of response to MVAC therapy, and as markers of response to taxanes. C. Validation of Candidate Markers with Tissue Arrays. We will use tissue arrays to validate markers which are identified in Aim 1 and tested in Aims 2A-B. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GROWTH, DIFFERENTIATION AND DISEASE OF UROTHELIUM 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 2004; Project Start 01-MAR-1999; Project End 30-JUN-2009 Summary: During the past four and half years (since March 1, 1999), we have worked closely as a team consisting of five investigators with diverse expertise in the areas of epithelial cell biology, structural biology, membrane trafficking, and cancer biology to study, in four closely interrelated projects, the cell and molecular biology and diseases of mammalian urothelium. This Program Project focuses on, as a central theme, a group of integral membrane proteins called uroplakins that represent major differentiation markers of mammalian urothelium. During the last (first) granting period, our team has made several major advances including the knockout of uroplakin II and III genes elucidating the biological functions of uroplakin and yielding mouse models of vesicoureteral reflux; the demonstration that uroplakin heterodimer formation in ER is an early step of AUM assembly; the identification of Rab27b as a urothelium-enriched GTPase that may play a role in targeting uroplakin vesicles to the apical surface; the identification of uroplakin Ia as the receptor for typelfimbriated E. coli causing urinary tract infection; the localization of the uroplakin Ia receptor on the 6 inner subdomains of

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the 16 nm uroplakin particle; the visualization of mouse AUM by cryo-EM at 10 A resolution thus providing a structural basis for the permeability barrier function of urothelial plaques; and the generation of several well-characterized transgenic mice expressing specific oncogenes in their urothelia allowing a systematic study of the pathways of bladder cancer formation. Our team has therefore functioned well in pursuing biologically important problems related to urothelial growth, differentiation and diseases; in having synergetic interactions and extensive collaborations; in effectively sharing resources; and in having made significant progresses. During the next five-year grant period, we will continue to work as a team to pursue the following aims: What is the pathophysiological consequences of uroplakin ablation and how do urothelial plaques interact with other cytosolic and membrane proteins (Project 1)? What are the roles of different uroplakin subdomains in plaque assembly, and how are the uroplakin vesicles delivered and targeted to the urothelial apical surface (Project 2)? How do the individual uroplakins assemble into the 16 nm particle and whether these particles undergo conformational changes in respond to bacterial binding (Project 3)? What kind of oncogenic changes underline the various pathways of bladder tumorigenesis (Project 4)? Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEDGEHOG SIGNALING LINKS BLADDER INJURY AND CANCER Principal Investigator & Institution: Berman, David M.; Molecular Biology and Genetics; Johns Hopkins University W400 Wyman Park Building Baltimore, Md 212182680 Timing: Fiscal Year 2006; Project Start 01-JUL-2006; Project End 30-APR-2011 Summary: (provided by applicant): A variety of environmental insults induce the normally quiescent urothelium to mount a transient proliferative response and restore homeostasis. However, some insults, especially those with both potent mitogenic and mutagenic activities, lead to persistent urothelial proliferation that can progress to cancer, including urothelial (transitional cell) carcinoma, the most common cause of bladder cancer death in the United States. A better understanding of the events that promote bladder repair and influence the decision between a return to quiescence vs. prolonged growth and cancer formation could lead to improved therapies aimed at promoting normal growth or repair or controlling cancer. Based on extensive preliminary evidence, this application investigates the hypothesis that signaling by the Hedgehog (Hh) family of secreted morphogens promotes urothelial proliferation in response to chemical insults and becomes constitutively active in urothelial cancers. Mechanistically, we propose that Hh signaling in bladder injury repair is induced by expression of the 7 transmembrane span protein Smoothened (Smo), and activates several aspects of the malignant phenotype, including enhance proliferation, epithelial to mesenchymal transition (EMT), and cell motility. Since repair of tissue injury appears to be the proliferative stimulus resulting from exposure to chemical carcinogens, our findings suggest that urothelial carcinoma may originate as part of an epithelial repair program. To test this hypothesis, we propose a series of experiments to characterize the expression and roles of Hh pathway activity in urothelial homeostasis and carcinogenesis. The Aims to be pursued are: 1) To characterize the induction of Hh signaling, EMT, and stem cell activation in regenerating urothelium. 2) To test the effects of Hh pathway blockade on urothelial injury repair; 3) To test whether Hh signaling is necessary for urothelial carcinoma growth. 4) To test whether continuously enforced Hh signaling is sufficient to induce urothelial carcinogenesis. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HIGH TECHNOLOGY

PRODUCTIVITY

EUKARYOTIC

CELL

CULTURE

Principal Investigator & Institution: Felder, Robin A.; Professor of Pathology, Director Medical; Medical Robotics, Inc. 909 King St Charlottesville, Va 22903 Timing: Fiscal Year 2004; Project Start 01-AUG-2004; Project End 01-JUN-2006 Summary: (provided by applicant): The goals of this project are to develop a method to increase eukaryotic cell production and cell quality for research and drug discovery. We have preliminary data that demonstrates that we have developed a neutral buoyancy hydrogel based microcarrier process that can dramatically increase the density, viability, and diversity of cells available to researchers while dealing with their limited space and increase productivity needs. Our novel microcarrier based cell culture process allows anchorage dependent cells to be transferred from the growth media directly into an analytical process without the need to use trypsin (or other means) to remove cells from their anchorage surface. Our microcarriers are optically clear and do not exhibit any autofluorescence, thus they are ideal for light based microscopy and in vitro fluorescence studies. We have demonstrated that the density of the microcarriers can be manipulated though the addition of glass bubbles and paramagnetic particles to allow suspension growth without the use of impellers. Non-contact magnetic manipulation permits the entire cell growth process to be used with laboratory automation. Given our preliminary data, this proposal is centered on three specific aims: 1. We will refine our preliminary method for producing neutral buoyancy microcarriers that are optimized for the growth of a variety of prostate cancer and bladder cancer cells in order to make them microcarriers available to cancer center research scientists for user feedback. 2. We will culture cells on our novel microcarriers in order to measure cell viability, density, and morphology. 3. We will develop a conceptual framework for the design of an automated cell culture system based on our many years of experience in laboratory automation and cell culture. Our novel neutral density microcarriers will improve the productivity, quality, and availability of eukaryotic cells for research scientists. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HIGH THROUGHPUT GENETIC ANALYSIS OF BLADDER CANCER Principal Investigator & Institution: Sidransky, David; Professor; Otolaryngology/Head and Neck Surgery; Johns Hopkins University W400 Wyman Park Building Baltimore, Md 212182680 Timing: Fiscal Year 2005; Project Start 01-DEC-1999; Project End 30-NOV-2009 Summary: (provided by applicant): A program project is proposed by researchers at the Johns Hopkins Medical Institutions and the University of California at Berkeley entitled, “High Throughput Genetic Analysis of Bladder Cancer and Urine Sediment.” The goals of this proposal are to improve our understanding of the molecular genetic changes that drive bladder cancer progression as we develop and integrate novel high throughput approaches for the detection of these genetic alterations. These approaches will be used to translate our findings into the clinical setting where we will evaluate genetic alterations as predictors of disease outcome and targets for molecular detection. Unlike traditional methods of isolated investigators, this program emphasizes sharing of subjects, tissue samples, resources, technical expertise and data analysis strategies. Our program will not only offer clinical direction for basic research efforts, but will also facilitate the direct translation of state of the art high throughput technology into the basic laboratory and clinical arena. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IDENTIFICATION OF GENES INVOLVED IN BLADDER CANCER Principal Investigator & Institution: Clifford, John L.; Biochemistry and Molecular Biology; Louisiana State Univ Hsc Shreveport 1501 Kings Hwy Shreveport, La 711303932 Timing: Fiscal Year 2006; Project Start 25-SEP-2006; Project End 30-AUG-2008 Summary: (provided by applicant): Project Summary: Transitional cell carcinoma of the bladder (TCC) ranks 4th in incidence of all cancers in the developed world, yet the mechanisms of its origin and progression remain poorly understood. There are also few useful diagnostic or prognostic biomarkers for this disease. The long-term aim of this proposal is to determine molecular mechanisms involved in early and late steps in the development of TCC. In addition we hope to identify new biomarkers for detection, diagnosis and prognosis of TCC. To accomplish this we will use a mouse model for bladder cancer in which the SV40 large T antigen (SV40 T) is expressed under the control of the uroplakin promoter, which restricts expression to the bladder urothelium. These mice (UPII- SV40T) develop TCC, which is preceded by a condition resembling human CIS. The hypothesis underlying this proposal is that there are differences in gene expression profiles and gene regulatory networks between invasive TCC and CIS and between CIS and distant normal appearing urothelium, and that these changes are indicative of the malignant state. This hypothesis is based on the multistep carcinogenesis concept. An extension of our hypothesis is that CIS is an intermediate step between normal urothelium and invasive TCC and that there should be changes in gene expression corresponding to this intermediate state. The specific aims are: 1. Identify the genes and gene regulatory networks that are differentially expressed between the normal urothelium of nontransgenic and UPII-SV40T mice, CIS and TCC, using Affymetrix GeneChip(r) Arrays. The relevence of individual genes to human TCC will be validated by assessing expression of the human homologs in patient TCC and normal urothelium specimens. In silico analysis of the microarray data, which includes generating gene expression profiles (clustering analysis) and the development of promoter models based on the promoter sequences of the differentially expressed genes will be performed. 2. Assess the function and potential relevance to bladder carcinogenesis of these genes in vivo by stable overexpression, or siRNA-mediated suppression, of the validated genes in human bladder-derived cell lines. Relevence: Completion of these studies should advance our understanding of the molecular events underlying TCC development. In addition, the identification of genes differentially expressed between normal urothelium, CIS and TCC will provide much needed diagnostic and prognostic markers for this disease. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INTRAVESICAL RF-GMCSF AND RF-TRICOM IN THE TREATMENT OF ADVANCED BLADDER CANCER Principal Investigator & Institution: Lattime, Edmund C.; Professor; Surgery; Univ of Med/Dent Nj-R W Johnson Med Sch Robert Wood Johnson Medical Sch Piscataway, Nj 088548021 Timing: Fiscal Year 2006; Project Start 08-AUG-2006; Project End 31-JUL-2008 Summary: (provided by applicant): The overall goal of this proposed treatment strategy is the development of effective systemic immunity to bladder cancer following the rationally designed manipulation of the bladder microenvironment. For a number of years, we have focused on characterizing immune parameters at the tumor microenvironment as a means of identifying targets for manipulation with the ultimate

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goal of inducing tumor-specific immunity. Our novel hypothesis that manipulation of the tumor microenvironment via gene transfer using poxvirus recombinants led us to perform a series of Phase I studies of intralesional wild type vaccinia and recombinant vaccinia encoding GM-CSF in melanoma and subsequently intravesical wild type vaccinia in bladder cancer. Our current study of intravesical gene transfer in bladder cancer is a direct translation of our preclinical studies and early clinical trials. This study, required by the FDA as it represents a first-in-man intravesical administration of recombinant poxvirus, provides us a unique opportunity to assess critical questions as to the ability to modulate the bladder microenvironment with the ultimate goal of engendering a positive immune response. We have chosen agents, rF-GM-CSF and rFTRICOM, based on our preclinical studies demonstrating depressed antigen presentation associated with the tumor-associated cytokine profile. In addition, we are using recombinants with the reporter gene B-galactosidase (B-gal) to not only quantitate efficiency of transfection but also as an antigen with which to study the ability to immunize via the bladder compartment which has not been done previously. These studies will provide critical data for subsequent use of recombinant poxvirus recombinants as local/systemic therapy for bladder cancer. More specifically, we propose to: 1. Determine local and systemic toxicity associated with the intravesical instillation of rF-GM-CSF and/or TRICOM and establish an MTD/Phase II dose. 2. Determine the efficiency of infection/transfection of the urothelium arid tumor following intravesical rF-GM-CSF and/or rF-TRICOM 3. Define the localized immune response in the bladder following intravesical rF-GM-CSF and/or rF-TRICOM and 4. Assess the ability to immunize bladder cancer patients via the bladder compartment. We believe that the results of these studies will provide critical insights as to the ability to use intravesical gene transfer as a therapeutic modality for bladder cancer and allow us an enhanced ability to design critical Phase II trials. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ISOTHIOCYANATES IN THE CHEMOPREVENTION OF BLADDER CANCER Principal Investigator & Institution: Zhang, Yuesheng; Roswell Park Cancer Institute Corp Elm & Carlton Streets Buffalo, Ny 14263 Timing: Fiscal Year 2004; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): This Project focuses on determining the cancerpreventive activity of isothiocyanates (ITCs) in the bladder. The hypothesis to be tested is that selected ITCs can suppress bladder carcinogenesis by disrupting multiple steps in the carcinogenic process: induction of Phase 2 enzymes, induction of apoptosis, and inhibition of cell proliferation. Molecular markers relevant to these biological events, as well as inhibition of tumorigenesis, will be studied. Bladder cancer is an important health problem; effective chemopreventive agents are needed. ITCs are abundant in vegetables and many are known anticarcinogens in non-bladder animal organs. Ingested ITCs are efficiently absorbed and almost exclusively excreted in urine as Nacetylcysteine conjugates (NAC-ITCs), which also are anticarcinogens and can release ITCs, making the bladder epithelium the most exposed tissue to ITCs/NAC-ITCs. The overwhelming majority of bladder cancers originate from the epithelial cells. Four dietary ITCs that displayed potent anti-carcinogenic activity in non-bladder animal organs and their NAC conjugates will be evaluated. Aim 1 is designed to see whether ITCs or NAC-ITCs effectively induce critical Phase 2 detoxification enzymes, including glutathione transferase, quinone reductase-1, and UDPglucuronosyltransferase, whose deficiencies have been linked to increased bladder carcinogenesis. Aim 2 will determine

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the protective efficacy of ITCs or NAC-ITCs against carcinogen-induced DNA damage in bladder epithelial cells, using total DNA adducts and unscheduled DNA synthesis (UDS) as markers. Imbalance between apoptosis and proliferation also is a risk factor of bladder cancer. Aim 3 will determine whether ITCs or NAC-ITCs can correct the imbalance between apoptosis and proliferation associated with bladder carcinogenesis: Do ITCs or NAC-ITCs induce apoptosis and/or inhibit cell cycle progression in bladder cancer cells? If so, what is the underlying mechanism(s)? Aim 4 will evaluate in rivo the effect of orally administered ITCs on important biomarkers, including the Phase 2 enzymes described in Aim 1, apoptosis (TUNEL), and proliferation (PCNA) in the bladder epithelium of F344 rats. Aim 5 will determine the efficacy of an orally administered ITC in inhibiting N-butyl-N- (4-hydroxybutyl)-nitrosamine-induced bladder tumorigenesis in F344 rats. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: KAVA EXTRACT, FLAVOKAWAINS AND BLADDER CANCER PREVENTION Principal Investigator & Institution: Zi, Xiaolin; Assistant Researcher; Urology; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2004; Project Start 13-JUL-2004; Project End 30-JUN-2006 Summary: (provided by applicant) Bladder cancer remains a major public health burden. Kava has a long history of serving as a beverage, medicine and in socioreligious functions in the South Pacific Islands, similar to the Western use of wine. Consumption of traditional aqueous kava preparation without major side effects for centuries correlates with lower and uncustomary sex ratio (more cancer in women than men) of, cancer incidences in kava-drinking countries such as Fiji, Vatu and Western Samoa. We recently have identified a kava extract and three chalcones from the extract as inducers of apoptosis in bladder cancer cells. Furthermore, we found that the apoptotic effect of flavokawain A, a major chalcone, was associated with the induction of the mitochondrial apoptotic pathway and inhibition of NF-kappa B mediated antiapoptotic pathway. Since studies suggest that frequent alterations in apoptotic pathways leading to resistance of apoptosis may be obligatory for bladder carcinogenesis, agents that can induce apoptotic and inhibit anti-apoptotic signaling deserve study in bladder cancer prevention. We hypothesize that kava extracts that contain flavokawain A have antineoplastic and chemopreventive activities against bladder cancer via a robust induction of apoptosis in pre-malignant and malignant cells. Our specific aims are two fold. First, we will determine the ability of kava extracts and flavokwain A to reduce tumor formation and growth of the transplanted bladder cancer cells in nude mice, and the requirement of flavokawain A for kava extracts’ effect. Second, we will define and compare the mechanisms of flavokawain A and kava extracts’ actions on apoptotic and anti-apoptotic signaling in normal, pre-malignant and malignant bladder cancer cells. The knowledge generated from these studies should allow us to 1) devise better kava product with optimized ratio of flavokawain A and kavalactones for translation research in bladder cancer prevention; 2) design better epidemiological study to investigate the relationship between use of kava products or kava and risk of bladder cancer in particular and health effects in general. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: M. D. ANDERSON CANCER SPORE IN GENITOURINARY CANCERS Principal Investigator & Institution: Dinney, Colin P.; Professor; Surgical Oncology & Cell Biol; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009 Timing: Fiscal Year 2004; Project Start 25-SEP-2001; Project End 31-AUG-2006 Summary: The overall goal of this University of Texas MD Anderson Cancer Center SPORE is to facilitate innovative translational research in the prevention, detection, and treatment of bladder cancer leading to the elimination of this disease as a major health problem. Our Cancer Center contains a unique concentration of talented investigators who are dedicated to clinical, translational, and fundamental bladder cancer research. Our institution has given high priority to the Bladder Cancer Multi- disciplinary Program. The Program has recruited faculty within the institution, strengthened the research infrastructure, and funded several pilot studies. We are now poised to take advantage of the framework developed by this multi-disciplinary group to enable a rapid increase in the understanding of bladder cancer at the molecular and cellular level. Funding of this SPORE will greatly enhance our ability to translate insights from bladder cancer biology to more effective prevention, detection, and treatment of bladder cancer. The SPORE includes 5 projects that deal with 1) early detection and chemoprevention of bladder cancer, 2) epidemiology of bladder cancer 3) death receptors in bladder cancer progression and therapy, 4) biology and therapeutic targeting of the epidermal growth factor receptor in bladder cancer, and 5) improving gene therapy for superficial bladder cancer. This SPORE addresses clinical dilemmas develop effective strategies for chemoprevention, detection, molecular profiling and therapeutics, bioimmunotherapy, chemotherapy, supportive care, and community awareness. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MACHINE LEARNING PREDICTION OF CANCER SUSCEPTIBILITY Principal Investigator & Institution: Moore, Jason H.; Associate Professor; Genetics; Dartmouth College Office of Sponsored Projects Hanover, Nh 03755 Timing: Fiscal Year 2006; Project Start 01-SEP-2006; Project End 31-AUG-2010 Summary: (provided by applicant): Susceptibility to sporadic forms of cancer is determined by numerous genetic factors that interact in a nonlinear manner in the context of an individual’s age and environmental exposure. This complex genetic architecture has important implications for the use of genome-wide association studies for identifying susceptibility genes. The assumption of a simple architecture supports a strategy of testing each single- nucleotide polymorphism (SNP) individually using traditional univariate statistics followed by a correction for multiple tests. However, a complex genetic architecture that is characteristic of most types of cancer requires analytical methods that specifically model combinations of SNPs and environmental exposures. While new and novel methods are available for modeling interactions, exhaustive testing of all combinations of SNPs is not feasible on a genome-wide scale because the number of comparisons is effectively infinite. Thus, it is critical that we develop intelligent strategies for selecting subsets of SNPs prior to combinatorial modeling. Our objective is to develop a research strategy for the detection, characterization, and interpretation of gene-gene and gene-environment interactions in a genome-wide association study of bladder cancer susceptibility. To accomplish this objective, we will develop and evaluate modifications and extensions to the ReliefF

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algorithm for selecting or filtering subsets of single-nucleotide polymorphisms (SNPs) for multifactor dimensionality reduction. (MDR) analysis of gene-gene and geneenvironment interactions (AIM 1). We will develop and evaluate a stochastic wrapper or search strategy for MDR analysis of interactions that utilizes ReliefF values as a heuristic (AIM 2). The filter approach will be statisyically compared to the wrapper approach. The best ReliefF strategies will be provided as part of our open-source MDR software package (AIM 3). Finally, we will apply the best ReliefF-MDR analysis strategy to the detection, characterization, and interpretation of gene-gene and gene-environment interactions in a large genome-wide association study of bladder cancer susceptibility (AIM 4). The methods developed here will be applied to nearly 1500 haplotype tagging SNPs (tagSNPs) across approximately 300 cancer susceptibility genes measured in 542 subjects with bladder cancer and 745 healthy controls ascertained as part of a large epidemiological study from the state of New Hampshire. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MARKERS OF GENETIC SUSCEPTIBILITY TO BLADDER CANCER Principal Investigator & Institution: Wu, Xifeng; Professor; Epidemiology; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009 Timing: Fiscal Year 2004; Project Start 22-FEB-1999; Project End 31-JUL-2009 Summary: (provided by applicant): This proposal is a competitive renewal for the grant entitled “Genetic Susceptibility to Bladder Cancer: A Molecular Epidemiologic Approach”. The purpose of the initial project was to identify interindividual differences in susceptibility to tobacco-induced carcinogenesis, as risk factors for bladder cancer (BC). We now propose to build upon this epidemiologic and specimen resource of 600 cases and 600 controls and to recruit an additional 400 patients with newly diagnosed BC and 400 healthy controls matched to the cases on the basis of sex, age (+/- 5 years), and ethnicity. We intend to apply promising novel phenotypic biomarkers of constitutive genetic instability, such as telomere length and mutagen-induced DNA damage. Specifically, we plan to determine telomere length in peripheral blood lymphocytes (PBLs) of the newly recruited 400 BC patients and 400 controls using quantitative fluorescent in situ hybridization laser scanning cytometry (Q-FISH/LSC). Our hypothesis is that BC cases exhibit shortened telomeres compared with control subjects. To assess latent genetic instability, we plan to quantify mutagen-induced DNA damage using the comet assay in the PBLs of 400 BC patients and 400 controls. Our hypothesis is that BC patients exhibit increased levels of BPDE-induced and or gammaradiation-induced genetic damage. To evaluate the role of genetic variations, we will use a pathway approach to estimate the frequencies of single-nucleotide polymorphisms (SNPs) in DNA repair genes implicated in the nucleotide excision repair (NER), base excision repair (BER), and double-stranded break (DSB) pathways for all 1000 cases and 1000 controls. Our hypothesis is that individuals with adverse genotypes of the NER, BER, and DBS pathways are at increased risk for BC and that these genotypes predict higher levels of induced DATA damage. To assess whether surrogate (PBL) tissue reflects molecular events in the target tissue, we plan to determine telomere length in paired samples of urine epithelial cells and blood lymphocytes from 75 patients with superficial BC and 75 healthy controls. Our hypothesis is that there will be a positive correlation in telomere length between target and surrogate tissues. Finally, using a multi-color fluorescent in situ hybridization (FISH) assay that includes a mixture of probes for the centromeric regions in chromosomes 3, 7, and 17 and the 91321 region, we will test the hypothesis that individuals with short telomeres, adverse genotypes and or high mutagen-induced DNA damage in PBLs (surrogate tissue) exhibit higher levels of

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genetic instability in the target tissue. As a secondary aim, we will correlate the predicted functional significance of these SNPs using a computational algorithm approach with risk estimated from this proposal to develop new tools for future candidate SNPs selection. The ability to rapidly screen individuals for risk, using minimally invasive procedures (blood samples), has immense clinical implication, such as intensive screening and chemopreventive interventions. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MCAV IN ORGAN-CONFINED BLADDER CA BASED ON P53 STATUS Principal Investigator & Institution: Cote, Richard James.; Professor of Pathology and Virology; Pathology; University of Southern California Department of Contracts and Grants Los Angeles, Ca 90033 Timing: Fiscal Year 2004; Project Start 01-MAY-1997; Project End 31-MAR-2007 Summary: (provided by applicant): This is a renewal application to our on-going “p53/MVAC” study. Tumor progression in transitional cell carcinoma (TCC) of the urinary bladder is believed to occur through a multistep accumulation of genetic alterations. p53 alterations are involved in the transformation of normal urothelium to carcinoma-in-situ of the bladder and in the progression to invasive disease. We have shown that (1) adjuvant chemotherapy prolongs the recurrence free interval in a group of patients with invasive TCC at high risk for recurrence and that (2) detection of p53 alterations in a bladder tumor is significantly associated with an increased chance of progression in patients with organ-confined TCC managed by radical cystectomy. Our hypothesis is that p53 alterations organ-confined TCC of the bladder significantly increase the risk of recurrence and death, and that adjuvant chemotherapy will improve survival in these high risk patients. To test this we have designed a study that will enroll patients who have already undergone a radical cystectomy with a pathologic stage of P1, P2a/b N0 M0. Patients with TCC demonstrating p53 alterations (p53+) who are willing to be randomized will be assigned either to no further treatment, i.e. observation which is the standard of care for patients with organ-confined disease, or to 3 cycles of MVAC chemotherapy. Those who are p53+ and decline randomization, and those who are p53- (no alteration in p53), will be observed. The specific aims of this prospective study are to (I) compare the recurrence free interval and overall survival of p53+ patients who are treated with MVAC to p53+ patients who are observed, (II) compare the recurrence free and overall survival of p53+ patients who are observed to p53patients who are also observed, (III) study the expression of other genes involved in cell cycle regulation that may be involved in the response to chemotherapy, (IV) examine the association of p53 mutational gene status with p53 protein expression, outcome, and response to chemotherapy. This is a new aim to this renewal application. To date over 30 academic institutions in the United States, Canada and Europe participate in this prospective study. The study was activated at the Southwest Oncology Group (SWOG) in 2001 and we are making a substantial effort to attract other Canadian and European institutions to this study. As of May 2002, 281 patients have been registered to the study and 58 p53+ patients have been randomized to MVAC or observation, making this one of the largest adjuvant trials in bladder cancer. The infrastructure to support this study is firmly established including 1) Full compatibility of data management with SWOG. (2) Completion of the interim audit by July 2002. (3) Fourth Annual meeting of the Data Safety Monitoring Committee planned for August 2002. (4) Institution of the patient advocacy program, the first for bladder cancer. (5) The 5th annual investigator’s meeting took place May 2002. With the participation of new institutions and with

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patient accrual and randomization increasing, we expect to complete accrual by 2006 (approximately 33-35 patients randomized per year). This is the first study in bladder cancer in which therapeutic decisions are made based on the status of a molecular alteration. The results of this studio could fundamentally change the management of bladder cancer. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF BLADDER CANCER PROGRESSION Principal Investigator & Institution: Lokeshwar, Vinata B.; Urology; University of Miami-Medical School 1507 Levante Avenue Coral Gables, Fl 33124 Timing: Fiscal Year 2004; Project Start 01-JAN-1997; Project End 31-MAY-2007 Summary: (provided by applicant): Identification of “molecular determinants” that regulate bladder cancer (BCa) progression could improve treatment and recurrence monitoring for BCa patients. Hyaluronic acid (HA) is a glycosaminoglycan that promotes tumor metastasis. Hyaluronidase (HAase) is an enzyme that degrades HA into angiogenic fragments. HYAL1 is the major HAase expressed in bladder tumor (BT) cells. It regulates BCa growth and invasion both in vitro and in BT xenografts. While HYAL1 wild type (wt) is enzymatically active and is exclusively expressed in highgrade BCa, 5 HYAL1 variants are enzymatically inactive and expressed in normal and low-grade BCa tissues. In BT tissues, both tumor cells and the stroma produce HA, however, HAS1 type HA-synthase is exclusively expressed in BT cells. The measurement of urinary HA and HAase levels (HA-HAase test) has high accuracy in detecting BCa. This proposal is designed to investigate the therapeutic and prognostic potentials of HYAL1, HYAL1 splice variants, and HAS1 in BCa progression. Furthermore, in a multi-center trial whether the HA-HAase test, either alone or in combination with other urine tests, can be used for monitoring BCa recurrence will be evaluated. To define HYAL1 function(s) in BCa growth and progression, the efficacy of anti-HAase therapy will be tested in BT xenografts, following delivery of HYAL1antisense cDNA using a viral system or by treatment with a HAase inhibitor. The mechanism of HYAL1 action will be examined by analyzing alterations in cell cycle regulators, matrix degrading enzymes, and angiogenic factors (Aim 1). A possible neutralizing effect of HYAL1 variants on BCa growth and invasion will be examined by cDNA transfection of HYAL1wt expressing BT cells with HYAL1 splice variant cDNAs. Differential expression of HYAL1 variants in BT tissues will be correlated with BT prognosis (Aim 2). HAS1 function in BT growth and progression will be evaluated by transfecting BCa cells which either express or are blocked in HYAL1 production, using HAS1-sense and HAS1-antisense constructs. Expression of HAS1 and its variant (HAS1v) in BT tissues will be correlated with BCa prognosis (Aim 3). In a multi-center trial, the utility of the HA-HAase test, urine cytology, BTA-Stat, NMP22 tests, individually and in combination, will be examined for precision to monitor tumor recurrence in 100 to 150 BCa patients. The results will be compared to clinical findings (Aim 4). The proposed study will reveal the function, therapeutic and/or prognostic potentials of the HA, HYAL1 and related molecules in BT progression. Furthermore, it will establish whether the HA-HAase test or its combination with other tests can precisely monitor BCa recurrence. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: METABOLISM OF N ACETYLBENZIDINE & INITIATION OF BLADDER CANCER Principal Investigator & Institution: Zenser, t; Internal Medicine; Washington University 1 Brookings Dr, Campus Box 1054 Saint Louis, Mo 631304899 Timing: Fiscal Year 2004; Project Start 01-AUG-2003; Project End 31-JAN-2005 Summary: ABSTRACT NOT PROVIDED Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: METALLOTHIONEIN ISOFORM 3 URINARY MARKER BLADDER CANCER Principal Investigator & Institution: Sens, Donald A.; Professor; Biochem and Molecular Biology; University of North Dakota 264 Centennial Drive Grand Forks, Nd 58202 Timing: Fiscal Year 2006; Project Start 15-SEP-2006; Project End 31-JUL-2010 Summary: (provided by applicant): The applicant has shown that the 3rd isoform of metallothionein (MT-3) is overexpressed in most bladder cancers and that the level of expression correlates to the grade of the tumor, being highly elevated in aggressive tumors and moderately elevated in low grade tumors and some precursor lesions. An important observation in this study was that neither MT-3 mRNA or protein was expressed in the urothelium or any other cell comprising the human bladder. These findings strongly suggest that the expression of MT-3 can be translated to provide a biomarker predictive of the early cellular alterations that progress to the development of bladder cancer. It is the applicant’s hypothesis that the presence of MT-3 positive urothelial cells in the urine of patients is predictive of pre-malignant, malignant, or reoccurring malignant lesions of the urothelium. The basic science arm of this study employs the applicant’s newly developed model of environmentally-induced human bladder cancer. The applicant is the first to demonstrate the direct malignant transformation of human urothelial cells with cadmium (Cd+2) or arsenic (As+3). The tumor heterotransplants generated from these transformants displayed the histology expected of transitional cell carcinoma of the bladder. In addition, tumors generated from As+3-transformed cells displayed tumors having a prominent squamous component, while those from Cd+2-transformed cells had little, or no, squamous differentiation. It is the applicant’s hypothesis that these tumors will provide a platform to understand environmental influences on the development of bladder cancer and to address the fundamental problem of how chemical mixtures contribute to the development of bladder cancer. The specific aims are: To prove the hypothesis that MT3 expression is a biomarker for bladder cancer; To prove the hypothesis that the expression of MT-3 in Cd+2- and As+3- induced bladder cancer is similar to human bladder cancer and that expression is controlled at both the transcriptional and posttranscriptional level of gene regulation; and, To test the hypothesis that As+3-induced transitional cell cancers of the bladder have a prominent squamous component and that this fundamental departure in differentiation can be used to gain knowledge regarding the interaction of mixtures that cause environmentally-induced cancer. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MINORITY PREDOCTORAL FELLOWSHIP PROGRAM Principal Investigator & Institution: Varela, Juan C.; Pharmacology; Medical University of South Carolina Charleston, Sc 29425 Timing: Fiscal Year 2004; Project Start 30-SEP-2004; Project End 29-SEP-2009

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Summary: (provided by applicant): Immunotherapy using complement activating antibodies specific for tumor antigens has not yielded satisfactory results in the clinic. Complement inhibitors expressed on tumor cells (often at elevated levels) promote tumorigenesis and are an important factor in the resistance of tumor cells to antibodymediated immunotherapy. We hypothesize that downregulation of the expression of complement inhibitory proteins on the surface of tumor cells will increase sensitivity of tumor cells to anti-MUCI (a bladder cancer associated antigen) antibody-mediated immunotherapy and may also enhance the outcome of a normally ineffective immune response. It is proposed to use a clinically relevant syngeneic MUC1 transgenic model of bladder cancer to investigate the role of complement inhibitors in tumor immunity and in the resistance of tumor cells to anti-MUC1 antibody therapy in the context of immune sufficiency, tolerance and autoimmunity. The expression of complement inhibitors will be modulated by RNAi. The proposed studies have the potential to lead to the development of new immunotherapy strategies for the treatment of bladder cancer Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR DIVERSITY IN BLADDER CANCER Principal Investigator & Institution: Arap, Wadih; Professor; Genitourinary Medical Oncology; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009 Timing: Fiscal Year 2005; Project Start 01-JUN-2005; Project End 31-MAY-2010 Summary: (provided by applicant): We have developed an in vivo selection system in which peptides that home selectively to different tissues are recovered after intravenous administration of a phage random peptide library. In earlier work, we uncovered a previously unrecognized address system that makes possible organ-specific targeting and angiogenesis-related targeting of tumors. The corresponding receptors for the peptides targeting tumors are cell surface markers that are upregulated or activated during tumor progression. We also developed methods for assessing organ-specificity and cell-type distribution of such probes in vivo. Our working hypothesis is that there are tissue-related and tumor stage related heterogeneity in the bladder; such diversity may affect the responses to therapies. Here, we propose to define the cellular and molecular differences that exist (i) in normal urothelium and (ii) in bladder cancer. Under Specific Aim #1, we will explore novel strategies based on in vivo and ex-vivo phage display combined with Laser Capture Microdissection (LCM) technologies. We aim to isolate peptides that home in vivo to the mouse bladder or that bind ex vivo to various bladder cell types. Under Specific Aim #2, we will isolate peptides and antibodies that home to the bladder at different stages of tumor progression, from early to late metastatic disease. In a complementary strategy, we will select peptides that are recognized by the circulating pool of immunoglobulins at selected stages of bladder cancer progression. These specific probes will be used to identify new tumor- and tumor-associated antigens. Under Specific Aim #3, we will isolate, clone, and evaluate the expression pattern and function of these specific and tumor-specific markers in the context of bladder cancer progression. The identification of novel bladder and bladder cancer receptors may shed light in the complex cellular and molecular diversity of the bladder. Under Specific Aim #4, we will identify specific peptides that have the ability to internalize into urothelial cells. The combination of tight cell junctions, a specialized luminal cell surface bearing glycosaminoglycans (GAG), and a mucin layer protect the mammalian urothelium against concentrated urine chemicals and microbial adhesion. However, under pathological conditions, such features of the urothelium become obstacles to effective delivery of therapeutic agents to the bladder. Herein we propose to

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pursue candidate peptides with the ability to internalize into urothelial cells to develop therapeutic targeting strategies for the treatment of bladder cancer. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR EFFECTS OF LOW LEVEL ARSEN Principal Investigator & Institution: Gandolfi, a J.; Asst. Dean of Research; University of Arizona Po Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2005; Project Start 01-APR-2005; Project End 31-MAR-2010 Summary: Low-level exposure (1-50 ppb) arsenic causes a multitude of toxic effects. The new drinking water standard for arsenic (10 ppb) is based on the occurrence of bladder cancer. The mechanism(s) by which arsenic produces bladder cancer are unknown. Additionally the toxic effects of low-level arsenic exposure to produce bladder injury have not been adequately examined. Our studies will examine mechanisms of low-level arsenic exposure to bladder tissue. An immortalized human epithelial cell line (UTOtsa) will be the primary model system. In preliminary studies UROtsa cells were shown to be capable of biotransforming inorganic arsenic to more toxic methylated metabolites and low-level (1-50 ppb) arsenic chemical species were cytotoxic to the cells. Our Aims are to: 1.) Determine the role of biotransformation of arsenic in bladder to produce subcytotoxic effects. The biotransformation of inorganic arsenic will be manipulated to determine which arsenic metabolite is the ultimate toxicant. 2.) Determine if the lowlevel arsenic exposure to the bladder is producing toxicity via proteotoxic mechanisms. This study will examine if arsenic species produce toxic effects via direct interaction with critical sulfhydryl targets. 3.) Determine if the low-level arsenic exposure to the bladder produces toxicity via an oxidative stress mechanism. The production of reactive oxygen species and the ensuing toxic effects will be profiled for various arsenic chemical species, 4.) Determine if the low-level arsenic exposure to the bladder is affecting the ubiquitin pathway and its toxic consequences. Arsenic has been shown to alter the processing of proteins in a cell. Our studies show low-level arsenic to cause and an accumulation of ubiquinated proteins. Our studies will characterize this accumulation, identify if specific proteins are accumulated, and determine the impact of these accumulated proteins on cell viability. 5.) Determine if biomarkers of arsenic toxicity to the bladder result from the preceding studies. Bladder samples from surgical patients will be used for in vitro toxicity studies with arsenic to determine if we see similar effects to those seen with the cells and if the potential biomarkers are present (ubiquinated proteins). Overall, these studies will clarify the toxic effects of low-level arsenic in a human bladder model and provide potential biomarkers for arsenic-induced bladder injury. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR STUDIES OF THE P53 PATHWAY IN HUMAN CANCER Principal Investigator & Institution: Cordon-Cardo, Carlos; Director; Sloan-Kettering Institute for Cancer Res 1275 York Ave New York, Ny 100216007 Timing: Fiscal Year 2006; Project Start 01-APR-2006; Project End 31-JUL-2011 Summary: The objective of the proposed studies is to determine whether data on a patient’s p53 status aids clinicalmanagement of bladder cancer. Our working hypothesis is that mutations and altered expression of theTP53 gene, or those affecting certain regulatory genes involved in the p53 pathway, produce a selectiveadvantage for tumor growth and aggressive behavior in cancer patients. Our specific aims are as follows:Aim

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1. To conduct molecular and functional studies of the p53 pro-apoptotic response and itsclinical significance in bladder cancer. We will determine the clinical relevance of detecting TP53mutations and altered patterns of p53 expression using a combination of methods. To assess theconsequences of TP53 mutations, we will clone p53 mutants in expression vectors and ascertain theiractivities. Regulatory events of the p53 pathway will also be analyzed, centering on genetic and expressionstudies of HDM2 (collaboration with Project by Levine). We will also define the frequency and clinical significance ofaltered Bax, PUMA and Noxa expression, mainly in relation to treatment response (working with Project by Lowe).Aim 2. To define the clinical and biological implications of p53 DNA damage response in bladdercancer. We and others have observed that early bladder cancer, but not normal tissues, express markersassociated with an activated DNA damage response, such as phosphorylated Chk2. We have also identifiedCHK2 mutations in primary bladder tumors (collaborating with Project by Prives). We will assess the frequency ofCHK2 mutations in bladder cancer, and their association with increased genetic instability and tumorprogression. The phosphorylation status of Chk2, ATM, and p53 will be investigated in bladder cancer celllines and primary tumor samples. The consequences of CHK2 mutations will be studied by cloning Chk2mutants in expression vectors and determining their response to gamma-radiation. Aim 3. To ascertain the roleof p53 in senescence triggered by Pten inactivation in bladder cancer. We have recently reported theinvolvement of p53 at inducing senescence in response to inactivation of the Pten pathway. We also foundthat p53 and Pten have cooperative tumor suppressor roles in bladder cancer, their concomitant inactivationbeing associated with tumor progression and poor outcome. Using a combination of techniques, we willdetermine the clinical relevance of detecting PTEN abnormalities. In addition, the oncogenic potential of Aktconstitutive activation will be investigated (working with Project by Lowe). Mechanistic studies will be aimed atfurther defining the crosstalk between these two pathways (e.g., silencing PTEN and/or p53 expression byshRNA to pheno-copy the ablation of the senescent status, followed by gene expression profiling analyses).Identified target genes will be validated in bladder cancer cell lines and primary bladder tumors of knownPten and p53 status. The main goal is to translate basic research findings into clinically applied studies. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEAR-INFRARED QUANTUM DOTS FOR IN VIVO IMAGING Principal Investigator & Institution: Frangioni, John V.; Associate Professor of Medicine and Assi; Beth Israel Deaconess Medical Center 330 Brookline Avenue, Br 264 Boston, Ma 02215 Timing: Fiscal Year 2004; Project Start 01-SEP-2003; Project End 31-AUG-2007 Summary: (provided by applicant): The major hypothesis guiding this research is that fluorescent semiconductor nanocrystals (quantum dots) will be clinically useful reagents for in vivo imaging. As contrast agents, quantum dots offer several advantages over traditional fluorophores including broad absorption bands, extremely high extinction coefficients, quantum yields approaching 50%, photostability at high fluence rate, and high capacity for ligand conjugation. To date, however, quantum dots with optimal properties for in vivo imaging have not been developed. The long-range goal of this research is to improve cancer cell detection and vascular imaging by developing quantum dots with optimal in vivo properties. The R21 phase of the proposal focuses on the design, synthesis, and initial characterization of nearinfrared (NIR) quantum dots. Although invisible to the human eye, the NIR (700 nm to 900 nm) portion of the spectrum is characterized by low autofluorescence, deep tissue penetration, and low

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tissue scatter of light. Using a model that incorporates both tissue and quantum dot photonic properties, we have predicted the absorption and emission characteristics of “optimal” NIR quantum dots. We describe strategies to synthesize such contrast agents, and present preliminary data of how NIR quantum dots might be expected to perform in vivo by using an intraoperative imaging technique recently developed by our laboratory. The R33 phase of the proposal focuses on the in vivo characterization of NIR quantum dots. Two distinct clinical applications are explored: cancer cell detection/imaging and vascular imaging. Our laboratory has developed prostate and bladder cancer-specific low-molecular weight ligands that can be used to target contrast agents to tumor cells (see Preliminary Studies). We propose to conjugate these ligands to NIR quantum dots and to characterize their biodistribution, pharmacokinetics, and tumor localization. It is hypothesized that such contrast agents will provide unparalleled improvements in cancer cell detection in vivo. We also propose to optimize NIR quantum clots for intraoperative vascular imaging and image-guided delivery of cardiac gene therapy using animal models of cardiac ischemia and necrosis. If completed, the specific aims of this proposal will generate a clinically useful set of contrast agents, and a more complete understanding of the in vivo behavior of fluorescent semiconductor nanocrystals. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NONINVASIVE DIAGNOSIS OF EARLY BLADDER CANCERS Principal Investigator & Institution: Pan, Yingtian; Associate Professor; Biomedical Engineering; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2004; Project Start 15-MAR-2001; Project End 30-JUN-2008 Summary: (provided by applicant): This research proposes to apply our newly developed cystoscopic optical coherence tomography (COCT) to substantially enhance the image resolution and sensitivity/specificity of current endoscopic procedures in the diagnosis and staging of early bladder cancers. Advanced optical imaging techniques (e.g., bioMEMS, optical coherence tomography, and fluorescence endoscopy) will be used, thus allowing optical biopsy of early flat bladder cancers (e.g., carcinoma in situ) in vivo, noninvasivelv, instantaneously and at high resolution. Based on successful animal studies (in vivo imaging of normal porcine bladder and ex vivo imaging of rat bladder tumorigenesis and human specimens), early human trial is proposed. Symptomatic patients with suspected bladder carcinomas will be imaged with COCT in vivo under the guidance of a white-light or 5-ALA fluorescence cystoscope. Excisonal biopsy and histologic evaluations will be followed to examine the utility and limitations of the technology for early diagnosis of bladder malignancies. This will allow us to evaluate the sensitivity and specificity of COCT in diagnosing premalignant lesions, early flat bladder cancers such as carcinomas in situ, precisely detecting the margin of bladder cancers, and staging early invasions (to stage TA and T1). This technique will also allow us to noninvasively detect the cancer residuals post surgical removal. Bladder cancers originate from urothelial cells. Most bladder cancers are treatable if diagnosed prior to metastasis and treated appropriately. Although advances in molecular screening test permit a high sensitivity for detection of bladder malignancies, endoscopic visual inspection of surface lesions is presently the clinical standard to locate cancers following screening procedures. However, because of lack of resolution, conclusive diagnosis and staging of early malignancy relies on random biopsy and histologic examination, which may miss early flat bladder cancers such as carcinomas in situ. Therefore, a more effective imaging technique is highly desirable to allow noninvasive diagnosis and more precise staging of early bladder tumors. Current

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medical imaging methods (e.g., x-ray, CT, MRI, ultrasound and conventional cystoscopy) are inadequate because of their resolution limitations. COCT allows noninvasive visualization of cross-sectional micro-morphology of urothelium and the underlying bladder wall (e.g., lamina propria, upper muscular layers) at high-resolution (5-10mum and at depths of 2-3mm. Our preliminary results clearly demonstrate the potential value to provide urologists with rapid, noninvasive diagnosis of abnormalities. No other technique offers this potential at present. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NONPATHOGENIC MYCOBACTERIA:ANTI-BLADDER TUMOR THERAPY Principal Investigator & Institution: Fennelly, Glenn J.; Associate Professor; Microbiology and Immunology; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 30-JUN-2006 Summary: (provided by applicant): This R21 proposal is submitted in response to PA03-058 Exploratory/Developmental Bioengineering Researcy Grants. Our overall objective is to engineer a novel anti-tumor therapy with eukaryotic expression plasmids that encode therapeutic genes delivered in nonpathogenic mycobacteria, as a safer alternative to viral gene vectors. In particular, we will study the efficacy of wild type Mycobacterium smegmatis, and Mycobacterium bovis BCG, or alternative modified mycobacteria, for the delivery of genes that express functional cytokines or costimulatory molecules to bladder tumor cells. Intravesicular BCG therapy, the only US FDA-approved antitumor microbial agent in the US, has contributed to a > 20% decline in death rates from bladder cancer since 1980. Intravesicular BCG augments local production of immune mediators of tumor clearance (IFN-gamma, ICAM-1 and TNFalpha) and has direct anti-tumor activity. Nevertheless, BCG has no effect in > 20% of cases. M. smegmatis, a species that is less virulent than BCG, inhibits tumor cell growth in vitro more potently than BCG. Previous studies by us, and others, demonstrate that both S. flexneri and S. typhimurium can deliver plasmids to eukaryotic cells for genetic immunization. In a set of pilot experiments, we tested the ability of M. smegmatis to deliver eukaryotic expression plasmids to mammalian cells and clearly demonstrated, for the first time, that M. smegmatis can deliver plasmids expressing the green fluorescent protein from a eukaryotic promoter to macophages. Using this discovery, we plan to develop M. smegmatis and BCG as safe and efficient vectors for the delivery of ICAM-1 and TNF-alpha eukaryotic expression plasmids as gene therapy against bladder carcinoma in humans. Specifically, we propose to: 1. Optimize the ability of wild type M. smegmatis and BCG to deliver Mycobacterial Mammalian Shuttle plasmids (MMSP) to macrophages and murine or human bladder tumor cells in vitro and in mice. 2. Determine whether infection of murine bladder tumor cells with recombinant Mycobacteria harboring MMSP that encode murine ICAM-1 or TNF-alpha augment tumor cell expression of functional ICAM-1 or TNF-alpha in vitro and, 3. Evaluate the ability of recombinant Mycobacteria harboring MMSP that encode ICAM-1 or TNFalpha genes to enhance tumor regression in a murine MB49 syngeneic orthotopic bladder cancer model using C57BL/6 (immunocompetent). Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PARADIGM CARCINOGENESIS

OF

MULTISTEP

URINARY

BLADDER

Principal Investigator & Institution: Czerniak, Bogdan A.; Associate Professor; Pathology; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009 Timing: Fiscal Year 2004; Project Start 01-APR-1995; Project End 30-NOV-2006 Summary: (PROVIDED BY APPLICANT) Identification of early changes associated with the development of preneoplastic conditions and especially those that are responsible for their progression to invasive cancer would provide important clue on early cancer development and could aid in the development of novel markers for early identification of occult neoplasia. We have used a whole-genome approach to identify target loci on individual chromosomes, focusing our effort on those chromosomal regions that are involved early in the process of development of human urinary bladder neoplasia. From these data we selected several target loci for further characterization and development of diagnostically relevant probes for early cancer detection. We anticipate that this proposal will fill up an important gap in our knowledge on early occult events of human urinary bladder neoplasia. The overall goal of this project is to characterize target tumor suppressor gene loci on chromosomes 4, 8, 11 and 17, as well as minimally amplified regions on the chromosome 3q24-26 amplicon. On the basis of our strong preliminary data, we hypothesize that putative tumor suppressor and dominantly activated genes in these loci are involved in the development of early phases of urinary bladder neoplasia and that some of them play a role in the progression of preneoplastic intraurothelial conditions to invasive bladder cancer. From these loci, we propose to develop fluorescent in situ hybridization (FISH) and hypervariable DNA marker assays for early detection of occult urinary bladder neoplasia. The core preliminary data for this proposal are the result of the application of our genome-wide model of urinary bladder cancer progression from occult in situ preneoplastic conditions to invasive cancer. Using our whole organ histologic and genetic mapping method, we identified over 30 putative tumor suppressor gene foci involved in the development and progression of urinary %+%bold%+%bladder cancer.%?%. The most promising and putative tumor suppressor gene loci and the target amplicon were selected for further characterization, the development of markers to detect early occult urinary bladder neoplasia and its aggressive variants, and the testing of these markers under realistic clinical conditions. This project will provide two products of basic research and practical importance: (1) A public database consisting of all tested foci and the characterization of their minimally deleted or amplified regions as well as their transcriptionally active sequences; (2) A diagnostically relevant panel of FISH and hypervariable DNA markers for early detection of bladder cancer. As all transforming and tumor suppressor genes are relevant for more than one cancer type, these data will have a significant impact on our understanding of multistep human carcinogenesis in general and will serve as a paradigm for the development of markers and diagnostic strategies for early detection of other types of cancer. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHWAYS OF BLADDER TUMORGENESIS Principal Investigator & Institution: Wu, Xue-Ru; Professor; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 30-JUN-2009

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Summary: Although urothetium is a frequent site of tumor formation, relatively little is known about the molecular mechanisms of how urothelium is malignantly transformed by oncogenic events such as oncogene activation and tumor suppressor gene inactivation. During the last granting period, we studied bladder tumorigenesis by developing transgenic mouse models expressing several oncogenes under the direction of a urothelium-specific promoter. Urothelial expression of activated Ha-ras oncogene elicits urothelial hyperplasia followed by low-grade, superficial papillary tumors, whereas urothelial expression of SV40T oncogene induces high-grade, carcinoma in situ of the bladder, some of which progress into invasive and metastatic cancers. These results provide the first direct experimental evidence supporting the concept that bladder cancers arise and progress via distinctive phenotypic and genetic pathways. In the next granting period, we will examine the in vivo effects of inactivating several tumor suppressor genes on urothelial growth, differentiation and tumorigenesis, and will study the cooperative effects between oncogene-acfivation and tumor suppressor gene-inactivation on bladder tumor progression. Toward these goals, we will test the hypotheses that: (1) inactivation of p l6Ink4a tumor suppressor gene can synergize with Ha-ras activation to accelerate superficial papillary tumor formation; (2) inactivation of pi9Arf or p53 tumor suppressor gene can cooperate with Ha-ras activation to cause bladder tumor invasion; and (3) inactivation of both p53 and pRb tumor suppressor genes is required for the genesis of high-grade, invasive tumors of the bladder. We will employ a combination of transgenic, bi-transgenic, urothelium-specific gene knockout and double-knockout approaches to test these hypotheses. These studies will yield new insights regarding the molecular basis of bladder tumorigenesis, and the genetic causes of different bladder tumor progression pathways. The transgenic and knockout models that we will generate will serve as important in vivo platforms for evaluating novel diagnostic, preventive and therapeutic strategies for bladder cancers. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREVENTION OF BLADDER CANCER PROGRESSION BY SULFORAPHANE Principal Investigator & Institution: Zhou, Jin-Rong; Assistant Professor; Beth Israel Deaconess Medical Center 330 Brookline Avenue, Br 264 Boston, Ma 02215 Timing: Fiscal Year 2004; Project Start 30-SEP-2004; Project End 31-AUG-2006 Summary: (provided by applicant): This application is focused on exploring the chemopreventive effects of bioactive components in cruciferous vegetables on bladder cancer progression. The hypothesis to be tested is that increased consumption of cruciferous vegetables, especially broccoli, may serve as an effective nutritional regimen for the prevention of bladder cancer progression and metastasis by modulating bladder tumor apoptosis and proliferation. The rationale for supporting this hypothesis is based on the followings: (1) Epidemiological investigation suggests that intake of cruciferous vegetables is associated with a lower risk of bladder cancer; (2) Our preliminary in vitro studies indicate that a bioactive component in broccoli, sulforaphane, significantly inhibited the growth of bladder cancer cell lines via modulation of apoptosis and cell cycle progression. The objectives of this pilot project are to investigate the effects of sulforaphane on prevention of bladder cancer progression and to elucidate the underlying mechanisms of action. Specific Aim 1 is to determine the effects of sulforaphane on progression of both well differentiated, low metastatic and poorly differentiated, highly metastatic human bladder tumors. Two human bladder cancer cell lines, RT4 which forms well differentiated and low metastatic tumors in vivo and 253J B-V which forms poorly differentiated and highly metastatic tumors in vivo, will be

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used to develop orthotopic human bladder tumor models. Sulforaphane will be evaluated for its dose-dependent effects on preventing the growth and metastasis of both RT4 and 253J B-V tumors in vivo. Specific aim 2 is to determine the effect of sulforaphane on the expression of tumor biomarkers that are related to tumor cell apoptosis and proliferation in vivo. We will determine the effects of sulforaphane on modulation of apoptotic index and the expression of apoptotic inducers (bax, p21/waft, p53, bad) and apoptosis repressors (bcl-2, bcl-x1), and tumor proliferation index and expression of cell cycle related cyclins and Cdk protein kinases. Tumor angiogenesis will also be determined by measuring microvessel density and expression of angiogenic factors (VEGF, bFGF and angiopoictin-1) and anti-angiogenic factor (angiopoietin-2). It is expected that the results will provide important information on anti-bladder cancer progression activity of sulforaphane, and provide preliminary data for R01 grant application. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROEPITHELIN SIGNALING IN UROTHELIAL CELLS Principal Investigator & Institution: Morrione, Andrea; Urology; Thomas Jefferson University 201 South 11Th Street Philadelphia, Pa 191075587 Timing: Fiscal Year 2005; Project Start 01-MAY-2005; Project End 31-MAR-2010 Summary: (provided by applicant): Proepithelin is a secreted pluripotent growth factor that plays a significant role in cell proliferation and cell cycle progression in many cellular systems. Proepithelin is highly expressed in several aggressive tumors and it is also promoting cell migration, wound healing and tissue repair. Despite the strong connections with growth control and cancer, proepithelin ‘s mode of action is not well understood. Furthermore, the proepithelin receptor and/or proteins that mediate the early stages of proepithelin signaling from the plasma membrane have not been identified. The objective of this grant proposal is to elucidate the molecular mechanism(s) by which proepithelin promotes proliferation and migration of bladder cells. The central hypothesis of this application is that proepithelin plays a critical role in cell growth, migration and transformation of bladder cells. Our hypothesis is based on our preliminary findings, which indicates that proepithelin promotes proliferation and migration of bladder cells. We have also identified a novel proepithelin-interacting transmembrane protein that we hypothesized is the proepithelin receptor. We will test our hypothesis and accomplish the objectives of this application through the following specific aims:  Characterize the mechanism(s) that regulates proepithelin signaling in bladder cells  Investigate how the proepithelin receptor affects proepithelin signaling in bladder cells  Investigate the role of proepithelin in human bladder cancer. To address these specific aims this grant application proposes experiments focusing on normal and cancer urothelial cells. We will use small interfering RNA (siRNA), overexpression and dominant negative approaches to investigate the function of proepithelin and the proepithelin receptor in urothelial cells. A combination of assays for proliferation and migration and assays for proepithelin-dependent signal transduction will be employed. The significance of this grant proposal is not only in terms of a better knowledge of proepithelin action in the biology of bladder cells, but in the long range this studies could yield valuable information for translational research. Given the critical role of proepithelin in malignant transformation, it may prove a useful clinical target for prognosis and therapy. Furthermore, the identification of novel proteins and novel mechanism(s) that regulate proepithelin action will help us in designing novel therapeutic agents to target malignant cells in bladder tumors. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PROSPECTIVE STUDIES OF DIET AND CANCER IN MEN AND WONEN Principal Investigator & Institution: Willett, Walter C.; Professor and Chairman; Nutrition; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2004; Project Start 23-AUG-1991; Project End 31-MAR-2006 Summary: (provided by Applicant) This proposed Program will use prospectively collected dietary data and frozen plasma and DNA specimens to address a series of hypotheses regarding major cancers in men and women. In addition, these nutritional and genetic exposures will be examined in relation to specific molecular characteristics of tumors. The cancers to be studied are those of the prostate, colon and rectum, bladder, lung, kidney, and ovary. This Program Project supports, and depends on, the continued follow-up of 51,529 men who completed an extensive dietary questionnaire first in 1986 and again in 1990, 1994, and 1998 (the Health Professional?s Follow-up Study, HPFS), and is also closely linked to the Nurses? Health Study (NHS) of 121,700 women. The Program Project has already contributed substantially to information on diet and cancers of the breast, prostate, colon, and bladder. The proposed continuation will extend and refine observations from the first twelve years of follow-up and will also address new hypotheses related to both cancer incidence and survival. Project 1 will examine dietary (lycopene, calcium, and N-3 fatty acid intakes) and other predictors of prostate cancer incidence in relation to risk of PSA relapse among men with apparently successful treatment for localized prostate cancer. In addition, a series of dietary and hormonal factors will be related to specific characteristics of incident cancers, including expression of PTEN and COX-2 and markers of angiogenesis. Project 2 will address hypotheses relating intakes of folic acid, calcium and red meat and plasma levels of IGF1 and its binding proteins to risks of both colorectal cancer and adenomas. Interactions with germline polymorphisms and relationships with specific molecular tumor characteristics will be examined. Project 5 will examine dietary and related risk factors for bladder cancer in both men and women. Exposures will include intakes of cruciferous vegetables and total fluids, and biochemical indicators of selenium and arsenic exposure. Interactions with polymorphisms in carcinogen metabolizing genes and specific association with p53 expression in tumors will also be examined. Project 4 pools data from all eleven major published prospective studies of diet and cancer. Precise and unique information has already been obtained for breast, lung and colon cancers, and the proposed work will extend analyses to cancers of the pancreas and ovary. These highly interrelated studies that integrate dietary factors, established nondietary risk factors, endogenous hormone levels, genetic susceptibility, and molecular characteristics of tumors, will contribute importantly to the understanding and prevention of the major cancers of men and women. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PROSTATE CANCER MOLECULAR EPIDEMIOLOGY-RETINOID RECEPTOR Principal Investigator & Institution: Mao, Gloria E.; Epidemiology; University of California Los Angeles Office of Research Administration Los Angeles, Ca 90024 Timing: Fiscal Year 2004; Project Start 22-AUG-2003; Project End 28-FEB-2006 Summary: (provided by applicant): This proposal is designed to provide the applicant, Dr. Gloria Mao, with the scientific skills and career development necessary for a successful academic career in cancer prevention and control research. Together, with a

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targeted program of didactic instruction, guided mentorship, collaborative research, and participation in national meetings, this project will prepare the applicant to become a fully independent scientist. A molecular epidemiology study is proposed to characterize the role of the retinoid receptors in prostate carcinogenesis. The retinoic acid receptors, RARs, and the retinoid X receptors, RXRs, mediate the anticarcinogenic effects of retinoic acid. Prostate tissue, pathology records and a life-style/exposures questionnaire have been obtained from 118 prostate cancer cases and 102 bladder cancer cases that may serve as controls in this study. The specific aims of the study are: (1) measure the RARs and RXRs at different levels of expression regulation: mRNA and protein levels and RARbeta promoter methylation in paired prostate tissue containing normal prostate, prostatic intraepithelial neoplasia, and adenocarcinoma; (2) measure the correlations between molecular alterations in the retinoid receptors with clinical and pathological variables including tumor stage, grade, and patient survival; (3) measure the correlations between RARa promoter methylation and RARbeta mRNA and protein levels; (4) evaluate the strength of the associations between molecular alterations in the RARs and RXRs with patient demographics, environmental exposures, dietary factors and serum micronutrient levels. Differential expression of specific retinoid receptors and hypermethylation of the RARbeta promoter are hypothesized to exist between normal, PIN and adenocarcinoma. An assessment of whether retinoid receptor molecular alterations are useful biological markers of prostate cancer progression will be made. The strength of the associations between retinoid receptor status with environmental and dietary exposures may be used to identify potential gene-risk factor interactions for prostate cancer. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RAL IN HUMAN BLADDER CANCER PROGRESSION Principal Investigator & Institution: Theodorescu, Dan; Urology; University of Virginia Charlottesville Box 400195 Charlottesville, Va 229044195 Timing: Fiscal Year 2004; Project Start 01-SEP-1997; Project End 28-FEB-2008 Summary: (provided by applicant): Background and Significance: 40% of patients presenting with “superficial” (non-muscle-invasive) bladder cancer develop the “invasive” life-threatening form of the disease during follow up. In clinical studies, overexpression of Epidermal Growth Factor Receptor (EGFR), Ha-Ras mutation and loss of tumor suppressor gene PTEN have been associated with this phenotypic tumor transition. However, the exact molecular pathway by which these genes effectively trigger or facilitate the invasive process is incompletely understood. Our original R29 hypothesized that EGFR signaling enhances bladder tumor motility in vitro and invasion in vivo and intended to determine the signaling pathways used by EGFR in this process. Since funding of the R29 in 9/97, we have made the following important observations which support the original hypothesis and address the aims of the original application: 1) EGFR and Ras inhibition diminished the motility of invasive bladder cancer cells; 2) EGF stimulates motility in non-invasive cells via PI3K and this requires activity of Rho and Ras effector Rat; 3) In non-invasive cells, baseline RalA activity is low while invasive cells have constitutively higher activation; 4) Invasive cells have low levels of RhoGDI2 expression. Reconstitution of this gene leads to diminished motility and activity of RalA but not RhoA suggesting this gene may be the first RalGDI identified to function as an invasion suppressor; 5) Inhibition of PI3K activity via PTEN reconstitution in invasive cells with inactive PTEN, results in an inhibition of orthotopic invasion in vivo and a decrease in RhoA activity. Since the overall biology of both Ral and RhoGDI2 is poorly understood, but might be critical for regulating tumor invasion

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in patients with bladder cancer, we propose the Guiding Hypothesis that EGF mediates bladder tumor invasion via Ral activation. We will test this hypothesis with a matrix of technologies ranging from basic biochemistry to clinical oncology to address Ral biology in human bladder cancer. These include: 1) unique paired human bladder cancer cell lines with different invasive abilities; 2) a novel organotypic bladder model allowing in vitro study of tumor invasion; 3) an orthotopic assay evaluating the effects of candidate molecules on in vivo bladder cancer invasion; 4) transgenic and knockout mice with appropriate genetic and phenotypic profiles; 5) a human tissue bank with pathologically and clinically well characterized frozen specimens. Specific Aims: 1) Determine the role and pathobiology of Ral in bladder cancer invasion in organotypic, murine orthotopie and human tumor studies; 2) Determine the regulators of Ral activation (RhoGDI2, etc.) and their effect on intracellular Ral localization and bladder cancer nfigration and invasion; 3) Determine the protein complexes associated with Ral in vitro and in vivo, including those found in human cancer. Conclusion: Completion of these specific aims will provide biologically relevant molecular information on the signaling pathways regulating bladder cancer invasion in vivo and lead to the rational development of diagnostic and prognostic tools predicting the development of invasive disease and therapies to interfere with this process in patients with superficial bladder cancer. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RB4 INTRAVESICAL GENE THERAPY: MECHANISMS OF CELL DEATH Principal Investigator & Institution: Benedict, William F.; Professor; Gas Med Oncology & Digest Dis; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009 Timing: Fiscal Year 2004; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): A modified retinoblastoma gene construct utilizes the second start codon of the RB gene and encodes for a 94 KD protein (pRB94. It is a markedly more potent tumor suppressor and cytotoxic agent than the wild-type RB protein and has been effective against all tumor types tested to date irrespective of tissue type, RB or other gene status, except for that of telomerase. A long-term objective of this project is to understand the cellular and molecular pRB94 interactions that cause such potent effects. Preliminary results suggest that a key mechanism of pRB94 specific induced tumor cell death may involve the production of rapid telomere attrition and chromosomal crisis. These results make the mechanism(s) of RB94 cell kill and tumor suppression potentially unique from all other agents or modalities examined to date and has occurred in all telomerase positive tumors or immortalized cells but not in tumor or immortalized cells containing an ALT pathway, i.e. telomerase negative cells. RB94 also has been found not to be cytotoxic or growth inhibitory to normal human cells, including urothelial cells, which are also telomerase negative. One approach will therefore be to determine if interference with the normal telomere complex plays a key role in RB94 produced telomere attrition, with subsequent chromosomal instability and cell death. The role of centrosomes and changes in STK15 kinase activity will also be studied in depth. Techniques will be include the use of microarrays, confocal laser scanning, analysis of chromosomal and telomere status, examination of RB94 specific protein interactions by Western blotting and immunochemical staining as well as immunoprecipitation with sequencing of putative RB94-specific related proteins. Studies will be expanded to examine RB94 cell kill in additional telomerase positive or negative tumor cells and genetically altered, non-tumorigenic immortalized cells. Whether or not these changes are caspase dependent will also be studied. Another

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specific aim is to optimize intravesical gene therapy and determine the effect of AdRB94 on superficial bladder cancer. An intravesical human bladder cancer model developed by us using GFP expressing cells will be utilized for this purpose. To increase adenovirus-mediated transfer the reagent, Syn3, will be used. Syn3 has been found to markedly increase adenoviralmediated gene transfer without being toxic itself. If these studies are successful, it could have a significant influence in developing a new modality of treatment for recurrent superficial bladder cancer and potentially for other tumor types as well as provide the molecular basis for the unique properties of RB94. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE SUPPRESSION

OF

MISMATCH

REPAIR

IN

SPORADIC

TUMOR

Principal Investigator & Institution: Li, Guo-Min; Associate Professor; Pharmacology; University of Kentucky 109 Kinkead Hall Lexington, Ky 405060057 Timing: Fiscal Year 2004; Project Start 14-FEB-2001; Project End 31-JAN-2006 Summary: (Applicant’s abstract): The long-term objectives of this project are to understand the molecular mechanism of human mismatch repair and its impact on human cancer. DNA mismatch repair plays a crucial role in maintaining genomic stability by correcting mismatches generated from DNA biosynthetic errors and DNA recombination. Defects in human mismatch repair are the primary cause of both hereditary colorectal cancer and sporadic colorectal cancers that display microsatellite instability. Microsatellite instability, which correlates with mismatch repair deficiency, has also been demonstrated in a substantial fraction of many types of sporadic cancer, including bladder cancers. Recently, sporadic bladder cancers have been shown to display a higher rate of microsatellite instability than other sporadic cancers. The goals of this application are to determine if mismatch repair deficiency is associated with sporadic bladder cancers and to isolate and characterize novel mismatch repair components/genes. Experiments will be developed in the following three specific areas. 1) The mismatch repair proficiency of bladder cell lines with microsatellite instability will be determined using an in vitro biochemical mismatch repair assay. 2) Novel mismatch repair activities will be first characterized by complementation experiments using the known mismatch repair proteins and/or mutant cell lines, and then be purified from HeLa nuclear extracts by virtue of their ability to restore mismatch repair to the novel mutant cell lines. 3) The gene(s) encoding the novel protein(s) will be cloned by the “reverse genetic” approach. Peptide sequences will be obtained from the novel protein(s) and used for designing degenerate primers to amplify DNA fragments of interest, which are in turn used to identify full length cDNAs. This study will not only provide insight into the etiology of sporadic bladder cancers, but also lead to the identification of novel mismatch repair components. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLES AND REGULATION OF P53 Principal Investigator & Institution: Prives, Carol L.; Professor; Biological Sciences; Columbia Univ New York Morningside Research Administration New York, Ny 100277003 Timing: Fiscal Year 2006; Project Start 30-SEP-2000; Project End 31-JUL-2011 Summary: (provided by applicant): The goals of this program are to use an interdisciplinary and collaborative approach to elucidate the roles and regulation of p53 and related proteins in tumorigenesis using biochemistry, cell based assays, mouse

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models, informatics and analysis of human tumors. Carol Prives will study the regulation of the p53 family by the checkpoint kinases 1 and 2, will characterize the interactions of p53 family members with newly identified proteins and with each other and will determine how different family members are regulated and interact with their target genes in DMA. Arnold Levine will identify and characterize the single nucleotide polymorphisms (SNP’s) that are found in the genes which compose the p53 pathway in cells, and will utilize a previously designed algorithm to identify novel p53 target genes in the mouse and human genome. Scott Lowe will use the Ep. -myc transgenic model to determine how survival signaling through the PI3K/Akt pathway promotes chemoresistance in vivo, and how genes involved in apoptosis, senescence, and survival signaling influence p53 action and treatment outcome. He will also utilize the availability of RNAi libraries to identify new genes that influence chemotherapy outcome in this model. Carlos Cordon-Cardo will evaluate the predictive significance of alterations in the p53 pathway, p53 DNA damage response and the PTEN/AKT pathway in bladder cancers from human patients. Multiple collaborative projects between these different Principal Investigator’s are planned that cannot be accomplished by any single investigator. This program will thus exploit the individual and combined expertise of four researchers who are using complementary approaches to develop a translational approach for treatment and diagnosis of cancer. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLES OF NITRIC OXIDE AND SUPEROXIDE IN CYSTITIS Principal Investigator & Institution: Kanai, Anthony John.; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2005; Project Start 01-AUG-2005; Project End 31-MAY-2010 Summary: (provided by applicant): Irradiation of the pelvic region can result in bladder inflammation and dysfunction. This cystitis or its likelihood also increases the incidence of bladder cancer, prohibits radiation treatment for bladder tumors, and limits the allowable radiation dose for treating other pelvic malignancies. The mechanism of radiation cystitis is unclear. It may involve activation of a mitochondria nitric oxide (NO) synthase (mtNOS) unique to the umbrella cells, disruption of the permeability barrier and infiltration of urine into the lamina propria. This in turn can lead to inflammation and increased collagen III deposition in the lamina propria. Decreased bladder compliance and dysfunction result. We have developed rodent models of radiation cystitis where irradiation results in decreased transepithelial resistance and increased urea and water permeabilities within 12 hours. At six months, cystometrograms show that bladder compliances and intercontractile intervals are decreased while residual volumes and baseline pressures are increased-features indicative of fibrosis. Prior transfection with the radioprotectant manganese superoxide dismutase (MnSOD) is only partially effective, most likely due to decreased peroxidase activity and excess hydrogen peroxide formation. However, novel intravesical therapy with a NOS inhibitor during irradiation, or irradiation of bladders devoid of mtNOS, offers almost complete protection. Inhibition of NO can prevent its reaction with superoxide (O2) to form peroxynitrite (ONO2-), which can damage complexes I and III of the respiratory chain and lead to apoptotic/necrotic cell death. Specific Aim 1 will test the hypothesis that ionizing radiation activates mtNOS, resulting in reactive nitrogen and oxygen species (RNS and ROS) which disrupt the urothelial permeability barrier. We have developed NO and ONO2- microsensors which allow us to simultaneously measure in real-time, the changing levels of these metabolites in intact mouse bladders and cultured urothelial cells. These measurements will be correlated with assayed

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changes in mitochondrial enzyme functions. Specific Aim 2 will test the hypothesis that the intravesical administration of NOS antagonists or MnSOD or SOD mimetics with peroxidase activity protect the bladder against radiation cystitis. The effectiveness of these therapies in irradiated mouse bladders will be assessed at 1 to 6 months by employing permeability measurements, cystometry and histochemical analyses for collagen deposition. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SOUTHWEST ONCOLOGY GROUP Principal Investigator & Institution: Lenz, Heinz Josef.; Associate Professor; Medicine; University of Southern California Department of Contracts and Grants Los Angeles, Ca 90033 Timing: Fiscal Year 2004; Project Start 01-FEB-1993; Project End 31-DEC-2009 Summary: (provided by applicant): The USC Norris Comprehensive Cancer Center first participated in the research activities of SWOG in 1987 and was initially funded in 1992. This five-year grant cycle has had increased administrative and academic participation, with maintenance of high clinical and correlative trial entry, commensurate with available SWOG funding and added resources from USC. The major emphases of the USC team are (a) to explore the utility of molecular prognostication with the correlation of specific genes with outcomes of therapy; (b) to investigate novel strategies of chemotherapy for common solid tumors in cancer patients, with a particular emphasis on minority populations and the elderly; (c) to develop novel strategies of prevention of GU and GI cancers. Thus, USC investigators have contributed extensively to SWOG trials and administrative/academic leadership, facilitating the translation of specific themes of investigation to SWOG. Activities have included (a) administrative and scientific leadership (Vice Chairs of GU Committee and GI Committee; cadre membership in Breast, Melanoma and Committee for Women/Special Populations; Scientific Advisory Board; External Advisory Boards of EORTC and Cancer Research UK; Data and Safety Monitoring Committee of SWOG and Chair of DSMC of National Wilms Tumor Study Group; core labs for pharmacology and molecular prognostication studies of GU and GI Committees); (b) educational -Convener of the GU Committee Young Investigator Program & 3 Young Investigator Awards; (c) scientific research agendas translated from USC to SWOG have included the P53 molecular prognostication bladder cancer trial (NCI), international GC vs. GCT bladder CA trial; NCI UO-1 funded pharmacology and molecular prediction of outcome studies in phase II geriatric oncology trials; fluoropyrimidine response correlations in GI cancer and correlative pharmacogenomic studies; (d) continuing high levels of clinical trial accrual with majority of cases from USC itself rather than affiliates; particular progress in clinical trial recruitment within the UCOP population, with the appointment of Dr. Skinner as UCOP PRINCIPAL INVESTIGATOR and active support from USC medical oncologists has led to a nearly 50 GU cases in 2002; major success in minority recruitment with enhancement awards from NCI because of success; (e) multidisciplinary recruitment of 10 new investigators from Med Onc, Neurology/Neurosurgery, Urology, Pathology, Surgery & Pharmacology. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SPECIFIC BIOMARKERS IN BLADDER CANCER PREVENTION Principal Investigator & Institution: Getzenberg, Robert H.; Director of Urological Research & Profes; Pathology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260

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Timing: Fiscal Year 2004; Project Start 01-JUN-2003; Project End 31-DEC-2004 Summary: (provided by applicant) Bladder cancer is a significant health problem in the United States and throughout the world. An estimated 56,500 cases will be diagnosed this year in the U.S. alone. One of the highest risk groups for developing bladder cancer is former smokers. Smokers have more than a four-fold increased risk for developing bladder cancer as compared with non-smokers. The high risk of former smokers for developing bladder cancer and the extended period of time which typically elapses prior to the observation of bladder cancer in these individuals make them appropriate for following with markers that can detect the disease early as well as the application of chemopreventive agents in those identified with early disease. Instead of treating all smokers with chemopreventive agents as a first course, we are proposing to apply a biomarker which appears to specifically and sensitively detect bladder cancer at an early stage in its development and then focus the chemopreventive agents on these individuals. If these studies prove successful, these chemopreventive approaches can then be applied to the large population of former smokers using the marker, BLCA-4, as a measure of effectiveness. When bladder cancer is detected early, the five-year survival rate is approximately 94% while patients with disease that has spread, have significantly lower survival rates. The hypothesis being addressed here is that urine levels of BLCA-4 can serve as a surrogate biomarker to evaluate chemopreventive agents in an animal model of bladder cancer. To address this hypothesis we propose the following specific aims: 1. To examine the time course of BLCA-4 expression in the development of bladder cancer utilizing an animal model of the disease representing former smokers. 2. To determine the utility of BLCA-4 as a surrogate marker of bladder cancer permitting the rapid evaluation of chemopreventive compounds. 3. To test in a pilot study, the use of BLCA-4 as a biomarker with which to detect bladder cancer in former smokers at an early stage, prior to the development of gross lesions and therefore making them candidates for chemopreventive therapies both intravesically as well as systemic. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SYNTHESIS, ASSEMBLY AND TARGETING OF UROPLANKINS Principal Investigator & Institution: Kreibich, Gert; Associate Professor; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 30-JUN-2009 Summary: The urinary bladder is lined by a stratified (urothelium) that protects the underlying tissues from the non-physiological urine composition by forming a differentiated umbrella cell layer that elaborates an apical plasma membrane with a crystalline, asymmetric unit membrane (AUM) structure. This unique membrane is mainly composed of four polypeptides, the uroplakins (UPs) Ia, Ib, II and III, which assemble in post-Golgi vesicles (discoidal and fusiform vesicles) into two-dimensional crystalline arrays. Fusiform vesicles function in the regulated insertion of pre-assembled AUMs into the apical membrane of umbrella cells. Thus, the urothelium offers unique opportunities to study the processing, assembly and targeting of membrane proteins in polarized epithelial cells. In our efforts to understand the structural requirements for uroplakin assembly we will express in 293T cells modified forms of UPs to monitor the formation of specific UP pairs. Using MDCK zells as a polarized epithelial cell model, we will test whether the information for apical targeting of the UPIb/UPIII heterodimer is contained in the cytoplasmic domain of UPIII. We have demonstrated that Rab27b is rather selectively expressed in urothelial cells where it binds to fusiform vesicles. To test our working hypothesis that Rab27b functions in the delivery of fusiform vesicles to the apical plasma membrane, we plan to identify and characterize homologues of

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melanophilin and other not yet identified proteins that interact directly or indirectly with Rab27b. We will also generate conditional knockout mice where Rab27b expression is eliminated in an urotheliun-specific fashion. To this effect we will cross mice that express cre under the control of the UPII promotor with a strain that harbors a “fluxed” form of Rab27b. The morphological, functional and physiological characterization of these knockout mice compared with wild-type mice is expected to provide information on the specific step(s) in which Rab27b functions in the delivery of fusiform vesicles to the apical plasma membranes of urothelial umbrella cells. Such studies should help us better understand the normal physiology of the urothelium, and the mechanisms involved in bladder infection and bladder cancer. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TARGETING GENE THERAPY TO BLADDER CANCER Principal Investigator & Institution: Dougherty, Graeme John.; Professor; Radiation Oncology; University of California Los Angeles Office of Research Administration Los Angeles, Ca 90024 Timing: Fiscal Year 2004; Project Start 15-APR-2003; Project End 31-OCT-2004 Summary: (provided by applicant): Bladder cancer is a common malignancy with approximately 55,000 new cases and nearly 12,000 deaths reported in the US annually. Although a high proportion of patients (65-70 percent) present with well or moderately well differentiated superficial transitional cell carcinomas, approximately 60-70 percent of these nevertheless go on to develop recurrent disease after resection of primary lesions. For this reason, surgery is often combined with various adjuvant therapies including intravesical chemotherapy and/or immunotherapy (i.e. BCG). While such treatments do improve control, relapses remain common encouraging consideration of various alternative approaches including gene therapy. The major objective of this proposal is to evaluate a novel gene therapy-based approach to the treatment of bladder cancer in which alternative splicing is used as a means of targeting the expression of the enzyme alkaline phosphatase (ALP) to tumor cells in vivo. Specifically, adenoviral vectors will be constructed in which the expression of ALP is dependent upon the accurate removal from chimeric pre-mRNA transcripts of alternatively spliced intronic sequences. These vectors will be used to confirm the targeting specificity of alternative splicing in vitro following transduction of a panel of bladder tumor cell lines that differ in expression of various alternatively spliced isoforms of the adhesion protein CD44. Adenoviral vectors will also be tested both in vitro and in an ex vivo explant model for their ability to sensitize bladder tumor cells that differ in alternative splicing ability, to killing by the inactive prodrug Etopophos, which is converted to the potent topoisomerase II inhibitor etoposide upon dephosphorylation by ALP. Finally, in order to better identify those patients most likely to benefit for this targeted therapy, studies will be initiated to define the transacting factors and cis-acting sequences that regulate the alternative splicing of CD44 in bladder tumor cells. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THE PROTECTIVE ROLE OF NRF2 IN ARSENIC-INDUCED TOXICITY AND CARCINOGENICITY Principal Investigator & Institution: Zhang, Donna D.; Pharmacology and Toxicology; University of Arizona Po Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2006; Project Start 01-SEP-2006; Project End 31-AUG-2011

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Summary: (provided by applicant) The overall goal of our research is to understand the molecular mechanisms of toxicity/carcinogenicity of environmental pollutants and the endogenous cellular defense systems to cope with pollutants. Drinking water contaminated with arsenic, a known carcinogen, is a worldwide public health issue. Epidemiology studies have linked arsenic exposure to human cancers, including skin, liver, lung, kidney, prostate, and bladder cancer. Arsenic can also cause cellular damage through generation of reactive oxygen species (ROS) that are even involved in the initiation, promotion, and progression of tumors. Although arsenic is a well defined carcinogen, it is not mutagenic and induces malignant transformation possibly by an epigenetic or cell signaling mechanism. Eukaryotic cells have evolved several defense mechanisms to cope with stress from the environment, one of which is the antioxidant response utilized by mammalian cells to neutralize ROS and to maintain cellular redox homeostasis. This antioxidant system is mediated through the antioxidant response element (ARE) sequence present in the promoters of several antioxidant and Phase II detoxification genes including glutathione S-transferase, NAD(P)H quinone oxidoreductase, glutamylcysteine synthetase, and heme-oxygenase. The antioxidant response system is mainly controlled by the transcription factor Nrf2. Activated by compounds possessing anti-cancer properties, the ARE-Nrf2-Keap1 signaling pathway has been clearly demonstrated to have profound effects on tumorigenesis. More significantly, Nrf2 knockout mice display increased sensitivity to chemical toxicants and carcinogens and are refractory to the protective actions of chemopreventive compounds. Therefore, we hypothesize that activation of the ARE-Nrf2-Keap1 pathway acts as an endogenous protective system against arsenic-induced toxicity and carcinogenicity. The following specific aims are intended to further elucidate the mechanism of Nrf2activation in protection from arsenic-induced toxicity/tumorigenicity. This knowledge can potentially serve the scientific and medical community in our objective to create novel chemopreventive agents with increased specificity and efficacy, which will have broad impact on human health worldwide. We propose to (1) determine the protective role of the ARE-Nrf2- Keapl pathway in arsenic-induced toxicity and carcinogenicity, (2) define the molecular mechanisms of activation of the ARE-Nrf2-Keap1 pathway by arsenic, and (3) define the protective role of the ARE-Nrf2-Keap1 pathway in arsenicinduced toxicity and tumorigenicity using the Nrf2 knockout mouse model. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE ROLE OF ACTIN POLYMERIZATION IN TUMOR METASTASIS Principal Investigator & Institution: Zhan, Steven; Associate Professor; Pathology; University of Maryland Balt Prof School 110 South Paca Street, 4Th Fl Baltimore, Md 21201 Timing: Fiscal Year 2004; Project Start 01-JUL-2002; Project End 30-JUN-2007 Summary: (provided by applicant) The long-term goal of this application is to understand the molecular mechanism ot tumor metastasis. Prior works have established that amplification of the chromosome 11q13, which occurs frequently in breast cancer, head and neck squamous carcinomas and bladder cancer, results in overexpression of cortactin or EMS 1, a prominent substrate of protein tyrosine kinase Src with potential to associate with actin filaments. Patients with gene amplification of cortactin tend to have poor prognosis and increased possibility of relapse. However, the mechanism by which cortactin contributes to tumor progression is still unknown. There has been accumulated evidence that cortactin is implicated in the modulation of cell cytoskeletal changes associated with cell motility and cell shape changes. Our recent study further demonstrated that cortactin plays an important role in actin polymerization via

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interaction with Arp2/3 complex, a key protein machinery to initiate actin polymerization within cells. Furthermore, cortactin modulates the activity of Arp2/3 complex for actin nucleation and actin branching, two important steps in the formation of cell leading edge structures. We also found that overexpression of wild-type cortactin can enhance cell motility in vitro and facilitate tumor metastasis in vivo, whereas overexpression of cortactin mutants either in tyrosine phosphorylation or Arp2/3 binding can impair cell migration and bone metastasis. Based on these observations, we hypothesize that actin polymerization mediated by Arp2/3 complex and cortactin plays an important role in tumor metastasis. To test this hypothesis, we propose to delineate the detailed interactions among Arp2/3 complex and cortactin, explore the regulation of cortactin/Arp2/3 complex by Src, PIP2 and other cellular factors, and to test the hypothesis whether or not inhibition of actin polymerization by disruption of these interactions would be effectively able to compromise metastasis in vivo. Thus, the specific aims for this application include: (1) Characterization of the mechanism by which cortactin activates the activity of Arp2/3 complex for actin nucleation and branching. We will characterize the structural basis for the interactions between cortactin and Arp2/3 complex, examine the mechanism by which cortactin enhances actin nucleation and promotes and stabilizes actin branching. (2) Study of the regulation of cortactin/Arp2/3-mediated actin nucleation and branching. We will assess the effect of Src and PIP2 on the actin nucleation and branching mediated by cortactin/Arp2/3 complex in vitro, and search for other cellular factor(s) through which Src, PIP2, Cdc42 and Rac may regulate the function of cortactin/Arp2/3 complex. (3) Analysis of the effects of the mutants derived from Arp2/3 and cortactin on tumor metastasis. We will introduce using retrovirus functional peptides derived from Arp2/3 and cortactin that can disrupt or enhance actin polymerization into MDA-MB-23 1 tumor cells. Next, we will evaluate the motility and metastatic potentials of these cells both in vitro and in vivo. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE ROLE OF CAR AND ITS APPLICATION IN BLADDER CANCER Principal Investigator & Institution: Hsieh, Jer-Tsong; Associate Professor; Urology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2004; Project Start 01-FEB-2003; Project End 31-JAN-2007 Summary: This abstract is not available. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THE ROLE OF THROMBOXANE A2 IN BLADDER CANCER Principal Investigator & Institution: Watson, Dennis K.; Professor; Pathology and Lab Medicine; Medical University of South Carolina Charleston, Sc 29425 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): In the US, bladder cancer is the fourth most common cancer in men and the eighth most common cancer in women. The clinical course in urinary bladder cancer has been difficult or impossible to predict: Unfortunately, recurrence, invasion, and metastasis, even after a seemingly successful treatment at early stage, are characteristic of bladder cancer. Our long-term goal is the identification of the alterations that are functionally critical for tumorigenesis and progression that will lead to more reliable patient stratification and outcome prediction and development of novel therapies. We have recently used a combination of genetic approaches to identify genes that may be functionally involved in the progression of

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bladder cancer. Thromboxane synthase (TXAS) was among the genes identified based upon its overexpression in a bladder cancer. Our preliminary data demonstrate that TXAS mRNA and protein are overexpressed in human bladder cancer and bladder cancer-derived cell lines. The frequency of TXAS overexpression is highest in high grade (G3) and late stage (T4) minors. We further determined that the Thromboxane A2 (TP) receptors are overexpressed in human bladder cancer and cell lines. Based upon our observations, we hypothesize that TXA2 contributes to metastatic bladder cancer via its control on cell proliferation, migration, and angiogenesis. We believe that TXA2regulated pathways function in autocrine as well as paracrine pathways that affect the cancer cell and endothelial cells, respectively. We further hypothesize that inhibition of TP receptor signaling may provide a new therapeutic target for the treatment of bladder cancer. In this exploratory (R21) proposal, we will use pharmacological and molecular approaches to elucidate TXAS and TP receptor function in vitro and in vivo. Specifically, we will determine the effects of TP receptor antagonists or agonists and TXAS inhibitors on growth, migration, invasion of bladder cancer cells. These studies will be complemented by molecular loss of function and gain of function studies. We will evaluate clinical samples to determine whether the expression of TXAS and TP receptors is correlated with aggressive human bladder cancer. Collectively, these studies have the potential to reveal a new approach for the treatment of bladder cancer. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THERAPEUTIC TARGETING AGENTS FOR BLADDER CANCER Principal Investigator & Institution: Luo, Yi; Urology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2004; Project Start 01-MAY-2004; Project End 30-APR-2006 Summary: (provided by applicant): The purpose of this project is to develop novel cellselective therapeutic targeting agents for treating bladder cancer. Making use of two non-overlapping phage-display derived bladder cancer-specific binding peptides (BCSBPs) already developed, conjugates will be created between these BCSBPs and both an active chemotherapeutic drug (Epirubicin) and two biologic proteins (cytokines IL-2 and IL-12). Binding and functional activity of these BCSBPs will be optimized against a mouse bladder cancer cell line previously shown to share the same binding characteristics for these BCSBPs as multiple human bladder cancer cell lines. The longterm goal is to develop the necessary methodology for translating these targeting motifs into clinical use immunotherapeutic against human bladder cancer. Towards achieving these goals, two specific aims will be undertaken: Specific Aim 1: To chemically conjugate BCSBPs with the chemotherapeutic drug Epirubicin, and to assess cytotoxicity of the conjugates in targeting bladder cancer cells. The conjugates will be made through a chemical coupling process that explores positional effects, number of targeting motifs and use of spacers to achieve maximal binding specificity, affinity, and functional cytotoxic activity. Specific aim 2: To genetically conjugate BCSBPs with Thl cytokines IL2 and IL-12, and to assess the binding and biological activities of these fusion proteins upon targeted bladder cancer cells. These fusion proteins will be made using prokaryotic or insect expression systems. Binding specificity will be optimized using a GFP-conjugate prototype. Biological activity for IL-2 and IL-12, alone and as synergistic agents will be tested using well-established bioassays. Successful completion of this study will result in future pre-clinical studies using these novel therapeutic conjugates in animal bladder cancer models that may further lead to a quick translation of this strategy into a clinically useful treatment modality for human bladder cancer. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THROMBOSPONDIN-1 IN PROSTATE DEVELOPMENT AND NEOPLASIA Principal Investigator & Institution: Crawford, Susan E.; Associate Professor; Pathology; Northwestern University 750 N. Lake Shore Drive, 7Th Chicago, Il 60611 Timing: Fiscal Year 2004; Project Start 01-AUG-2003; Project End 31-JUL-2006 Summary: (provided by applicant): Thrombospondin-1 (TSP-1) is a homotrimeric secreted glycoprotein that functions in a wide variety of biologic activities including embryonic development, tissue differentiation, neurite outgrowth, and responses to injury and inflammation. TSP-1 is also a potent inhibitor of angiogenesis, the growth of new blood vessels from the existing vasculature. Decreased TSP-1 expression contributes to the angiogenic environment that supports the growth of glioblastoma, fibrosarcomas and bladder cancer. Data is presented that show TSP-1 expression is down-regulated or lost in benign prostatic hyperplasia (BPH) and prostate cancer and identify TSP-1 as a key functional inhibitor of angiogenesis in the prostate. The normal and diseased prostate is exquisitely sensitive to changes in TSP-1 levels as TSP-1 null mice develop prostatic hyperplasia and TSP-1 expression increased after androgen ablation therapy in human prostate cancer specimens. Thus, we hypothesize that TSP- 1 plays a key role in the regulation of normal prostatic growth and that dysregulated TSP1 expression contributes to disease. To study the functions of TSP-1 in normal prostate growth and discern how dysregulated expression contributes to disease states, we plan to 1) characterize the prostate phenotype in the TSP-1 null mice, establishing a time course of disease development, and determine the underlying mechanism of the hyperplasia (i.e. increased proliferation or angiogenesis, decreased apoptosis or a combination of these), and 2) determine if androgen regulation of TSP-1 expression is critical to modulation of prostatic growth, using in vitro methods and the TSP-1 null mouse model. Results from these experiments should establish the function of TSP-1 in prostatic growth regulation and determine how TSP-1 may be useful as a prognostic indicator or as a treatment for prostatic diseases. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TOBACCO AND CANCER RISK--DOSE, METABOLISM AND GENETICS Principal Investigator & Institution: Lazarus, Philip; Professor; Pharmacology; Pennsylvania State Univ Hershey Med Ctr Milton S. Hershey Medical Center Hershey, Pa 170330850 Timing: Fiscal Year 2004; Project Start 08-SEP-1995; Project End 31-AUG-2007 Summary: (Applicant’s Description) Studies from our group and others have demonstrated that the risk for tobacco-related cancers differs by race, gender and type of tobacco product consumed. These important public health differences cannot be fully explained by existing patterns of tobacco consumption. We hypothesize that risk is related to the type of cigarette smoked (e.g., low versus medium yield of carcinogens), the manner in which an individual’s smoking habit regulates the dosage that reaches the lungs, metabolic capacity to activate and detoxify smoke-borne carcinogens, and susceptibility to cancer related to genetic factors that may affect metabolism or DNA repair. During the first three years of the study, the program focused on epidemiology, dosage and biomarkers of dose, and metabolic pathways of carcinogen activation and detoxification. In the coming period, the former Project (epidemiology) will be replaced by an epidemiological core facility (Core C) to provide appropriate study subjects for the two continuing projects and one new project. The current Project (Dosimetry of

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Lung and Bladder Cancer Risk among Cigarette Smokers) is about how smoking behavior affects the “delivered” carcinogen dose, and in turn how dose is related to biomarkers of carcinogen metabolites. Project (Metabolic Epidemiology of TobaccoRelated Cancers in Black and White Americans) is a study of differences between African Americans and Caucasians in metabolic activation and/or detoxification of an array of carcinogens derived from cigarette smoking, such as NNK (a potent lung carcinogen) and 4-aminobiphenyl (a bladder carcinogen). It utilizes metabolic and molecular techniques to study pathways of activation of tobacco-derived nitrosamines related to lung cancer, which is higher in African Americans compared to Caucasians, as well as detoxification of aromatic amines involved in bladder cancer, the rate of which is lower. Project (UDP Glucuronosyltransferases, Detoxification of NNK and Lung Cancer Risk) focuses on a family of detoxification enzymes that may be related to individual risk for developing lung or bladder cancer, and for which genetic polymorphisms exist that might explain variation in cancer risk. A broader understanding of these factors, both individually and comprehensively, will contribute greatly to our understanding of the causes of tobacco-related cancers in a way that can help improve our prevention strategies. The investigators are leaders in their respective fields with a strong history of collaboration. The program is supported by an Administrative Core with an Advisory Board of distinguished scientists and a community representative, by a Biostatistics and Computing Core Facility to provide efficient data management and statistical support, and by an Epidemiology Core Facility to manage accrual of subjects, interviews, acquisition of buccal cells, urine, and blood for biomarker assays, and pathological review. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TOXIC METALS IN THE NORTHEAST: FROM BIOLOGICAL TO ENVIRO Principal Investigator & Institution: Hamilton, Joshua W.; Associate Professor; Pharmacology and Toxicology; Dartmouth College Office of Sponsored Projects Hanover, Nh 03755 Timing: Fiscal Year 2004; Project Start 01-MAY-1995; Project End 31-MAR-2005 Summary: The overall goal of the Dartmouth SBRP Program Project, Toxic Metals in the Northeast: From Biological to Environmental Implications, is to determine the impact of toxic metals found at Superfund sites, at other waste sites, and in the environment on adverse effects on human health and the environment. Eight of the twenty-two agents on the ATSDR priority list. Over 60% of all Superfund sites contain significant toxic metal contamination, and more than 70% of these contain arsenic, which is the top ATSDR agent of concern. The distinct and program-wide focus of this research program is on toxic metals, and particularly on arsenic, which is being examined in all their goals and scientific focus, including chromium, nickel, cadmium, mercury, cobalt and lead. This program consists of five biomedical projects (Projects 1-5), two non-biomedical projects (Projects 6, 7), and three program support cores (Molecular Biology, Trace Metals Analysis and Biostatistics), plus an Administrative core, Training laboratory investigations on the cellular and molecular mechanisms of toxic metal actions in humans and include Project 1 (arsenic-induced vascular disease), Project 2 (arsenic- and chromium- induced cancer), Project 3 (arsenic effects on xenobiotic metabolism) and Project 5 (interactions of toxic metals with cellular proteins). The second includes Project 4 (human epidemiology of arsenic and skin and bladder cancer), Project 6 (sources, fate and third area involves development and implementation of molecular biomarkers of toxic metal exposure and health elucidate the sub-set of genes, mRNAs and proteins

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whose expression is specifically modified by toxic metal mechanistic laboratory studies and in the ecology and epidemiology projects. The multi- disciplinary nature of this program, combined with its unique program- wide focus on arsenic and other toxic metals, is designed to create and foster an environment for truly inter-disciplinary yet focused research, training and outreach. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRAINING OF ACADEMIC UROLOGIC ONCOLOGISTS Principal Investigator & Institution: Grossman, H. Barton.; Professor; Urology; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009 Timing: Fiscal Year 2005; Project Start 01-AUG-2000; Project End 30-JUN-2010 Summary: (provided by applicant): The University of Texas M. D. Anderson Cancer Center Urology Fellowship has played a leadership role in the development of highly qualified Urologic physician-scientists, who have been a significant resource to the medical care of the United States. This three-year fellowship has attracted outstanding applicants who have garnered notable awards during their training and then obtained prestigious academic positions ensuring continued advances in the care of patients with urologic cancers. The three-year training program integrates “bench research” and clinical training resulting in translational efforts that will ultimately result in improvements in routine patient care. Our two SPOREs focused on prostate and bladder cancer are evidence of the excellence in translational research in the Genitourinary Program of the M. D. Anderson Cancer Center. The primary goal of this program is to train academic urologic oncologists, who are excellent clinicians, surgeons, and scientists. Fellows completing this program will be capable of establishing or upgrading academic Urologic Oncology programs in major teaching institutions. To accomplish this task, the graduating fellows will need to obtain organizational, leadership, and didactic skills along with clinical and research expertise. The success of this T32 training program is based upon our ability to provide the trainee with a working knowledge of the laboratory and clinically defined biology of genitourinary cancer. This understanding will enable the trainee to critically evaluate current methods of cancer prevention, diagnosis, and treatment and develop improved strategies based upon rigorous laboratory data, translational research, and clinical observations. An important but secondary goal of our training program is a post-doctoral laboratory training effort, which has included both physicians and research scientists. Post-doctoral fellows have the opportunity to work closely with clinicians during their training. This association with outstanding clinicians will help integrate their future research into translational efforts. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: UROTHELIAL CELL PHYSIOLOGY IN NORMAL AND DISEASE STATES Principal Investigator & Institution: Saban, Ricardo; Professor; Physiology; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 731171213 Timing: Fiscal Year 2005; Project Start 15-JUL-2005; Project End 28-FEB-2006 Summary: (provided by applicant): The present application is in support of 2-days symposium entitled “Urothelial Cell Physiology in Normal and Disease States” (www.urothelium2005.com) that was accepted by the International Physiology as satellite and will precede (March 29-30, 2005) the primary event (XXXV International Congress of Physiological Sciences). This symposium will be held in San Diego, CA. The

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symposium specific objectives are: 1.To review bladder physiology. 2. To raise awareness of clinical aspects of lower urinary tract dysfunction including: detrusor instability, stress incontinence, interstitial cystitis, bladder cancer, infection, inflammation, and immunity. 3. To identify new post-genomic research approaches. The symposium specific goals are: 1. To attract new scientists to this important area or research. 2.To stimulate the participation of postdoctoral fellows and graduate students by providing travel awards for selected poster presentations. In order to accomplish these goals, 35 (21 national and 14 international) world’s experts in UT physiology, pathology, and clinics will introduce the clinical aspects of the disease followed by the latest accomplishments in basic research. The symposium agenda is divided in 7 podium sections and one poster presentation. The podium sections include: I) Bladder Physiology; II) Genomics of bladder detrusor function; III) Urothelial Permeability; IV) Growth Factors; V) Sensory Peptides; VI) Angiogenesis and Lymphangiogenesis; and VII) Bladder Pathology (cancer and infection). In each of the sections key note speakers and outstanding researchers will address the most relevant aspects of the translational research. In this context, Prof. William C. de Groat (University of Pittsburgh) will review the basic aspects of bladder physiology and Dr. Karl-Erik Andersson (Lund University) will introduce the clinical an overview about the functional and disease implications of uroplakins whereas Prof. Scott-Hultgren (Washington U) will discuss the molecular basis of persistent bladder infections. The bladder cancer discussion will be chaired by Drs. Robert Hurst (Oklahoma U) and Jenny Southgate (U. York). Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: YEAST ASSAY FOR P53 MOLECULAR ANALYSIS IN BLADDER CANCER Principal Investigator & Institution: Devere White, Ralph W.; Director; Urology; University of California Davis Office of Research - Sponsored Programs Davis, Ca 95618 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): Bladder cancer is the fifth most frequently diagnosed tumor in the United States, with more than 57,400 new cases and 12,500 deaths annually. Eighty-five percent of these deaths come from the 25% of patients who present with muscle-invasive disease. Reduction in morbidity and mortality will come from improving outcome in this group of patients. Having rapid access to molecular analysis data and knowing its relationship to clinical outcome could be invaluable to patient management and treatment. The long-term objectives of this R21/R33 application are to 1) standardize the protocol for an archival-based yeast functional assay (aYFA) that will lead to broad clinical utilization, and 2) determine what clinical relevance molecular analysis may provide when detecting and evaluating p53 functionality in bladder cancer. A yeast functional assay is an existing methodology that detects p53 mutations in human cancers. In this assay, both p53 expression plasmids and reporter plasmids are co-transfected into yeast. The expressed wild-type (wt) p53 is able to bind to a p53-response element, whereas mutant p53 lacks the ability to bind. This binding and lack of binding leads to color differences in transactivational activity. Use of this current version of the yeast assay has one serious drawback: it was designed for the study of mRNA from cell lines and fresh-frozen tissue. Unfortunately, in large clinical trials, fresh-frozen tissue is rarely available for comparing genetic markers to patient outcome. Therefore, an archival-based yeast functional assay could prove to be extremely suitable for rapid, accurate, and treatment-relevant molecular analysis in a wider bladder cancer population. The specific aim of the R21 phase of this grant is to optimize the technology and methodology for a broader utilization of the archival-based

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yeast functional assay in the clinical setting. The specific aim of the R33 phase of this grant is to determine the clinical relevance of different p53 mutations (alterations and functionality) in bladder cancer. It is expected that the archival-based yeast functional assay technology will impact the molecular analysis of bladder cancer by proving to be both rapid and clinically relevant. The archival-based yeast functional assay technology is innovative in that it would give clinicians, regardless of location, the ability to obtain molecular analysis information that could prove valuable to patient outcome prior to actual treatment initiation. Currently, with fresh-frozen tissue required to perform the standard yeast assay, timely accessibility of individual patient molecular data for the clinician is virtually impossible to obtain. This makes the standard yeast assay less than optimal for widespread use and subsequently hampers future research endeavors. This grant proposes to compare p53 molecular analysis data and its relationship to patient clinical outcomes in bladder cancer patients. Three groups of patients that have already been reported on will form the basis of the R33 pilot study. The archival-based yeast functional assay technology will be used in testing bladder cancer specimens (cystectomy and TURBT) and then comparing their p53 status to patient clinical outcomes. The results obtained during the period of this grant will form the basis for future studies that should affect treatment strategies for this disease. Website: crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen NTIS (National Technical Information Service) The NTIS (www.ntis.gov), a service of the U.S. Department of Commerce, has published the following information on sponsored studies related to bladder cancer: •

“Noninvasive identification of Bladder cancer with sub-surface backscattered light,” published in 1994. Sponsored by: Los Alamos National Lab., NM.; Department of Energy, Washington, DC. Written by: I. J. Bigio, J. R. Mourant, J. Boyer, T. Johnson and T. Shimada. Abstract: A non-invasive diagnostic tool that could identify malignancy in situ and in real time would have a major impact on the detection and treatment of cancer. We have developed and are testing early prototypes of an optical biopsy system (OBS) for detection of cancer and other tissue pathologies. The OBS invokes a unique approach to optical diagnosis of tissue pathologies based on the elastic scattering properties, over a wide range of wavelengths, of the microscopic structure of the tissue. Absorption bands in the tissue also add useful complexity to the spectral data collected. The use of elastic scattering as the key to optical tissue diagnostics in the OBS is based on the fact that many tissue pathologies, including a majority of cancer forms, manifest significant architectural changes at the cellular and sub-cellular level. Since the cellular components that cause elastic scattering have dimensions typically on the order of visible to near-IR wavelengths, the elastic (Mie) scattering properties will be strongly wavelength dependent. Thus, morphology and size changes can be expected to cause significant changes in an optical signature that is derived from the wavelength-dependence of elastic scattering as well as absorption. The data acquisition and storage/display time with the OBS instrument is (approximately)1 second. Thus, in addition to the reduced invasiveness of this technique compared with current state-of-the-art methods (surgical biopsy and pathology analysis), the OBS offers the possibility of impressively faster diagnostic assessment. The OBS employs a small fiber-optic probe that is amenable to use with any endoscope, catheter or hypodermic, or to direct surface examination (e.g.,

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as in skin cancer or cervical cancer). We report here specifically on its potential application in the detection of bladder cancer. •

“Pilot Project to Assess Mortality among Former Chromium Smelter Workers,” published in September 1993. Sponsored by: Michigan State Univ., East Lansing. Coll. of Human Medicine.; National Inst. for Occupational Safety and Health, Cincinnati, OH. Written by: K. D. Rosenman. Abstract: A mortality study of former workers from four chromate production facilities in northern New Jersey was conducted, and the feasibility of identifying and notifying workers from closed facilities without access to personnel records or recent address information was examined. Social Security records were used to identify a cohort of 3,408 former workers from the four facilities. It was possible to trace 83% of the total cohort. Of these, 1,787 workers were decreased. At least 65.4% of the cohort presumed to be alive received notification. Mortality analysis indicated that workers at these facilities remained at an elevated risk for the development of lung cancer more than 20 years after the end of their employment. A cluster of bladder cancer among former black workers was noted at one facility. There were 306 former chromate workers who expressed interest in participating in a lung cancer screening program. Another 41 were interested in receiving more information. The author notes that in spite of the absence of personnel records or recent addresses, it was possible to determine the vital status of over 80% of all former workers and over and 90% of former workers with more than 1 year of work at these facilities.

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“Report on the third international workshop on chromosome 9,” published in April 1994. Sponsored by: Brigham and Women’s Hospital, Boston, MA.; Department of Energy, Washington, DC. Written by: S. Povey, J. A. White and J. Armour. Abstract: The Third International Workshop on human chromosome 9 was held at Queens’ College, Cambridge 9-11 April, 1994. The meeting was attended by 74 participants from 12 countries. On the morning of 12 April a satellite meeting was held on Tuberous Sclerosis, and because of its relevance to chromosome 9 a summary of this meeting is also presented within this report. The division consisted of a group with global interests, four regional groups 9p, 9q11-q21, 9q22-q33 and 9q33-qter, a group interested in mapping putative suppressor genes in ovarian and bladder cancer and a comparative mapping group. There was also discussion of resources, both physical and informatic. The amount of information on chromosome 9 has increased greatly in the past two years and it is clear that the integration of different types of information and the display of such information is an urgent problem. At this meeting two possible systems were explored, SIGMA and 1db. As described in the global group report an attempt was made to enter all mapping information into SIGMA, a program developed by Michael Cinkosky at Los Alamos. Within the text of this report a name without a date refers to an abstract at this meeting. A name with a date refers to a publication listed in the references and these are in general confined to very recent or (open quote)in press(close quote) references. A verbal communication at the meeting is identified as a personal communication. For authoritative referencing of published information and also for all primer sequences (except a few actually listed in the abstracts) the reader

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should consult GDB. The proceedings of the two previous workshops have been published and are listed in the references. It was decided that a fourth workshop would be held in about a year’s time. Dr. Margaret Pericak-Vance offered to host this at Duke University, North Carolina. •

“Surveillance, Epidemiology, and End Results Program (SEER): Landmark Studies,” published in 2003. Abstract: The report presents short, one page descriptions of ‘Landmark Studies’ of the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute (NCI). Partial Contents include: Surveillance - Adenocarcinoma of the Esophagus and Gastric Cardia; Health Disparities in Underserved Populations; and Lifetime Risk of Breast Cancer. Epidemiology - National Bladder Cancer Study; Cancer and Steroid Hormone Study; Diet and Cancer; and Physical Activity and Cancer. End Results - Prostate Cancer Outcomes Study; Breast Cancer Surveillance Consortium; SEER-Medicare Database; and Health Policy: Colorectal Cancer.

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.9 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 bladder cancer, simply go to the PubMed Web site at www.ncbi.nlm.nih.gov/pubmed. Type bladder cancer (or synonyms) into the search box, and click Go. The following is the type of output you can expect from PubMed for bladder cancer (hyperlinks lead to article summaries): •

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A non-invasive QPCR method monitoring DNA based therapy of bladder cancer patients. Author(s): Ayesh S, Abu-Lail R, Hochberg A. Source: Vaccine. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16545506&query_hl=5&itool=pubmed_docsum

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 novel method for gene expression mapping of metastatic competence in human bladder cancer. Author(s): Wu Z, Siadaty MS, Riddick G, Frierson HF Jr, Lee JK, Golden W, Knuutila S, Hampton GM, El-Rifai W, Theodorescu D. Source: Neoplasia (New York, N.Y.). www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16611411&query_hl=5&itool=pubmed_docsum

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A re-staging transurethral resection predicts early progression of superficial bladder cancer. Author(s): Herr HW, Donat SM. Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16566813&query_hl=5&itool=pubmed_docsum

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Adaptive radiotherapy for invasive bladder cancer: a feasibility study. Author(s): Pos FJ, Hulshof M, Lebesque J, Lotz H, van Tienhoven G, Moonen L, Remeijer P. Source: International Journal of Radiation Oncology, Biology, Physics. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16458776&query_hl=5&itool=pubmed_docsum

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Adjuvant and neoadjuvant chemotherapy for bladder cancer: management and controversies. Author(s): Garcia JA, Dreicer R. Source: Nat Clin Pract Urol. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16474574&query_hl=5&itool=pubmed_docsum

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Adjuvant chemotherapy for invasive bladder cancer (individual patient data). Author(s): Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Source: Cochrane Database Syst Rev. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16625650&query_hl=5&itool=pubmed_docsum

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Aggressive management of elderly patients with muscle-invasive bladder cancer. Author(s): Weizer AZ, Montie JE, Lee CT. Source: Nat Clin Pract Urol. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16835604&query_hl=5&itool=pubmed_docsum

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Alterations in transcription clusters underlie development of bladder cancer along papillary and nonpapillary pathways. Author(s): Kim JH, Tuziak T, Hu L, Wang Z, Bondaruk J, Kim M, Fuller G, Dinney C, Grossman HB, Baggerly K, Zhang W, Czerniak B. Source: Laboratory Investigation; a Journal of Technical Methods and Pathology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15778693&query_hl=5&itool=pubmed_docsum

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Angiotensin II type 1 receptor antagonist candesartan as an angiogenic inhibitor in a xenograft model of bladder cancer. Author(s): Kosugi M, Miyajima A, Kikuchi E, Horiguchi Y, Murai M. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16675585&query_hl=5&itool=pubmed_docsum

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Angiotensin-II combined intra-arterial chemotherapy for locally advanced bladder cancer: a case series study at a single institution. Author(s): Shimabukuro T, Nakamura K, Uchiyama K, Tei Y, Aoki A, Naito K. Source: Hinyokika Kiyo. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16541762&query_hl=5&itool=pubmed_docsum

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Annular rectal constriction due to infiltration by bladder cancer. Author(s): Kobayashi S, Kato H, Iijima K, Kinebuchi Y, Igawa Y, Nishizawa O. Source: Hinyokika Kiyo. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16910593&query_hl=5&itool=pubmed_docsum

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Antitumor activity of the antimicrobial peptide magainin II against bladder cancer cell lines. Author(s): Lehmann J, Retz M, Sidhu SS, Suttmann H, Sell M, Paulsen F, Harder J, Unteregger G, Stockle M. Source: European Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16476519&query_hl=5&itool=pubmed_docsum

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Are bladder cancer patients with pT0 disease following radical cystectomy cured of cancer? Author(s): Thalmann G. Source: Nat Clin Pract Urol. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=17031377&query_hl=5&itool=pubmed_docsum

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Are nomograms better than currently available stage groupings for bladder cancer? Author(s): Sternberg CN. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16864852&query_hl=5&itool=pubmed_docsum

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Arsenic methylation and bladder cancer risk in case-control studies in Argentina and the United States. Author(s): Steinmaus C, Bates MN, Yuan Y, Kalman D, Atallah R, Rey OA, Biggs ML, Hopenhayn C, Moore LE, Hoang BK, Smith AH. Source: Journal of Occupational and Environmental Medicine / American College of Occupational and Environmental Medicine. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16688004&query_hl=5&itool=pubmed_docsum

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Association of cyclooxygenase-2 immunoreactivity with tumor recurrence and disease progression in superficial urothelial bladder cancer. Author(s): Mokos I, Jakic-Razumovic J, Marekovic Z, Pasini J. Source: Tumori. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16724691&query_hl=5&itool=pubmed_docsum

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Association of interleukin-1Ra gene polymorphism in patients with bladder cancer: case control study from North India. Author(s): Bid HK, Manchanda PK, Mittal RD. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16698387&query_hl=5&itool=pubmed_docsum

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Bacillus Calmette-Guerin induces the expression of peroxisome proliferator-activated receptor gamma in bladder cancer cells. Author(s): Lodillinsky C, Umerez MS, Jasnis MA, Casabe A, Sandes E, Eijan AM. Source: International Journal of Molecular Medicine. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16391825&query_hl=5&itool=pubmed_docsum

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Biological characteristics in bladder cancer depend on the type of genetic instability. Author(s): Yamamoto Y, Matsuyama H, Kawauchi S, Furuya T, Liu XP, Ikemoto K, Oga A, Naito K, Sasaki K. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16675567&query_hl=5&itool=pubmed_docsum

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Bladder cancer after managing upper urinary tract transitional cell carcinoma: predictive factors and pathology. Author(s): Raman JD, Ng CK, Boorjian SA, Vaughan ED Jr, Sosa RE, Scherr DS. Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16225523&query_hl=5&itool=pubmed_docsum

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Bladder cancer clinical trials. Author(s): Lerner SP. Source: Urologic Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16018944&query_hl=5&itool=pubmed_docsum

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Bladder cancer diagnosis and recurrence prognosis: comparison of markers with emphasis on survivin. Author(s): Schultz IJ, Witjes JA, Swinkels DW, de Kok JB. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16480698&query_hl=5&itool=pubmed_docsum

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Bladder cancer mortality and private well use in New England: an ecological study. Author(s): Ayotte JD, Baris D, Cantor KP, Colt J, Robinson GR Jr, Lubin JH, Karagas M, Hoover RN, Fraumeni JF Jr, Silverman DT. Source: Journal of Epidemiology and Community Health. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16415269&query_hl=5&itool=pubmed_docsum

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Bladder cancer predisposition: a multigenic approach to DNA-repair and cell-cyclecontrol genes. Author(s): Wu X, Gu J, Grossman HB, Amos CI, Etzel C, Huang M, Zhang Q, Millikan RE, Lerner S, Dinney CP, Spitz MR. Source: American Journal of Human Genetics. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16465622&query_hl=5&itool=pubmed_docsum

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Bladder cancer prevention--could a carrot be the stick? Author(s): Konety BR. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16890640&query_hl=5&itool=pubmed_docsum

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Bladder cancer risk as modified by family history and smoking. Author(s): Lin J, Spitz MR, Dinney CP, Etzel CJ, Grossman HB, Wu X. Source: Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16845665&query_hl=5&itool=pubmed_docsum

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Bladder cancer risk in painters: a review of the epidemiological evidence, 1989-2004. Author(s): Bosetti C, Pira E, La Vecchia C. Source: Cancer Causes & Control : Ccc. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16184465&query_hl=5&itool=pubmed_docsum

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Bladder cancer risk in sales workers: artefact or cause for concern? Author(s): ‘t Mannetje A, Pearce N. Source: American Journal of Industrial Medicine. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16421931&query_hl=5&itool=pubmed_docsum

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Bladder cancer screening and monitoring of 4,4’-methylenebis(2-chloroaniline) exposure among workers in Taiwan. Author(s): Chen HI, Liou SH, Loh CH, Uang SN, Yu YC, Shih TS. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16098360&query_hl=5&itool=pubmed_docsum

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Bladder cancer stage and outcome by array-based comparative genomic hybridization. Author(s): Blaveri E, Brewer JL, Roydasgupta R, Fridlyand J, DeVries S, Koppie T, Pejavar S, Mehta K, Carroll P, Simko JP, Waldman FM. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16203795&query_hl=5&itool=pubmed_docsum

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Bladder cancer with obstructive uremia: oncologic outcome after definitive surgical management. Author(s): El-Tabey NA, Osman Y, Mosbah A, Mohsen T, Abol-Enein H. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16140072&query_hl=5&itool=pubmed_docsum

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Bladder cancer: current optimal intravesical treatment. Author(s): Lamm DL, McGee WR, Hale K. Source: Urologic Nursing : Official Journal of the American Urological Association Allied. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16294610&query_hl=5&itool=pubmed_docsum

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Bladder cancer: epidemiology, staging and grading, and diagnosis. Author(s): Kirkali Z, Chan T, Manoharan M, Algaba F, Busch C, Cheng L, Kiemeney L, Kriegmair M, Montironi R, Murphy WM, Sesterhenn IA, Tachibana M, Weider J. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16399414&query_hl=5&itool=pubmed_docsum

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Bladder cancer: in search of the right operation for the right patient. Author(s): Fisher HA. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16697781&query_hl=5&itool=pubmed_docsum

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Bladder cancer: revealing news about a hidden threat. Author(s): Campbell BD. Source: Nursing. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16582750&query_hl=5&itool=pubmed_docsum

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Bladder cancer: toward state of the art multidisciplinary molecular medicine. Author(s): Rashid HH, Koeneman KS. Source: Urologic Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16818185&query_hl=5&itool=pubmed_docsum

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Can a point-of-care urine protein assay monitor bladder cancer recurrence? Author(s): O’donnell MA. Source: Nat Clin Pract Oncol. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16955086&query_hl=5&itool=pubmed_docsum

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Can intravesical bacillus Calmette-Guerin reduce recurrence in patients with superficial bladder cancer? A meta-analysis of randomized trials. Author(s): Han RF, Pan JG. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16765182&query_hl=5&itool=pubmed_docsum

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Can the levels of nitric oxide in the urine, serum and tumor tissue be putative markers for bladder cancer? Author(s): Kilic S, Bayraktar N, Beytur A, Ergin H, Bayraktar M, Egri M. Source: International Journal of Urology : Official Journal of the Japanese Urological Association. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16903933&query_hl=5&itool=pubmed_docsum

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Cancer-testis antigen expression in bladder cancer. Author(s): Fradet Y, Picard V, Bergeron A, LaRue H. Source: Prog Urol. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=17069033&query_hl=5&itool=pubmed_docsum

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C-choline positron emission tomography in bladder cancer: report of four cases. Author(s): Yoshida S, Nakagomi K, Goto S, Futatsubashi M, Torizuka T. Source: International Journal of Urology : Official Journal of the Japanese Urological Association. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16834674&query_hl=5&itool=pubmed_docsum

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Characterization of genes associated with different phenotypes of human bladder cancer cells. Author(s): Yang YC, Li X, Chen W. Source: Acta Biochim Biophys Sin (Shanghai). www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16953298&query_hl=5&itool=pubmed_docsum

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Cholecystectomy for asymptomatic gallstones can reduce gall bladder cancer mortality in northern Indian women. Author(s): Mohandas KM, Patil PS. Source: Indian J Gastroenterol. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16877830&query_hl=5&itool=pubmed_docsum

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Cholecystectomy in patients with asymptomatic gallstones to prevent gall bladder cancer--the case against. Author(s): Kapoor VK. Source: Indian J Gastroenterol. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16877831&query_hl=5&itool=pubmed_docsum

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Clinical characteristics of bladder cancer in patients previously treated with radiation for prostate cancer. Author(s): Sandhu JS, Vickers AJ, Bochner B, Donat SM, Herr HW, Dalbagni G. Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16626308&query_hl=5&itool=pubmed_docsum

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Clinical model of lifetime cost of treating bladder cancer and associated complications. Author(s): Avritscher EB, Cooksley CD, Grossman HB, Sabichi AL, Hamblin L, Dinney CP, Elting LS. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16979735&query_hl=5&itool=pubmed_docsum

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Clinical outcome after cystectomy in patients with lymph node-positive bladder cancer. Author(s): Nagele U, Anastasiadis AG, Merseburger AS, Sievert KD, Stenzl A, Kuczyk M. Source: Expert Review of Anticancer Therapy. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16761930&query_hl=5&itool=pubmed_docsum

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Comparative outcomes of bladder cancer. Author(s): Cardenas-Turanzas M, Cooksley C, Pettaway CA, Sabichi A, Grossman HB, Elting L. Source: Obstetrics and Gynecology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16816072&query_hl=5&itool=pubmed_docsum

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Comparing the effect of ATRA, 4-HPR, and CD437 in bladder cancer cells. Author(s): Zou C, Zhou J, Qian L, Feugang JM, Liu J, Wang X, Wu S, Ding H, Zou C, Liebert M, Grossman HB. Source: Frontiers in Bioscience : a Journal and Virtual Library. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16720286&query_hl=5&itool=pubmed_docsum

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Comparison of seven screening methods in the diagnosis of bladder cancer. Author(s): Sun Y, He DL, Ma Q, Wan XY, Zhu GD, Li L, Luo Y, He H, Yang L. Source: Chinese Medical Journal. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=17097029&query_hl=5&itool=pubmed_docsum

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Complement factor H as a marker for detection of bladder cancer. Author(s): Cheng ZZ, Corey MJ, Parepalo M, Majno S, Hellwage J, Zipfel PF, Kinders RJ, Raitanen M, Meri S, Jokiranta TS. Source: Clinical Chemistry. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15774575&query_hl=5&itool=pubmed_docsum

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Computed tomography urography for diagnosing bladder cancer. Author(s): Turney BW, Willatt JM, Nixon D, Crew JP, Cowan NC. Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16879676&query_hl=5&itool=pubmed_docsum

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Conditionally replicating adenovirus-mediated gene therapy in bladder cancer: an orthotopic in vivo model. Author(s): Melquist JJ, Kacka M, Li Y, Malaeb BS, Elmore J, Baseman AG, Hsieh JT, Koeneman KS. Source: Urologic Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16818192&query_hl=5&itool=pubmed_docsum

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Controversial issues and optimal management of stage T1G3 bladder cancer. Author(s): Metwalli AR, Kamat AM. Source: Expert Review of Anticancer Therapy. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16925494&query_hl=5&itool=pubmed_docsum

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Cutaneous complications of intravesical treatments for bladder cancer: granulomatous inflammation of the penis following BCG therapy and penile gangrene following mitomycin therapy. Author(s): Kureshi F, Kalaaji AN, Halvorson L, Pittelkow MR, Davis MD. Source: Journal of the American Academy of Dermatology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16844523&query_hl=5&itool=pubmed_docsum

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Defining molecular profiles of poor outcome in patients with invasive bladder cancer using oligonucleotide microarrays. Author(s): Sanchez-Carbayo M, Socci ND, Lozano J, Saint F, Cordon-Cardo C. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16432078&query_hl=5&itool=pubmed_docsum

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Delayed high-dose intravesical epirubicin therapy of superficial bladder cancer. A way to reduce the side effects and increase the efficacy--a phase 2 trial. Author(s): Bassi P, Spinadin R, Longo F, Saraeb S, Pappagallo GL, Zattoni F, Pagano F. Source: Urologia Internationalis. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12053020&query_hl=5&itool=pubmed_docsum

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Detection of bladder cancer using a proteomic assay. Author(s): Ciatto S. Source: Jama : the Journal of the American Medical Association. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15914744&query_hl=5&itool=pubmed_docsum

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Detection of bladder cancer using a proteomic assay. Author(s): Louria DB. Source: Jama : the Journal of the American Medical Association. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15914741&query_hl=5&itool=pubmed_docsum

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Detection of immune responses against urinary bladder cancer in sentinel lymph nodes. Author(s): Marits P, Karlsson M, Sherif A, Garske U, Thorn M, Winqvist O. Source: European Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16321468&query_hl=5&itool=pubmed_docsum

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Detection of micrometastases in pelvic lymph nodes in patients undergoing radical cystectomy for locally invasive bladder cancer by real-time reverse transcriptase-PCR for cytokeratin 19 and uroplakin II. Author(s): Kurahashi T, Hara I, Oka N, Kamidono S, Eto H, Miyake H. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15897575&query_hl=5&itool=pubmed_docsum

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Diet and bladder cancer: a case-control study. Author(s): Radosavljevic V, Jankovic S, Marinkovic J, Dokic M. Source: International Urology and Nephrology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16142557&query_hl=5&itool=pubmed_docsum

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Differences between urologists in United States and Canada in approach to bladder cancer. Author(s): Chung D, Hersey K, Fleshner N. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15882724&query_hl=5&itool=pubmed_docsum

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Differential expression of trypsinogen and tumor-associated trypsin inhibitor (TATI) in bladder cancer. Author(s): Hotakainen K, Bjartell A, Sankila A, Jarvinen R, Paju A, Rintala E, Haglund C, Stenman UH. Source: International Journal of Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16327984&query_hl=5&itool=pubmed_docsum

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Disease specific survival as endpoint of outcome for bladder cancer patients following radical cystectomy. Author(s): Gschwend JE, Dahm P, Fair WR. Source: European Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12074817&query_hl=5&itool=pubmed_docsum

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Distribution of photosensitizers in bladder cancer spheroids: implications for intravesical instillation of photosensitizers for photodynamic therapy of bladder cancer. Author(s): Xiao Z, Hansen CB, Allen TM, Miller GG, Moore RB. Source: Journal of Pharmacy & Pharmaceutical Sciences [electronic Resource] : a Publication of the Canadian Society for Pharmaceutical Sciences, Societe Canadienne Des Sciences Pharmaceutiques. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16401399&query_hl=5&itool=pubmed_docsum

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DNA repair gene polymorphisms and probability of p53 mutation in bladder cancer. Author(s): Stern MC, Conway K, Li Y, Mistry K, Taylor JA. Source: Molecular Carcinogenesis. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16652373&query_hl=5&itool=pubmed_docsum

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DNA-based molecular cytology for bladder cancer surveillance. Author(s): Jones JS. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16530074&query_hl=5&itool=pubmed_docsum

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Do patients with frank haematuria referred under the two-week rule have a higher incidence of bladder cancer? Author(s): Sugiono M, Hammonds JC. Source: Annals of the Royal College of Surgeons of England. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16460635&query_hl=5&itool=pubmed_docsum

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Do patients with frank haematuria referred under the two-week rule have a higher incidence of bladder cancer? Author(s): Thiruchelvam N, Mostafid H. Source: Annals of the Royal College of Surgeons of England. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16176693&query_hl=5&itool=pubmed_docsum

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Do vascular, lymphatic, and perineural invasion have prognostic implications for bladder cancer after radical cystectomy? Author(s): Hong SK, Kwak C, Jeon HG, Lee E, Lee SE. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15833511&query_hl=5&itool=pubmed_docsum

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Does body mass index affect survival of patients undergoing radical or partial cystectomy for bladder cancer? Author(s): Hafron J, Mitra N, Dalbagni G, Bochner B, Herr H, Donat SM. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15821470&query_hl=5&itool=pubmed_docsum

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Does prolonging the time to bladder cancer surgery affect long-term cancer control: a systematic review of the literature. Author(s): Fradet Y, Aprikian A, Dranitsaris G, Siemens R, Tsihlias J, Fleshner N; Canadian surgical wait times (SWAT) initiative. Source: Can J Urol. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16818011&query_hl=5&itool=pubmed_docsum

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E2F3 is the main target gene of the 6p22 amplicon with high specificity for human bladder cancer. Author(s): Oeggerli M, Schraml P, Ruiz C, Bloch M, Novotny H, Mirlacher M, Sauter G, Simon R. Source: Oncogene. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16953223&query_hl=5&itool=pubmed_docsum

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Early bladder cancer: concept, diagnosis, and management. Author(s): Kitamura H, Tsukamoto T. Source: International Journal of Clinical Oncology / Japan Society of Clinical Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16508726&query_hl=5&itool=pubmed_docsum

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Early cystectomy for clinical stage T1 bladder cancer. Author(s): Hollenbeck BK, Montie JE. Source: Nat Clin Pract Urol. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16474441&query_hl=5&itool=pubmed_docsum

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E-cadherin promoter polymorphism (C-160A) and risk of recurrence in patients with superficial bladder cancer. Author(s): Lin J, Dinney CP, Grossman HB, Jhamb M, Zhu Y, Spitz MR, Wu X. Source: Clinical Genetics. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16922727&query_hl=5&itool=pubmed_docsum

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Economic impact of screening for bladder cancer using bladder tumor markers: a decision analysis. Author(s): Svatek RS, Sagalowsky AI, Lotan Y. Source: Urologic Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16818188&query_hl=5&itool=pubmed_docsum

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Effect of small interfering RNA targeting survivin gene on biological behaviour of bladder cancer. Author(s): Hou JQ, He J, Wang XL, Wen DG, Chen ZX. Source: Chinese Medical Journal. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=17097022&query_hl=5&itool=pubmed_docsum

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Effect of sulforaphane on cell growth, G(0)/G(1) phase cell progression and apoptosis in human bladder cancer T24 cells. Author(s): Shan Y, Sun C, Zhao X, Wu K, Cassidy A, Bao Y. Source: International Journal of Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16964384&query_hl=5&itool=pubmed_docsum

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Endoscopic therapy of superficial bladder cancer in high-risk patients: Holmium laser versus transurethral resection. Author(s): Muraro GB, Grifoni R, Spazzafumo L. Source: Surg Technol Int. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16525976&query_hl=5&itool=pubmed_docsum

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Enhanced expression of peroxiredoxin I and VI correlates with development, recurrence and progression of human bladder cancer. Author(s): Quan C, Cha EJ, Lee HL, Han KH, Lee KM, Kim WJ. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16516038&query_hl=5&itool=pubmed_docsum

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95

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Entrez into the immunogenetics of superficial bladder cancer response to bacillus Calmette-Guerin. Author(s): O’Donnell M. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16515958&query_hl=5&itool=pubmed_docsum

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Epigenetic inactivation of Wnt inhibitory factor-1 plays an important role in bladder cancer through aberrant canonical Wnt/beta-catenin signaling pathway. Author(s): Urakami S, Shiina H, Enokida H, Kawakami T, Tokizane T, Ogishima T, Tanaka Y, Li LC, Ribeiro-Filho LA, Terashima M, Kikuno N, Adachi H, Yoneda T, Kishi H, Shigeno K, Konety BR, Igawa M, Dahiya R. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16428476&query_hl=5&itool=pubmed_docsum

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EUS-guided FNA for the diagnosis of recurrent bladder cancer through the ileal conduit: a novel approach. Author(s): Eloubeidi MA, Varadarajulu S, El-Galley R, Bueschen AJ, Eltoum I. Source: Gastrointestinal Endoscopy. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16923503&query_hl=5&itool=pubmed_docsum

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Evaluating the effect of reducing the high-dose volume on the toxicity of radiotherapy in the treatment of bladder cancer. Author(s): Mangar SA, Foo K, Norman A, Khoo V, Shahidi M, Dearnaley DP, Horwich A, Huddart RA. Source: Clin Oncol (R Coll Radiol). www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16909970&query_hl=5&itool=pubmed_docsum

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Evaluation of serum and urine clusterin as a potential tumor marker for urinary bladder cancer. Author(s): Stejskal D, Fiala RR. Source: Neoplasma. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16830064&query_hl=5&itool=pubmed_docsum

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Evaluation of survivin reverse transcriptase-polymerase chain reaction for noninvasive detection of bladder cancer. Author(s): Moussa O, Abol-Enein H, Bissada NK, Keane T, Ghoneim MA, Watson DK. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16697865&query_hl=5&itool=pubmed_docsum

96

Bladder Cancer

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Expression and antigenicity of survivin, an inhibitor of apoptosis family member, in bladder cancer: implications for specific immunotherapy. Author(s): Kitamura H, Torigoe T, Honma I, Asanuma H, Nakazawa E, Shimozawa K, Hirohashi Y, Sato E, Sato N, Tsukamoto T. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16635519&query_hl=5&itool=pubmed_docsum

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Expression and significance of vascular endothelial growth factor receptor 2 in bladder cancer. Author(s): Xia G, Kumar SR, Hawes D, Cai J, Hassanieh L, Groshen S, Zhu S, Masood R, Quinn DI, Broek D, Stein JP, Gill PS. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16515971&query_hl=5&itool=pubmed_docsum

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Expression of E-cadherin and alpha-, beta-, gamma-catenins in patients with bladder cancer: identification of gamma-catenin as a new prognostic marker of neoplastic progression in T1 superficial urothelial tumors. Author(s): Clairotte A, Lascombe I, Fauconnet S, Mauny F, Felix S, Algros MP, Bittard H, Kantelip B. Source: American Journal of Clinical Pathology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16483000&query_hl=5&itool=pubmed_docsum

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Expression of estrogen receptors-alpha and -beta in bladder cancer cell lines and human bladder tumor tissue. Author(s): Shen SS, Smith CL, Hsieh JT, Yu J, Kim IY, Jian W, Sonpavde G, Ayala GE, Younes M, Lerner SP. Source: Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16700038&query_hl=5&itool=pubmed_docsum

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FDG-PET for preoperative staging of bladder cancer. Author(s): Drieskens O, Oyen R, Van Poppel H, Vankan Y, Flamen P, Mortelmans L. Source: European Journal of Nuclear Medicine and Molecular Imaging. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16133380&query_hl=5&itool=pubmed_docsum

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FGFR3 and p53 protein expressions in patients with pTa and pT1 urothelial bladder cancer. Author(s): Mhawech-Fauceglia P, Cheney RT, Fischer G, Beck A, Herrmann FR. Source: European Journal of Surgical Oncology : the Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16412606&query_hl=5&itool=pubmed_docsum

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97

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Final results from a national multicenter phase II trial of combination bacillus Calmette-Guerin plus interferon alpha-2B for reducing recurrence of superficial bladder cancer. Author(s): Joudi FN, Smith BJ, O’Donnell MA; National BCG-Interferon Phase 2 Investigator Group. Source: Urologic Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16818189&query_hl=5&itool=pubmed_docsum

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Flexible cystoscopy assisted by hexaminolevulinate induced fluorescence: a new approach for bladder cancer detection and surveillance? Author(s): Loidl W, Schmidbauer J, Susani M, Marberger M. Source: European Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15716195&query_hl=5&itool=pubmed_docsum

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Fluid intake and urinary bladder cancer. Author(s): Allam MF. Source: European Journal of Cancer Prevention : the Official Journal of the European Cancer Prevention Organisation (Ecp). www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15677899&query_hl=5&itool=pubmed_docsum

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Fluorescence cystoscopy in the management of bladder cancer: a help for the urologist! Author(s): Jichlinski P, Leisinger HJ. Source: Urologia Internationalis. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15756058&query_hl=5&itool=pubmed_docsum

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Fluorescence diagnosis of bladder cancer. Author(s): Chatterton K, Ray E, O’Brien TS. Source: British Journal of Nursing (Mark Allen Publishing). www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16835527&query_hl=5&itool=pubmed_docsum

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Four tumour markers for urinary bladder cancer--tissue polypeptide antigen (TPA), HER-2/neu (ERB B2), urokinase-type plasminogen activator receptor (uPAR) and TP53 mutation. Author(s): Ecke TH, Schlechte HH, Schulze G, Lenk SV, Loening SA. Source: Anticancer Res. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15816639&query_hl=5&itool=pubmed_docsum

98

Bladder Cancer

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Four years experience in bladder preserving management for muscle invasive bladder cancer. Author(s): Lodde M, Palermo S, Comploj E, Signorello D, Mian C, Lusuardi L, Longhi E, Zanon P, Mian M, Pycha A. Source: European Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15925072&query_hl=5&itool=pubmed_docsum

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Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer. Author(s): Iliopoulos D, Guler G, Han SY, Johnston D, Druck T, McCorkell KA, Palazzo J, McCue PA, Baffa R, Huebner K. Source: Oncogene. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15674328&query_hl=5&itool=pubmed_docsum

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Free DNA in urine: a new marker for bladder cancer? Preliminary data. Author(s): Zancan M, Franceschini R, Mimmo C, Vianello M, Di Tonno F, Mazzariol C, Malossini G, Gion M. Source: Int J Biol Markers. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16011045&query_hl=5&itool=pubmed_docsum

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Frequencies of poor metabolizers of cytochrome P450 2C19 in esophagus cancer, stomach cancer, lung cancer and bladder cancer in Chinese population. Author(s): Shi WX, Chen SQ. Source: World Journal of Gastroenterology : Wjg. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15222046&query_hl=5&itool=pubmed_docsum

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Fruit consumption reduces the effect of smoking on bladder cancer risk. The Belgian case control study on bladder cancer. Author(s): Kellen E, Zeegers M, Paulussen A, Van Dongen M, Buntinx F. Source: International Journal of Cancer. Journal International Du Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16380991&query_hl=5&itool=pubmed_docsum

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Functional analysis of bladder cancer-related protein gene: a putative cervical cancer tumor suppressor gene in cervical carcinoma. Author(s): Zuo Z, Zhao M, Liu J, Gao G, Wu X. Source: Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16675915&query_hl=5&itool=pubmed_docsum

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99

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Functional polymorphisms in the promoter regions of the FAS and FAS ligand genes and risk of bladder cancer in south China: a case-control analysis. Author(s): Li C, Wu W, Liu J, Qian L, Li A, Yang K, Wei Q, Zhou J, Zhang Z. Source: Pharmacogenet Genomics. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16538171&query_hl=5&itool=pubmed_docsum

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Furosemide reverses multidrug resistance status in bladder cancer cells in vitro. Author(s): Speers AG, Lwaleed BA, Featherstone JM, Sallis BJ, Cooper AJ. Source: Journal of Clinical Pathology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16556663&query_hl=5&itool=pubmed_docsum

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Future directions: bladder cancer. Author(s): Coptcoat MJ, Oliver RT. Source: Cancer Surv. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15281323&query_hl=5&itool=pubmed_docsum

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Gall bladder cancer. Author(s): Krishnan R. Source: Med J Malaysia. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16108196&query_hl=5&itool=pubmed_docsum

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Ganglioside G(M3) overexpression induces apoptosis and reduces malignant potential in murine bladder cancer. Author(s): Watanabe R, Ohyama C, Aoki H, Takahashi T, Satoh M, Saito S, Hoshi S, Ishii A, Saito M, Arai Y. Source: Cancer Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12097299&query_hl=5&itool=pubmed_docsum

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Gastric and duodenal ulcer and risk of bladder cancer. Author(s): Pelucchi C, Negri E, Talamini R, Franceschi S, La Vecchia C. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15734988&query_hl=5&itool=pubmed_docsum

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Gender and geographic influence on the racial disparity in bladder cancer mortality in the US. Author(s): Underwood W 3rd, Dunn RL, Williams C, Lee CT. Source: Journal of the American College of Surgeons. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16427554&query_hl=5&itool=pubmed_docsum

100

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Gender, smoking, glutathione-S-transferase variants and bladder cancer incidence: a population-based study. Author(s): Karagas MR, Park S, Warren A, Hamilton J, Nelson HH, Mott LA, Kelsey KT. Source: Cancer Letters. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15694665&query_hl=5&itool=pubmed_docsum

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Gene therapy for superficial bladder cancer. Author(s): Rosser CJ, Benedict WF, Dinney CP. Source: Expert Review of Anticancer Therapy. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12113085&query_hl=5&itool=pubmed_docsum

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Genetic alterations of p16INK4a and p14ARF genes in human bladder cancer. Author(s): Chang LL, Yeh WT, Yang SY, Wu WJ, Huang CH. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12853838&query_hl=5&itool=pubmed_docsum

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Genetic and epigenetic aspects of bladder cancer. Author(s): Kim WJ, Quan C. Source: Journal of Cellular Biochemistry. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15759278&query_hl=5&itool=pubmed_docsum

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Genetic and immunophenotype analyses of TP53 in bladder cancer: TP53 alterations are associated with tumor progression. Author(s): Erill N, Colomer A, Verdu M, Roman R, Condom E, Hannaoui N, Banus JM, Cordon-Cardo C, Puig X. Source: Diagnostic Molecular Pathology : the American Journal of Surgical Pathology, Part B. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15538112&query_hl=5&itool=pubmed_docsum

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Genetic polymorphism of drug metabolizing enzymes (CYP2E1, GSTP1) and susceptibility to bladder cancer in North India. Author(s): Mittal RD, Srivastava DS, A M, B M. Source: Asian Pac J Cancer Prev. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15780023&query_hl=5&itool=pubmed_docsum

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Genetic polymorphisms of CYP2D6, GSTM1, and GSTT1 genes and bladder cancer risk in North India. Author(s): Sobti RC, Al-Badran AI, Sharma S, Sharma SK, Krishan A, Mohan H. Source: Cancer Genetics and Cytogenetics. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15588859&query_hl=5&itool=pubmed_docsum

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101

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Genetic susceptibility to bladder cancer. Author(s): Taioli E, Raimondi S. Source: Lancet. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16112283&query_hl=5&itool=pubmed_docsum

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Genetic variation in the nucleotide excision repair pathway and bladder cancer risk. Author(s): Garcia-Closas M, Malats N, Real FX, Welch R, Kogevinas M, Chatterjee N, Pfeiffer R, Silverman D, Dosemeci M, Tardon A, Serra C, Carrato A, Garcia-Closas R, Castano-Vinyals G, Chanock S, Yeager M, Rothman N. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16537713&query_hl=5&itool=pubmed_docsum

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Genotypes of TNF-alpha, VEGF, hOGG1, GSTM1, and GSTT1: useful determinants for clinical outcome of bladder cancer. Author(s): Kim EJ, Jeong P, Quan C, Kim J, Bae SC, Yoon SJ, Kang JW, Lee SC, Jun Wee J, Kim WJ. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15667866&query_hl=5&itool=pubmed_docsum

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Glutathione peroxidase 1 gene polymorphism and risk of recurrence in patients with superficial bladder cancer. Author(s): Zhao H, Liang D, Grossman HB, Wu X. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16230136&query_hl=5&itool=pubmed_docsum

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Glutathione S-transferase M1, T1 and P1 polymorphisms and bladder cancer risk in Egyptians. Author(s): Saad AA, O’Connor PJ, Mostafa MH, Metwalli NE, Cooper DP, Povey AC, Margison GP. Source: Int J Biol Markers. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15832776&query_hl=5&itool=pubmed_docsum

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Granulocyte colony-stimulating receptor promotes beta1-integrin-mediated adhesion and invasion of bladder cancer cells. Author(s): Chakraborty A, White SM, Guha S. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16844458&query_hl=5&itool=pubmed_docsum

102

Bladder Cancer

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Growth inhibition efficacy of an adenovirus expressing dual therapeutic genes, wildtype p53, and anti-erbB2 ribozyme, against human bladder cancer cells. Author(s): Irie A, Matsumoto K, Anderegg B, Kuruma H, Kashani-Sabet M, Scanlon KJ, Uchida T, Baba S. Source: Cancer Gene Therapy. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16110311&query_hl=5&itool=pubmed_docsum

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Growth inhibitory effect of doxazosin on prostate and bladder cancer cells. Is the serotonin receptor pathway involved? Author(s): Siddiqui EJ, Shabbir M, Thompson CS, Mumtaz FH, Mikhailidis DP. Source: Anticancer Res. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16309229&query_hl=5&itool=pubmed_docsum

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Guidelines on bladder cancer. Author(s): Oosterlinck W, Lobel B, Jakse G, Malmstrom PU, Stockle M, Sternberg C; European Association of Urology (EAU) Working Group on Oncological Urology. Source: European Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12074395&query_hl=5&itool=pubmed_docsum

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Habitual intake of lactic acid bacteria and risk reduction of bladder cancer. Author(s): Ohashi Y, Nakai S, Tsukamoto T, Masumori N, Akaza H, Miyanaga N, Kitamura T, Kawabe K, Kotake T, Kuroda M, Naito S, Koga H, Saito Y, Nomata K, Kitagawa M, Aso Y. Source: Urologia Internationalis. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12053032&query_hl=5&itool=pubmed_docsum

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Hair dye use is not associated with risk for bladder cancer: evidence from a casecontrol study in Spain. Author(s): Kogevinas M, Fernandez F, Garcia-Closas M, Tardon A, Garcia-Closas R, Serra C, Carrato A, Castano-Vinyals G, Yeager M, Chanock SJ, Lloreta J, Rothman N, Real FX, Dosemeci M, Malats N, Silverman D. Source: European Journal of Cancer (Oxford, England : 1990). www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16740387&query_hl=5&itool=pubmed_docsum

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Healing focal “flare” phenomenon after radiotherapy in a bone metastasis from bladder cancer. Author(s): Sugawara Y, Kajihara M, Semba T, Ochi T, Fujii T, Mochizuki T. Source: Clinical Nuclear Medicine. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16166838&query_hl=5&itool=pubmed_docsum

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Health related quality of life after radical cystectomy and urinary diversion for bladder cancer: a systematic review and critical analysis of the literature. Author(s): Porter MP, Penson DF. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15758789&query_hl=5&itool=pubmed_docsum

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Health related quality of life assessments for patients with bladder cancer. Author(s): Parkinson JP, Konety BR. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15538218&query_hl=5&itool=pubmed_docsum

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HER2/neu expression in bladder cancer: relationship to cell cycle kinetics. Author(s): Eissa S, Ali HS, Al Tonsi AH, Zaglol A, El Ahmady O. Source: Clinical Biochemistry. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15642276&query_hl=5&itool=pubmed_docsum

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Herpes simplex virus type 1 mutant HF10 oncolytic viral therapy for bladder cancer. Author(s): Kohno S, Luo C, Goshima F, Nishiyama Y, Sata T, Ono Y. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16286150&query_hl=5&itool=pubmed_docsum

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Hexyl aminolevulinate: in the detection of bladder cancer. Author(s): Frampton JE, Plosker GL. Source: Drugs. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16597168&query_hl=5&itool=pubmed_docsum

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Highly specific urine-based marker of bladder cancer. Author(s): Van Le TS, Miller R, Barder T, Babjuk M, Potter DM, Getzenberg RH. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16360453&query_hl=5&itool=pubmed_docsum

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High-throughput tissue microarray analysis of CMYC amplificationin urinary bladder cancer. Author(s): Zaharieva B, Simon R, Ruiz C, Oeggerli M, Mihatsch MJ, Gasser T, Sauter G, Toncheva D. Source: International Journal of Cancer. Journal International Du Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15986448&query_hl=5&itool=pubmed_docsum

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High-throughput tissue microarray analysis of COX2 expression in urinary bladder cancer. Author(s): Wild PJ, Kunz-Schughart LA, Stoehr R, Burger M, Blaszyk H, Simon R, Gasser T, Mihatsch M, Sauter G, Hartmann A. Source: International Journal of Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16010419&query_hl=5&itool=pubmed_docsum

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Histone deacetylase inhibitor trichostatin A inhibits the growth of bladder cancer cells through induction of p21WAF1 and G1 cell cycle arrest. Author(s): Li GC, Zhang X, Pan TJ, Chen Z, Ye ZQ. Source: International Journal of Urology : Official Journal of the Japanese Urological Association. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16771729&query_hl=5&itool=pubmed_docsum

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Histone deacetylase inhibitors upregulate expression of the coxsackie adenovirus receptor (CAR) preferentially in bladder cancer cells. Author(s): Sachs MD, Ramamurthy M, Poel H, Wickham TJ, Lamfers M, Gerritsen W, Chowdhury W, Li Y, Schoenberg MP, Rodriguez R. Source: Cancer Gene Therapy. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15118762&query_hl=5&itool=pubmed_docsum

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Hormonal and reproductive factors and the risk of bladder cancer in women. Author(s): McGrath M, Michaud DS, De Vivo I. Source: American Journal of Epidemiology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16319290&query_hl=5&itool=pubmed_docsum

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Human urinary bladder cancer T24 cells are susceptible to the Antrodia camphorata extracts. Author(s): Peng CC, Chen KC, Peng RY, Su CH, Hsieh-Li HM. Source: Cancer Letters. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16455193&query_hl=5&itool=pubmed_docsum

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Hybrid SPECT-CT: an additional technique for sentinel node detection of patients with invasive bladder cancer. Author(s): Sherif A, Garske U, de la Torre M, Thorn M. Source: European Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16632191&query_hl=5&itool=pubmed_docsum

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105

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Hyperphosphorylation of pRb: a mechanism for RB tumour suppressor pathway inactivation in bladder cancer. Author(s): Chatterjee SJ, George B, Goebell PJ, Alavi-Tafreshi M, Shi SR, Fung YK, Jones PA, Cordon-Cardo C, Datar RH, Cote RJ. Source: The Journal of Pathology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15221935&query_hl=5&itool=pubmed_docsum

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Hypoxia-inducible factor 1 alpha expression correlates with angiogenesis and unfavorable prognosis in bladder cancer. Author(s): Theodoropoulos VE, Lazaris ACh, Sofras F, Gerzelis I, Tsoukala V, Ghikonti I, Manikas K, Kastriotis I. Source: European Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15245814&query_hl=5&itool=pubmed_docsum

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Identification and validation of suitable endogenous reference genes for gene expression studies of human bladder cancer. Author(s): Ohl F, Jung M, Radonic A, Sachs M, Loening SA, Jung K. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16600798&query_hl=5&itool=pubmed_docsum

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Identification of differentially expressed genes in human bladder cancer through genome-wide gene expression profiling. Author(s): Kawakami K, Enokida H, Tachiwada T, Gotanda T, Tsuneyoshi K, Kubo H, Nishiyama K, Takiguchi M, Nakagawa M, Seki N. Source: Oncol Rep. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16865252&query_hl=5&itool=pubmed_docsum

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Ileocaecal vs ileal neobladder after radical cystectomy in patients with bladder cancer: a comparative study. Author(s): Khafagy M, Shaheed FA, Moneim TA. Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16536777&query_hl=5&itool=pubmed_docsum

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Immediate administration of intravesical mitomycin C after tumour resection for superficial bladder cancer. Author(s): Mostafid AH, Rajkumar RG, Stewart AB, Singh R. Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16469017&query_hl=5&itool=pubmed_docsum

106

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Immediate administration of intravesical mitomycin C after tumour resection for superficial bladder cancer. Author(s): Besarani D, Al-Akraa M. Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16831177&query_hl=5&itool=pubmed_docsum

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In vitro synergistic cytotoxicity of gemcitabine and pemetrexed and pharmacogenetic evaluation of response to gemcitabine in bladder cancer patients. Author(s): Mey V, Giovannetti E, De Braud F, Nannizzi S, Curigliano G, Verweij F, De Cobelli O, Pece S, Del Tacca M, Danesi R. Source: British Journal of Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16868547&query_hl=5&itool=pubmed_docsum

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Inhibition of 5-lipoxygenase pathway suppresses the growth of bladder cancer cells. Author(s): Hayashi T, Nishiyama K, Shirahama T. Source: International Journal of Urology : Official Journal of the Japanese Urological Association. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16903934&query_hl=5&itool=pubmed_docsum

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Interaction effect in bladder cancer between N-acetyltransferase 2 genotype and alcohol drinking. Author(s): Lu CM, Chung MC, Huang CH, Ko YC. Source: Urologia Internationalis. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16327307&query_hl=5&itool=pubmed_docsum

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Intra-arterial chemiotherapy for invasive bladder cancer. Author(s): Mambrini A, Fiorentini G, Zamagni D, Muttini M, Pennucci C, Caudana R, Cantore M. Source: J Exp Clin Cancer Res. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16767901&query_hl=5&itool=pubmed_docsum

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Intra-arterial chemotherapy in elderly patients with invasive bladder cancer. Author(s): Mambrini A, Bondavalli C, Caudana R, Amoroso V, Pacetti P, Fiorentini G, Cantore M. Source: Clin Oncol (R Coll Radiol). www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16372497&query_hl=5&itool=pubmed_docsum

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Intraoperative sentinel node detection improves nodal staging in invasive bladder cancer. Author(s): Liedberg F, Chebil G, Davidsson T, Gudjonsson S, Mansson W. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16406877&query_hl=5&itool=pubmed_docsum

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107

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Intravesical bacillus Calmette-Guerin combined with electromotive mitomycin for high-risk superficial bladder cancer. Author(s): Bochner BH. Source: Nat Clin Pract Oncol. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16955082&query_hl=5&itool=pubmed_docsum

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Intravesical chemotherapy for superficial bladder cancer. Author(s): Witjes JA, Debruyne FM. Source: Nat Clin Pract Urol. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16474497&query_hl=5&itool=pubmed_docsum

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Intravesical gemcitabine for superficial bladder cancer: rationale for a new treatment option. Author(s): Gontero P, Marini L, Frea B. Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16225511&query_hl=5&itool=pubmed_docsum

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Is a second transurethral resection necessary for newly diagnosed pT1 bladder cancer? Author(s): Divrik T, Yildirim U, Eroglu AS, Zorlu F, Ozen H. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16515974&query_hl=5&itool=pubmed_docsum

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Is adjuvant chemotherapy for bladder cancer safer in patients with an ileal conduit than a neobladder? Author(s): Sofikerim M, Tatlisen A. Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16536794&query_hl=5&itool=pubmed_docsum

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Is adjuvant chemotherapy for bladder cancer safer in patients with an ileal conduit than a neobladder? Author(s): Manoharan M, Reyes MA, Kava BR, Singal R, Kim SS, Soloway MS. Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16287446&query_hl=5&itool=pubmed_docsum

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Is aneusomy of chromosome 9 alone a valid biomarker for urinary bladder cancer screening? Author(s): Panani AD, Kozirakis D, Anastasiou J, Babanaraki A, Malovrouvas D, Roussos C. Source: Anticancer Res. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16619518&query_hl=5&itool=pubmed_docsum

108

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JAMA patient page. Bladder cancer. Author(s): Torpy JM, Lynm C, Glass RM. Source: Jama : the Journal of the American Medical Association. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15713779&query_hl=5&itool=pubmed_docsum

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Ki67, p53, nm23, and DNA cytometry in bladder cancer: potential markers for detection of recurrence? Author(s): Feil G, Krause FS, Zumbraegel A, Wechsel HW, Bichler KH. Source: Advances in Experimental Medicine and Biology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15088899&query_hl=5&itool=pubmed_docsum

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KIAA1096, a gene on chromosome 1q, is amplified and overexpressed in bladder cancer. Author(s): Huang WC, Taylor S, Nguyen TB, Tomaszewski JE, Libertino JA, Malkowicz SB, McGarvey TW. Source: Dna and Cell Biology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12443540&query_hl=5&itool=pubmed_docsum

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Kinetics of carboplatin-DNA binding in genomic DNA and bladder cancer cells as determined by accelerator mass spectrometry. Author(s): Hah SS, Stivers KM, de Vere White RW, Henderson PT. Source: Chemical Research in Toxicology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16696564&query_hl=5&itool=pubmed_docsum

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Laparoscopic radical cystectomy and bilateral ureteric ligation for muscle-invasive bladder cancer in a patient on hemodialysis. Author(s): Ishii D, Irie A, Matsumoto K, Tojo T, Taoka Y, Iwamura M, Yoshida K, Baba S. Source: International Journal of Urology : Official Journal of the Japanese Urological Association. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16882077&query_hl=5&itool=pubmed_docsum

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Levels of tissue inhibitor of metalloproteinases 1 in plasma and urine from patients with bladder cancer. Author(s): Holten-Andersen MN, Brunner N, Nielsen HJ, Christensen IJ, Sorensen NM, Rasmussen AS, Primdahl H, Orntoft T. Source: Int J Biol Markers. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16711508&query_hl=5&itool=pubmed_docsum

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109

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Limited significance of routine excretory urography in the follow-up of patients with superficial bladder cancer after transurethral resection. Author(s): Miyake H, Hara I, Yamanaka K, Inoue TA, Fujisawa M. Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16536761&query_hl=5&itool=pubmed_docsum

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Long-term benefit of 5-aminolevulinic acid fluorescence assisted transurethral resection of superficial bladder cancer: 5-year results of a prospective randomized study. Author(s): Daniltchenko DI, Riedl CR, Sachs MD, Koenig F, Daha KL, Pflueger H, Loening SA, Schnorr D. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16280742&query_hl=5&itool=pubmed_docsum

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Long-term effects of ileal conduit urinary diversion on upper urinary tract in bladder cancer. Author(s): Yang WJ, Cho KS, Rha KH, Lee HY, Chung BH, Hong SJ, Yang SC, Choi YD. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16904445&query_hl=5&itool=pubmed_docsum

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Loss of heterozygosity on chromosome 9q and p53 alterations in human bladder cancer. Author(s): Hirao S, Hirao T, Marsit CJ, Hirao Y, Schned A, Devi-Ashok T, Nelson HH, Andrew A, Karagas MR, Kelsey KT. Source: Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16149093&query_hl=5&itool=pubmed_docsum

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LRIG1, a candidate tumour-suppressor gene in human bladder cancer cell line BIU87. Author(s): Yang WM, Yan ZJ, Ye ZQ, Guo DS. Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16978290&query_hl=5&itool=pubmed_docsum

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Lymph node metastasis in bladder cancer. Author(s): Liedberg F, Mansson W. Source: European Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16203077&query_hl=5&itool=pubmed_docsum

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Lymphadenectomy for invasive bladder cancer. II. technical aspects and prognostic factors. Author(s): Stein JP, Quek ML, Skinner DG. Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16430619&query_hl=5&itool=pubmed_docsum

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Lymphadenectomy for invasive bladder cancer: I. historical perspective and contemporary rationale. Author(s): Stein JP, Quek ML, Skinner DG. Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16430618&query_hl=5&itool=pubmed_docsum

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Lymphadenectomy in bladder cancer: how high is “high enough”? Author(s): Stein JP. Source: Urologic Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16818190&query_hl=5&itool=pubmed_docsum

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Lymphangiogenesis and angiogenesis in bladder cancer: prognostic implications and regulation by vascular endothelial growth factors-A, -C, and -D. Author(s): Miyata Y, Kanda S, Ohba K, Nomata K, Hayashida Y, Eguchi J, Hayashi T, Kanetake H. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16467091&query_hl=5&itool=pubmed_docsum

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Mad1 suppresses bladder cancer cell proliferation by inhibiting human telomerase reverse transcriptase transcription and telomerase activity. Author(s): Zou L, Zhang P, Luo C, Tu Z. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16765199&query_hl=5&itool=pubmed_docsum

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MDM2 T309G polymorphism is associated with bladder cancer. Author(s): Onat OE, Tez M, Ozcelik T, Toruner GA. Source: Anticancer Res. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=17094469&query_hl=5&itool=pubmed_docsum

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Meat intake and bladder cancer risk in 2 prospective cohort studies. Author(s): Michaud DS, Holick CN, Giovannucci E, Stampfer MJ. Source: The American Journal of Clinical Nutrition. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=17093172&query_hl=5&itool=pubmed_docsum

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Mechanisms of disease: The epidemiology of bladder cancer. Author(s): Pelucchi C, Bosetti C, Negri E, Malvezzi M, La Vecchia C. Source: Nat Clin Pract Urol. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16763645&query_hl=5&itool=pubmed_docsum

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111

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Methylguanine DNA methyl transferase activities, glutathione s transferase and nitric oxide in bladder cancer patients. Author(s): Saygili EI, Akcay T, Dincer Y, Obek C, Kural AR, Cakalir C. Source: Cancer Investigation. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16809152&query_hl=5&itool=pubmed_docsum

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Molecular biology of bladder cancer: prognostic and clinical implications. Author(s): Mitra AP, Lin H, Datar RH, Cote RJ. Source: Clin Genitourin Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16859582&query_hl=5&itool=pubmed_docsum

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Molecular genetics of bladder cancer: targets for diagnosis and therapy. Author(s): Baffa R, Letko J, McClung C, LeNoir J, Vecchione A, Gomella LG. Source: J Exp Clin Cancer Res. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16918124&query_hl=5&itool=pubmed_docsum

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Molecular markers in bladder cancer: a critical appraisal. Author(s): Konety BR. Source: Urologic Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16818187&query_hl=5&itool=pubmed_docsum

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Multicolor fluorescence in situ hybridization (M-FISH) on cells from urine for the detection of bladder cancer. Author(s): Junker K, Fritsch T, Hartmann A, Schulze W, Schubert J. Source: Cytogenetic and Genome Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16954667&query_hl=5&itool=pubmed_docsum

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Multiprobe fluorescence in situ hybridisation: prognostic perspectives in superficial bladder cancer. Author(s): Mian C, Lodde M, Comploj E, Lusuardi L, Palermo S, Mian M, Maier K, Pycha A. Source: Journal of Clinical Pathology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16935973&query_hl=5&itool=pubmed_docsum

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N-acetylglucosaminyltransferase V and beta1-6 branching N-linked oligosaccharides are associated with good prognosis of patients with bladder cancer. Author(s): Ishimura H, Takahashi T, Nakagawa H, Nishimura S, Arai Y, Horikawa Y, Habuchi T, Miyoshi E, Kyan A, Hagisawa S, Ohyama C. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16638859&query_hl=5&itool=pubmed_docsum

112

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N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk. Author(s): Hein DW. Source: Oncogene. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16550165&query_hl=5&itool=pubmed_docsum

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Neuro-fuzzy modeling: an accurate and interpretable method for predicting bladder cancer progression. Author(s): Catto JW, Abbod MF, Linkens DA, Hamdy FC. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16406976&query_hl=5&itool=pubmed_docsum

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Nitrate intake does not influence bladder cancer risk: the Netherlands cohort study. Author(s): Zeegers MP, Selen RF, Kleinjans JC, Goldbohm RA, van den Brandt PA. Source: Environmental Health Perspectives. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=17035137&query_hl=5&itool=pubmed_docsum

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NMP22 and surveillance for recurrent bladder cancer. Author(s): Eggener S, Herr H. Source: Jama : the Journal of the American Medical Association. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16820545&query_hl=5&itool=pubmed_docsum

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NMP22 and surveillance for recurrent bladder cancer. Author(s): Wilson CT. Source: Jama : the Journal of the American Medical Association. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16820544&query_hl=5&itool=pubmed_docsum

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No association between SOD2 or NQO1 genotypes and risk of bladder cancer. Author(s): Terry PD, Umbach DM, Taylor JA. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15767364&query_hl=5&itool=pubmed_docsum

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No evidence for large-scale germline genomic aberrations in hereditary bladder cancer patients with high-resolution array-based comparative genomic hybridization. Author(s): Kiemeney LA, Kuiper RP, Pfundt R, van Reijmersdal S, Schoenberg MP, Aben KK, Niermeijer MF, Witjes JA, Schoenmakers EF. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16434610&query_hl=5&itool=pubmed_docsum

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Nonplatinum therapy in advanced bladder cancer. Author(s): Srinivas S, Colocci N. Source: Expert Review of Anticancer Therapy. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16761932&query_hl=5&itool=pubmed_docsum

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Novel prophylactic effect of doxifluridine in superficial bladder cancer. Author(s): Matsuyama H, Baba Y, Shimabukuro T, Uchiyama K, Aoki A, Suga A, Jojima K, Suyama K, Yamamoto N, Naito K. Source: Scandinavian Journal of Urology and Nephrology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15764246&query_hl=5&itool=pubmed_docsum

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Occupation and bladder cancer: a cohort study in Sweden. Author(s): Ji J, Granstrom C, Hemminki K. Source: British Journal of Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15770207&query_hl=5&itool=pubmed_docsum

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Occupational bladder cancer in a 4,4 -methylenebis(2-chloroaniline) (MBOCA)exposed worker. Author(s): Liu CS, Liou SH, Loh CH, Yu YC, Uang SN, Shih TS, Chen HI. Source: Environmental Health Perspectives. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15929884&query_hl=5&itool=pubmed_docsum

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Occupational bladder cancer in New Zealand: a 1-year review of cases notified to the New Zealand Cancer Registry. Author(s): Dryson E, Walls C, McLean D, Pearce N. Source: Internal Medicine Journal. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15892763&query_hl=5&itool=pubmed_docsum

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Occupational bladder cancer: from cohort study to biologic molecular marker. Author(s): Matsumoto K, Irie A, Satoh T, Kuruma H, Arakawa T, Baba S. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16192913&query_hl=5&itool=pubmed_docsum

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Oncolytic viral therapy by bladder instillation using an E1A, E1B double-restricted adenovirus in an orthotopic bladder cancer model. Author(s): Wang H, Satoh M, Abe H, Sunamura M, Moriya T, Ishidoya S, Saito S, Hamada H, Arai Y. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16979729&query_hl=5&itool=pubmed_docsum

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Organ-sparing treatment in muscle-invasive bladder cancer. Author(s): Dunst J, Diestelhorst A, Kuhn R, Muller AC, Scholz HJ, Fornara P. Source: Strahlentherapie Und Onkologie : Organ Der Deutschen Rontgengesellschaft. [et Al]. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16220401&query_hl=5&itool=pubmed_docsum

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Outcome of patients with fortuitous prostate cancer after radical cystoprostatectomy for bladder cancer. Author(s): Delongchamps NB, Mao K, Theng H, Zerbib M, Debre B, Peyromaure M. Source: European Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16126325&query_hl=5&itool=pubmed_docsum

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Overexpression of alpha-defensin is associated with bladder cancer invasiveness. Author(s): Holterman DA, Diaz JI, Blackmore PF, Davis JW, Schellhammer PF, Corica A, Semmes OJ, Vlahou A. Source: Urologic Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16520271&query_hl=5&itool=pubmed_docsum

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Overexpression of PML induced apoptosis in bladder cancer cell by caspase dependent pathway. Author(s): Li L, He D, He H, Wang X, Zhang L, Luo Y, Nan X. Source: Cancer Letters. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16216409&query_hl=5&itool=pubmed_docsum

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Overexpression of polo-like kinase 1 (PLK1) and chromosomal instability in bladder cancer. Author(s): Yamamoto Y, Matsuyama H, Kawauchi S, Matsumoto H, Nagao K, Ohmi C, Sakano S, Furuya T, Oga A, Naito K, Sasaki K. Source: Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16837776&query_hl=5&itool=pubmed_docsum

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Pelvic chemoradiotherapy after chemotherapy for metastatic bladder cancer. Author(s): Passaperuma K, Ash R, Venkatesan V, Rodrigues G, Winquist E. Source: Can J Urol. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16672111&query_hl=5&itool=pubmed_docsum

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Personal permanent hair dye use is not associated with bladder cancer risk: evidence from a case-control study. Author(s): Lin J, Dinney CP, Grossman HB, Wu X. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16985040&query_hl=5&itool=pubmed_docsum

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Phase I/II pilot study of intravesical apaziquone (EO9) for superficial bladder cancer. Author(s): Puri R, Palit V, Loadman PM, Flannigan M, Shah T, Choudry GA, Basu S, Double JA, Lenaz G, Chawla S, Beer M, Van Kalken C, de Boer R, Beijnen JH, Twelves CJ, Phillips RM. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16952628&query_hl=5&itool=pubmed_docsum

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Phase II marker lesion study with intravesical instillation of apaziquone for superficial bladder cancer: toxicity and marker response. Author(s): van der Heijden AG, Moonen PM, Cornel EB, Vergunst H, de Reijke TM, van Boven E, Barten EJ, Puri R, van Kalken CK, Witjes JA. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16952629&query_hl=5&itool=pubmed_docsum

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Possible correlation between polymorphism in the tumor necrosis factor-beta gene and the clinicopathological features of bladder cancer in Japanese patients. Author(s): Nonomura N, Tokizane T, Nakayama M, Inoue H, Nishimura K, Muramatsu M, Okuyama A. Source: International Journal of Urology : Official Journal of the Japanese Urological Association. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16882065&query_hl=5&itool=pubmed_docsum

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Postoperative nomogram predicting risk of recurrence after radical cystectomy for bladder cancer. Author(s): International Bladder Cancer Nomogram Consortium; Bochner BH, Kattan MW, Vora KC. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16864855&query_hl=5&itool=pubmed_docsum

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Proepithelin promotes migration and invasion of 5637 bladder cancer cells through the activation of ERK1/2 and the formation of a paxillin/FAK/ERK complex. Author(s): Monami G, Gonzalez EM, Hellman M, Gomella LG, Baffa R, Iozzo RV, Morrione A. Source: Cancer Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16849556&query_hl=5&itool=pubmed_docsum

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Prostatic involvement by transitional cell carcinoma in patients with bladder cancer and its prognostic significance. Author(s): Shen SS, Lerner SP, Muezzinoglu B, Truong LD, Amiel G, Wheeler TM. Source: Human Pathology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16733214&query_hl=5&itool=pubmed_docsum

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Protective effects of plasma carotenoids on the risk of bladder cancer. Author(s): Hung RJ, Zhang ZF, Rao JY, Pantuck A, Reuter VE, Heber D, Lu QY. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16890724&query_hl=5&itool=pubmed_docsum

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Quality of care: partial cystectomy for bladder cancer--a case of inappropriate use? Author(s): Hollenbeck BK, Taub DA, Dunn RL, Wei JT. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16094056&query_hl=5&itool=pubmed_docsum

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Quality of life after radical treatment for invasive bladder cancer. Author(s): Zietman A, Skinner E. Source: Seminars in Radiation Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15662608&query_hl=5&itool=pubmed_docsum

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Quality of life in long-term survivors of bladder cancer. Author(s): Allareddy V, Kennedy J, West MM, Konety BR. Source: Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16649218&query_hl=5&itool=pubmed_docsum

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Quality of life in patients with bladder cancer. Author(s): Gerharz EW, Mansson A, Mansson W. Source: Urologic Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15907722&query_hl=5&itool=pubmed_docsum

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Quality of life issues in bladder cancer patients following cystectomy and urinary diversion. Author(s): Porter MP, Wei JT, Penson DF. Source: The Urologic Clinics of North America. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15862618&query_hl=5&itool=pubmed_docsum

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Quantitation of promoter methylation of multiple genes in urine DNA and bladder cancer detection. Author(s): Hoque MO, Begum S, Topaloglu O, Chatterjee A, Rosenbaum E, Van Criekinge W, Westra WH, Schoenberg M, Zahurak M, Goodman SN, Sidransky D. Source: Journal of the National Cancer Institute. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16849682&query_hl=5&itool=pubmed_docsum

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Quantitative analysis of cyclin E and protein p34 cdc2 expression in superficial bladder cancer. Author(s): Kaczmarek P, Tosik D, Majewska E, Baj Z. Source: Pol J Pathol. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16739882&query_hl=5&itool=pubmed_docsum

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Quantitative analysis of survivin mRNA expression in urine and tumor tissue of bladder cancer patients and its potential relevance for disease detection and prognosis. Author(s): Weikert S, Christoph F, Schrader M, Krause H, Miller K, Muller M. Source: International Journal of Cancer. Journal International Du Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15761870&query_hl=5&itool=pubmed_docsum

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Quantitative evaluation of telomerase subunits in urine as biomarkers for noninvasive detection of bladder cancer. Author(s): Weikert S, Krause H, Wolff I, Christoph F, Schrader M, Emrich T, Miller K, Muller M. Source: International Journal of Cancer. Journal International Du Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15900578&query_hl=5&itool=pubmed_docsum

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Quantitative molecular urinary cytology by fluorescence in situ hybridization: a tool for tailoring surveillance of patients with superficial bladder cancer? Author(s): Bollmann M, Heller H, Bankfalvi A, Griefingholt H, Bollmann R. Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15892805&query_hl=5&itool=pubmed_docsum

118

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Racial disparity in bladder cancer: trends in tumor presentation at diagnosis. Author(s): Lee CT, Dunn RL, Williams C, Underwood W 3rd. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16890657&query_hl=5&itool=pubmed_docsum

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Radical cystectomy in septuagenarian patients with bladder cancer. Author(s): Gupta NP, Goel R, Hemal AK, Dogra PN, Seth A, Aron M, Kumar R, Ansari MS. Source: International Urology and Nephrology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15783105&query_hl=5&itool=pubmed_docsum

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Radical cystectomy with ultrasound-guided partial prostatectomy for bladder cancer: a complication-preventing concept. Author(s): Wunderlich H, Wolf M, Reichelt O, Frober R, Schubert J. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16979737&query_hl=5&itool=pubmed_docsum

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Re: A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of published results of randomized clinical trials. Author(s): Stewart AB, Mostafid H. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15758827&query_hl=5&itool=pubmed_docsum

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Recent improvements in the detection and treatment of nonmuscle-invasive bladder cancer. Author(s): Kausch I, Doehn C, Jocham D. Source: Expert Review of Anticancer Therapy. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=17020462&query_hl=5&itool=pubmed_docsum

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Relevance of extracapsular extension of pelvic lymph node metastasis in patients with bladder cancer treated in the contemporary era. Author(s): Kassouf W, Leibovici D, Luongo T, Munsell MF, Vakar F, Dinney CP, Grossman HB, Kamat AM. Source: Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16894527&query_hl=5&itool=pubmed_docsum

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Removal of more lymph nodes may provide better outcome, as well as more accurate pathologic findings, in patients with bladder cancer--analysis of role of pelvic lymph node dissection. Author(s): Honma I, Masumori N, Sato E, Maeda T, Hirobe M, Kitamura H, Takahashi A, Itoh N, Tamakawa M, Tsukamoto T. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16979723&query_hl=5&itool=pubmed_docsum

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Reproductive factors, exogenous hormone use and bladder cancer risk in a prospective study. Author(s): Cantwell MM, Lacey JV Jr, Schairer C, Schatzkin A, Michaud DS. Source: International Journal of Cancer. Journal International Du Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16894568&query_hl=5&itool=pubmed_docsum

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Role of fruit consumption in gall bladder cancer. Author(s): Rai A, Mohapatra SC, Shukla HS. Source: Indian J Gastroenterol. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15778530&query_hl=5&itool=pubmed_docsum

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Role of phosphatidylinositol-3 kinase/Akt pathway in bladder cancer cell apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand. Author(s): Oka N, Tanimoto S, Taue R, Nakatsuji H, Kishimoto T, Izaki H, Fukumori T, Takahashi M, Nishitani M, Kanayama HO. Source: Cancer Science. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16984382&query_hl=5&itool=pubmed_docsum

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Sexual function after surgery for prostate or bladder cancer. Author(s): Miranda-Sousa AJ, Davila HH, Lockhart JL, Ordorica RC, Carrion RE. Source: Cancer Control : Journal of the Moffitt Cancer Center. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16885913&query_hl=5&itool=pubmed_docsum

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Should we screen for bladder cancer in a high-risk population?: A cost per life-year saved analysis. Author(s): Lotan Y, Svatek RS, Sagalowsky AI. Source: Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16862567&query_hl=5&itool=pubmed_docsum

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Single nucleotide polymorphisms in DNA repair genes might be prognostic factors in muscle-invasive bladder cancer patients treated with chemoradiotherapy. Author(s): Sakano S, Wada T, Matsumoto H, Sugiyama S, Inoue R, Eguchi S, Ito H, Ohmi C, Matsuyama H, Naito K. Source: British Journal of Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16880786&query_hl=5&itool=pubmed_docsum

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Smoking and bladder cancer in Spain: effects of tobacco type, timing, environmental tobacco smoke, and gender. Author(s): Samanic C, Kogevinas M, Dosemeci M, Malats N, Real FX, Garcia-Closas M, Serra C, Carrato A, Garcia-Closas R, Sala M, Lloreta J, Tardon A, Rothman N, Silverman DT. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16835335&query_hl=5&itool=pubmed_docsum

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Stage-associated overexpression of the ubiquitin-like protein, ISG15, in bladder cancer. Author(s): Andersen JB, Aaboe M, Borden EC, Goloubeva OG, Hassel BA, Orntoft TF. Source: British Journal of Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16641915&query_hl=5&itool=pubmed_docsum

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Superficial (pT2a) and deep (pT2b) muscle invasion in pathological staging of bladder cancer following radical cystectomy. Author(s): Yu RJ, Stein JP, Cai J, Miranda G, Groshen S, Skinner DG. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16813876&query_hl=5&itool=pubmed_docsum

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Survivin: role in diagnosis, prognosis, and treatment of bladder cancer. Author(s): Akhtar M, Gallagher L, Rohan S. Source: Advances in Anatomic Pathology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16778475&query_hl=5&itool=pubmed_docsum

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Systemic chemotherapy in locally advanced and/or metastatic bladder cancer. Author(s): Pectasides D, Pectasides M, Economopoulos T. Source: Cancer Treatment Reviews. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16935429&query_hl=5&itool=pubmed_docsum

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Systemic chemotherapy options for metastatic bladder cancer. Author(s): Siefker-Radtke A. Source: Expert Review of Anticancer Therapy. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16761931&query_hl=5&itool=pubmed_docsum

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The effect of ofloxacin on bacillus calmette-guerin induced toxicity in patients with superficial bladder cancer: results of a randomized, prospective, double-blind, placebo controlled, multicenter study. Author(s): Colombel M, Saint F, Chopin D, Malavaud B, Nicolas L, Rischmann P. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16890660&query_hl=5&itool=pubmed_docsum

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The prognostic and staging value of lymph node dissection in the treatment of invasive bladder cancer. Author(s): Sanderson KM, Skinner D, Stein JP. Source: Nat Clin Pract Urol. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16964190&query_hl=5&itool=pubmed_docsum

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The relation between survival and expression of HER1 and HER2 depends on the expression of HER3 and HER4: a study in bladder cancer patients. Author(s): Memon AA, Sorensen BS, Meldgaard P, Fokdal L, Thykjaer T, Nexo E. Source: British Journal of Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16685269&query_hl=5&itool=pubmed_docsum

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The role of urinary cytology for detection of bladder cancer. Author(s): Planz B, Jochims E, Deix T, Caspers HP, Jakse G, Boecking A. Source: European Journal of Surgical Oncology : the Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15780568&query_hl=5&itool=pubmed_docsum

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The use of genetic programming in the analysis of quantitative gene expression profiles for identification of nodal status in bladder cancer. Author(s): Mitra AP, Almal AA, George B, Fry DW, Lenehan PF, Pagliarulo V, Cote RJ, Datar RH, Worzel WP. Source: Bmc Cancer [electronic Resource]. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16780590&query_hl=5&itool=pubmed_docsum

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Thymidine phosphorylase expression as a prognostic marker for predicting recurrence in primary superficial bladder cancer. Author(s): Aoki S, Yamada Y, Nakamura K, Taki T, Tobiume M, Honda N. Source: Oncol Rep. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16820903&query_hl=5&itool=pubmed_docsum

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Timing cystectomy and perioperative chemotherapy in the treatment of muscle invasive bladder cancer. Author(s): Izawa JI, Chin JL, Winquist E. Source: Can J Urol. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16818012&query_hl=5&itool=pubmed_docsum

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Tobacco smoke and bladder cancer--in the European Prospective Investigation into Cancer and Nutrition. Author(s): Bjerregaard BK, Raaschou-Nielsen O, Sorensen M, Frederiksen K, Christensen J, Tjonneland A, Overvad K, Chapelon FC, Nagel G, Chang-Claude J, Bergmann MM, Boeing H, Trichopoulos D, Trichopoulou A, Oikonomou E, Berrino F, Palli D, Tumino R, Vineis P, Panico S, Peeters PH, Bueno-de-Mesquita HB, Kiemeney L, Gram IT, Braaten T, Lund E, Gonzalez CA, Berglund G, Allen N, Roddam A, Bingham S, Riboli E. Source: International Journal of Cancer. Journal International Du Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16894557&query_hl=5&itool=pubmed_docsum

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Treatment of high-risk, non-muscle-invasive bladder cancer. Author(s): Lerner SP. Source: Nat Clin Pract Urol. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16902498&query_hl=5&itool=pubmed_docsum

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Treatment outcome and prognostic variables for local control and survival in patients receiving radical radiotherapy for urinary bladder cancer. Author(s): Fokdal L, Hoyer M, von der Maase H. Source: Acta Oncologica (Stockholm, Sweden). www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15764221&query_hl=5&itool=pubmed_docsum

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Update on clinical and radiological staging and surveillance of bladder cancer. Author(s): Sharir S. Source: Can J Urol. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16526987&query_hl=5&itool=pubmed_docsum

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Up-regulation of endothelial delta-like 4 expression correlates with vessel maturation in bladder cancer. Author(s): Patel NS, Dobbie MS, Rochester M, Steers G, Poulsom R, Le Monnier K, Cranston DW, Li JL, Harris AL. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16914569&query_hl=5&itool=pubmed_docsum

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Urine prothymosin-alpha as novel tumor marker for detection and follow-up of bladder cancer. Author(s): Tzai TS, Tsai YS, Shiau AL, Wu CL, Shieh GS, Tsai HT. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16461079&query_hl=5&itool=pubmed_docsum

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Urine telomerase and bladder cancer detection. Author(s): Liu BC. Source: Jama : the Journal of the American Medical Association. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16507796&query_hl=5&itool=pubmed_docsum

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Urine telomerase and bladder cancer detection. Author(s): Weikert S, Christoph F, Miller K. Source: Jama : the Journal of the American Medical Association. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16507795&query_hl=5&itool=pubmed_docsum

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Urine test boosts detection of recurrent bladder cancer. Author(s): Hilton L. Source: Rn. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16640017&query_hl=5&itool=pubmed_docsum

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Use of a multitarget fluorescence in situ hybridization assay to diagnose bladder cancer in patients with hematuria. Author(s): Sarosdy MF, Kahn PR, Ziffer MD, Love WR, Barkin J, Abara EO, Jansz K, Bridge JA, Johansson SL, Persons DL, Gibson JS. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16753364&query_hl=5&itool=pubmed_docsum

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Use of analgesics and nonsteroidal anti-inflammatory drugs, genetic predisposition, and bladder cancer risk in Spain. Author(s): Fortuny J, Kogevinas M, Garcia-Closas M, Real FX, Tardon A, Garcia-Closas R, Serra C, Carrato A, Lloreta J, Rothman N, Villanueva C, Dosemeci M, Malats N, Silverman D. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16985032&query_hl=5&itool=pubmed_docsum

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Use of selenium in chemoprevention of bladder cancer. Author(s): Brinkman M, Buntinx F, Muls E, Zeegers MP. Source: The Lancet Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16945772&query_hl=5&itool=pubmed_docsum

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Using tree analysis pattern and SELDI-TOF-MS to discriminate transitional cell carcinoma of the bladder cancer from noncancer patients. Author(s): Liu W, Guan M, Wu D, Zhang Y, Wu Z, Xu M, Lu Y. Source: European Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15774241&query_hl=5&itool=pubmed_docsum

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Valproic acid inhibits invasiveness in bladder cancer but not in prostate cancer cells. Author(s): Chen CL, Sung J, Cohen M, Chowdhury WH, Sachs MD, Li Y, Lakshmanan Y, Yung BY, Lupold SE, Rodriguez R. Source: The Journal of Pharmacology and Experimental Therapeutics. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16868035&query_hl=5&itool=pubmed_docsum

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Value of 11C-choline PET and contrast-enhanced CT for staging of bladder cancer: correlation with histopathologic findings. Author(s): Picchio M, Treiber U, Beer AJ, Metz S, Bossner P, van Randenborgh H, Paul R, Weirich G, Souvatzoglou M, Hartung R, Schwaiger M, Piert M. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16741302&query_hl=5&itool=pubmed_docsum

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Value of selective upper tract cytology for recognition of upper tract tumors after treatment of superficial bladder cancer. Author(s): Gogus C, Baltaci S, Sahinli S, Turkolmez K, Beduk Y, Gogus O. Source: International Journal of Urology : Official Journal of the Japanese Urological Association. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12694462&query_hl=5&itool=pubmed_docsum

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Variability in the performance of nuclear matrix protein 22 for the detection of bladder cancer. Author(s): Shariat SF, Marberger MJ, Lotan Y, Sanchez-Carbayo M, Zippe C, Ludecke G, Boman H, Sawczuk I, Friedrich MG, Casella R, Mian C, Eissa S, Akaza H, Serretta V, Huland H, Hedelin H, Raina R, Miyanaga N, Sagalowsky AI, Roehrborn CG, Karakiewicz PI. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16890655&query_hl=5&itool=pubmed_docsum

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Vascular endothelial growth factor antisense pretreatment of bladder cancer cells significantly enhances the cytotoxicity of mitomycin C, gemcitabine and Cisplatin. Author(s): Krause S, Forster Y, Kraemer K, Fuessel S, Kotzsch M, Schmidt U, Wirth MP, Meye A, Schwenzer B. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15947684&query_hl=5&itool=pubmed_docsum

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Visualisation of bladder cancer using (11)C-choline PET: first clinical experience. Author(s): de Jong IJ, Pruim J, Elsinga PH, Jongen MM, Mensink HJ, Vaalburg W. Source: European Journal of Nuclear Medicine and Molecular Imaging. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12271408&query_hl=5&itool=pubmed_docsum

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Visualizing superficial human bladder cancer cell growth in vivo by green fluorescent protein expression. Author(s): Zhou JH, Rosser CJ, Tanaka M, Yang M, Baranov E, Hoffman RM, Benedict WF. Source: Cancer Gene Therapy. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12136429&query_hl=5&itool=pubmed_docsum

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What do I tell my patients about drinking water and the risk of bladder cancer? Author(s): Moyad MA. Source: Urologic Nursing : Official Journal of the American Urological Association Allied. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=14621363&query_hl=5&itool=pubmed_docsum

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What has been learned from meta-analyses of neoadjuvant and adjuvant chemotherapy in bladder cancer? Author(s): Sternberg CN, Collette L. Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16925739&query_hl=5&itool=pubmed_docsum

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What is the ratio of urethral recurrence risk after radical cystoprostatectomy for bladder cancer? Author(s): Sevin G, Soyupek S, Armagan A, Hoscan MB, Dilmen C, Tukel O. Source: International Urology and Nephrology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15787329&query_hl=5&itool=pubmed_docsum

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Where are the ‘poster boys’ for bladder cancer? Author(s): Soloway MS. Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12780826&query_hl=5&itool=pubmed_docsum

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WIF1, a component of the Wnt pathway, is down-regulated in prostate, breast, lung, and bladder cancer. Author(s): Wissmann C, Wild PJ, Kaiser S, Roepcke S, Stoehr R, Woenckhaus M, Kristiansen G, Hsieh JC, Hofstaedter F, Hartmann A, Knuechel R, Rosenthal A, Pilarsky C. Source: The Journal of Pathology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=14517837&query_hl=5&itool=pubmed_docsum

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XPD codon 751 polymorphism, metabolism genes, smoking, and bladder cancer risk. Author(s): Stern MC, Johnson LR, Bell DA, Taylor JA. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12376500&query_hl=5&itool=pubmed_docsum

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You’re the flight surgeon. Bladder cancer. Author(s): Hilton AD. Source: Aviation, Space, and Environmental Medicine. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=14620482&query_hl=5&itool=pubmed_docsum

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CHAPTER 2. ALTERNATIVE MEDICINE AND BLADDER CANCER Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to bladder cancer. 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 (nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to bladder cancer and complementary medicine. To search the database, go to the following Web site: www.nlm.nih.gov/nccam/camonpubmed.html. Select CAM on PubMed. Enter bladder cancer (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 bladder cancer: •

A phase II study of vinflunine in bladder cancer patients progressing after first-line platinum-containing regimen. Author(s): Culine S, Theodore C, De Santis M, Bui B, Demkow T, Lorenz J, Rolland F, Delgado FM, Longerey B, James N. Source: British Journal of Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16622447&query_hl=1&itool=pubmed_docsum

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A randomized trial comparing methotrexate and vinblastine (MV) with cisplatin, methotrexate and vinblastine (CMV) in advanced transitional cell carcinoma: results and a report on prognostic factors in a Medical Research Council study. MRC Advanced Bladder Cancer Working Party. Author(s): Mead GM, Russell M, Clark P, Harland SJ, Harper PG, Cowan R, Roberts JT, Uscinska BM, Griffiths GO, Parmar MK.

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Source: British Journal of Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=9792152&query_hl=1&itool=pubmed_docsum •

A third-generation bisphosphonate, minodronic acid (YM529), successfully prevented the growth of bladder cancer in vitro and in vivo. Author(s): Sato K, Yuasa T, Nogawa M, Kimura S, Segawa H, Yokota A, Maekawa T. Source: British Journal of Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=17043684&query_hl=1&itool=pubmed_docsum

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Adenovirus-mediated delivery of p16 to p16-deficient human bladder cancer cells confers chemoresistance to cisplatin and paclitaxel. Author(s): Grim J, D’Amico A, Frizelle S, Zhou J, Kratzke RA, Curiel DT. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=9815642&query_hl=1&itool=pubmed_docsum

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Adenovirus-mediated gene therapy for bladder cancer: efficient gene delivery to normal and malignant human urothelial cells in vitro and ex vivo. Author(s): Chester JD, Kennedy W, Hall GD, Selby PJ, Knowles MA. Source: Gene Therapy. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12571646&query_hl=1&itool=pubmed_docsum

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Adjuvant and neoadjuvant chemotherapy for invasive bladder cancer. Author(s): Natale RB. Source: Current Oncology Reports. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11122869&query_hl=1&itool=pubmed_docsum

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Adjuvant chemotherapy with paclitaxel and carboplatin in patients with advanced bladder cancer: a study by the Hellenic Cooperative Oncology Group. Author(s): Bamias A, Deliveliotis Ch, Aravantinos G, Kalofonos Ch, Karayiannis A, Dimopoulos MA; Hellenic Cooperative Oncology Group. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15017199&query_hl=1&itool=pubmed_docsum

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Adjuvant cisplatin plus methotrexate versus methotrexate, vinblastine, epirubicin, and cisplatin in locally advanced bladder cancer: results of a randomized, multicenter, phase III trial (AUO-AB 05/95). Author(s): Lehmann J, Retz M, Wiemers C, Beck J, Thuroff J, Weining C, Albers P, Frohneberg D, Becker T, Funke PJ, Walz P, Langbein S, Reiher F, Schiller M, Miller K, Roth S, Kalble T, Sternberg D, Wellek S, Stockle M; AUO-AB 05/95.

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Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15939920&query_hl=1&itool=pubmed_docsum •

Adjuvant intravesical treatment of superficial bladder cancer with a standardized mistletoe extract. Author(s): Elsasser-Beile U, Leiber C, Wolf P, Lucht M, Mengs U, Wetterauer U. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15947582&query_hl=1&itool=pubmed_docsum

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Adjuvant intravesical treatment with a standardized mistletoe extract to prevent recurrence of superficial urinary bladder cancer. Author(s): Elsasser-Beile U, Leiber C, Wetterauer U, Buhler P, Wolf P, Lucht M, Mengs U. Source: Anticancer Res. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16334168&query_hl=1&itool=pubmed_docsum

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Advances in chemotherapy of invasive bladder cancer. Author(s): Akaza H. Source: Current Opinion in Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11005451&query_hl=1&itool=pubmed_docsum

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Aloe-emodin induces apoptosis in T24 human bladder cancer cells through the p53 dependent apoptotic pathway. Author(s): Lin JG, Chen GW, Li TM, Chouh ST, Tan TW, Chung JG. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16406939&query_hl=1&itool=pubmed_docsum

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Antitumor effect of ascorbic acid, lysine, proline, arginine, and green tea extract on bladder cancer cell line T-24. Author(s): Roomi MW, Ivanov V, Kalinovsky T, Niedzwiecki A, Rath M. Source: International Journal of Urology : Official Journal of the Japanese Urological Association. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16734861&query_hl=1&itool=pubmed_docsum

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Antitumor effects of lipoxygenase inhibitors on murine bladder cancer cell line (MBT-2). Author(s): Ikemoto S, Sugimura K, Kuratukuri K, Nakatani T. Source: Anticancer Res. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15161019&query_hl=1&itool=pubmed_docsum

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Antitumor effects of Scutellariae radix and its components baicalein, baicalin, and wogonin on bladder cancer cell lines. Author(s): Ikemoto S, Sugimura K, Yoshida N, Yasumoto R, Wada S, Yamamoto K, Kishimoto T. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=10840124&query_hl=1&itool=pubmed_docsum

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Apoptosis-inducing effects of curcumin derivatives in human bladder cancer cells. Author(s): Tong QS, Zheng LD, Lu P, Jiang FC, Chen FM, Zeng FQ, Wang L, Dong JH. Source: Anti-Cancer Drugs. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16520656&query_hl=1&itool=pubmed_docsum

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beta-lapachone induces growth inhibition and apoptosis in bladder cancer cells by modulation of Bcl-2 family and activation of caspases. Author(s): Lee JI, Choi DY, Chung HS, Seo HG, Woo HJ, Choi BT, Choi YH. Source: Exp Oncol. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16614704&query_hl=1&itool=pubmed_docsum

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Biochemical mechanism of cross-resistance to paclitaxel in a mitomycin c-resistant human bladder cancer cell line. Author(s): Bleicher RJ, Xia H, Zaren HA, Singh SV. Source: Cancer Letters. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=10704734&query_hl=1&itool=pubmed_docsum

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Bladder cancer “adjuvant-lite”: tastes great (works as well) and less filling (less toxic)? Author(s): Galsky MD, Scher HI. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15939919&query_hl=1&itool=pubmed_docsum

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Bladder cancer chemotherapy trial generates more questions than it answers. Author(s): Newman L. Source: Journal of the National Cancer Institute. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11438559&query_hl=1&itool=pubmed_docsum

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Bladder cancer prevention. Part I: what do I tell my patients about lifestyle changes and dietary supplements? Author(s): Moyad MA. Source: Current Opinion in Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12917512&query_hl=1&itool=pubmed_docsum

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Bladder cancer recurrence: Part II. What do I tell my patients about lifestyle changes and dietary supplements? Author(s): Moyad MA. Source: Current Opinion in Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12917513&query_hl=1&itool=pubmed_docsum

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Camptothecin analogues/cisplatin: an effective treatment of advanced bladder cancer in a preclinical in vivo model system. Author(s): Keane TE, El-Galley RE, Sun C, Petros JA, Dillahey D, Gomaa A, Graham SD Jr, McGuire WP 3rd. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=9628659&query_hl=1&itool=pubmed_docsum

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CG0070, a conditionally replicating granulocyte macrophage colony-stimulating factor--armed oncolytic adenovirus for the treatment of bladder cancer. Author(s): Ramesh N, Ge Y, Ennist DL, Zhu M, Mina M, Ganesh S, Reddy PS, Yu DC. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16397056&query_hl=1&itool=pubmed_docsum

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Chemoprevention for bladder cancer. Author(s): Busby JE, Kamat AM. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=17070211&query_hl=1&itool=pubmed_docsum

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Chemoprevention of bladder cancer. Author(s): Kamat AM, Lamm DL. Source: The Urologic Clinics of North America. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12109342&query_hl=1&itool=pubmed_docsum

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Chemoprevention of superficial bladder cancer. Author(s): Kamat AM. Source: Expert Review of Anticancer Therapy. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=14686702&query_hl=1&itool=pubmed_docsum

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Chemotherapy for bladder cancer. Author(s): Munoz A, Barcelo JR, Lopez-Vivanco G. Source: The New England Journal of Medicine. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=14657442&query_hl=1&itool=pubmed_docsum

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Chemotherapy for metastatic bladder cancer. Author(s): Roberts JT. Source: Clin Oncol (R Coll Radiol). www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16238139&query_hl=1&itool=pubmed_docsum

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Clinical application of an in vitro chemosensitivity test, the Histoculture Drug Response Assay, to urological cancers: wide distribution of inhibition rates in bladder cancer and renal cell cancer. Author(s): Hirano Y, Ushiyama T, Suzuki K, Fujita K. Source: Urological Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=10651138&query_hl=1&itool=pubmed_docsum

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Combined local bladder hyperthermia and intravesical chemotherapy for the treatment of high-grade superficial bladder cancer. Author(s): Gofrit ON, Shapiro A, Pode D, Sidi A, Nativ O, Leib Z, Witjes JA, van der Heijden AG, Naspro R, Colombo R. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15028439&query_hl=1&itool=pubmed_docsum

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Comparative study of apoptotic antitumor effect between angiogenesis inhibitor AGM-1470 and MVAC chemotherapy on rat urinary bladder cancer. Author(s): Sejima T, Isoyama T, Miyagawa I. Source: Urologia Internationalis. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15539841&query_hl=1&itool=pubmed_docsum

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Comparative study of sequential combinations of paclitaxel and methotrexate on a human bladder cancer cell line. Author(s): Cos J, Bellmunt J, Soler C, Ribas A, Lluis JM, Murio JE, Margarit C. Source: Cancer Investigation. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=10834027&query_hl=1&itool=pubmed_docsum

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Complete long-term survival data from a trial of adjuvant chemotherapy vs control after radical cystectomy for locally advanced bladder cancer. Author(s): Birtle AJ, Huddart RA. Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16686740&query_hl=1&itool=pubmed_docsum

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Complete long-term survival data from a trial of adjuvant chemotherapy vs control after radical cystectomy for locally advanced bladder cancer. Author(s): Lehmann J, Franzaring L, Thuroff J, Wellek S, Stockle M.

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Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16336326&query_hl=1&itool=pubmed_docsum •

COX-2 inhibition demonstrates potent anti-proliferative effects on bladder cancer in vitro. Author(s): Mohseni H, Zaslau S, McFadden D, Riggs DR, Jackson BJ, Kandzari S. Source: The Journal of Surgical Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15145695&query_hl=1&itool=pubmed_docsum

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CpG oligonucleotide therapy cures subcutaneous and orthotopic tumors and evokes protective immunity in murine bladder cancer. Author(s): Ninalga C, Loskog A, Klevenfeldt M, Essand M, Totterman TH. Source: Journal of Immunotherapy (Hagerstown, Md. : 1997). www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15614041&query_hl=1&itool=pubmed_docsum

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Cross-resistance and combined cytotoxic effects of paclitaxel and cisplatin in bladder cancer cells. Author(s): Pu YS, Chen J, Huang CY, Guan JY, Lu SH, Hour TC. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11371932&query_hl=1&itool=pubmed_docsum

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Current and future perspectives in advanced bladder cancer: is there a new standard? Author(s): von der Maase H. Source: Seminars in Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11894002&query_hl=1&itool=pubmed_docsum

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Current and new strategies in immunotherapy for superficial bladder cancer. Author(s): Perabo FG, Muller SC. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15351555&query_hl=1&itool=pubmed_docsum

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Current state of immunotherapy for bladder cancer. Author(s): Kassouf W, Kamat AM. Source: Expert Review of Anticancer Therapy. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15606331&query_hl=1&itool=pubmed_docsum

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Current trends in bladder cancer treatment. Author(s): Lamm DL, Allaway M.

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Source: Ann Chir Gynaecol. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11079794&query_hl=1&itool=pubmed_docsum •

Determining patient preferences for improved chemotoxicity during treatment for advanced bladder cancer. Author(s): Aristides M, Von Der Maase H, Roberts T, Brown A, Kielhorn A, Bhalla S. Source: European Journal of Cancer Care. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15842461&query_hl=1&itool=pubmed_docsum

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Diallyl disulfide (DADS) induced apoptosis undergo caspase-3 activity in human bladder cancer T24 cells. Author(s): Lu HF, Sue CC, Yu CS, Chen SC, Chen GW, Chung JG. Source: Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15304301&query_hl=1&itool=pubmed_docsum

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Dietary soy and increased risk of bladder cancer: the Singapore Chinese Health Study. Author(s): Sun CL, Yuan JM, Arakawa K, Low SH, Lee HP, Yu MC. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12496060&query_hl=1&itool=pubmed_docsum

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Different adhesion and migration properties of human HCV29 non-malignant urothelial and T24 bladder cancer cells: role of glycosylation. Author(s): Przybylo M, Litynska A, Pochec E. Source: Biochimie. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15760705&query_hl=1&itool=pubmed_docsum

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DNA ploidy and S-phase fraction as predictive factors of response and outcome following neoadjuvant methotrexate, vinblastine, epirubicin and cisplatin (M-VEC) chemotherapy for invasive bladder cancer. Author(s): Turkolmez K, Baltaci S, Beduk Y, Muftuoglu YZ, Gogus O. Source: Scandinavian Journal of Urology and Nephrology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12002357&query_hl=1&itool=pubmed_docsum

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EDTA-induced urothelial cell shedding for the treatment of superficial bladder cancer in the mouse. Author(s): Nativ O, Dalal E, Hidas G, Aronson M.

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Source: International Journal of Urology : Official Journal of the Japanese Urological Association. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=17010016&query_hl=1&itool=pubmed_docsum •

Effect of an epidermal growth factor receptor tyrosine kinase inhibitor on actin remodeling in an in vitro bladder cancer carcinogenesis model. Author(s): Jin Y, Iwata KK, Belldegrun A, Figlin R, Pantuck A, Zhang ZF, Lieberman R, Rao J. Source: Molecular Cancer Therapeutics. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16891461&query_hl=1&itool=pubmed_docsum

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Efficacy of paclitaxel released from bio-adhesive polymer microspheres on model superficial bladder cancer. Author(s): Le Visage C, Rioux-Leclercq N, Haller M, Breton P, Malavaud B, Leong K. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=14767342&query_hl=1&itool=pubmed_docsum

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Enhanced immunocompetence by garlic: role in bladder cancer and other malignancies. Author(s): Lamm DL, Riggs DR. Source: The Journal of Nutrition. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11238818&query_hl=1&itool=pubmed_docsum

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Enhancement by cyclosporin A of taxol-induced apoptosis of human urinary bladder cancer cells. Author(s): Nomura T, Yamamoto H, Mimata H, Shitashige M, Shibasaki F, Miyamoto E, Nomura Y. Source: Urological Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12086014&query_hl=1&itool=pubmed_docsum

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Evaluation of an unconventional treatment modality with mistletoe lectin to prevent recurrence of superficial bladder cancer: a randomized phase II trial. Author(s): Goebell PJ, Otto T, Suhr J, Rubben H. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12050495&query_hl=1&itool=pubmed_docsum

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Evaluation of chemotherapy in advanced urinary bladder cancer with fast dynamic contrast-enhanced MR imaging. Author(s): Barentsz JO, Berger-Hartog O, Witjes JA, Hulsbergen-van der Kaa C, Oosterhof GO, VanderLaak JA, Kondacki H, Ruijs SH.

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Source: Radiology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=9609906&query_hl=1&itool=pubmed_docsum •

Evaluation of the influence of systemic neoadjuvant chemotherapy on the survival of patients treated for invasive bladder cancer. Author(s): Kolaczyk W, Dembowski J, Lorenz J, Dudek K. Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11942977&query_hl=1&itool=pubmed_docsum

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Flavokawain A, a novel chalcone from kava extract, induces apoptosis in bladder cancer cells by involvement of Bax protein-dependent and mitochondria-dependent apoptotic pathway and suppresses tumor growth in mice. Author(s): Zi X, Simoneau AR. Source: Cancer Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15833884&query_hl=1&itool=pubmed_docsum

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Flavopiridol, an inhibitor of cyclin-dependent kinases, induces growth inhibition and apoptosis in bladder cancer cells in vitro and in vivo. Author(s): Wirger A, Perabo FG, Burgemeister S, Haase L, Schmidt DH, Doehn C, Mueller SC, Jocham D. Source: Anticancer Res. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16309238&query_hl=1&itool=pubmed_docsum

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Formulas calculating creatinine clearance are inadequate for determining eligibility for Cisplatin-based chemotherapy in bladder cancer. Author(s): Raj GV, Iasonos A, Herr H, Donat SM. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16809735&query_hl=1&itool=pubmed_docsum

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Functional p53 mutation as a molecular determinant of paclitaxel and gemcitabine susceptibility in human bladder cancer. Author(s): Kielb SJ, Shah NL, Rubin MA, Sanda MG. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11458051&query_hl=1&itool=pubmed_docsum

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Ganoderma lucidum extracts inhibit growth and induce actin polymerization in bladder cancer cells in vitro. Author(s): Lu QY, Jin YS, Zhang Q, Zhang Z, Heber D, Go VL, Li FP, Rao JY. Source: Cancer Letters. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15500944&query_hl=1&itool=pubmed_docsum

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Gemcitabine and cisplatin for advanced, metastatic bladder cancer. Author(s): Cohen MH, Rothmann M. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11181690&query_hl=1&itool=pubmed_docsum

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Gemcitabine and cisplatin in locally advanced and/or metastatic bladder cancer. Author(s): von der Maase H. Source: European Journal of Cancer (Oxford, England : 1990). www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=10908843&query_hl=1&itool=pubmed_docsum

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Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. Author(s): von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11001674&query_hl=1&itool=pubmed_docsum

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Gemcitabine in advanced bladder cancer. Author(s): von der Maase H. Source: Seminars in Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11372046&query_hl=1&itool=pubmed_docsum

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High incidence of brain metastases in patients treated with an M-VAC regimen for advanced bladder cancer. Author(s): Dhote R, Beuzeboc P, Thiounn N, Flam T, Zerbib M, Christoforov B, Debre B. Source: European Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=9612683&query_hl=1&itool=pubmed_docsum

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High intake of specific carotenoids and flavonoids does not reduce the risk of bladder cancer. Author(s): Garcia R, Gonzalez CA, Agudo A, Riboli E. Source: Nutrition and Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=10693178&query_hl=1&itool=pubmed_docsum

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Hypericum perforatum L. extract - novel photosensitizer against human bladder cancer cells. Author(s): Stavropoulos NE, Kim A, Nseyo UU, Tsimaris I, Chung TD, Miller TA, Redlak M, Nseyo UO, Skalkos D.

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Source: Journal of Photochemistry and Photobiology. B, Biology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16540336&query_hl=1&itool=pubmed_docsum •

HYTAD1-p20: a new paclitaxel-hyaluronic acid hydrosoluble bioconjugate for treatment of superficial bladder cancer. Author(s): Rosato A, Banzato A, De Luca G, Renier D, Bettella F, Pagano C, Esposito G, Zanovello P, Bassi P. Source: Urologic Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16678050&query_hl=1&itool=pubmed_docsum

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Impact of surgical resection of bladder cancer metastases refractory to systemic therapy on performance score: a phase II trial. Author(s): Otto T, Krege S, Suhr J, Rubben H. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11164143&query_hl=1&itool=pubmed_docsum

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In vitro cytotoxicity following specific activation of amygdalin by beta-glucosidase conjugated to a bladder cancer-associated monoclonal antibody. Author(s): Syrigos KN, Rowlinson-Busza G, Epenetos AA. Source: International Journal of Cancer. Journal International Du Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=9833764&query_hl=1&itool=pubmed_docsum

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In vitro evaluation of flavopiridol, a novel cell cycle inhibitor, in bladder cancer. Author(s): Chien M, Astumian M, Liebowitz D, Rinker-Schaeffer C, Stadler WM. Source: Cancer Chemotherapy and Pharmacology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=10367753&query_hl=1&itool=pubmed_docsum

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In vitro transfection of human bladder cancer cells by acoustic energy. Author(s): Schaaf A, Langbein S, Knoll T, Alken P, Michel MS. Source: Anticancer Res. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=14981938&query_hl=1&itool=pubmed_docsum

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Induction of G2/M arrest and inhibition of cyclooxygenase-2 activity by curcumin in human bladder cancer T24 cells. Author(s): Park C, Kim GY, Kim GD, Choi BT, Park YM, Choi YH. Source: Oncol Rep. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16596191&query_hl=1&itool=pubmed_docsum

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Inhibition of human bladder cancer cell motility by genistein is dependent on epidermal growth factor receptor but not p21ras gene expression. Author(s): Theodorescu D, Laderoute KR, Calaoagan JM, Guilding KM.

Alternative Medicine

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Source: International Journal of Cancer. Journal International Du Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=9833772&query_hl=1&itool=pubmed_docsum •

Integrated therapy for locally advanced bladder cancer: final report of a randomized trial of cystectomy plus adjuvant M-VAC versus cystectomy with both preoperative and postoperative M-VAC. Author(s): Millikan R, Dinney C, Swanson D, Sweeney P, Ro JY, Smith TL, Williams D, Logothetis C. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11600601&query_hl=1&itool=pubmed_docsum

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Intravesical administration of small interfering RNA targeting PLK-1 successfully prevents the growth of bladder cancer. Author(s): Nogawa M, Yuasa T, Kimura S, Tanaka M, Kuroda J, Sato K, Yokota A, Segawa H, Toda Y, Kageyama S, Yoshiki T, Okada Y, Maekawa T. Source: The Journal of Clinical Investigation. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15761500&query_hl=1&itool=pubmed_docsum

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Invasive bladder cancer: a single-institution experience with bladder-sparing approach. Author(s): Zapatero A, Martin de Vidales C, Marin A, Cerezo L, Arellano R, Rabadan M, Perez-Torrubia A. Source: International Journal of Cancer. Journal International Du Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11091353&query_hl=1&itool=pubmed_docsum

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Invasive bladder cancer: our experience with bladder sparing approach. Author(s): Cervek J, Cufer T, Zakotnik B, Kragelj B, Borstnar S, Matos T, Zumer-Pregelj M. Source: International Journal of Radiation Oncology, Biology, Physics. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=9607341&query_hl=1&itool=pubmed_docsum

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Involvement of mitochondrial pathway in Taxol-induced apoptosis of human T24 bladder cancer cells. Author(s): Yuan SY, Hsu SL, Tsai KJ, Yang CR. Source: Urological Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12389115&query_hl=1&itool=pubmed_docsum

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Localized bladder cancer. Author(s): Izawa JI, Grossman HB. Source: Curr Treat Options Oncol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12057150&query_hl=1&itool=pubmed_docsum

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Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. Author(s): von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16034041&query_hl=1&itool=pubmed_docsum

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Luteolin induces N-acetylation and DNA adduct of 2-aminofluorene accompanying N-acetyltransferase activity and gene expression in human bladder cancer T24 cell line. Author(s): Su CC, Chen GW, Yeh CC, Yang MD, Hung CF, Chung JG. Source: Anticancer Res. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12680237&query_hl=1&itool=pubmed_docsum

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Management and prognosis of transitional cell carcinoma superficial recurrence in muscle-invasive bladder cancer after bladder preservation. Author(s): Pieras E, Palou J, Salvador J, Rosales A, Marcuello E, Villavicencio H. Source: European Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12875942&query_hl=1&itool=pubmed_docsum

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Mechanism of increased coxsackie and adenovirus receptor gene expression and adenovirus uptake by phytoestrogen and histone deacetylase inhibitor in human bladder cancer cells and the potential clinical application. Author(s): Pong RC, Roark R, Ou JY, Fan J, Stanfield J, Frenkel E, Sagalowsky A, Hsieh JT. Source: Cancer Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16951199&query_hl=1&itool=pubmed_docsum

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Methotrexate-paclitaxel-epirubicin-carboplatin (M-TEC) combination chemotherapy in patients with advanced bladder cancer: an open label phase II study. Author(s): Tsavaris N, Kosmas C, Skopelitis H, Dimitrakopoulos A, Kopterides P, Bougas D, Stravodimos K, Mitropoulos D, Alamanis C, Giannopoulos A. Source: J Chemother. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16167525&query_hl=1&itool=pubmed_docsum

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MVAC chemotherapy-induced apoptosis and p53 alterations in the rat model of bladder cancer. Author(s): Zhang X, Jin L, Takenaka I. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=9801132&query_hl=1&itool=pubmed_docsum

Alternative Medicine

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N-acetyltransferase activity is involved in paclitaxel-induced N-acetylation of 2aminofluorene in human bladder cancer cells (T24). Author(s): Yang CC, Yang JH, Lu HF, Chen SY, Lin SY, Chung JG. Source: Anticancer Res. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15274316&query_hl=1&itool=pubmed_docsum

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Neoadjuvant chemotherapy and bladder-sparing surgery for invasive bladder cancer: ten-year outcome. Author(s): Herr HW, Bajorin DF, Scher HI. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=9552029&query_hl=1&itool=pubmed_docsum

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Neoadjuvant chemotherapy is not (yet) standard treatment for muscle-invasive bladder cancer. Author(s): Sternberg CN, Parmar MK. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11560967&query_hl=1&itool=pubmed_docsum

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Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. Author(s): Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, deVere White RW, Sarosdy MF, Wood DP Jr, Raghavan D, Crawford ED. Source: The New England Journal of Medicine. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12944571&query_hl=1&itool=pubmed_docsum

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Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscleinvasive bladder cancer: a randomised controlled trial. Author(s): Droller MJ. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=10798921&query_hl=1&itool=pubmed_docsum

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Neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin for histologically proven lymph node positive bladder cancer. Author(s): Nieuwenhuijzen JA, Bex A, Meinhardt W, Kerst JM, Schornagel JH, VAN Tinteren H, Horenblas S. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15947583&query_hl=1&itool=pubmed_docsum

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New approaches to treatment of metastatic bladder cancer. Author(s): Edelman MJ.

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Source: Current Oncology Reports. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11122868&query_hl=1&itool=pubmed_docsum •

New chemotherapy combinations for advanced bladder cancer. Author(s): Bellmunt J, Albiol S. Source: Current Opinion in Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11493774&query_hl=1&itool=pubmed_docsum

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New chemotherapy regimens for advanced bladder cancer. Author(s): Fagbemi SO, Stadler WM. Source: Semin Urol Oncol. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=9508079&query_hl=1&itool=pubmed_docsum

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Overexpression of Bcl-2 regulates sodium butyrate- and/or docetaxel-induced apoptosis in human bladder cancer cells both in vitro and in vivo. Author(s): Miyake H, Hara S, Arakawa S, Kamidono S, Hara I. Source: International Journal of Cancer. Journal International Du Cancer. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11391617&query_hl=1&itool=pubmed_docsum

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Overexpression of HER-2/neu enhances the sensitivity of human bladder cancer cells to urinary isoflavones. Author(s): Su S, Lai M, Yeh T, Chow N. Source: European Journal of Cancer (Oxford, England : 1990). www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11435074&query_hl=1&itool=pubmed_docsum

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Paclitaxel and carboplatin in bladder cancer: recent developments. Author(s): Vaughn DJ. Source: European Journal of Cancer (Oxford, England : 1990). www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=10908842&query_hl=1&itool=pubmed_docsum

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Paclitaxel-loaded gelatin nanoparticles for intravesical bladder cancer therapy. Author(s): Lu Z, Yeh TK, Tsai M, Au JL, Wientjes MG. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15570001&query_hl=1&itool=pubmed_docsum

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Phase 1/2 study of synchronous methotrexate, cisplatin, vincristine (MOPq10) chemotherapy and radiation for patients with locally advanced bladder cancer. Author(s): Goonewardene TI, Bozcuk H, Oliver RT, Barua J, Nargund V, Philip T, Mair G, Gibbs S.

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Source: Urologia Internationalis. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11741131&query_hl=1&itool=pubmed_docsum •

Phase I trial of intravesical docetaxel in the management of superficial bladder cancer refractory to standard intravesical therapy. Author(s): McKiernan JM, Masson P, Murphy AM, Goetzl M, Olsson CA, Petrylak DP, Desai M, Benson MC. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16809732&query_hl=1&itool=pubmed_docsum

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Phase II study of radiochemotherapy with vinblastine in invasive bladder cancer. Author(s): Kragelj B, Zaletel-Kragelj L, Sedmak B, Cufer T, Cervek J. Source: Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15878100&query_hl=1&itool=pubmed_docsum

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Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. Author(s): Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=9817278&query_hl=1&itool=pubmed_docsum

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Phenotypic characterization of bladder cancer. Author(s): Fradet Y. Source: European Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=9615196&query_hl=1&itool=pubmed_docsum

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Photodynamic therapy for refractory superficial bladder cancer: long-term clinical outcomes of single treatment using intravesical diffusion medium. Author(s): Manyak MJ, Ogan K. Source: Journal of Endourology / Endourological Society. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=14622483&query_hl=1&itool=pubmed_docsum

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Plasma glutathione S-transferase pi 1-1 AND alpha 1-1 levels in patients with bladder cancer. Author(s): Berendsen CL, Mulder TP, Peters WH.

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Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11061940&query_hl=1&itool=pubmed_docsum •

Plenary debate of randomized phase III trial of neoadjuvant MVAC plus cystectomy versus cystectomy alone in patients with locally advanced bladder cancer. Author(s): Bajorin DF. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11560966&query_hl=1&itool=pubmed_docsum

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Potential lifestyle and dietary supplement options for the prevention and postdiagnosis of bladder cancer. Author(s): Moyad MA. Source: The Urologic Clinics of North America. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12109354&query_hl=1&itool=pubmed_docsum

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Preclinical evaluation of gemcitabine/paclitaxel-interactions in human bladder cancer lines. Author(s): Perabo FG, Lindner H, Schmidt D, Huebner D, Blatter J, Fimmers R, Muller SC, Albers P. Source: Anticancer Res. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=14981929&query_hl=1&itool=pubmed_docsum

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Predicting response to methotrexate, vinblastine, doxorubicin, and cisplatin neoadjuvant chemotherapy for bladder cancers through genome-wide gene expression profiling. Author(s): Takata R, Katagiri T, Kanehira M, Tsunoda T, Shuin T, Miki T, Namiki M, Kohri K, Matsushita Y, Fujioka T, Nakamura Y. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15814643&query_hl=1&itool=pubmed_docsum

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Preliminary results of simultaneous radiochemotherapy with paclitaxel for urinary bladder cancer. Author(s): Dunst J, Weigel C, Heynemann H, Becker A. Source: Strahlentherapie Und Onkologie : Organ Der Deutschen Rontgengesellschaft. [et Al]. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=10554638&query_hl=1&itool=pubmed_docsum

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Prevention of bladder cancer: a review. Author(s): Leppert JT, Shvarts O, Kawaoka K, Lieberman R, Belldegrun AS, Pantuck AJ.

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Source: European Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16413099&query_hl=1&itool=pubmed_docsum •

Progress in the management of metastatic bladder cancer. Author(s): Parimoo D, Raghavan D. Source: Cancer Control : Journal of the Moffitt Cancer Center. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=10895129&query_hl=1&itool=pubmed_docsum

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Prospective study of dietary supplements, macronutrients, micronutrients, and risk of bladder cancer in US men. Author(s): Michaud DS, Spiegelman D, Clinton SK, Rimm EB, Willett WC, Giovannucci E. Source: American Journal of Epidemiology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11130620&query_hl=1&itool=pubmed_docsum

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Proton beam therapy for invasive bladder cancer: a prospective study of bladderpreserving therapy with combined radiotherapy and intra-arterial chemotherapy. Author(s): Hata M, Miyanaga N, Tokuuye K, Saida Y, Ohara K, Sugahara S, Kagei K, Igaki H, Hashimoto T, Hattori K, Shimazui T, Akaza H, Akine Y. Source: International Journal of Radiation Oncology, Biology, Physics. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16580495&query_hl=1&itool=pubmed_docsum

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Recent advances in bladder cancer chemotherapy. Author(s): Vaughn DJ, Malkowicz SB. Source: Cancer Investigation. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11291559&query_hl=1&itool=pubmed_docsum

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Recent developments in chemotherapy for bladder cancer. Author(s): Vaughn DJ, Malkowicz SB. Source: Oncology (Williston Park). www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11430208&query_hl=1&itool=pubmed_docsum

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Reversal of P-glycoprotein-mediated paclitaxel resistance by new synthetic isoprenoids in human bladder cancer cell line. Author(s): Enokida H, Gotanda T, Oku S, Imazono Y, Kubo H, Hanada T, Suzuki S, Inomata K, Kishiye T, Tahara Y, Nishiyama K, Nakagawa M. Source: Japanese Journal of Cancer Research : Gann. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12359058&query_hl=1&itool=pubmed_docsum

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Schedule dependent efficacy of gefitinib and docetaxel for bladder cancer. Author(s): Kassouf W, Luongo T, Brown G, Adam L, Dinney CP.

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Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16813948&query_hl=1&itool=pubmed_docsum •

Secondary leukaemia after treating advanced bladder cancer with methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy and radiotherapy. Author(s): Theodore C, Bayle C, Bernheim A, Wibault P. Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12175412&query_hl=1&itool=pubmed_docsum

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Second-line chemotherapy in advanced bladder cancer. Author(s): Pavone-Macaluso M, Sternberg C. Source: Urologia Internationalis. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=10810266&query_hl=1&itool=pubmed_docsum

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Soy phytochemicals prevent orthotopic growth and metastasis of bladder cancer in mice by alterations of cancer cell proliferation and apoptosis and tumor angiogenesis. Author(s): Singh AV, Franke AA, Blackburn GL, Zhou JR. Source: Cancer Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16452247&query_hl=1&itool=pubmed_docsum

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St John’s wort helps to fight bladder cancer. Author(s): Orellane C. Source: The Lancet Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11905732&query_hl=1&itool=pubmed_docsum

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Suppression of primary breast, colon, gastric and bladder cancers cell growth in vitro by CKBM, a natural product. Author(s): Zhang W, Liu ES, Fu J, Tian HM, Wu YJ, Pang SF. Source: Investigational New Drugs. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16096703&query_hl=1&itool=pubmed_docsum

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Taxol resistance and its reversal by synthetic isoprenoids in human bladder cancer cell line. Author(s): Nakagawa M, Enokida H, Gotanda T, Tachiwada T, Imazono Y, Kubo H, Nishiyama K, Suzuki S, Inomata K, Kishiye T. Source: Aktuelle Urologie. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=14566676&query_hl=1&itool=pubmed_docsum

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Tea consumption: fluid intake and bladder cancer risk in Southern Taiwan. Author(s): Lu CM, Lan SJ, Lee YH, Huang JK, Huang CH, Hsieh CC.

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Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=10565741&query_hl=1&itool=pubmed_docsum •

The current status of perioperative chemotherapy for invasive bladder cancer: a multiinstitutional retrospective study in Japan. Author(s): Matsui Y, Nishiyama H, Watanabe J, Teramukai S, Ono Y, Ohshima S, Fujimoto K, Hirao Y, Fukushima M, Ogawa O. Source: International Journal of Clinical Oncology / Japan Society of Clinical Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15864700&query_hl=1&itool=pubmed_docsum

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The DNA damaging agent VP16 induces the expression of a subset of ligands from the EGF system in bladder cancer cells, whereas none of the four EGF receptors are induced. Author(s): Sorensen BS, Torring N, Bor MV, Nexo E. Source: Molecular and Cellular Biochemistry. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15228094&query_hl=1&itool=pubmed_docsum

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The effect of cystectomy, and perioperative methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy on the risk and pattern of relapse in patients with muscle invasive bladder cancer. Author(s): Ennis RD, Petrylak DP, Singh P, Bagiella E, O’Toole KM, Benson MC, Olsson CA. Source: The Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=10751847&query_hl=1&itool=pubmed_docsum

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The efficacy of neoadjuvant chemotherapy in invasive bladder cancer. Author(s): Cam K, Yildirim A, Ozveri H, Turkeri L, Akdas A. Source: International Urology and Nephrology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12090338&query_hl=1&itool=pubmed_docsum

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The immunotherapy of prostate and bladder cancer. Author(s): Totterman TH, Loskog A, Essand M. Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16144528&query_hl=1&itool=pubmed_docsum

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The natural history of a T1 bladder cancer: life-long tumour diathesis. Author(s): Herr HW. Source: Bju International. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=10571647&query_hl=1&itool=pubmed_docsum

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The potential application of Allium sativum (garlic) for the treatment of bladder cancer. Author(s): Lamm DL, Riggs DR. Source: The Urologic Clinics of North America. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=10696254&query_hl=1&itool=pubmed_docsum

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The present and future of combination chemotherapy in bladder cancer. Author(s): Culine S. Source: Seminars in Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12094336&query_hl=1&itool=pubmed_docsum

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The prognostic value of angiogenesis factor expression for predicting recurrence and metastasis of bladder cancer after neoadjuvant chemotherapy and radical cystectomy. Author(s): Inoue K, Slaton JW, Karashima T, Yoshikawa C, Shuin T, Sweeney P, Millikan R, Dinney CP. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11156246&query_hl=1&itool=pubmed_docsum

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The role of adjuvant chemotherapy for locally advanced bladder cancer. Author(s): Lehmann J, Retz M, Stockle M. Source: World Journal of Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=11374316&query_hl=1&itool=pubmed_docsum

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The role of combined method in organ-sparing treatment of muscle-invasive bladder cancer recurrences. Author(s): Startsev VY. Source: Arch Ital Urol Androl. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12161935&query_hl=1&itool=pubmed_docsum

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The role of taxanes in the management of bladder cancer. Author(s): Galsky MD. Source: The Oncologist. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=16314289&query_hl=1&itool=pubmed_docsum

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The systemic treatment of advanced and metastatic bladder cancer. Author(s): Hussain SA, James ND. Source: The Lancet Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12901963&query_hl=1&itool=pubmed_docsum

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Tolerance of radiotherapy and chemotherapy in elderly patients with bladder cancer. Author(s): Goffin JR, Rajan R, Souhami L. Source: American Journal of Clinical Oncology : the Official Publication of the American Radium Society. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15057157&query_hl=1&itool=pubmed_docsum

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TP53 accumulation predicts improved survival in patients resistant to systemic cisplatin-based chemotherapy for muscle-invasive bladder cancer. Author(s): Qureshi KN, Griffiths TR, Robinson MC, Marsh C, Roberts JT, Hall RR, Lunec J, Neal DE. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=10589764&query_hl=1&itool=pubmed_docsum

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Treatment of invasive bladder cancer: lessons from the past and perspective for the future. Author(s): Tsukamoto T, Kitamura H, Takahashi A, Masumori N. Source: Japanese Journal of Clinical Oncology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15333680&query_hl=1&itool=pubmed_docsum

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Tyrosine kinase inhibitors of the epidermal growth factor receptor as adjuncts to systemic chemotherapy for muscle-invasive bladder cancer. Author(s): McHugh LA, Griffiths TR, Kriajevska M, Symonds RP, Mellon JK. Source: Urology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=15072863&query_hl=1&itool=pubmed_docsum

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Vitamin C and vitamin E supplement use and bladder cancer mortality in a large cohort of US men and women. Author(s): Jacobs EJ, Henion AK, Briggs PJ, Connell CJ, McCullough ML, Jonas CR, Rodriguez C, Calle EE, Thun MJ. Source: American Journal of Epidemiology. www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract Plus&list_uids=12446256&query_hl=1&itool=pubmed_docsum

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.: www.herbmed.org/

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AOL: health.aol.com/healthyliving/althealth

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Chinese Medicine: www.newcenturynutrition.com/

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drkoop.com®: www.drkoop.com/naturalmedicine.html

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Family Village: www.familyvillage.wisc.edu/med_altn.htm

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Google: directory.google.com/Top/Health/Alternative/

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Healthnotes: www.healthnotes.com/

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Open Directory Project: dmoz.org/Health/Alternative/

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Yahoo.com: dir.yahoo.com/Health/Alternative_Medicine/

The following is a specific Web list relating to bladder cancer; 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 Cancer Prevention (Reducing the Risk) Source: Prima Communications, Inc.www.personalhealthzone.com Cancer Prevention and Diet Source: Healthnotes, Inc.; www.healthnotes.com Colon Cancer Source: Healthnotes, Inc.; www.healthnotes.com Lung Cancer Source: Healthnotes, Inc.; www.healthnotes.com

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Herbs and Supplements Beta-Carotene Source: Prima Communications, Inc.www.personalhealthzone.com Cysteine Source: Integrative Medicine Communications; www.drkoop.com

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 dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at 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 3. DISSERTATIONS ON BLADDER CANCER Overview In this chapter, we will give you a bibliography on recent dissertations relating to bladder cancer. 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 “bladder cancer” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on bladder cancer, we have not necessarily excluded non-medical dissertations in this bibliography.

Dissertations on Bladder Cancer ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to bladder cancer. 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: •

Lifetime exposure to arsenic in drinking water in southeastern Michigan: Application to a bladder cancer case-control study Meliker, Jaymie R. from University of Michigan, 2006, 310 pages wwwlib.umi.com/dissertations/fullcit/3208509

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Mechanism of IFN-induced apoptosis and sensitization by the proteasome inhibitor bortezomib in bladder cancer cells Papageorgiou, Paraskevi Angeliki from the University of Texas Grad. Sch. of Biomed. Sci. at Houston, 2006, 291 pages wwwlib.umi.com/dissertations/fullcit/3218717

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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 wwwlib.umi.com/dissertations.

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CHAPTER 4. PATENTS ON BLADDER CANCER 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.10 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 “bladder cancer” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on bladder cancer, we have not necessarily excluded non-medical patents in this bibliography.

Patent Applications on Bladder Cancer As of December 2000, U.S. patent applications are open to public viewing.11 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 bladder cancer:

10Adapted

from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm. 11 This has been a common practice outside the United States prior to December 2000.

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Biological compositions and methods for treatment of bladder cancer Inventor(s): Cheung, Ling Yuk; (Hong Kong, HK) Correspondence: Jones Day; 222 East 41st ST; New York; NY; 10017; US Patent Application Number: 20040253265 Date filed: June 11, 2003 Abstract: The present invention relates to pharmaceutical compositions and dietary supplement comprising yeast cells that can produce a healthful benefit in a subject inflicted with bladder cancer. The biological compositions can be used to retard the growth of bladder cancer cells and/or prolonging the time of survival of the subject. The invention also relates to methods for manufacturing the biological compositions. Excerpt(s): The invention relates to oral compositions comprising yeast cells that can produce a healthful benefit in a subject inflicted with bladder cancer. The invention also relates to methods for manufacturing the oral compositions and methods of use thereof. Bladder cancer is the most common malignant tumor of the urinary tract and the sixth most common cancer in the United States, excluding non-melanoma skin cancers. Bladder cancer is more common in men than in women. The American Cancer Society estimates that in 2002 there were about 56,500 new cases of bladder cancer diagnosed in the United States (about 41,500 men and 15,000 women). Bladder cancer accounts for 2% of all cancer deaths in the United States, with 8,600 men and 4,000 women (2:1 ratio) dying from bladder cancer in 2002. Most bladder cancers are found on the lateral and posterior walls of the bladder as well as the trigone area. The highest incidence rates for bladder cancer are found in industrialized countries such as the United States, Canada, France, Denmark, Italy, and Spain. The lowest rates are in Asia and South America, where the incidence is only about 30% as high as in the United States. As with most other cancers, the exact cause of bladder cancer is uncertain. However, several factors may contribute to the development of bladder cancer. The greatest risk factor is tobacco use. Cigarette smoking has been shown to increase the risk of developing bladder cancer up to five times that of non-smokers. As many as 50% of all bladder cancer in men and 30% in women may be attributable to cigarette smoke. Studies show that one in four cases of bladder cancer can be attributed to occupational exposure to known carcinogens such as arylamines. Aniline dye used in the textile, rubber, and cable industries has been identified as an etiologic factor. Beta-naphthylamine, 4-aminodiphenyl, and tobacco tar have been shown to cause tumors in animals. Women who received radiation therapy for the treatment of cervical cancer have an increased risk of developing transitional cell bladder cancer, as do some people who received the chemotherapy drug, cyclophosphamide (Cytoxan). Web site: appft1.uspto.gov/netahtml/PTO/search-bool.html

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BPC-1: a secreted brain-specific protein expressed and secreted by prostate and bladder cancer cells Inventor(s): Afar, Daniel E.; (Pacific Palisades, CA), Hubert, Rene S.; (Los Angeles, CA), Jakobovits, Aya; (Beverly Hills, CA), Leong, Kahan; (Playa Del Rey, CA), Raitano, Arthur B.; (Los Angeles, CA), Saffran, Douglas C.; (Los Angeles, CA) Correspondence: Attention OF Karen S. Canady; Gates & Cooper Llp; Howard Hughes Center; 6701 Center Drive West, Suite 1050; Los Angeles; CA; 90045; US Patent Application Number: 20020161212 Date filed: June 21, 2001 Abstract: Described is a novel gene and its encoded secreted tumor antigen, termed BPC-1, and to diagnostic and therapeutic methods and compositions useful in the management of various cancers which express BPC-1, particularly including prostate cancer and bladder cancer. In human normal tissues, BPC-1 is only expressed in certain tissues of the brain. However, BPC-1 is expressed at high levels in prostate cancer cells and is also expressed in bladder cancer cells. The structure of BPC-1 includes a signal sequence and a CUB domain. BPC-1 protein is secreted. Preliminary experimental evidence suggests that BPC-1 is directly involved in oncogenesis or maintenance of the transformed phenotype of cancer cells expressing BPC-1. BPC-1 also appears to bind specifically to a cellular protein expressed in prostate cancer cells and other cells. Excerpt(s): The invention described herein relates to a novel gene and its encoded secreted tumor antigen, termed BPC-1, and to diagnostic and therapeutic methods and compositions useful in the management of various cancers which express BPC-1, particularly including prostate cancer and bladder cancer. Cancer is the second leading cause of human death next to coronary disease. Worldwide, millions of people die from cancer every year. In the United States alone, cancer causes the death of well over a halfmillion people each year, with some 1.4 million new cases diagnosed per year. While deaths from heart disease have been declining significantly, those resulting from cancer generally are on the rise. In the early part of the next century, cancer is predicted to become the leading cause of death. Worldwide, several cancers stand out as the leading killers. In particular, carcinomas of the lung, prostate, breast, colon, pancreas, and ovary represent the primary causes of cancer death. These and virtually all other carcinomas share a common lethal feature. With very few exceptions, metastatic disease from a carcinoma is fatal. Moreover, even for those cancer patients who initially survive their primary cancers, common experience has shown that their lives are dramatically altered. Many cancer patients experience strong anxieties driven by the awareness of the potential for recurrence or treatment failure. Many cancer patients experience physical debilitations following treatment. Many cancer patients experience a recurrence. Web site: appft1.uspto.gov/netahtml/PTO/search-bool.html

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Genetic testing kits and a method of bladder cancer Inventor(s): Fukuzono, Shinichi; (Hitachinaka, JP), Kanda, Takayuki; (Hitachinaka, JP), Maeda, Koshi; (Hitachinaka, JP), Sugano, Kokichi; (Urayasu, JP) Correspondence: Dickstein Shapiro Morin & Oshinsky Llp; 2101 L Street, NW; Washington; DC; 20037; US Patent Application Number: 20050009072 Date filed: May 27, 2004 Abstract: A deletion in the end region of the long arm of a Chromosome 9 is efficiently detected.A genetic testing kit of bladder cancer according to the present invention includes a primer allowing for efficient amplification of a region containing a site of genetic polymorphism present in the ABO blood group genes of Chromosome 9. In the site of genetic polymorphism present in the ABO blood group genes, the frequency of heterozygote (heterozygosity) in the population is extremely high. Therefore, by detecting LOH using a polymorphic site present in the ABO blood group genes, it is possible to reliably detect a deletion near the polymorphic site, in other words, a deletion near the end of the long arm of Chromosome 9. Excerpt(s): The present invention relates to a genetic test for bladder cancer by analyzing a chromosome. It has been reported that when canceration of the bladder cells occurs, a loss in a chromosome takes place, and consequently loss of heterozygosity (LOH) frequently occurs at 4p, 8p, 9p, 9q, 11p and 17p sites (see nonpatent documents 1 to 5). Therefore, bladder cancer can be effectively tested by detecting LOH. However, this method uses the tissue cells excised from bladder cancer, and therefore, a more simplified method has been strongly desired. The patent document 1 discloses a method of testing bladder cancer by analyzing LOH of Chromosome 9 using nucleic acids recovered from the urine of an early-stage bladder cancer patients. In this test method, a deletion in chromosome 9 is detected by using a single nucleotide polymorphism (SNP) and a microsatellite type polymorphic site which differs in number of repeat units by one or more, in the short arm (9p) and the long arm (9q) of Chromosome 9. More specifically, after the region having a genetic polymorphism on Chromosome 9 is amplified by PCR, the resultant PCR product is blunted, and the obtained nucleic acid fragment is analyzed by a single-strand conformation polymorphism (SSCP) to detect LOH at a site of genetic polymorphism. Web site: appft1.uspto.gov/netahtml/PTO/search-bool.html

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HURP gene as a molecular marker for bladder cancer Inventor(s): Chiu, Allen W.; (Yung Kang City, TW), Chou, Chen-Kung; (Yung Kang City, TW), Huang, Yu-Lun; (Yung Kang City, TW) Correspondence: Foley And Lardner; Suite 500; 3000 K Street NW; Washington; DC; 20007; US Patent Application Number: 20040072166 Date filed: September 30, 2002 Abstract: Hepatoma up-regulated protein (HURP) gene serves as a useful molecular marker in the detection, preliminary screening and monitoring of bladder cancer in a human subject. A method for the detection of bladder cancer, in particular transitional cell carcinoma (TCC) of the bladder, in a human subject is disclosed, in which the

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detected expression of the human HURP gene in a sample taken from a subject suspected to have bladder cancer is indicative of the presence of the bladder cancer. The present invention further provides a non-invasive method for the detection, preliminary screening or monitoring of urinary TCC in a suspected subject, in which a urine sample taken from the subject is analyzed to determine an expression of the human HURP gene, the presence of which is indicative of the presence of urinary TCC. Excerpt(s): The present invention relates to the use of a human hepatoma up-regulated protein (HURP) gene as a molecular marker in the detection, preliminary screening or monitoring of bladder cancer in a human subject, in which the detected expression of the human HURP gene in a sample taken from a human subject suspected to have bladder cancer is indicative of the presence of the bladder cancer. The present invention thus provides an efficient method for the detection of bladder cancer, in particular transitional cell carcinoma (TCC) of the bladder, in a human subject. The present invention further provides a non-invasive method for the detection, preliminary screening or monitoring of urinary TCC in a human subject with high accuracy and convenience, in which a urine sample taken from a suspected human subject is analyzed to determine an expression of the human HURP gene, the presence of which is indicative of the presence of urinary TCC. Urothelial carcinoma is the second most common malignancy of the genitourinary tract and is also the second leading cause of death among all genitourinary tumors (Konety B R and Getzenberg R H: Urine based markers of urological malignancy. J Urol 165: 600-611, 2001). Transitional cell carcinoma (TCC) of the bladder is responsible for more than 90% of urothelial neoplasms and it either presents as papillary superficial lesions with low malignant potential or high grade tumors that can be invasive and lethal. When bladder cancer is detected early during a localized stage, the 5-year survival rate is 94%. Once the disease has spread regionally or distally, the 5-year survival rate drops to 49% and 6%, respectively (Droller M J: Individualizing the approach to invasive bladder cancer. Contemp. Urol., July/August, pp. 54-61, 1990). It is thus important to detect the early events in the recurrence of superficial cancer before the cancer cells have time to change their behavior to invasive. Classical cytology and cystoscopy under scheduled follow-up protocols are the main methods for the surveillance of patients with urinary TCC. The low sensitivity for low-grade tumor using voided urine cytology requires the frequent use of invasive cystoscopy, thus eliciting the associated discomfort and the potential risk of infection by urethral instrumentation during cystoscopy. The development of a sensitive noninvasive diagnostic test that could specifically detect bladder carcinoma in the early stages would improve the clinical outcomes by starting the treatment earlier. Web site: appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method for the in vitro diagnosis of a predisposition to bladder cancer or of the occurrence of bladder cancer and a kit for performing said diagnostic method Inventor(s): Gaub, Marie-Pierre; (Strasbourg, FR), Jacqmin, Didier; (Lingolsheim, FR), Lang, Herve; (Strasbourg, FR), Oudet, Pierre; (Strasbourg, FR), Schneider, Anne; (Strasbourg, FR) Correspondence: Young & Thompson; 745 South 23rd Street 2nd Floor; Arlington; VA; 22202 Patent Application Number: 20030113758 Date filed: August 14, 2002

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Abstract: A new in vitro method for diagnosing the predisposition of a human individual to bladder cancer or for diagnosing the occurrence of a bladder cancer in a human individual, makes use of a comparison between the allelic ratios of a serial of microsatellite markers associated with this disease, respectively in the urine DNA and in the blood cell DNA of said human individual. Excerpt(s): The present invention relates to a new in vitro method for diagnosing the predisposition of a human individual to bladder cancer or for diagnosing the occurrence of a bladder cancer in a human individual, wherein said method makes use of a comparison between the allelic ratios of a serial of microsatellite markers associated with this disease, respectively in the urine DNA and in the blood cell DNA of said human individual. It is also directed to diagnostic kits which are useful for carrying out the method above. Throughout this Application, various publications are cited. The disclosures of these publications referenced in this Application are hereby incorporated by reference into the present disclosure to more fully describe the state of the art to which this invention pertains. Web site: appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods and compositions for intravesical therapy of bladder cancer Inventor(s): Goldenberg, David M.; (Mendham, NJ), Griffiths, Gary; (Morristown, NJ) Correspondence: Foley And Lardner; Suite 500; 3000 K Street NW; Washington; DC; 20007; US Patent Application Number: 20040022726 Date filed: May 30, 2003 Abstract: A method for treating bladder cancer by administering via the urethra a multispecific antibody comprising at least one targeting arm that binds a bladder cancer antigen and at least one capture arm that binds a carrier conjugated to one or more therapeutic agents, allowing said multispecific antibody to localize at the site of said bladder cancer, allowing any free multispecific antibody to substantially clear from the patient; and (b) administering a therapeutically effective amount of the carrier conjugated to one or more therapeutic agents. Excerpt(s): Bladder cancer is a relatively common cancer, particularly prevalent among men, and its incidence is slowly increasing. Superficial cancers are generally treated by endoscopic resection, although virtually all patients develop new tumors in the bladder, many of which progress to a higher stage. Further treatments over time can include further resections, radiation, and various intravesical therapies including those using chemotherapy agents and bacillus Calmette-Guerin. All therapies have adverse side effects. Ultimately, disease can spread such that a cystectomy (removal of the entire bladder and multiple surrounding tissues) is necessitated. Because bladder cancer is often diagnosed at an early stage it is amenable to, and often responsive to, certain treatments administered intravesically. Unfortunately, none is curative, and few in fact provide regressions of any meaningful duration. Further, when the bladder carcinoma spreads beyond this organ, virtually all patients succumb to this metastatic disease. Even when the bladder carcinoma remains within the bladder but penetrates beyond the superficial epithelium into the deeper muscular layer, potential for cure relies only on total bladder extirpation, which then requires a urinary pouch to be made from the patient’s gut, and which provides much difficulty to the patient and a major effect on the patient’s quality of life. Radioimmunotherapy (RAIT) with monoclonal antibodies

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(mAbs) is a very promising modality for the targeted and specific treatment of various cancers, and promises substantially improved outcomes compared to standard radiotherapy and chemotherapy approaches to cancer treatment. It does, however, suffer from the disadvantage that when a radiolabeled mAb is injected into a cancer patient a finite amount of time is needed for the radioimmunoconjugate to both maximize in tumor target tissue, and clear from background tissues and circulation. During this time, which is quite long for an intact radiolabeled immunoglobulin IgG and somewhat shorter for radiolabeled IgG fragments and sub-Fab’ fragments, the patient is exposed to non-disease targeted radiation. This non-targeted radiation, primarily received during the mAb localization phase, translates directly to radiotoxicity. This, in turn, limits the total amount of radiolabeled mAb that can be administered, preventing dose escalation to achieve optimal RAIT, which can require tumor doses in the range of 50 to 80 Gy, because most solid tumors (carcinomas) are relatively radioresistant, as compared to hematopoietic neoplasms. To overcome this problem, delivery of radionuclide has been separated from the initial targeting step in a method generally called pretargeting. In this system a localization moiety, typically a multispecific antibody (msAb) that has at least one arm that binds to a tumor antigen and at least one other arm that binds to a low molecular weight hapten (example: a bispecific antibody (bsAb)), is given to a patient, and allowed to maximize in tumor tissue while also clearing normal tissues. Some time later the low molecular weight hapten is given in a radiolabeled form. The latter localizes to the multispecific antibody pretargeted to the tumor but otherwise rapidly clears the circulation and normal tissues. The ability to localize the radioactive species to the tumor target via the multispecific antibody almost immediately post-administration while the unbound radioactivity is eliminated, via the kidneys and urine, dramatically shifts the therapeutic ratio in a positive manner. Increased amounts of radioactivity can be directed to the tumor target, while normal tissues are spared and overall toxicity thereby decreased. Web site: appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods for detecting and classifying bladder cancer via human uroplakin genes Inventor(s): Sun, Tung-Tien; (Scarsdale, NY), Wu, Xue-Ru; (New York, NY) Correspondence: Browdy And Neimark, P.L.L.C.; Patent And Trademark Causes; Suite 300; 624 Ninth Street, N.W.; Washington; DC; 20001-5303; US Patent Application Number: 20020009745 Date filed: June 1, 2001 Abstract: The human gene for uroplakin II is identified and sequenced. Using this gene, oligonucleotide primers were constructed which were then used to identify bladder cancer cells in blood and tissue. Excerpt(s): Histological differentiation markers are useful in the diagnosis of carcinoma metastases where the location of the primary tumor is uncertain or unknown. Unfortunately, markers specific for a single epithelium or organ are currently available for a only few types of carcinoma, e.g., prostate-specific antigen for prostate carcinomas and thyroglobulin for thyroid carcinomas. Less specific markers of transitional cell carcinomas have been identified and associated with malignant transformation, tumor progression and the prognosis. Many of these markers are epithelial membrane antigen (EMA) or oncogene/tumor suppressor gene products. For example, Summerhayes et al. (1985. JNCI 75:1025-1038) have described a series of monoclonal antibodies (group III),

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directed against the urothelium which produce luminal-membrane staining of normal superficial (umbrella) cells of the urothelium. Other markers are expressed in superficial bladder tumors but disappear in invasive and metastatic transitional cell carcinomas. All of these markers are antibodies most of which stain non-urinary epithelia and carcinomas too. Certain antigens such as involucrin, E48 antigen and SCC antigen are markers shared by both transitional and stratified squamous epithelia (of skin, esophagus, cervix, etc.) and their carcinomas. However, no differentiation or lineage marker specific for transitional cell carcinomas and their metastases has been identified to date. Normal urothelium contains tissue-specific differentiation products that have been well characterized morphologically and biochemically. It has been found that large numbers of urothelial plaques are present in the superficial plasma membrane of urothelial superficial or umbrella cells. These plaques are characterized by a highly unusual membrane structure, i.e., the asymmetric unit membrane (AUM), whose luminal leaflet is twice as thick as its cytoplasmic leaflet. The thickening of the luminal leaflet is due to the presence of particles exhibiting a semi-crystalline organization. The molecular constituents principally comprise four transmembrane proteins: uroplakin (UP) Ia (27 kDa); UP Ib (28 kDa); UP II (15 kDa) and UP III (47 kDa). These UPs, particularly UP Ia, Ib, and II, are characterized by their markedly asymmetric mass distribution, with the extracellular domain being considerably larger than the intracellular one. This accounts for the clearly visible ultrastructural thickening of the luminal leaflet of the unit membrane. UP III is believed to play a role in the formation of the urothelial glycocalyx and may interact, via its cytoplasmic portion, with the cytoskeleton. Web site: appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods of diagnosis of bladder cancer, compositions and methods of screening for modulators of bladder cancer Inventor(s): Aziz, Natasha; (Palo Alto, CA), Mack, David H.; (Menlo Park, CA) Correspondence: Howrey Simon Arnold & White, Llp; Box 34; 301 Ravenswood AVE.; Menlo Park; CA; 94025; US Patent Application Number: 20040076955 Date filed: July 2, 2002 Abstract: Described herein are genes whose expression are up-regulated or downregulated in bladder cancer. Also described are such genes whose expression is further up-regulated or down-regulated in drug-resistant bladder cancer cells. Related methods and compositions that can be used for diagnosis, prognosis, or treatment of bladder cancer are disclosed. Also described herein are methods that can be used to identify modulators of bladder cancer. Excerpt(s): This application is related to U.S. S No. 60/302,814, filed Jul. 3, 2001; U.S. S No. 60/310,099, filed Aug. 3, 2001; U.S. S No. 60/343,705, filed Nov. 8, 2001; U.S. S No. 60/350,666, filed Nov. 13, 2001; and U.S. S No. 60/372,246, filed Apr. 12, 2001, each of which is incorporated herein by reference. The invention relates to the identification of nucleic acid and protein expression profiles and nucleic acids, products, and antibodies thereto that are involved in bladder cancer; and to the use of such expression profiles and compositions in the diagnosis, prognosis, and therapy of bladder cancer. The invention further relates to methods for identifying and using agents and/or targets that inhibit bladder cancer. In the United States, over 50,000 new cases of bladder cancer are

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diagnosed annually, and more than 10,000 deaths will be attributed to bladder cancer. Bladder cancer is now the fourth most common cancer among American men and the ninth most common cancer among American women. It occurs three times more frequently in men than in women, and it occurs roughly twice more frequently in white versus black men. Web site: appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods to determine prognosis after therapy for bladder cancer Inventor(s): Lerner, Seth P.; (Houston, TX), Shariat, Shahrokh; (Dallas, TX), Slawin, Kevin M.; (Houston, TX) Correspondence: Schwegman, Lundberg, Woessner & Kluth, P.A.; P.O. Box 2938; Minneapolis; MN; 55402; US Patent Application Number: 20030032074 Date filed: May 24, 2002 Abstract: A method to diagnose, stage and predict prognosis of bladder cancer patients is provided, e.g., using TGF-.beta.1, IL-6, IL-6sR, uPA, uPAR and IGFBP-3. These markers, and potentially others, in combination with standard clinical and pathologic features, may be used to create a nomogram that would be useful for managing bladder cancer patients. Excerpt(s): This application claims the benefit of the filing date of U.S. application Serial No. 60/295,512, filed Jun. 1, 2001 under 35 U.S.C.sctn.119(e). Carcinoma of the urinary bladder is a significant cause of morbidity and mortality in the United States, accounting for an estimated 54,300 new cases and 12,400 resultant deaths in 2001 (Greenlee et al., 2001). At initial presentation, approximately 70% to 80% of the bladder cancers are confined to the epithelium or subepithelial connective tissue, whereas the remainder of patients present with muscle invasive cancer. Most of these patients respond well to local resection and adjuvant intravesical therapy. Unfortunately, 50% to 80% of these patients will experience recurrence within the first two years. Up to one-half of patients with invasive disease have either measurable metastatic disease or have disease destined to recur due to occult metastases. While patients with low-grade papillary disease (Ta, T1) rarely progress to muscle invasive transitional cell carcinoma (TCC), as many as 30% of patients with Tis or high-grade papillary disease are refractory to treatment with intravesical immunotherapy and/or chemotherapy and progress to more advance disease (Thrasher and Crawford, 1993). Radical cystectomy provides effective local control of refractory Ta, T1 and Tis bladder cancer and muscle invasive TCC (Stein et al., 2001). However, despite this, approximately 14%-33% of patients with nodenegative muscle invasive disease will die of their disease within five years of surgery, presumably due to dissemination of microscopic metastatic disease prior to cystectomy (Lerner and Skinner, 1999). Patients who have pathologically confirmed metastases to regional lymph nodes have an even higher risk of progression and death than those who do not (Lerner et al., 1993). Ultimately at least 50% of the patients undergoing cystectomy for muscle invasive disease will eventually develop clinical metastases and most of these patients will die of their disease (Raghavan et al., 1990; von der Maase et al., 2000). Conventional staging modalities such as transurethral bladder tumor resection (Lerner et al., 1993; Frazier et al, 1993; Pagano et al., 1991), computed tomography (Buszello et al., 1994; Nurmi et al. 1988, Voges et al., 1989), and magnetic resonance imaging (Persad et al., 1993) have a limited role in tumor staging and predicting lymph

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node involvement in patients with bladder cancer because of their poor performance in detecting early, small-volume metastases. Early detection of patients harboring occult micrometasteses, who have a high probability of developing disease progression and shortened survival, could potentially be spared either the morbidity of an unsuccessful local treatment or selected for a combined modality program. Web site: appft1.uspto.gov/netahtml/PTO/search-bool.html

Keeping Current In order to stay informed about patents and patent applications dealing with bladder cancer, you can access the U.S. Patent Office archive via the Internet at the following Web address: 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 bladder cancer (or a synonym) 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 bladder cancer. You can also use this procedure to view pending patent applications concerning bladder cancer. Simply go back to www.uspto.gov/patft/index.html. Select Quick Search under Published Applications. Then proceed with the steps listed above.

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CHAPTER 5. BOOKS ON BLADDER CANCER Overview This chapter provides bibliographic book references relating to bladder cancer. In addition to online booksellers such as www.amazon.com and www.bn.com, the National Library of Medicine is an excellent source for book titles on bladder cancer. Your local medical library also may have these titles available for loan.

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 bladder cancer at online booksellers’ Web sites, you may discover non-medical books that use the generic term “bladder cancer” (or a synonym) in their titles. The following is indicative of the results you might find when searching for bladder cancer (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

100 Q&A About Bladder Cancer (Class Health) Pamela Ellsworth (2005); ISBN: 0763732532; www.amazon.com/exec/obidos/ASIN/0763732532/icongroupinterna

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21st Century Complete Medical Guide to Bladder Cancer - Authoritative Government Documents and Clinical References for Patients and Physicians with Practical. on Diagnosis and Treatment Options PM Medical Health News (2002); ISBN: 1592480004; www.amazon.com/exec/obidos/ASIN/1592480004/icongroupinterna

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A Comprehensive guide to the therapeutic use of methotrexate in bladder cancer (Pharmanual) (1983); ISBN: 0919839010; www.amazon.com/exec/obidos/ASIN/0919839010/icongroupinterna

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Bcg: The Optimal Approach in Superficial Bladder Cancer (European Urology) A. Bohle (1999); ISBN: 3805570198; www.amazon.com/exec/obidos/ASIN/3805570198/icongroupinterna

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•

Enhanced immunocompetence by garlic: Role in bladder cancer and other malignancies: An article from: The Journal of Nutrition Donald L Lamm and Dale R Riggs (2001); ISBN: B000BCQ08S; www.amazon.com/exec/obidos/ASIN/B000BCQ08S/icongroupinterna

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Evaluation of Chemotherapy in Bladder Cancer (International Society of Urology Reports) Humberto Villavicencio and William R. Fair (1993); ISBN: 0443046441; www.amazon.com/exec/obidos/ASIN/0443046441/icongroupinterna

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Galactosyl transferase: A possible enzyme marker of bladder cancer cells in the rat and the human (Massachusetts Institute of Technology. Dept. of Nutrition and Food Science. Thesis. 1978. M.S) Susan Lynn Gilbert (1978); ISBN: B0007ARXJO; www.amazon.com/exec/obidos/ASIN/B0007ARXJO/icongroupinterna

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High-risk superficial bladder cancer (Seminars in urologic oncology) Eric A Klein (1997); ISBN: B0006QS3GQ; www.amazon.com/exec/obidos/ASIN/B0006QS3GQ/icongroupinterna

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Kuss Bladder Cancer - Radiation Local & Systemat IC Chemotherapy & New Treatment Modalities R KUSS (1984); ISBN: 0471833908; www.amazon.com/exec/obidos/ASIN/0471833908/icongroupinterna

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Lifetime exposure to arsenic in drinking water in southeastern Michigan: Application to a bladder cancer case-control study: (Dissertation) Jaymie R. Meliker (2006); ISBN: B000K2QF34; www.amazon.com/exec/obidos/ASIN/B000K2QF34/icongroupinterna

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Moments of decision in cancer of the bladder (Moments of decision series) William L Caldwell (1974); ISBN: B0006WCX6Q; www.amazon.com/exec/obidos/ASIN/B0006WCX6Q/icongroupinterna

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More bladder cancer seen in prostate cancer patients.(Urology): An article from: Internal Medicine News (2004); ISBN: B000848XNO; www.amazon.com/exec/obidos/ASIN/B000848XNO/icongroupinterna

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New study suggests water chlorination linked to bladder cancer risk (Statement) Cori Vanchieri (1988); ISBN: B00071DKTK; www.amazon.com/exec/obidos/ASIN/B00071DKTK/icongroupinterna

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Occupational bladder cancer in a 4,4’-methylenebis(2-chloroaniline) (MBOCA)exposed worker.(Environmental Medicine / Grand Rounds): An article from: Environmental Health Perspectives Chiu-Shong Liu, Saou-Hsing Liou, Ching-Hui Loh, and Yi-Chun Yu (2005); ISBN: B000AM49JG; www.amazon.com/exec/obidos/ASIN/B000AM49JG/icongroupinterna

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Problems in Urology: Bladder Cancer (Problems in Urology, Volume 2) Jr. MD, FACS George R. Prout and MD David F. Paulson (1988); ISBN: B000FI5WFA; www.amazon.com/exec/obidos/ASIN/B000FI5WFA/icongroupinterna

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Progress In Bladder Cancer Research (Horizons in Cancer Research) A. M. Mallory (2004); ISBN: 1594541299; www.amazon.com/exec/obidos/ASIN/1594541299/icongroupinterna

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Quickfacts on Bladder Cancer (Quickfacts) American Cancer Society (2007); ISBN: 0944235778; www.amazon.com/exec/obidos/ASIN/0944235778/icongroupinterna

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Request for assistance in preventing bladder cancer from exposure to o-toluidine and aniline (NIOSH alert) J. Donald Millar (1990); ISBN: 0160292034; www.amazon.com/exec/obidos/ASIN/0160292034/icongroupinterna

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The biochemistry of bladder cancer (American lectures in tumours) Eric Boyland (1963); ISBN: B0007DUL9U; www.amazon.com/exec/obidos/ASIN/B0007DUL9U/icongroupinterna

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The Guide to Living with Bladder Cancer (A Johns Hopkins Press Health Book) Mark P. Schoenberg (2000); ISBN: 0801864062; www.amazon.com/exec/obidos/ASIN/0801864062/icongroupinterna

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The use of city directories as a source of occupational data in a case-control study of bladder cancer in Hamilton County, Ohio: A dissertation in epidemiology Kyle Steenland (1985); ISBN: B00071KE6M; www.amazon.com/exec/obidos/ASIN/B00071KE6M/icongroupinterna

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Understanding bladder cancer. and what you should know about its diagnosis and treatment: a patient’s guide.: An article from: Ostomy Quarterly (1996); ISBN: B00096JM22; www.amazon.com/exec/obidos/ASIN/B00096JM22/icongroupinterna

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Urine test may aid early detection of bladder cancer (Update) Elaine Blume (1988); ISBN: B00071HSK2; www.amazon.com/exec/obidos/ASIN/B00071HSK2/icongroupinterna

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What you need to know about bladder cancer (SuDoc HE 20.3152:B 56/2/2001) U.S. Dept of Health and Human Services (2001); ISBN: B000115CAG; www.amazon.com/exec/obidos/ASIN/B000115CAG/icongroupinterna

The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, locatorplus.gov/, and then select LocatorPlus. Once you are in the search area, simply type bladder cancer (or synonyms) into the search box, and select the Quick Limit Option for Keyword, Title, or Journal Title Search: Books. From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine12: •

A Comprehensive guide to the therapeutic use of methotrexate in bladder cancer Author: Hall, Reginald R. (Reginald Ross),; Year: 1983; Chicago: PharmaLibri, c1983

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The Pathology of bladder cancer Author: Bryan, George T. (George Terrell),; Year: 1983; Boca Raton, Fla.: CRC Press, c1983

12

In addition to LocatorPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.

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APPENDIX A. HELP ME UNDERSTAND GENETICS Overview This appendix presents basic information about genetics in clear language and provides links to online resources.13

The Basics: Genes and How They Work This section gives you information on the basics of cells, DNA, genes, chromosomes, and proteins. What Is a Cell? Cells are the basic building blocks of all living things. The human body is composed of trillions of cells. They provide structure for the body, take in nutrients from food, convert those nutrients into energy, and carry out specialized functions. Cells also contain the body’s hereditary material and can make copies of themselves. Cells have many parts, each with a different function. Some of these parts, called organelles, are specialized structures that perform certain tasks within the cell. Human cells contain the following major parts, listed in alphabetical order: •

Cytoplasm: The cytoplasm is fluid inside the cell that surrounds the organelles.

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Endoplasmic reticulum (ER): This organelle helps process molecules created by the cell and transport them to their specific destinations either inside or outside the cell.

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Golgi apparatus: The golgi apparatus packages molecules processed by the endoplasmic reticulum to be transported out of the cell.

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Lysosomes and peroxisomes: These organelles are the recycling center of the cell. They digest foreign bacteria that invade the cell, rid the cell of toxic substances, and recycle worn-out cell components.

13 This appendix is an excerpt from the National Library of Medicine’s handbook, Help Me Understand Genetics. For the full text of the Help Me Understand Genetics handbook, see http://ghr.nlm.nih.gov/handbook.

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•

Mitochondria: Mitochondria are complex organelles that convert energy from food into a form that the cell can use. They have their own genetic material, separate from the DNA in the nucleus, and can make copies of themselves.

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Nucleus: The nucleus serves as the cell‘s command center, sending directions to the cell to grow, mature, divide, or die. It also houses DNA (deoxyribonucleic acid), the cell’s hereditary material. The nucleus is surrounded by a membrane called the nuclear envelope, which protects the DNA and separates the nucleus from the rest of the cell.

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Plasma membrane: The plasma membrane is the outer lining of the cell. It separates the cell from its environment and allows materials to enter and leave the cell.

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Ribosomes: Ribosomes are organelles that process the cell‘s genetic instructions to create proteins. These organelles can float freely in the cytoplasm or be connected to the endoplasmic reticulum. What Is DNA?

DNA, or deoxyribonucleic acid, is the hereditary material in humans and almost all other organisms. Nearly every cell in a person’s body has the same DNA. Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA). The information in DNA is stored as a code made up of four chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T). Human DNA consists of about 3 billion bases, and more than 99 percent of those bases are the same in all people. The order, or sequence, of these bases determines the information available for building and maintaining an organism, similar to the way in which letters of the alphabet appear in a certain order to form words and sentences. DNA bases pair up with each other, A with T and C with G, to form units called base pairs. Each base is also attached to a sugar molecule and a phosphate molecule. Together, a base, sugar, and phosphate are called a nucleotide. Nucleotides are arranged in two long strands that form a spiral called a double helix. The structure of the double helix is somewhat like a ladder, with the base pairs forming the ladder’s rungs and the sugar and phosphate molecules forming the vertical sidepieces of the ladder. An important property of DNA is that it can replicate, or make copies of itself. Each strand of DNA in the double helix can serve as a pattern for duplicating the sequence of bases. This is critical when cells divide because each new cell needs to have an exact copy of the DNA present in the old cell.

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DNA is a double helix formed by base pairs attached to a sugar-phosphate backbone. What Is Mitochondrial DNA? Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA. This genetic material is known as mitochondrial DNA or mtDNA. Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Each cell contains hundreds to thousands of mitochondria, which are located in the fluid that surrounds the nucleus (the cytoplasm). Mitochondria produce energy through a process called oxidative phosphorylation. This process uses oxygen and simple sugars to create adenosine triphosphate (ATP), the cell‘s main energy source. A set of enzyme complexes, designated as complexes I-V, carry out oxidative phosphorylation within mitochondria. In addition to energy production, mitochondria play a role in several other cellular activities. For example, mitochondria help regulate the self-destruction of cells (apoptosis). They are also necessary for the production of substances such as cholesterol and heme (a component of hemoglobin, the molecule that carries oxygen in the blood). Mitochondrial DNA contains 37 genes, all of which are essential for normal mitochondrial function. Thirteen of these genes provide instructions for making enzymes involved in oxidative phosphorylation. The remaining genes provide instructions for making molecules called transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), which are chemical cousins of

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DNA. These types of RNA help assemble protein building blocks (amino acids) into functioning proteins. What Is a Gene? A gene is the basic physical and functional unit of heredity. Genes, which are made up of DNA, act as instructions to make molecules called proteins. In humans, genes vary in size from a few hundred DNA bases to more than 2 million bases. The Human Genome Project has estimated that humans have between 20,000 and 25,000 genes. Every person has two copies of each gene, one inherited from each parent. Most genes are the same in all people, but a small number of genes (less than 1 percent of the total) are slightly different between people. Alleles are forms of the same gene with small differences in their sequence of DNA bases. These small differences contribute to each person’s unique physical features.

Genes are made up of DNA. Each chromosome contains many genes. What Is a Chromosome? In the nucleus of each cell, the DNA molecule is packaged into thread-like structures called chromosomes. Each chromosome is made up of DNA tightly coiled many times around proteins called histones that support its structure. Chromosomes are not visible in the cell‘s nucleus—not even under a microscope—when the cell is not dividing. However, the DNA that makes up chromosomes becomes more tightly packed during cell division and is then visible under a microscope. Most of what researchers know about chromosomes was learned by observing chromosomes during cell division. Each chromosome has a constriction point called the centromere, which divides the chromosome into two sections, or “arms.” The short arm of the chromosome is labeled the “p arm.” The long arm of the chromosome is labeled the “q arm.” The location of the centromere on each chromosome gives the chromosome its characteristic shape, and can be used to help describe the location of specific genes.

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DNA and histone proteins are packaged into structures called chromosomes. How Many Chromosomes Do People Have? In humans, each cell normally contains 23 pairs of chromosomes, for a total of 46. Twentytwo of these pairs, called autosomes, look the same in both males and females. The 23rd pair, the sex chromosomes, differ between males and females. Females have two copies of the X chromosome, while males have one X and one Y chromosome.

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The 22 autosomes are numbered by size. The other two chromosomes, X and Y, are the sex chromosomes. This picture of the human chromosomes lined up in pairs is called a karyotype. How Do Geneticists Indicate the Location of a Gene? Geneticists use maps to describe the location of a particular gene on a chromosome. One type of map uses the cytogenetic location to describe a gene’s position. The cytogenetic location is based on a distinctive pattern of bands created when chromosomes are stained with certain chemicals. Another type of map uses the molecular location, a precise description of a gene’s position on a chromosome. The molecular location is based on the sequence of DNA building blocks (base pairs) that make up the chromosome. Cytogenetic Location Geneticists use a standardized way of describing a gene‘s cytogenetic location. In most cases, the location describes the position of a particular band on a stained chromosome: 17q12 It can also be written as a range of bands, if less is known about the exact location: 17q12-q21 The combination of numbers and letters provide a gene‘s “address” on a chromosome. This address is made up of several parts: •

The chromosome on which the gene can be found. The first number or letter used to describe a gene’s location represents the chromosome. Chromosomes 1 through 22 (the autosomes) are designated by their chromosome number. The sex chromosomes are designated by X or Y.

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•

The arm of the chromosome. Each chromosome is divided into two sections (arms) based on the location of a narrowing (constriction) called the centromere. By convention, the shorter arm is called p, and the longer arm is called q. The chromosome arm is the second part of the gene‘s address. For example, 5q is the long arm of chromosome 5, and Xp is the short arm of the X chromosome.

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The position of the gene on the p or q arm. The position of a gene is based on a distinctive pattern of light and dark bands that appear when the chromosome is stained in a certain way. The position is usually designated by two digits (representing a region and a band), which are sometimes followed by a decimal point and one or more additional digits (representing sub-bands within a light or dark area). The number indicating the gene position increases with distance from the centromere. For example: 14q21 represents position 21 on the long arm of chromosome 14. 14q21 is closer to the centromere than 14q22.

Sometimes, the abbreviations “cen” or “ter” are also used to describe a gene‘s cytogenetic location. “Cen” indicates that the gene is very close to the centromere. For example, 16pcen refers to the short arm of chromosome 16 near the centromere. “Ter” stands for terminus, which indicates that the gene is very close to the end of the p or q arm. For example, 14qter refers to the tip of the long arm of chromosome 14. (“Tel” is also sometimes used to describe a gene’s location. “Tel” stands for telomeres, which are at the ends of each chromosome. The abbreviations “tel” and “ter” refer to the same location.)

The CFTR gene is located on the long arm of chromosome 7 at position 7q31.2.

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Molecular Location The Human Genome Project, an international research effort completed in 2003, determined the sequence of base pairs for each human chromosome. This sequence information allows researchers to provide a more specific address than the cytogenetic location for many genes. A gene‘s molecular address pinpoints the location of that gene in terms of base pairs. For example, the molecular location of the APOE gene on chromosome 19 begins with base pair 50,100,901 and ends with base pair 50,104,488. This range describes the gene’s precise position on chromosome 19 and indicates the size of the gene (3,588 base pairs). Knowing a gene’s molecular location also allows researchers to determine exactly how far the gene is from other genes on the same chromosome. Different groups of researchers often present slightly different values for a gene‘s molecular location. Researchers interpret the sequence of the human genome using a variety of methods, which can result in small differences in a gene’s molecular address. For example, the National Center for Biotechnology Information (NCBI) identifies the molecular location of the APOE gene as base pair 50,100,901 to base pair 50,104,488 on chromosome 19. The Ensembl database identifies the location of this gene as base pair 50,100,879 to base pair 50,104,489 on chromosome 19. Neither of these addresses is incorrect; they represent different interpretations of the same data. For consistency, Genetics Home Reference presents data from NCBI for the molecular location of genes. What Are Proteins and What Do They Do? Proteins are large, complex molecules that play many critical roles in the body. They do most of the work in cells and are required for the structure, function, and regulation of the body’s tissues and organs. Proteins are made up of hundreds or thousands of smaller units called amino acids, which are attached to one another in long chains. There are 20 different types of amino acids that can be combined to make a protein. The sequence of amino acids determines each protein’s unique 3-dimensional structure and its specific function.

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Examples of Protein Functions Proteins can be described according to their large range of functions in the body, listed in alphabetical order: Function Antibody

Description Antibodies bind to specific foreign particles, such as viruses and bacteria, to help protect the body.

Example Immunoglobulin G (IgG)

Enzyme

Enzymes carry out almost all of the thousands of chemical reactions that take place in cells. They also assist with the formation of new molecules by reading the genetic information stored in DNA.

Phenylalanine hydroxylase

Messenger

Messenger proteins, such as some types of hormones, transmit signals to coordinate biological processes between different cells, tissues, and organs.

Growth hormone

Structural component

These proteins provide structure and support for cells. On a larger scale, they also allow the body to move. These proteins bind and carry atoms and small molecules within cells and throughout the body.

Actin

Transport/storage

Ferritin

How Does a Gene Make a Protein? Most genes contain the information needed to make functional molecules called proteins. (A few genes produce other molecules that help the cell assemble proteins.) The journey from gene to protein is complex and tightly controlled within each cell. It consists of two major steps: transcription and translation. Together, transcription and translation are known as gene expression. During the process of transcription, the information stored in a gene‘s DNA is transferred to a similar molecule called RNA (ribonucleic acid) in the cell nucleus. Both RNA and DNA are made up of a chain of nucleotide bases, but they have slightly different chemical properties. The type of RNA that contains the information for making a protein is called messenger RNA (mRNA) because it carries the information, or message, from the DNA out of the nucleus into the cytoplasm. Translation, the second step in getting from a gene to a protein, takes place in the cytoplasm. The mRNA interacts with a specialized complex called a ribosome, which “reads” the sequence of mRNA bases. Each sequence of three bases, called a codon, usually codes for

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one particular amino acid. (Amino acids are the building blocks of proteins.) A type of RNA called transfer RNA (tRNA) assembles the protein, one amino acid at a time. Protein assembly continues until the ribosome encounters a “stop” codon (a sequence of three bases that does not code for an amino acid). The flow of information from DNA to RNA to proteins is one of the fundamental principles of molecular biology. It is so important that it is sometimes called the “central dogma.”

Through the processes of transcription and translation, information from genes is used to make proteins.

Can Genes Be Turned On and Off in Cells? Each cell expresses, or turns on, only a fraction of its genes. The rest of the genes are repressed, or turned off. The process of turning genes on and off is known as gene regulation. Gene regulation is an important part of normal development. Genes are turned on and off in different patterns during development to make a brain cell look and act different from a liver cell or a muscle cell, for example. Gene regulation also allows cells to react quickly to changes in their environments. Although we know that the regulation of genes is critical for life, this complex process is not yet fully understood. Gene regulation can occur at any point during gene expression, but most commonly occurs at the level of transcription (when the information in a gene’s DNA is transferred to mRNA). Signals from the environment or from other cells activate proteins called transcription factors. These proteins bind to regulatory regions of a gene and increase or decrease the level of transcription. By controlling the level of transcription, this process can determine the amount of protein product that is made by a gene at any given time.

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How Do Cells Divide? There are two types of cell division: mitosis and meiosis. Most of the time when people refer to “cell division,” they mean mitosis, the process of making new body cells. Meiosis is the type of cell division that creates egg and sperm cells. Mitosis is a fundamental process for life. During mitosis, a cell duplicates all of its contents, including its chromosomes, and splits to form two identical daughter cells. Because this process is so critical, the steps of mitosis are carefully controlled by a number of genes. When mitosis is not regulated correctly, health problems such as cancer can result. The other type of cell division, meiosis, ensures that humans have the same number of chromosomes in each generation. It is a two-step process that reduces the chromosome number by half—from 46 to 23—to form sperm and egg cells. When the sperm and egg cells unite at conception, each contributes 23 chromosomes so the resulting embryo will have the usual 46. Meiosis also allows genetic variation through a process of DNA shuffling while the cells are dividing.

Mitosis and meiosis, the two types of cell division. How Do Genes Control the Growth and Division of Cells? A variety of genes are involved in the control of cell growth and division. The cell cycle is the cell’s way of replicating itself in an organized, step-by-step fashion. Tight regulation of this process ensures that a dividing cell’s DNA is copied properly, any errors in the DNA are repaired, and each daughter cell receives a full set of chromosomes. The cycle has checkpoints (also called restriction points), which allow certain genes to check for mistakes and halt the cycle for repairs if something goes wrong.

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If a cell has an error in its DNA that cannot be repaired, it may undergo programmed cell death (apoptosis). Apoptosis is a common process throughout life that helps the body get rid of cells it doesn’t need. Cells that undergo apoptosis break apart and are recycled by a type of white blood cell called a macrophage. Apoptosis protects the body by removing genetically damaged cells that could lead to cancer, and it plays an important role in the development of the embryo and the maintenance of adult tissues. Cancer results from a disruption of the normal regulation of the cell cycle. When the cycle proceeds without control, cells can divide without order and accumulate genetic defects that can lead to a cancerous tumor.

Genetic Mutations and Health This section presents basic information about gene mutations, chromosomal changes, and conditions that run in families.14 What Is a Gene Mutation and How Do Mutations Occur? A gene mutation is a permanent change in the DNA sequence that makes up a gene. Mutations range in size from a single DNA building block (DNA base) to a large segment of a chromosome. Gene mutations occur in two ways: they can be inherited from a parent or acquired during a person’s lifetime. Mutations that are passed from parent to child are called hereditary mutations or germline mutations (because they are present in the egg and sperm cells, which are also called germ cells). This type of mutation is present throughout a person’s life in virtually every cell in the body. Mutations that occur only in an egg or sperm cell, or those that occur just after fertilization, are called new (de novo) mutations. De novo mutations may explain genetic disorders in which an affected child has a mutation in every cell, but has no family history of the disorder. Acquired (or somatic) mutations occur in the DNA of individual cells at some time during a person’s life. These changes can be caused by environmental factors such as ultraviolet radiation from the sun, or can occur if a mistake is made as DNA copies itself during cell division. Acquired mutations in somatic cells (cells other than sperm and egg cells) cannot be passed on to the next generation. Mutations may also occur in a single cell within an early embryo. As all the cells divide during growth and development, the individual will have some cells with the mutation and some cells without the genetic change. This situation is called mosaicism. Some genetic changes are very rare; others are common in the population. Genetic changes that occur in more than 1 percent of the population are called polymorphisms. They are common enough to be considered a normal variation in the DNA. Polymorphisms are 14

This section has been adapted from the National Library of Medicine’s handbook, Help Me Understand Genetics, which presents basic information about genetics in clear language and provides links to online resources: http://ghr.nlm.nih.gov/handbook.

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responsible for many of the normal differences between people such as eye color, hair color, and blood type. Although many polymorphisms have no negative effects on a person’s health, some of these variations may influence the risk of developing certain disorders. How Can Gene Mutations Affect Health and Development? To function correctly, each cell depends on thousands of proteins to do their jobs in the right places at the right times. Sometimes, gene mutations prevent one or more of these proteins from working properly. By changing a gene’s instructions for making a protein, a mutation can cause the protein to malfunction or to be missing entirely. When a mutation alters a protein that plays a critical role in the body, it can disrupt normal development or cause a medical condition. A condition caused by mutations in one or more genes is called a genetic disorder. In some cases, gene mutations are so severe that they prevent an embryo from surviving until birth. These changes occur in genes that are essential for development, and often disrupt the development of an embryo in its earliest stages. Because these mutations have very serious effects, they are incompatible with life. It is important to note that genes themselves do not cause disease—genetic disorders are caused by mutations that make a gene function improperly. For example, when people say that someone has “the cystic fibrosis gene,” they are usually referring to a mutated version of the CFTR gene, which causes the disease. All people, including those without cystic fibrosis, have a version of the CFTR gene. Do All Gene Mutations Affect Health and Development? No, only a small percentage of mutations cause genetic disorders—most have no impact on health or development. For example, some mutations alter a gene‘s DNA base sequence but do not change the function of the protein made by the gene. Often, gene mutations that could cause a genetic disorder are repaired by certain enzymes before the gene is expressed (makes a protein). Each cell has a number of pathways through which enzymes recognize and repair mistakes in DNA. Because DNA can be damaged or mutated in many ways, DNA repair is an important process by which the body protects itself from disease. A very small percentage of all mutations actually have a positive effect. These mutations lead to new versions of proteins that help an organism and its future generations better adapt to changes in their environment. For example, a beneficial mutation could result in a protein that protects the organism from a new strain of bacteria. For More Information about DNA Repair and the Health Effects of Gene Mutations •

The University of Utah Genetic Science Learning Center provides information about genetic disorders that explains why some mutations cause disorders but others do not. (Refer to the questions in the far right column.) See http://learn.genetics.utah.edu/units/disorders/whataregd/.

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Additional information about DNA repair is available from the NCBI Science Primer. In the chapter called “What Is A Cell?”, scroll down to the heading “DNA Repair Mechanisms.” See http://www.ncbi.nlm.nih.gov/About/primer/genetics_cell.html. What Kinds of Gene Mutations Are Possible?

The DNA sequence of a gene can be altered in a number of ways. Gene mutations have varying effects on health, depending on where they occur and whether they alter the function of essential proteins. The types of mutations include: •

Missense mutation: This type of mutation is a change in one DNA base pair that results in the substitution of one amino acid for another in the protein made by a gene.

•

Nonsense mutation: A nonsense mutation is also a change in one DNA base pair. Instead of substituting one amino acid for another, however, the altered DNA sequence prematurely signals the cell to stop building a protein. This type of mutation results in a shortened protein that may function improperly or not at all.

•

Insertion: An insertion changes the number of DNA bases in a gene by adding a piece of DNA. As a result, the protein made by the gene may not function properly.

•

Deletion: A deletion changes the number of DNA bases by removing a piece of DNA. Small deletions may remove one or a few base pairs within a gene, while larger deletions can remove an entire gene or several neighboring genes. The deleted DNA may alter the function of the resulting protein(s).

•

Duplication: A duplication consists of a piece of DNA that is abnormally copied one or more times. This type of mutation may alter the function of the resulting protein.

•

Frameshift mutation: This type of mutation occurs when the addition or loss of DNA bases changes a gene‘s reading frame. A reading frame consists of groups of 3 bases that each code for one amino acid. A frameshift mutation shifts the grouping of these bases and changes the code for amino acids. The resulting protein is usually nonfunctional. Insertions, deletions, and duplications can all be frameshift mutations.

•

Repeat expansion: Nucleotide repeats are short DNA sequences that are repeated a number of times in a row. For example, a trinucleotide repeat is made up of 3-base-pair sequences, and a tetranucleotide repeat is made up of 4-base-pair sequences. A repeat expansion is a mutation that increases the number of times that the short DNA sequence is repeated. This type of mutation can cause the resulting protein to function improperly. Can Changes in Chromosomes Affect Health and Development?

Changes that affect entire chromosomes or segments of chromosomes can cause problems with growth, development, and function of the body’s systems. These changes can affect many genes along the chromosome and alter the proteins made by those genes. Conditions caused by a change in the number or structure of chromosomes are known as chromosomal disorders. Human cells normally contain 23 pairs of chromosomes, for a total of 46 chromosomes in each cell. A change in the number of chromosomes leads to a chromosomal disorder. These changes can occur during the formation of reproductive cells (eggs and sperm) or in early fetal development. A gain or loss of chromosomes from the normal 46 is called aneuploidy.

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The most common form of aneuploidy is trisomy, or the presence of an extra chromosome in each cell. “Tri-” is Greek for “three”; people with trisomy have three copies of a particular chromosome in each cell instead of the normal two copies. Down syndrome is an example of a condition caused by trisomy—people with Down syndrome typically have three copies of chromosome 21 in each cell, for a total of 47 chromosomes per cell. Monosomy, or the loss of one chromosome from each cell, is another kind of aneuploidy. “Mono-” is Greek for “one”; people with monosomy have one copy of a particular chromosome in each cell instead of the normal two copies. Turner syndrome is a condition caused by monosomy. Women with Turner syndrome are often missing one copy of the X chromosome in every cell, for a total of 45 chromosomes per cell. Chromosomal disorders can also be caused by changes in chromosome structure. These changes are caused by the breakage and reunion of chromosome segments when an egg or sperm cell is formed or in early fetal development. Pieces of DNA can be rearranged within one chromosome, or transferred between two or more chromosomes. The effects of structural changes depend on their size and location. Many different structural changes are possible; some cause medical problems, while others may have no effect on a person’s health. Many cancer cells also have changes in their chromosome number or structure. These changes most often occur in somatic cells (cells other than eggs and sperm) during a person’s lifetime. Can Changes in Mitochondrial DNA Affect Health and Development? Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA (known as mitochondrial DNA or mtDNA). In some cases, inherited changes in mitochondrial DNA can cause problems with growth, development, and function of the body’s systems. These mutations disrupt the mitochondria’s ability to generate energy efficiently for the cell. Conditions caused by mutations in mitochondrial DNA often involve multiple organ systems. The effects of these conditions are most pronounced in organs and tissues that require a lot of energy (such as the heart, brain, and muscles). Although the health consequences of inherited mitochondrial DNA mutations vary widely, frequently observed features include muscle weakness and wasting, problems with movement, diabetes, kidney failure, heart disease, loss of intellectual functions (dementia), hearing loss, and abnormalities involving the eyes and vision. Mitochondrial DNA is also prone to noninherited (somatic) mutations. Somatic mutations occur in the DNA of certain cells during a person’s lifetime, and typically are not passed to future generations. Because mitochondrial DNA has a limited ability to repair itself when it is damaged, these mutations tend to build up over time. A buildup of somatic mutations in mitochondrial DNA has been associated with some forms of cancer and an increased risk of certain age-related disorders such as heart disease, Alzheimer disease, and Parkinson disease. Additionally, research suggests that the progressive accumulation of these mutations over a person’s lifetime may play a role in the normal process of aging.

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What Are Complex or Multifactorial Disorders? Researchers are learning that nearly all conditions and diseases have a genetic component. Some disorders, such as sickle cell anemia and cystic fibrosis, are caused by mutations in a single gene. The causes of many other disorders, however, are much more complex. Common medical problems such as heart disease, diabetes, and obesity do not have a single genetic cause—they are likely associated with the effects of multiple genes in combination with lifestyle and environmental factors. Conditions caused by many contributing factors are called complex or multifactorial disorders. Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a person’s risk of inheriting or passing on these disorders. Complex disorders are also difficult to study and treat because the specific factors that cause most of these disorders have not yet been identified. By 2010, however, researchers predict they will have found the major contributing genes for many common complex disorders. What Information about a Genetic Condition Can Statistics Provide? Statistical data can provide general information about how common a condition is, how many people have the condition, or how likely it is that a person will develop the condition. Statistics are not personalized, however—they offer estimates based on groups of people. By taking into account a person’s family history, medical history, and other factors, a genetics professional can help interpret what statistics mean for a particular patient. Common Statistical Terms Some statistical terms are commonly used when describing genetic conditions and other disorders. These terms include: Statistical Term Incidence

Description The incidence of a gene mutation or a genetic disorder is the number of people who are born with the mutation or disorder in a specified group per year. Incidence is often written in the form “1 in [a number]” or as a total number of live births.

Examples About 1 in 200,000 people in the United States are born with syndrome A each year. An estimated 15,000 infants with syndrome B were born last year worldwide.

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Prevalence

The prevalence of a gene mutation or a genetic disorder is the total number of people in a specified group at a given time who have the mutation or disorder. This term includes both newly diagnosed and preexisting cases in people of any age. Prevalence is often written in the form “1 in [a number]” or as a total number of people who have a condition.

Approximately 1 in 100,000 people in the United States have syndrome A at the present time. About 100,000 children worldwide currently have syndrome B.

Mortality

Mortality is the number of deaths from a particular disorder occurring in a specified group per year. Mortality is usually expressed as a total number of deaths.

An estimated 12,000 people worldwide died from syndrome C in 2002.

Lifetime risk

Lifetime risk is the average risk of developing a particular disorder at some point during a lifetime. Lifetime risk is often written as a percentage or as “1 in [a number].” It is important to remember that the risk per year or per decade is much lower than the lifetime risk. In addition, other factors may increase or decrease a person’s risk as compared with the average.

Approximately 1 percent of people in the United States develop disorder D during their lifetimes. The lifetime risk of developing disorder D is 1 in 100.

Naming Genetic Conditions Genetic conditions are not named in one standard way (unlike genes, which are given an official name and symbol by a formal committee). Doctors who treat families with a particular disorder are often the first to propose a name for the condition. Expert working groups may later revise the name to improve its usefulness. Naming is important because it allows accurate and effective communication about particular conditions, which will ultimately help researchers find new approaches to treatment. Disorder names are often derived from one or a combination of sources: •

The basic genetic or biochemical defect that causes the condition (for example, alpha-1 antitrypsin deficiency)

•

One or more major signs or symptoms of the disorder (for example, sickle cell anemia)

•

The parts of the body affected by the condition (for example, retinoblastoma)

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•

The name of a physician or researcher, often the first person to describe the disorder (for example, Marfan syndrome, which was named after Dr. Antoine Bernard-Jean Marfan)

•

A geographic area (for example, familial Mediterranean fever, which occurs mainly in populations bordering the Mediterranean Sea)

•

The name of a patient or family with the condition (for example, amyotrophic lateral sclerosis, which is also called Lou Gehrig disease after a famous baseball player who had the condition).

Disorders named after a specific person or place are called eponyms. There is debate as to whether the possessive form (e.g., Alzheimer’s disease) or the nonpossessive form (Alzheimer disease) of eponyms is preferred. As a rule, medical geneticists use the nonpossessive form, and this form may become the standard for doctors in all fields of medicine. Genetics Home Reference uses the nonpossessive form of eponyms. Genetics Home Reference consults with experts in the field of medical genetics to provide the current, most accurate name for each disorder. Alternate names are included as synonyms. Naming genes The HUGO Gene Nomenclature Committee (HGNC) designates an official name and symbol (an abbreviation of the name) for each known human gene. Some official gene names include additional information in parentheses, such as related genetic conditions, subtypes of a condition, or inheritance pattern. The HGNC is a non-profit organization funded by the U.K. Medical Research Council and the U.S. National Institutes of Health. The Committee has named more than 13,000 of the estimated 20,000 to 25,000 genes in the human genome. During the research process, genes often acquire several alternate names and symbols. Different researchers investigating the same gene may each give the gene a different name, which can cause confusion. The HGNC assigns a unique name and symbol to each human gene, which allows effective organization of genes in large databanks, aiding the advancement of research. For specific information about how genes are named, refer to the HGNC’s Guidelines for Human Gene Nomenclature. Genetics Home Reference describes genes using the HGNC’s official gene names and gene symbols. Genetics Home Reference frequently presents the symbol and name separated with a colon (for example, FGFR4: Fibroblast growth factor receptor 4).

Inheriting Genetic Conditions This section gives you information on inheritance patterns and understanding risk. What Does It Mean If a Disorder Seems to Run in My Family? A particular disorder might be described as “running in a family” if more than one person in the family has the condition. Some disorders that affect multiple family members are caused by gene mutations, which can be inherited (passed down from parent to child). Other conditions that appear to run in families are not inherited. Instead, environmental factors

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such as dietary habits or a combination of genetic and environmental factors are responsible for these disorders. It is not always easy to determine whether a condition in a family is inherited. A genetics professional can use a person’s family history (a record of health information about a person’s immediate and extended family) to help determine whether a disorder has a genetic component.

Some disorders are seen in more than one generation of a family. Why Is It Important to Know My Family Medical History? A family medical history is a record of health information about a person and his or her close relatives. A complete record includes information from three generations of relatives,

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including children, brothers and sisters, parents, aunts and uncles, nieces and nephews, grandparents, and cousins. Families have many factors in common, including their genes, environment, and lifestyle. Together, these factors can give clues to medical conditions that may run in a family. By noticing patterns of disorders among relatives, healthcare professionals can determine whether an individual, other family members, or future generations may be at an increased risk of developing a particular condition. A family medical history can identify people with a higher-than-usual chance of having common disorders, such as heart disease, high blood pressure, stroke, certain cancers, and diabetes. These complex disorders are influenced by a combination of genetic factors, environmental conditions, and lifestyle choices. A family history also can provide information about the risk of rarer conditions caused by mutations in a single gene, such as cystic fibrosis and sickle cell anemia. While a family medical history provides information about the risk of specific health concerns, having relatives with a medical condition does not mean that an individual will definitely develop that condition. On the other hand, a person with no family history of a disorder may still be at risk of developing that disorder. Knowing one’s family medical history allows a person to take steps to reduce his or her risk. For people at an increased risk of certain cancers, healthcare professionals may recommend more frequent screening (such as mammography or colonoscopy) starting at an earlier age. Healthcare providers may also encourage regular checkups or testing for people with a medical condition that runs in their family. Additionally, lifestyle changes such as adopting a healthier diet, getting regular exercise, and quitting smoking help many people lower their chances of developing heart disease and other common illnesses. The easiest way to get information about family medical history is to talk to relatives about their health. Have they had any medical problems, and when did they occur? A family gathering could be a good time to discuss these issues. Additionally, obtaining medical records and other documents (such as obituaries and death certificates) can help complete a family medical history. It is important to keep this information up-to-date and to share it with a healthcare professional regularly. What Are the Different Ways in which a Genetic Condition Can Be Inherited? Some genetic conditions are caused by mutations in a single gene. These conditions are usually inherited in one of several straightforward patterns, depending on the gene involved: Inheritance Pattern Autosomal dominant

Description One mutated copy of the gene in each cell is sufficient for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent. Autosomal dominant disorders tend to occur in every generation of an affected family.

Examples Huntington disease, neurofibromatosis type 1

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Autosomal recessive

Two mutated copies of the gene are present in each cell when a person has an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene (and are referred to as carriers). Autosomal recessive disorders are typically not seen in every generation of an affected family.

cystic fibrosis, sickle cell anemia

X-linked dominant

X-linked dominant disorders are caused by mutations in genes on the X chromosome. Females are more frequently affected than males, and the chance of passing on an X-linked dominant disorder differs between men and women. Families with an X-linked dominant disorder often have both affected males and affected females in each generation. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission).

fragile X syndrome

X-linked recessive

X-linked recessive disorders are also caused by mutations in genes on the X chromosome. Males are more frequently affected than females, and the chance of passing on the disorder differs between men and women. Families with an X-linked recessive disorder often have affected males, but rarely affected females, in each generation. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission).

hemophilia, Fabry disease

Codominant

In codominant inheritance, two different versions (alleles) of a gene can be expressed, and each version makes a slightly different protein. Both alleles influence the genetic trait or determine the characteristics of the genetic condition.

ABO blood group, alpha-1 antitrypsin deficiency

Mitochondrial

This type of inheritance, also known as maternal inheritance, applies to genes in mitochondrial DNA. Mitochondria, which are structures in each cell that convert molecules into energy, each contain a small amount of DNA. Because only egg cells contribute mitochondria to the developing embryo, only females can pass on mitochondrial conditions to their children. Mitochondrial disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass mitochondrial traits to their children.

Leber hereditary optic neuropathy (LHON)

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Many other disorders are caused by a combination of the effects of multiple genes or by interactions between genes and the environment. Such disorders are more difficult to analyze because their genetic causes are often unclear, and they do not follow the patterns of inheritance described above. Examples of conditions caused by multiple genes or gene/environment interactions include heart disease, diabetes, schizophrenia, and certain types of cancer. Disorders caused by changes in the number or structure of chromosomes do not follow the straightforward patterns of inheritance listed above. Other genetic factors can also influence how a disorder is inherited. If a Genetic Disorder Runs in My Family, What Are the Chances That My Children Will Have the Condition? When a genetic disorder is diagnosed in a family, family members often want to know the likelihood that they or their children will develop the condition. This can be difficult to predict in some cases because many factors influence a person’s chances of developing a genetic condition. One important factor is how the condition is inherited. For example: •

Autosomal dominant inheritance: A person affected by an autosomal dominant disorder has a 50 percent chance of passing the mutated gene to each child. The chance that a child will not inherit the mutated gene is also 50 percent.

•

Autosomal recessive inheritance: Two unaffected people who each carry one copy of the mutated gene for an autosomal recessive disorder (carriers) have a 25 percent chance with each pregnancy of having a child affected by the disorder. The chance with each pregnancy of having an unaffected child who is a carrier of the disorder is 50 percent, and the chance that a child will not have the disorder and will not be a carrier is 25 percent.

•

X-linked dominant inheritance: The chance of passing on an X-linked dominant condition differs between men and women because men have one X chromosome and one Y chromosome, while women have two X chromosomes. A man passes on his Y chromosome to all of his sons and his X chromosome to all of his daughters. Therefore, the sons of a man with an X-linked dominant disorder will not be affected, but all of his daughters will inherit the condition. A woman passes on one or the other of her X chromosomes to each child. Therefore, a woman with an X-linked dominant disorder has a 50 percent chance of having an affected daughter or son with each pregnancy.

•

X-linked recessive inheritance: Because of the difference in sex chromosomes, the probability of passing on an X-linked recessive disorder also differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected, and his daughters will carry one copy of the mutated gene. With each pregnancy, a woman who carries an X-linked recessive disorder has a 50 percent chance of having sons who are affected and a 50 percent chance of having daughters who carry one copy of the mutated gene.

•

Codominant inheritance: In codominant inheritance, each parent contributes a different version of a particular gene, and both versions influence the resulting genetic trait. The chance of developing a genetic condition with codominant inheritance, and the characteristic features of that condition, depend on which versions of the gene are passed from parents to their child.

•

Mitochondrial inheritance: Mitochondria, which are the energy-producing centers inside cells, each contain a small amount of DNA. Disorders with mitochondrial inheritance result from mutations in mitochondrial DNA. Although mitochondrial

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disorders can affect both males and females, only females can pass mutations in mitochondrial DNA to their children. A woman with a disorder caused by changes in mitochondrial DNA will pass the mutation to all of her daughters and sons, but the children of a man with such a disorder will not inherit the mutation. It is important to note that the chance of passing on a genetic condition applies equally to each pregnancy. For example, if a couple has a child with an autosomal recessive disorder, the chance of having another child with the disorder is still 25 percent (or 1 in 4). Having one child with a disorder does not “protect” future children from inheriting the condition. Conversely, having a child without the condition does not mean that future children will definitely be affected. Although the chances of inheriting a genetic condition appear straightforward, factors such as a person’s family history and the results of genetic testing can sometimes modify those chances. In addition, some people with a disease-causing mutation never develop any health problems or may experience only mild symptoms of the disorder. If a disease that runs in a family does not have a clear-cut inheritance pattern, predicting the likelihood that a person will develop the condition can be particularly difficult. Estimating the chance of developing or passing on a genetic disorder can be complex. Genetics professionals can help people understand these chances and help them make informed decisions about their health. Factors that Influence the Effects of Particular Genetic Changes Reduced penetrance and variable expressivity are factors that influence the effects of particular genetic changes. These factors usually affect disorders that have an autosomal dominant pattern of inheritance, although they are occasionally seen in disorders with an autosomal recessive inheritance pattern. Reduced Penetrance Penetrance refers to the proportion of people with a particular genetic change (such as a mutation in a specific gene) who exhibit signs and symptoms of a genetic disorder. If some people with the mutation do not develop features of the disorder, the condition is said to have reduced (or incomplete) penetrance. Reduced penetrance often occurs with familial cancer syndromes. For example, many people with a mutation in the BRCA1 or BRCA2 gene will develop cancer during their lifetime, but some people will not. Doctors cannot predict which people with these mutations will develop cancer or when the tumors will develop. Reduced penetrance probably results from a combination of genetic, environmental, and lifestyle factors, many of which are unknown. This phenomenon can make it challenging for genetics professionals to interpret a person’s family medical history and predict the risk of passing a genetic condition to future generations. Variable Expressivity Although some genetic disorders exhibit little variation, most have signs and symptoms that differ among affected individuals. Variable expressivity refers to the range of signs and

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symptoms that can occur in different people with the same genetic condition. For example, the features of Marfan syndrome vary widely— some people have only mild symptoms (such as being tall and thin with long, slender fingers), while others also experience lifethreatening complications involving the heart and blood vessels. Although the features are highly variable, most people with this disorder have a mutation in the same gene (FBN1). As with reduced penetrance, variable expressivity is probably caused by a combination of genetic, environmental, and lifestyle factors, most of which have not been identified. If a genetic condition has highly variable signs and symptoms, it may be challenging to diagnose. What Do Geneticists Mean by Anticipation? The signs and symptoms of some genetic conditions tend to become more severe and appear at an earlier age as the disorder is passed from one generation to the next. This phenomenon is called anticipation. Anticipation is most often seen with certain genetic disorders of the nervous system, such as Huntington disease, myotonic dystrophy, and fragile X syndrome. Anticipation typically occurs with disorders that are caused by an unusual type of mutation called a trinucleotide repeat expansion. A trinucleotide repeat is a sequence of three DNA building blocks (nucleotides) that is repeated a number of times in a row. DNA segments with an abnormal number of these repeats are unstable and prone to errors during cell division. The number of repeats can change as the gene is passed from parent to child. If the number of repeats increases, it is known as a trinucleotide repeat expansion. In some cases, the trinucleotide repeat may expand until the gene stops functioning normally. This expansion causes the features of some disorders to become more severe with each successive generation. Most genetic disorders have signs and symptoms that differ among affected individuals, including affected people in the same family. Not all of these differences can be explained by anticipation. A combination of genetic, environmental, and lifestyle factors is probably responsible for the variability, although many of these factors have not been identified. Researchers study multiple generations of affected family members and consider the genetic cause of a disorder before determining that it shows anticipation. What Is Genomic Imprinting? Genomic imprinting is a factor that influences how some genetic conditions are inherited. People inherit two copies of their genes—one from their mother and one from their father. Usually both copies of each gene are active, or “turned on,” in cells. In some cases, however, only one of the two copies is normally turned on. Which copy is active depends on the parent of origin: some genes are normally active only when they are inherited from a person’s father; others are active only when inherited from a person’s mother. This phenomenon is known as genomic imprinting. In genes that undergo genomic imprinting, the parent of origin is often marked, or “stamped,” on the gene during the formation of egg and sperm cells. This stamping process, called methylation, is a chemical reaction that attaches small molecules called methyl groups to certain segments of DNA. These molecules identify which copy of a gene was inherited

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from the mother and which was inherited from the father. The addition and removal of methyl groups can be used to control the activity of genes. Only a small percentage of all human genes undergo genomic imprinting. Researchers are not yet certain why some genes are imprinted and others are not. They do know that imprinted genes tend to cluster together in the same regions of chromosomes. Two major clusters of imprinted genes have been identified in humans, one on the short (p) arm of chromosome 11 (at position 11p15) and another on the long (q) arm of chromosome 15 (in the region 15q11 to 15q13). What Is Uniparental Disomy? Uniparental disomy is a factor that influences how some genetic conditions are inherited. Uniparental disomy (UPD) occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent. UPD can occur as a random event during the formation of egg or sperm cells or may happen in early fetal development. In many cases, UPD likely has no effect on health or development. Because most genes are not imprinted, it doesn’t matter if a person inherits both copies from one parent instead of one copy from each parent. In some cases, however, it does make a difference whether a gene is inherited from a person’s mother or father. A person with UPD may lack any active copies of essential genes that undergo genomic imprinting. This loss of gene function can lead to delayed development, mental retardation, or other medical problems. Several genetic disorders can result from UPD or a disruption of normal genomic imprinting. The most well-known conditions include Prader-Willi syndrome, which is characterized by uncontrolled eating and obesity, and Angelman syndrome, which causes mental retardation and impaired speech. Both of these disorders can be caused by UPD or other errors in imprinting involving genes on the long arm of chromosome 15. Other conditions, such as Beckwith-Wiedemann syndrome (a disorder characterized by accelerated growth and an increased risk of cancerous tumors), are associated with abnormalities of imprinted genes on the short arm of chromosome 11. Are Chromosomal Disorders Inherited? Although it is possible to inherit some types of chromosomal abnormalities, most chromosomal disorders (such as Down syndrome and Turner syndrome) are not passed from one generation to the next. Some chromosomal conditions are caused by changes in the number of chromosomes. These changes are not inherited, but occur as random events during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction results in reproductive cells with an abnormal number of chromosomes. For example, a reproductive cell may accidentally gain or lose one copy of a chromosome. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have an extra or missing chromosome in each of the body’s cells.

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Changes in chromosome structure can also cause chromosomal disorders. Some changes in chromosome structure can be inherited, while others occur as random accidents during the formation of reproductive cells or in early fetal development. Because the inheritance of these changes can be complex, people concerned about this type of chromosomal abnormality may want to talk with a genetics professional. Some cancer cells also have changes in the number or structure of their chromosomes. Because these changes occur in somatic cells (cells other than eggs and sperm), they cannot be passed from one generation to the next. Why Are Some Genetic Conditions More Common in Particular Ethnic Groups? Some genetic disorders are more likely to occur among people who trace their ancestry to a particular geographic area. People in an ethnic group often share certain versions of their genes, which have been passed down from common ancestors. If one of these shared genes contains a disease-causing mutation, a particular genetic disorder may be more frequently seen in the group. Examples of genetic conditions that are more common in particular ethnic groups are sickle cell anemia, which is more common in people of African, African-American, or Mediterranean heritage; and Tay-Sachs disease, which is more likely to occur among people of Ashkenazi (eastern and central European) Jewish or French Canadian ancestry. It is important to note, however, that these disorders can occur in any ethnic group.

Genetic Consultation This section presents information on finding and visiting a genetic counselor or other genetics professional. What Is a Genetic Consultation? A genetic consultation is a health service that provides information and support to people who have, or may be at risk for, genetic disorders. During a consultation, a genetics professional meets with an individual or family to discuss genetic risks or to diagnose, confirm, or rule out a genetic condition. Genetics professionals include medical geneticists (doctors who specialize in genetics) and genetic counselors (certified healthcare workers with experience in medical genetics and counseling). Other healthcare professionals such as nurses, psychologists, and social workers trained in genetics can also provide genetic consultations. Consultations usually take place in a doctor’s office, hospital, genetics center, or other type of medical center. These meetings are most often in-person visits with individuals or families, but they are occasionally conducted in a group or over the telephone.

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Why Might Someone Have a Genetic Consultation? Individuals or families who are concerned about an inherited condition may benefit from a genetic consultation. The reasons that a person might be referred to a genetic counselor, medical geneticist, or other genetics professional include: •

A personal or family history of a genetic condition, birth defect, chromosomal disorder, or hereditary cancer.

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Two or more pregnancy losses (miscarriages), a stillbirth, or a baby who died.

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A child with a known inherited disorder, a birth defect, mental retardation, or developmental delay.

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A woman who is pregnant or plans to become pregnant at or after age 35. (Some chromosomal disorders occur more frequently in children born to older women.)

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Abnormal test results that suggest a genetic or chromosomal condition.

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An increased risk of developing or passing on a particular genetic disorder on the basis of a person’s ethnic background.

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People related by blood (for example, cousins) who plan to have children together. (A child whose parents are related may be at an increased risk of inheriting certain genetic disorders.)

A genetic consultation is also an important part of the decision-making process for genetic testing. A visit with a genetics professional may be helpful even if testing is not available for a specific condition, however. What Happens during a Genetic Consultation? A genetic consultation provides information, offers support, and addresses a patient’s specific questions and concerns. To help determine whether a condition has a genetic component, a genetics professional asks about a person’s medical history and takes a detailed family history (a record of health information about a person’s immediate and extended family). The genetics professional may also perform a physical examination and recommend appropriate tests. If a person is diagnosed with a genetic condition, the genetics professional provides information about the diagnosis, how the condition is inherited, the chance of passing the condition to future generations, and the options for testing and treatment. During a consultation, a genetics professional will: •

Interpret and communicate complex medical information.

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Help each person make informed, independent decisions about their health care and reproductive options.

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Respect each person’s individual beliefs, traditions, and feelings.

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Tell a person which decision to make.

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Advise a couple not to have children.

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Recommend that a woman continue or end a pregnancy.

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Tell someone whether to undergo testing for a genetic disorder. How Can I Find a Genetics Professional in My Area?

To find a genetics professional in your community, you may wish to ask your doctor for a referral. If you have health insurance, you can also contact your insurance company to find a medical geneticist or genetic counselor in your area who participates in your plan. Several resources for locating a genetics professional in your community are available online: •

GeneTests from the University of Washington provides a list of genetics clinics around the United States and international genetics clinics. You can also access the list by clicking on “Clinic Directory” at the top of the GeneTests home page. Clinics can be chosen by state or country, by service, and/or by specialty. State maps can help you locate a clinic in your area. See http://www.genetests.org/.

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The National Society of Genetic Counselors offers a searchable directory of genetic counselors in the United States. You can search by location, name, area of practice/specialization, and/or ZIP Code. See http://www.nsgc.org/resourcelink.cfm.

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The National Cancer Institute provides a Cancer Genetics Services Directory, which lists professionals who provide services related to cancer genetics. You can search by type of cancer or syndrome, location, and/or provider name at the following Web site: http://cancer.gov/search/genetics_services/.

Genetic Testing This section presents information on the benefits, costs, risks, and limitations of genetic testing. What Is Genetic Testing? Genetic testing is a type of medical test that identifies changes in chromosomes, genes, or proteins. Most of the time, testing is used to find changes that are associated with inherited disorders. The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a person’s chance of developing or passing on a genetic disorder. Several hundred genetic tests are currently in use, and more are being developed. Genetic testing is voluntary. Because testing has both benefits and limitations, the decision about whether to be tested is a personal and complex one. A genetic counselor can help by providing information about the pros and cons of the test and discussing the social and emotional aspects of testing. What Are the Types of Genetic Tests? Genetic testing can provide information about a person’s genes and chromosomes. Available types of testing include:

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Newborn screening is used just after birth to identify genetic disorders that can be treated early in life. Millions of babies are tested each year in the United States. All states currently test infants for phenylketonuria (a genetic disorder that causes mental retardation if left untreated) and congenital hypothyroidism (a disorder of the thyroid gland). Most states also test for other genetic disorders.

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Diagnostic testing is used to identify or rule out a specific genetic or chromosomal condition. In many cases, genetic testing is used to confirm a diagnosis when a particular condition is suspected based on physical signs and symptoms. Diagnostic testing can be performed before birth or at any time during a person’s life, but is not available for all genes or all genetic conditions. The results of a diagnostic test can influence a person’s choices about health care and the management of the disorder.

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Carrier testing is used to identify people who carry one copy of a gene mutation that, when present in two copies, causes a genetic disorder. This type of testing is offered to individuals who have a family history of a genetic disorder and to people in certain ethnic groups with an increased risk of specific genetic conditions. If both parents are tested, the test can provide information about a couple’s risk of having a child with a genetic condition.

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Prenatal testing is used to detect changes in a fetus‘s genes or chromosomes before birth. This type of testing is offered during pregnancy if there is an increased risk that the baby will have a genetic or chromosomal disorder. In some cases, prenatal testing can lessen a couple’s uncertainty or help them make decisions about a pregnancy. It cannot identify all possible inherited disorders and birth defects, however.

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Preimplantation testing, also called preimplantation genetic diagnosis (PGD), is a specialized technique that can reduce the risk of having a child with a particular genetic or chromosomal disorder. It is used to detect genetic changes in embryos that were created using assisted reproductive techniques such as in-vitro fertilization. In-vitro fertilization involves removing egg cells from a woman’s ovaries and fertilizing them with sperm cells outside the body. To perform preimplantation testing, a small number of cells are taken from these embryos and tested for certain genetic changes. Only embryos without these changes are implanted in the uterus to initiate a pregnancy.

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Predictive and presymptomatic types of testing are used to detect gene mutations associated with disorders that appear after birth, often later in life. These tests can be helpful to people who have a family member with a genetic disorder, but who have no features of the disorder themselves at the time of testing. Predictive testing can identify mutations that increase a person’s risk of developing disorders with a genetic basis, such as certain types of cancer. Presymptomatic testing can determine whether a person will develop a genetic disorder, such as hemochromatosis (an iron overload disorder), before any signs or symptoms appear. The results of predictive and presymptomatic testing can provide information about a person’s risk of developing a specific disorder and help with making decisions about medical care.

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Forensic testing uses DNA sequences to identify an individual for legal purposes. Unlike the tests described above, forensic testing is not used to detect gene mutations associated with disease. This type of testing can identify crime or catastrophe victims, rule out or implicate a crime suspect, or establish biological relationships between people (for example, paternity).

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How Is Genetic Testing Done? Once a person decides to proceed with genetic testing, a medical geneticist, primary care doctor, specialist, or nurse practitioner can order the test. Genetic testing is often done as part of a genetic consultation. Genetic tests are performed on a sample of blood, hair, skin, amniotic fluid (the fluid that surrounds a fetus during pregnancy), or other tissue. For example, a procedure called a buccal smear uses a small brush or cotton swab to collect a sample of cells from the inside surface of the cheek. The sample is sent to a laboratory where technicians look for specific changes in chromosomes, DNA, or proteins, depending on the suspected disorder. The laboratory reports the test results in writing to a person’s doctor or genetic counselor. Newborn screening tests are done on a small blood sample, which is taken by pricking the baby’s heel. Unlike other types of genetic testing, a parent will usually only receive the result if it is positive. If the test result is positive, additional testing is needed to determine whether the baby has a genetic disorder. Before a person has a genetic test, it is important that he or she understands the testing procedure, the benefits and limitations of the test, and the possible consequences of the test results. The process of educating a person about the test and obtaining permission is called informed consent. What Is Direct-to-Consumer Genetic Testing? Traditionally, genetic tests have been available only through healthcare providers such as physicians, nurse practitioners, and genetic counselors. Healthcare providers order the appropriate test from a laboratory, collect and send the samples, and interpret the test results. Direct-to-consumer genetic testing refers to genetic tests that are marketed directly to consumers via television, print advertisements, or the Internet. This form of testing, which is also known as at-home genetic testing, provides access to a person’s genetic information without necessarily involving a doctor or insurance company in the process. If a consumer chooses to purchase a genetic test directly, the test kit is mailed to the consumer instead of being ordered through a doctor’s office. The test typically involves collecting a DNA sample at home, often by swabbing the inside of the cheek, and mailing the sample back to the laboratory. In some cases, the person must visit a health clinic to have blood drawn. Consumers are notified of their results by mail or over the telephone, or the results are posted online. In some cases, a genetic counselor or other healthcare provider is available to explain the results and answer questions. The price for this type of at-home genetic testing ranges from several hundred dollars to more than a thousand dollars. The growing market for direct-to-consumer genetic testing may promote awareness of genetic diseases, allow consumers to take a more proactive role in their health care, and offer a means for people to learn about their ancestral origins. At-home genetic tests, however, have significant risks and limitations. Consumers are vulnerable to being misled by the results of unproven or invalid tests. Without guidance from a healthcare provider, they may make important decisions about treatment or prevention based on inaccurate, incomplete, or misunderstood information about their health. Consumers may also experience an invasion of genetic privacy if testing companies use their genetic information in an unauthorized way.

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Genetic testing provides only one piece of information about a person’s health—other genetic and environmental factors, lifestyle choices, and family medical history also affect a person’s risk of developing many disorders. These factors are discussed during a consultation with a doctor or genetic counselor, but in many cases are not addressed by athome genetic tests. More research is needed to fully understand the benefits and limitations of direct-to-consumer genetic testing. What Do the Results of Genetic Tests Mean? The results of genetic tests are not always straightforward, which often makes them challenging to interpret and explain. Therefore, it is important for patients and their families to ask questions about the potential meaning of genetic test results both before and after the test is performed. When interpreting test results, healthcare professionals consider a person’s medical history, family history, and the type of genetic test that was done. A positive test result means that the laboratory found a change in a particular gene, chromosome, or protein of interest. Depending on the purpose of the test, this result may confirm a diagnosis, indicate that a person is a carrier of a particular genetic mutation, identify an increased risk of developing a disease (such as cancer) in the future, or suggest a need for further testing. Because family members have some genetic material in common, a positive test result may also have implications for certain blood relatives of the person undergoing testing. It is important to note that a positive result of a predictive or presymptomatic genetic test usually cannot establish the exact risk of developing a disorder. Also, health professionals typically cannot use a positive test result to predict the course or severity of a condition. A negative test result means that the laboratory did not find a change in the gene, chromosome, or protein under consideration. This result can indicate that a person is not affected by a particular disorder, is not a carrier of a specific genetic mutation, or does not have an increased risk of developing a certain disease. It is possible, however, that the test missed a disease-causing genetic alteration because many tests cannot detect all genetic changes that can cause a particular disorder. Further testing may be required to confirm a negative result. In some cases, a negative result might not give any useful information. This type of result is called uninformative, indeterminate, inconclusive, or ambiguous. Uninformative test results sometimes occur because everyone has common, natural variations in their DNA, called polymorphisms, that do not affect health. If a genetic test finds a change in DNA that has not been associated with a disorder in other people, it can be difficult to tell whether it is a natural polymorphism or a disease-causing mutation. An uninformative result cannot confirm or rule out a specific diagnosis, and it cannot indicate whether a person has an increased risk of developing a disorder. In some cases, testing other affected and unaffected family members can help clarify this type of result. What Is the Cost of Genetic Testing, and How Long Does It Take to Get the Results? The cost of genetic testing can range from under $100 to more than $2,000, depending on the nature and complexity of the test. The cost increases if more than one test is necessary or if multiple family members must be tested to obtain a meaningful result. For newborn

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screening, costs vary by state. Some states cover part of the total cost, but most charge a fee of $15 to $60 per infant. From the date that a sample is taken, it may take a few weeks to several months to receive the test results. Results for prenatal testing are usually available more quickly because time is an important consideration in making decisions about a pregnancy. The doctor or genetic counselor who orders a particular test can provide specific information about the cost and time frame associated with that test. Will Health Insurance Cover the Costs of Genetic Testing? In many cases, health insurance plans will cover the costs of genetic testing when it is recommended by a person’s doctor. Health insurance providers have different policies about which tests are covered, however. A person interested in submitting the costs of testing may wish to contact his or her insurance company beforehand to ask about coverage. Some people may choose not to use their insurance to pay for testing because the results of a genetic test can affect a person’s health insurance coverage. Instead, they may opt to pay out-of-pocket for the test. People considering genetic testing may want to find out more about their state’s privacy protection laws before they ask their insurance company to cover the costs. What Are the Benefits of Genetic Testing? Genetic testing has potential benefits whether the results are positive or negative for a gene mutation. Test results can provide a sense of relief from uncertainty and help people make informed decisions about managing their health care. For example, a negative result can eliminate the need for unnecessary checkups and screening tests in some cases. A positive result can direct a person toward available prevention, monitoring, and treatment options. Some test results can also help people make decisions about having children. Newborn screening can identify genetic disorders early in life so treatment can be started as early as possible. What Are the Risks and Limitations of Genetic Testing? The physical risks associated with most genetic tests are very small, particularly for those tests that require only a blood sample or buccal smear (a procedure that samples cells from the inside surface of the cheek). The procedures used for prenatal testing carry a small but real risk of losing the pregnancy (miscarriage) because they require a sample of amniotic fluid or tissue from around the fetus. Many of the risks associated with genetic testing involve the emotional, social, or financial consequences of the test results. People may feel angry, depressed, anxious, or guilty about their results. In some cases, genetic testing creates tension within a family because the results can reveal information about other family members in addition to the person who is tested. The possibility of genetic discrimination in employment or insurance is also a concern.

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Genetic testing can provide only limited information about an inherited condition. The test often can’t determine if a person will show symptoms of a disorder, how severe the symptoms will be, or whether the disorder will progress over time. Another major limitation is the lack of treatment strategies for many genetic disorders once they are diagnosed. A genetics professional can explain in detail the benefits, risks, and limitations of a particular test. It is important that any person who is considering genetic testing understand and weigh these factors before making a decision. What Is Genetic Discrimination? Genetic discrimination occurs when people are treated differently by their employer or insurance company because they have a gene mutation that causes or increases the risk of an inherited disorder. People who undergo genetic testing may be at risk for genetic discrimination. The results of a genetic test are normally included in a person’s medical records. When a person applies for life, disability, or health insurance, the insurance company may ask to look at these records before making a decision about coverage. An employer may also have the right to look at an employee’s medical records. As a result, genetic test results could affect a person’s insurance coverage or employment. People making decisions about genetic testing should be aware that when test results are placed in their medical records, the results might not be kept private. Fear of discrimination is a common concern among people considering genetic testing. Several laws at the federal and state levels help protect people against genetic discrimination; however, genetic testing is a fast-growing field and these laws don’t cover every situation. How Does Genetic Testing in a Research Setting Differ from Clinical Genetic Testing? The main differences between clinical genetic testing and research testing are the purpose of the test and who receives the results. The goals of research testing include finding unknown genes, learning how genes work, and advancing our understanding of genetic conditions. The results of testing done as part of a research study are usually not available to patients or their healthcare providers. Clinical testing, on the other hand, is done to find out about an inherited disorder in an individual patient or family. People receive the results of a clinical test and can use them to help them make decisions about medical care or reproductive issues. It is important for people considering genetic testing to know whether the test is available on a clinical or research basis. Clinical and research testing both involve a process of informed consent in which patients learn about the testing procedure, the risks and benefits of the test, and the potential consequences of testing.

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Gene Therapy This section presents information on experimental techniques, safety, ethics, and availability of gene therapy. What Is Gene Therapy? Gene therapy is an experimental technique that uses genes to treat or prevent disease. In the future, this technique may allow doctors to treat a disorder by inserting a gene into a patient’s cells instead of using drugs or surgery. Researchers are testing several approaches to gene therapy, including: •

Replacing a mutated gene that causes disease with a healthy copy of the gene.

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Inactivating, or “knocking out,” a mutated gene that is functioning improperly.

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Introducing a new gene into the body to help fight a disease.

Although gene therapy is a promising treatment option for a number of diseases (including inherited disorders, some types of cancer, and certain viral infections), the technique remains risky and is still under study to make sure that it will be safe and effective. Gene therapy is currently only being tested for the treatment of diseases that have no other cures. How Does Gene Therapy Work? Gene therapy is designed to introduce genetic material into cells to compensate for abnormal genes or to make a beneficial protein. If a mutated gene causes a necessary protein to be faulty or missing, gene therapy may be able to introduce a normal copy of the gene to restore the function of the protein. A gene that is inserted directly into a cell usually does not function. Instead, a carrier called a vector is genetically engineered to deliver the gene. Certain viruses are often used as vectors because they can deliver the new gene by infecting the cell. The viruses are modified so they can’t cause disease when used in people. Some types of virus, such as retroviruses, integrate their genetic material (including the new gene) into a chromosome in the human cell. Other viruses, such as adenoviruses, introduce their DNA into the nucleus of the cell, but the DNA is not integrated into a chromosome. The vector can be injected or given intravenously (by IV) directly into a specific tissue in the body, where it is taken up by individual cells. Alternately, a sample of the patient’s cells can be removed and exposed to the vector in a laboratory setting. The cells containing the vector are then returned to the patient. If the treatment is successful, the new gene delivered by the vector will make a functioning protein. Researchers must overcome many technical challenges before gene therapy will be a practical approach to treating disease. For example, scientists must find better ways to deliver genes and target them to particular cells. They must also ensure that new genes are precisely controlled by the body.

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A new gene is injected into an adenovirus vector, which is used to introduce the modified DNA into a human cell. If the treatment is successful, the new gene will make a functional protein.

Is Gene Therapy Safe? Gene therapy is under study to determine whether it could be used to treat disease. Current research is evaluating the safety of gene therapy; future studies will test whether it is an effective treatment option. Several studies have already shown that this approach can have very serious health risks, such as toxicity, inflammation, and cancer. Because the techniques are relatively new, some of the risks may be unpredictable; however, medical researchers, institutions, and regulatory agencies are working to ensure that gene therapy research is as safe as possible. Comprehensive federal laws, regulations, and guidelines help protect people who participate in research studies (called clinical trials). The U.S. Food and Drug Administration (FDA) regulates all gene therapy products in the United States and oversees research in this area. Researchers who wish to test an approach in a clinical trial must first obtain permission from the FDA. The FDA has the authority to reject or suspend clinical trials that are suspected of being unsafe for participants. The National Institutes of Health (NIH) also plays an important role in ensuring the safety of gene therapy research. NIH provides guidelines for investigators and institutions (such as universities and hospitals) to follow when conducting clinical trials with gene therapy. These guidelines state that clinical trials at institutions receiving NIH funding for this type of research must be registered with the NIH Office of Biotechnology Activities. The protocol, or plan, for each clinical trial is then reviewed by the NIH Recombinant DNA Advisory Committee (RAC) to determine whether it raises medical, ethical, or safety issues that warrant further discussion at one of the RAC’s public meetings.

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An Institutional Review Board (IRB) and an Institutional Biosafety Committee (IBC) must approve each gene therapy clinical trial before it can be carried out. An IRB is a committee of scientific and medical advisors and consumers that reviews all research within an institution. An IBC is a group that reviews and approves an institution’s potentially hazardous research studies. Multiple levels of evaluation and oversight ensure that safety concerns are a top priority in the planning and carrying out of gene therapy research. What Are the Ethical Issues surrounding Gene Therapy? Because gene therapy involves making changes to the body’s set of basic instructions, it raises many unique ethical concerns. The ethical questions surrounding gene therapy include: •

How can “good” and “bad” uses of gene therapy be distinguished?

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Who decides which traits are normal and which constitute a disability or disorder?

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Will the high costs of gene therapy make it available only to the wealthy?

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Could the widespread use of gene therapy make society less accepting of people who are different?

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Should people be allowed to use gene therapy to enhance basic human traits such as height, intelligence, or athletic ability?

Current gene therapy research has focused on treating individuals by targeting the therapy to body cells such as bone marrow or blood cells. This type of gene therapy cannot be passed on to a person’s children. Gene therapy could be targeted to egg and sperm cells (germ cells), however, which would allow the inserted gene to be passed on to future generations. This approach is known as germline gene therapy. The idea of germline gene therapy is controversial. While it could spare future generations in a family from having a particular genetic disorder, it might affect the development of a fetus in unexpected ways or have long-term side effects that are not yet known. Because people who would be affected by germline gene therapy are not yet born, they can’t choose whether to have the treatment. Because of these ethical concerns, the U.S. Government does not allow federal funds to be used for research on germline gene therapy in people. Is Gene Therapy Available to Treat My Disorder? Gene therapy is currently available only in a research setting. The U.S. Food and Drug Administration (FDA) has not yet approved any gene therapy products for sale in the United States. Hundreds of research studies (clinical trials) are under way to test gene therapy as a treatment for genetic conditions, cancer, and HIV/AIDS. If you are interested in participating in a clinical trial, talk with your doctor or a genetics professional about how to participate. You can also search for clinical trials online. ClinicalTrials.gov, a service of the National Institutes of Health, provides easy access to information on clinical trials. You can search for specific trials or browse by condition or trial sponsor. You may wish to refer to a list of gene therapy trials that are accepting (or will accept) patients.

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The Human Genome Project and Genomic Research This section presents information on the goals, accomplishments, and next steps in understanding the human genome. What Is a Genome? A genome is an organism’s complete set of DNA, including all of its genes. Each genome contains all of the information needed to build and maintain that organism. In humans, a copy of the entire genome—more than 3 billion DNA base pairs—is contained in all cells that have a nucleus. What Was the Human Genome Project and Why Has It Been Important? The Human Genome Project was an international research effort to determine the sequence of the human genome and identify the genes that it contains. The Project was coordinated by the National Institutes of Health and the U.S. Department of Energy. Additional contributors included universities across the United States and international partners in the United Kingdom, France, Germany, Japan, and China. The Human Genome Project formally began in 1990 and was completed in 2003, 2 years ahead of its original schedule. The work of the Human Genome Project has allowed researchers to begin to understand the blueprint for building a person. As researchers learn more about the functions of genes and proteins, this knowledge will have a major impact in the fields of medicine, biotechnology, and the life sciences. What Were the Goals of the Human Genome Project? The main goals of the Human Genome Project were to provide a complete and accurate sequence of the 3 billion DNA base pairs that make up the human genome and to find all of the estimated 20,000 to 25,000 human genes. The Project also aimed to sequence the genomes of several other organisms that are important to medical research, such as the mouse and the fruit fly. In addition to sequencing DNA, the Human Genome Project sought to develop new tools to obtain and analyze the data and to make this information widely available. Also, because advances in genetics have consequences for individuals and society, the Human Genome Project committed to exploring the consequences of genomic research through its Ethical, Legal, and Social Implications (ELSI) program. What Did the Human Genome Project Accomplish? In April 2003, researchers announced that the Human Genome Project had completed a high-quality sequence of essentially the entire human genome. This sequence closed the gaps from a working draft of the genome, which was published in 2001. It also identified the locations of many human genes and provided information about their structure and

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organization. The Project made the sequence of the human genome and tools to analyze the data freely available via the Internet. In addition to the human genome, the Human Genome Project sequenced the genomes of several other organisms, including brewers’ yeast, the roundworm, and the fruit fly. In 2002, researchers announced that they had also completed a working draft of the mouse genome. By studying the similarities and differences between human genes and those of other organisms, researchers can discover the functions of particular genes and identify which genes are critical for life. The Project’s Ethical, Legal, and Social Implications (ELSI) program became the world’s largest bioethics program and a model for other ELSI programs worldwide. What Were Some of the Ethical, Legal, and Social Implications Addressed by the Human Genome Project? The Ethical, Legal, and Social Implications (ELSI) program was founded in 1990 as an integral part of the Human Genome Project. The mission of the ELSI program was to identify and address issues raised by genomic research that would affect individuals, families, and society. A percentage of the Human Genome Project budget at the National Institutes of Health and the U.S. Department of Energy was devoted to ELSI research. The ELSI program focused on the possible consequences of genomic research in four main areas: •

Privacy and fairness in the use of genetic information, including the potential for genetic discrimination in employment and insurance.

•

The integration of new genetic technologies, such as genetic testing, into the practice of clinical medicine.

•

Ethical issues surrounding the design and conduct of genetic research with people, including the process of informed consent.

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The education of healthcare professionals, policy makers, students, and the public about genetics and the complex issues that result from genomic research. What Are the Next Steps in Genomic Research?

Discovering the sequence of the human genome was only the first step in understanding how the instructions coded in DNA lead to a functioning human being. The next stage of genomic research will begin to derive meaningful knowledge from the DNA sequence. Research studies that build on the work of the Human Genome Project are under way worldwide. The objectives of continued genomic research include the following: •

Determine the function of genes and the elements that regulate genes throughout the genome.

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Find variations in the DNA sequence among people and determine their significance. These variations may one day provide information about a person’s disease risk and response to certain medications.

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Discover the 3-dimensional structures of proteins and identify their functions.

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Explore how DNA and proteins interact with one another and with the environment to create complex living systems.

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Develop and apply genome-based strategies for the early detection, diagnosis, and treatment of disease.

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Sequence the genomes of other organisms, such as the rat, cow, and chimpanzee, in order to compare similar genes between species.

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Develop new technologies to study genes and DNA on a large scale and store genomic data efficiently.

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Continue to explore the ethical, legal, and social issues raised by genomic research. What Is Pharmacogenomics?

Pharmacogenomics is the study of how genes affect a person’s response to drugs. This relatively new field combines pharmacology (the science of drugs) and genomics (the study of genes and their functions) to develop effective, safe medications and doses that will be tailored to a person’s genetic makeup. Many drugs that are currently available are “one size fits all,” but they don’t work the same way for everyone. It can be difficult to predict who will benefit from a medication, who will not respond at all, and who will experience negative side effects (called adverse drug reactions). Adverse drug reactions are a significant cause of hospitalizations and deaths in the United States. With the knowledge gained from the Human Genome Project, researchers are learning how inherited differences in genes affect the body’s response to medications. These genetic differences will be used to predict whether a medication will be effective for a particular person and to help prevent adverse drug reactions. The field of pharmacogenomics is still in its infancy. Its use is currently quite limited, but new approaches are under study in clinical trials. In the future, pharmacogenomics will allow the development of tailored drugs to treat a wide range of health problems, including cardiovascular disease, Alzheimer disease, cancer, HIV/AIDS, and asthma.

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APPENDIX B. 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 Institute15: •

National Institutes of Health (NIH); guidelines consolidated across agencies available at http://health.nih.gov/

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National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/Publications/FactSheets.htm

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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/cancertopics/pdq

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National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/health/

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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/HealthInformation/Publications/

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National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/Publications/

15

These publications are typically written by one or more of the various NIH Institutes.

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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.nidcr.nih.gov/HealthInformation/

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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/healthinformation/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 Biomedical Imaging and Bioengineering; general information at http://www.nibib.nih.gov/HealthEdu

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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

NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.16 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

16

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).

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citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine17: •

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

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HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

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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/index.html

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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/

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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

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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

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See http://www.nlm.nih.gov/databases/index.html.

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The NLM Gateway18 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.19 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type bladder cancer (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 33493 241 72 7 0 33813

HSTAT20 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.21 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.22 Simply search by bladder cancer (or synonyms) at the following Web site: http://text.nlm.nih.gov.

Coffee Break: Tutorials for Biologists23 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 18

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.

19

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). 20 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 21 22

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. 23 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.

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used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.24 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.25 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: •

MD Consult: Access to electronic clinical resources, see http://www.mdconsult.com/.

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Medical Matrix: Lists over 6000 medical Web sites and links to over 1.5 million documents with clinical content, see http://www.medmatrix.org/.

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Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

The Genome Project and Bladder Cancer In the following section, we will discuss databases and references which relate to the Genome Project and bladder cancer. 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).26 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. To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type bladder cancer (or synonyms) into the search box, and click Go. 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. The following is an example of the results you can obtain from the OMIM for bladder cancer: 24

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. 25 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. 26 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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BREAST and BLADDER CANCER OVEREXPRESSED GENE 1 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606048

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BREAST and BLADDER CANCER OVEREXPRESSED GENE 1 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606048

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DELETED in BLADDER CANCER CHROMOSOME REGION CANDIDATE 1; DBCCR1 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602865

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DELETED in BLADDER CANCER CHROMOSOME REGION CANDIDATE 1; DBCCR1 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602865 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

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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

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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

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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

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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, Prader-Willi syndrome, Rett syndrome, spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html

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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

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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: •

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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GEO DataSets: Curated gene expression and molecular abundance data sets assembled from the Gene Expression Omnibus (GEO) repository, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

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GEO Profiles: Individual gene expression and molecular abundance profiles assembled from the Gene Expression Omnibus (GEO) repository, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

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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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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/gquery/gquery.fcgi, and then select the database that you would like to search. Or, to search across databases, you can enter bladder cancer (or synonyms) into the search box and click Go. Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database27 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 Database28 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the GDB Human 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 Name/GDB ID. Type bladder cancer (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).

27

Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 28 Adapted from the Genome Database: http://www.gdb.org/gdb/aboutGDB.html#mission.

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APPENDIX C. 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 bladder cancer 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 This section directs you to sources which either publish fact sheets or can help you find additional guidelines on topics related to bladder cancer. 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 bladder cancer. 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 bladder cancer:

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Bladder Cancer http://www.nlm.nih.gov/medlineplus/bladdercancer.html Bladder Diseases http://www.nlm.nih.gov/medlineplus/bladderdiseases.html Cancer http://www.nlm.nih.gov/medlineplus/cancer.html Gallbladder Diseases http://www.nlm.nih.gov/medlineplus/gallbladderdiseases.html Kidney Cancer http://www.nlm.nih.gov/medlineplus/kidneycancer.html Prostate Cancer http://www.nlm.nih.gov/medlineplus/prostatecancer.html Prostate Diseases http://www.nlm.nih.gov/medlineplus/prostatediseases.html

Within the health topic page dedicated to bladder cancer, the following was listed: •

Diagnosis/Symptoms Cystoscopy - Male http://www.nlm.nih.gov/medlineplus/tutorials/cystoscopymale/htm/index.htm Cystoscopy - Women http://www.nlm.nih.gov/medlineplus/tutorials/cystoscopyfemale/htm/index.ht m Cystoscopy and Ureteroscopy Source: National Institute of Diabetes and Digestive and Kidney Diseases http://kidney.niddk.nih.gov/kudiseases/pubs/cystoscopy/ Hematuria (Blood in the Urine) Source: National Institute of Diabetes and Digestive and Kidney Diseases http://kidney.niddk.nih.gov/kudiseases/pubs/hematuria/ Intravenous Pyelogram http://www.nlm.nih.gov/medlineplus/tutorials/ivp/htm/index.htm Radiography-Intravenous Pyelogram Source: American College of Radiology, Radiological Society of North America http://www.radiologyinfo.org/en/info.cfm?pg=ivp

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From the National Institutes of Health Bladder Cancer (PDQ): Treatment Source: National Cancer Institute http://www.cancer.gov/cancerinfo/pdq/treatment/bladder/patient/ What You Need to Know about Bladder Cancer Source: National Cancer Institute http://www.cancer.gov/cancerinfo/wyntk/bladder/

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Latest News Bacon Tied to Greater Bladder Cancer Risk Source: 11/27/2006, Reuters Health http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_41769 .html Home Urine Test Spots Bladder Cancer Early Source: 11/29/2006, Reuters Health http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_41910 .html

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Organizations American Cancer Society http://www.cancer.org/ National Cancer Institute http://www.cancer.gov/

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Prevention/Screening Bladder and Other Urothelial Cancers (PDQ): Screening Source: National Cancer Institute http://www.cancer.gov/cancerinfo/pdq/screening/bladder/patient/

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Research New Urine Test Helps Find Bladder Cancer Recurrences Source: 01/23/2006, American Cancer Society http://www.cancer.org/docroot/NWS/content/NWS_1_1x_New_Urine_Test_Hel ps_Find_Bladder_Cancer_Recurrences.asp Postponing Bladder Cancer Surgery Might Be Fatal Source: 05/08/2006, American Cancer Society http://www.cancer.org/docroot/NWS/content/NWS_1_1x_Postponing_Bladder_ Cancer_Surgery_Might_Be_Fatal.asp

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Statistics Cancer Stat Facts: Cancer of the Urinary Bladder Source: National Cancer Institute http://seer.cancer.gov/statfacts/html/urinb.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.

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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 bladder cancer (or synonyms). The following was recently posted: •

Screening for bladder cancer in adults: recommendation statement Source: United States Preventive Services Task Force - Independent Expert Panel; 2004; 5 pages http://www.guideline.gov/summary/summary.aspx?doc_id=5268&nbr=003595& amp;string=Malignant+AND+tumor+AND+urinary+AND+bladder 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: •

Artificial Sweeteners and Cancer: Q and A - National Cancer. Source: www.cancer.gov http://www.cancer.gov/cancertopics/factsheet/Risk/artificial-sweeteners

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Bladder Cancer Advocacy Network Source: www.bcan.org http://www.bcan.org/index.php?name=Home&op=show_newly

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Bladder Cancer Home Page - National Cancer Institute Source: www.cancer.gov http://www.cancer.gov/cancertopics/types/bladder/

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Bladder Cancer Treatment Guidelines for Patients – Version II. Source: www.nccn.org http://www.nccn.org/patients/patient_gls/_english/_bladder/1_introduction.asp

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Diagnosing Bladder Cancer Source: www.nccn.org http://www.nccn.org/patients/patient_gls/_english/_bladder/3_work-up.asp

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MedlinePlus: Bladder Cancer Source: www.nlm.nih.gov http://www.nlm.nih.gov/medlineplus/bladdercancer.html

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Types of Bladder Cancer Source: www.nccn.org http://www.nccn.org/patients/patient_gls/_english/_bladder/2_types.asp

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 bladder cancer. 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://health.nih.gov/index.asp. Under Search Health Topics, type bladder cancer (or synonyms) into the search box, and click Search. 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: •

Family Village: http://www.familyvillage.wisc.edu/specific.htm

•

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/

•

WebMD®Health: http://www.webmd.com/diseases_and_conditions/default.htm

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to bladder cancer. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with bladder cancer.

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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 bladder cancer. 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://sis.nlm.nih.gov/dirline.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. Simply type in bladder cancer (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://healthhotlines.nlm.nih.gov/. 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 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 bladder cancer (or a synonym) into the search box, and click Submit Query.

Resources for Patients and Families The following are organizations that provide support and advocacy for patient with genetic conditions and their families29: •

Genetic Alliance: http://geneticalliance.org

•

Genetic and Rare Diseases Information Center: http://rarediseases.info.nih.gov/html/resources/info_cntr.html

•

Madisons Foundation: http://www.madisonsfoundation.org/

•

March of Dimes: http://www.marchofdimes.com

•

National Organization for Rare Disorders (NORD): http://www.rarediseases.org/

29

Adapted from the National Library of Medicine: http://ghr.nlm.nih.gov/ghr/resource/patients.

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For More Information on Genetics The following publications offer detailed information for patients about the science of genetics: •

What Is a Genome?: http://www.ncbi.nlm.nih.gov/About/primer/genetics_genome.html

•

A Science Called Genetics: http://publications.nigms.nih.gov/genetics/science.html

•

Genetic Mapping: http://www.genome.gov/10000715

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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

•

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/archive//20040831/nichsr/ta101/ta10108.html

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). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on bladder cancer: •

Basic Guidelines for Bladder Cancer Bladder cancer Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000486.htm Cancer Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001289.htm Carcinoma Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001289.htm Tumor Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001310.htm

•

Signs & Symptoms for Bladder Cancer Abdominal pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003120.htm

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Anemia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000560.htm Blood in the urine Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003138.htm Bone pain or tenderness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003180.htm Dysuria Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003145.htm Fatigue Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Flank pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003113.htm Hematuria Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003138.htm Incontinence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003142.htm Lethargy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Malaise Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003089.htm Nausea Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003117.htm Painful urination Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003145.htm Stress Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003211.htm Swelling Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003103.htm Tiredness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Urinary frequency Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003140.htm Urinary urgency Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003140.htm

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Vesicles Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003939.htm Weakness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003174.htm Weight loss Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003107.htm •

Diagnostics and Tests for Bladder Cancer Biopsy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003416.htm Bladder biopsy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003902.htm Bone scan Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003833.htm CBC Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003642.htm Complete blood count Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003642.htm CT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003330.htm Cystoscopy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003903.htm Intravenous pyelogram - IVP Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003782.htm IVP Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003782.htm MRI Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003335.htm Ultrasound Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003336.htm Urinalysis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003579.htm Urine cytology Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003905.htm

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Surgery and Procedures for Bladder Cancer ORIF Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002966.htm

•

Background Topics for Bladder Cancer Anterior Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002232.htm Blood clots Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001124.htm Chemotherapy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002324.htm Chronic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002312.htm Cigarette smoking Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002032.htm Foley catheter Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003981.htm Incidence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002387.htm Invasive Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002384.htm Metastasis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002260.htm Mucosa Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002264.htm Physical examination Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002274.htm Radiation therapy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001918.htm Radiotherapy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001918.htm Renal Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002289.htm Smoking Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002032.htm

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Support group Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002150.htm Systemic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002294.htm Vagina Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002342.htm

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

•

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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BLADDER CANCER DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 3-dimensional: 3-D. A graphic display of depth, width, and height. Three-dimensional radiation therapy uses computers to create a 3-dimensional picture of the tumor. This allows doctors to give the highest possible dose of radiation to the tumor, while sparing the normal tissue as much as possible. [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] Acanthosis Nigricans: A circumscribed melanosis consisting of a brown-pigmented, velvety verrucosity or fine papillomatosis appearing in the axillae and other body folds. It occurs in association with endocrine disorders, underlying malignancy, administration of certain drugs, or as in inherited disorder. [NIH] 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] Acetylcysteine: The N-acetyl derivative of cysteine. It is used as a mucolytic agent to reduce the viscosity of mucous secretions. It has also been shown to have antiviral effects in patients with HIV due to inhibition of viral stimulation by reactive oxygen intermediates. [NIH] Acne: A disorder of the skin marked by inflammation of oil glands and hair glands. [NIH] Acne Vulgaris: A chronic disorder of the pilosebaceous apparatus associated with an increase in sebum secretion. It is characterized by open comedones (blackheads), closed comedones (whiteheads), and pustular nodules. The cause is unknown, but heredity and age are predisposing factors. [NIH] Acoustic: Having to do with sound or hearing. [NIH] Acrylonitrile: A highly poisonous compound used widely in the manufacture of plastics, adhesives and synthetic rubber. [NIH] Actin: Essential component of the cell skeleton. [NIH] Acute leukemia: A rapidly progressing cancer of the blood-forming tissue (bone marrow). [NIH]

Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adduct: Complex formed when a carcinogen combines with DNA or a protein. [NIH] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine

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derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenosine Triphosphate: Adenosine 5’-(tetrahydrogen triphosphate). An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter. [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] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] 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] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [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] 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. [NIH]

Age Groups: Persons classified by age from birth (infant, newborn) to octogenarians and older (aged, 80 and over). [NIH] Aged, 80 and Over: A person 80 years of age and older. [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] Alanine: A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and the central nervous system. [NIH] Alcohol Drinking: Behaviors associated with the ingesting of alcoholic beverages, including social drinking. [NIH] Alertness: A state of readiness to detect and respond to certain specified small changes occurring at random intervals in the environment. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH]

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Alkaline: Having the reactions of an alkali. [EU] Alkaline Phosphatase: An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. EC 3.1.3.1. [NIH] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allergic Rhinitis: Inflammation of the nasal mucous membrane associated with hay fever; fits may be provoked by substances in the working environment. [NIH] Alopecia: Absence of hair from areas where it is normally present. [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] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [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] Alternative Splicing: A process whereby multiple protein isoforms are generated from a single gene. Alternative splicing involves the splicing together of nonconsecutive exons during the processing of some, but not all, transcripts of the gene. Thus a particular exon may be connected to any one of several alternative exons to form messenger RNA. The alternative forms produce proteins in which one part is common while the other part is different. [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] Aminolevulinic Acid: A compound produced from succinyl-CoA and glycine as an intermediate in heme synthesis. [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] Amnion: The extraembryonic membrane which contains the embryo and amniotic fluid. [NIH]

Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH]

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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] Amygdalin: A cyanogenic glycoside found in the seeds of Rosaceae. [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] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] 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] Anaplasia: Loss of structural differentiation and useful function of neoplastic cells. [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] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Aneuploidy: The chromosomal constitution of cells which deviate from the normal by the addition or subtraction of chromosomes or chromosome pairs. In a normally diploid cell the loss of a chromosome pair is termed nullisomy (symbol: 2N-2), the loss of a single chromosome is monosomy (symbol: 2N-1), the addition of a chromosome pair is tetrasomy (symbol: 2N+2), the addition of a single chromosome is trisomy (symbol: 2N+1). [NIH] Angiogenesis Factor: Substance causing proliferation of new blood vessels. It is found in tissues with high metabolic requirements, such as the retina, and in certain cancers. The factor is also released by hypoxic macrophages at the edges or outer surfaces of wounds and initiates revascularization in wound healing. [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]

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

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supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Anthracycline: A member of a family of anticancer drugs that are also antibiotics. [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] Anticarcinogenic: Pertaining to something that prevents or delays the development of cancer. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Anticonvulsant: An agent that prevents or relieves convulsions. [EU] 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] Anti-infective: An agent that so acts. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress 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] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antimitotic: Inhibiting or preventing mitosis. [EU] Antimony: A metallic element that has the atomic symbol Sb, atomic number 51, and atomic weight 121.75. It is used as a metal alloy and as medicinal and poisonous salts. It is toxic and an irritant to the skin and the mucous membranes. [NIH] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] 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

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split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antipyretic: An agent that relieves or reduces fever. Called also antifebrile, antithermic and febrifuge. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Anuria: Inability to form or excrete urine. [NIH] Anus: The opening of the rectum to the outside of the body. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [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] Aqueous: Having to do with water. [NIH] Archaea: One of the three domains of life (the others being bacteria and Eucarya), formerly called Archaebacteria under the taxon Bacteria, but now considered separate and distinct. They are characterized by: 1) the presence of characteristic tRNAs and ribosomal RNAs; 2) the absence of peptidoglycan cell walls; 3) the presence of ether-linked lipids built from branched-chain subunits; and 4) their occurrence in unusual habitats. While archaea resemble bacteria in morphology and genomic organization, they resemble eukarya in their method of genomic replication. The domain contains at least three kingdoms: crenarchaeota, euryarchaeota, and korarchaeota. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arsenicals: Inorganic or organic compounds that contain arsenic. [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] Artery: Vessel-carrying blood from the heart to various parts of the body. [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] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astringents: Agents, usually topical, that cause the contraction of tissues for the control of bleeding or secretions. [NIH] Astrocytoma: A tumor that begins in the brain or spinal cord in small, star-shaped cells called astrocytes. [NIH] Asymptomatic: Having no signs or symptoms of disease. [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.

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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] ATP: ATP an abbreviation for adenosine triphosphate, a compound which serves as a carrier of energy for cells. [NIH] 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] 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] Bacillus: A genus of Bacillaceae that are spore-forming, rod-shaped cells. Most species are saprophytic soil forms with only a few species being pathogenic. [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] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Basal cell carcinoma: A type of skin cancer that arises from the basal cells, small round cells found in the lower part (or base) of the epidermis, the outer layer of the skin. [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] Base Sequence: The sequence of purines and pyrimidines in nucleic acids and polynucleotides. It is also called nucleotide or nucleoside sequence. [NIH] 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]

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Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Benign prostatic hyperplasia: A benign (noncancerous) condition in which an overgrowth of prostate tissue pushes against the urethra and the bladder, blocking the flow of urine. Also called benign prostatic hypertrophy or BPH. [NIH] Benzo(a)pyrene: A potent mutagen and carcinogen. It is a public health concern because of its possible effects on industrial workers, as an environmental pollutant, an as a component of tobacco smoke. [NIH] Beta-Glucosidase: An enzyme that catalyzes the hydrolysis of terminal non-reducing residues in beta-D-glucosides with release of beta-glucose. EC 3.2.1.21. [NIH] Bewilderment: Impairment or loss of will power. [NIH] Bilateral: Affecting both the right and left side of body. [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] Bioassays: Determination of the relative effective strength of a substance (as a vitamin, 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] Biological Markers: Measurable and quantifiable biological parameters (e.g., specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, psychiatric disorders, environmental exposure and its effects, disease diagnosis, metabolic processes, substance abuse, pregnancy, cell line development, epidemiologic studies, etc. [NIH] Biological response modifier: BRM. A substance that stimulates the body’s response to infection and disease. [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] Biological Transport: The movement of materials (including biochemical substances and drugs) across cell membranes and epithelial layers, usually by passive diffusion. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [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

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protein structure function analysis and prediction. [NIH] Biotransformation: The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alteration may be either nonsynthetic (oxidation-reduction, hydrolysis) or synthetic (glucuronide formation, sulfate conjugation, acetylation, methylation). This also includes metabolic detoxication and clearance. [NIH] Bivalent: Pertaining to a group of 2 homologous or partly homologous chromosomes during the zygotene stage of prophase to the first metaphase in meiosis. [NIH] Bladder: The organ that stores urine. [NIH] 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] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Glucose: Glucose in blood. [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] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [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] Boron: A trace element with the atomic symbol B, atomic number 5, and atomic weight 10.81. Boron-10, an isotope of boron, is used as a neutron absorber in boron neutron capture therapy. [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]

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Brain metastases: Cancer that has spread from the original (primary) tumor to the brain. [NIH]

Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Budesonide: A glucocorticoid used in the management of asthma, the treatment of various skin disorders, and allergic rhinitis. [NIH] Cadmium: An element with atomic symbol Cd, atomic number 48, and atomic weight 114. It is a metal and ingestion will lead to cadmium poisoning. [NIH] Cadmium Poisoning: Poisoning occurring after exposure to cadmium compounds or fumes. It may cause gastrointestinal syndromes, anemia, or pneumonitis. [NIH] Caffeine: A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine’s most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes smooth muscle, stimulates cardiac muscle, stimulates diuresis, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. [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] 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] 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] Carcinogenicity: The ability to cause cancer. [NIH] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Carcinoma in Situ: A malignant tumor that has not yet invaded the basement membrane of the epithelial cell of origin and has not spread to other tissues. [NIH]

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Cardiac: Having to do with the heart. [NIH] Cardiotoxicity: Toxicity that affects 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] Carotenoids: Substance found in yellow and orange fruits and vegetables and in dark green, leafy vegetables. May reduce the risk of developing cancer. [NIH] Carpal Tunnel Syndrome: A median nerve injury inside the carpal tunnel that results in symptoms of pain, numbness, tingling, clumsiness, and a lack of sweating, which can be caused by work with certain hand and wrist postures. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] Case-Control Studies: Studies which start with the identification of persons with a disease of interest and a control (comparison, referent) group without the disease. The relationship of an attribute to the disease is examined by comparing diseased and non-diseased persons with regard to the frequency or levels of the attribute in each group. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Catheter: A flexible tube used to deliver fluids into or withdraw fluids from the body. [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] CDC2: It is crucial for entry into mitosis of eukaryotic cells. [NIH] Celecoxib: A drug that reduces pain. Celecoxib belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is being studied for cancer prevention. [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 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]

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Cell Division: The fission of a cell. [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 motility: The ability of a cell to move. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell 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 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] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Centromere: The clear constricted portion of the chromosome at which the chromatids are joined and by which the chromosome is attached to the spindle during cell division. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebellar Diseases: Diseases that affect the structure or function of the cerebellum. Cardinal manifestations of cerebellar dysfunction include dysmetria, gait ataxia, and muscle hypotonia. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] 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] 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] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the “neck”) of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Chemoprevention: The use of drugs, vitamins, or other agents to try to reduce the risk of, or delay the development or recurrence of, cancer. [NIH] Chemopreventive: Natural or synthetic compound used to intervene in the early precancerous stages of carcinogenesis. [NIH]

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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] Chemotherapy: Treatment with anticancer drugs. [NIH] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [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] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chondrocytes: Polymorphic cells that form cartilage. [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] Chromium: A trace element that plays a role in glucose metabolism. It has the atomic symbol Cr, atomic number 24, and atomic weight 52. According to the Fourth Annual Report on Carcinogens (NTP85-002,1985), chromium and some of its compounds have been listed as known carcinogens. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosomal Proteins, Non-Histone: Nucleoproteins which in contrast to histones are acid insoluble. They are involved in chromosomal functions; e.g. they bind selectively to DNA, stimulate transcription resulting in tissue-specific RNA synthesis and undergo specific changes in response to various hormones or phytomitogens. [NIH] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chromosome Aberrations: Deviations from the normal number or structure of chromosomes, not necessarily associated with disease. [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 leukemia: A slowly progressing cancer of the blood-forming tissues. [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] Cirrhosis: A type of chronic, progressive liver disease. [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] Cisplatin: An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear

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to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle. [NIH] Clear cell carcinoma: A rare type of tumor of the female genital tract in which the inside of the cells looks clear when viewed under a microscope. [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] Clonic: Pertaining to or of the nature of clonus. [EU] 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] Cobalt: A trace element that is a component of vitamin B12. It has the atomic symbol Co, atomic number 27, and atomic weight 58.93. It is used in nuclear weapons, alloys, and pigments. Deficiency in animals leads to anemia; its excess in humans can lead to erythrocytosis. [NIH] Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [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] Cohort Studies: Studies in which subsets of a defined population are identified. These groups may or may not be exposed to factors hypothesized to influence the probability of the occurrence of a particular disease or other outcome. Cohorts are defined populations which, as a whole, are followed in an attempt to determine distinguishing subgroup characteristics. [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] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Colonoscopy: Endoscopic examination, therapy or surgery of the luminal surface of the colon. [NIH] Colony-Stimulating Factors: Glycoproteins found in a subfraction of normal mammalian 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

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interleukin-3 (IL-3), granulocyte colony-stimulating factor (G-CSF), macrophage colonystimulating factor (M-CSF), and granulocyte-macrophage colony-stimulating factor (GMCSF). [NIH] Colorectal: Having to do with the colon or the rectum. [NIH] Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person’s risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Combination chemotherapy: Treatment using more than one anticancer drug. [NIH] Combinatorial: A cut-and-paste process that churns out thousands of potentially valuable compounds at once. [NIH] Comet Assay: A genotoxicological technique for measuring DNA damage in an individual cell using single-cell gel electrophoresis. Cell DNA fragments assume a “comet with tail” formation on electrophoresis and are detected with an image analysis system. Alkaline assay conditions facilitate sensitive detection of single-strand damage. [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] Complementation: The production of a wild-type phenotype when two different mutations are combined in a diploid or a heterokaryon and tested in trans-configuration. [NIH]

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Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [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] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Concentric: Having a common center of curvature or symmetry. [NIH] 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] Confounding: Extraneous variables resulting in outcome effects that obscure or exaggerate the “true” effect of an intervention. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjugation: 1. The act of joining together or the state of being conjugated. 2. A sexual process seen in bacteria, ciliate protozoa, and certain fungi in which nuclear material is exchanged during the temporary fusion of two cells (conjugants). In bacterial genetics a form of sexual reproduction in which a donor bacterium (male) contributes some, or all, of its DNA (in the form of a replicated set) to a recipient (female) which then incorporates differing genetic information into its own chromosome by recombination and passes the recombined set on to its progeny by replication. In ciliate protozoa, two conjugants of separate mating types exchange micronuclear material and then separate, each now being a fertilized cell. In certain fungi, the process involves fusion of two gametes, resulting in union of their nuclei and formation of a zygote. 3. In chemistry, the joining together of two compounds to produce another compound, such as the combination of a toxic product with some substance in the body to form a detoxified product, which is then eliminated. [EU] 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] Consciousness: Sense of awareness of self and of the environment. [NIH]

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Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] Constriction: The act of constricting. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [NIH] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [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] 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] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Disease: Disorder of cardiac function due to an imbalance between myocardial function and the capacity of the coronary vessels to supply sufficient flow for normal function. It is a form of myocardial ischemia (insufficient blood supply to the heart muscle) caused by a decreased capacity of the coronary vessels. [NIH] 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 Vessels: The veins and arteries of the heart. [NIH] Corpus: The body of the uterus. [NIH] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Creatinine clearance: A test that measures how efficiently the kidneys remove creatinine and other wastes from the blood. Low creatinine clearance indicates impaired kidney function. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Cross-Sectional Studies: Studies in which the presence or absence of disease or other health-related variables are determined in each member of the study population or in a representative sample at one particular time. This contrasts with longitudinal studies which are followed over a period of time. [NIH] Cruciferous vegetables: A family of vegetables that includes kale, collard greens, broccoli, cauliflower, cabbage, brussels sprouts, and turnip. These vegetables contain substances that may protect against cancer. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Curcumin: A dye obtained from tumeric, the powdered root of Curcuma longa Linn. It is used in the preparation of curcuma paper and the detection of boron. Curcumin appears to possess a spectrum of pharmacological properties, due primarily to its inhibitory effects on metabolic enzymes. [NIH]

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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] Cyclin-Dependent Kinases: Protein kinases that control cell cycle progression in all eukaryotes and require physical association with cyclins to achieve full enzymatic activity. Cyclin-dependent kinases are regulated by phosphorylation and dephosphorylation events. [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, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] Cystectomy: Used for excision of the urinary bladder. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cysteinyl: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [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] Cystoscope: A thin, lighted instrument used to look inside the bladder and remove tissue samples or small tumors. [NIH] Cystoscopy: Endoscopic examination, therapy or surgery of the urinary bladder. [NIH] Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] 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]

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Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Data Collection: Systematic gathering of data for a particular purpose from various sources, including questionnaires, interviews, observation, existing records, and electronic devices. The process is usually preliminary to statistical analysis of the data. [NIH] Daunorubicin: Very toxic anthracycline aminoglycoside antibiotic isolated from Streptomyces peucetius and others, used in treatment of leukemias and other neoplasms. [NIH]

De novo: In cancer, the first occurrence of cancer in the body. [NIH] Deamination: The removal of an amino group (NH2) from a chemical compound. [NIH] Death Certificates: Official records of individual deaths including the cause of death certified by a physician, and any other required identifying information. [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] 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 relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [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] Deoxyribonucleic: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleic acid: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleotides: A purine or pyrimidine base bonded to a deoxyribose containing a bond to a phosphate group. [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] Dermatitis: Any inflammation of the skin. [NIH] Dermatology: A medical specialty concerned with the skin, its structure, functions, diseases, and treatment. [NIH] DES: Diethylstilbestrol. A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased risk of clear cell carcinoma of the vagina in daughters of women who used DES. DES may also increase the risk of breast cancer in women who used DES. [NIH] Detoxification: Treatment designed to free an addict from his drug habit. [EU] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH]

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Diagnostic procedure: A method used to identify a disease. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient’s blood. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Diathesis: A constitution or condition of the body which makes the tissues react in special ways to certain extrinsic stimuli and thus tends to make the person more than usually susceptible to certain diseases. [EU] 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] Dihydrotestosterone: Anabolic agent. [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 Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Dislocation: The displacement of any part, more especially of a bone. Called also luxation. [EU]

Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place, or identity. [EU] Disparity: Failure of the two retinal images of an object to fall on corresponding retinal points. [NIH] Dissection: Cutting up of an organism for study. [NIH] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person’s mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Diuresis: Increased excretion of urine. [EU] DNA Topoisomerase: An enzyme catalyzing ATP-independent breakage of single-stranded DNA, followed by passage and rejoining of another single-stranded DNA. This enzyme class brings about the conversion of one topological isomer of DNA into another, e.g., the relaxation of superhelical turns in DNA, the interconversion of simple and knotted rings of single-stranded DNA, and the intertwisting of single-stranded rings of complementary sequences. (From Enzyme Nomenclature, 1992) EC 5.99.1.2. [NIH] Docetaxel: An anticancer drug that belongs to the family of drugs called mitotic inhibitors. [NIH]

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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] Dose-dependent: Refers to the effects of treatment with a drug. If the effects change when the dose of the drug is changed, the effects are said to be dose dependent. [NIH] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Doxazosin: A selective alpha-1-adrenergic blocker that lowers serum cholesterol. It is also effective in the treatment of hypertension. [NIH] Doxorubicin: Antineoplastic antibiotic obtained from Streptomyces peucetics. It is a hydroxy derivative of daunorubicin and is used in treatment of both leukemia and solid tumors. [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 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] Duodenal Ulcer: An ulcer in the lining of the first part of the small intestine (duodenum). [NIH]

Duodenum: The first part of the small intestine. [NIH] Dwarfism: The condition of being undersized as a result of premature arrest of skeletal growth. It may be caused by insufficient secretion of growth hormone (pituitary dwarfism). [NIH]

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] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [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] Elastic: Susceptible of resisting and recovering from stretching, compression or distortion applied by a force. [EU] Elastin: The protein that gives flexibility to tissues. [NIH] Electric shock: A dangerous patho-physiological effect resulting from an electric current passing through the body of a human or animal. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in

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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] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [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] Emodin: Purgative anthraquinone found in several plants, especially Rhamnus frangula. It was formerly used as a laxative, but is now used mainly as tool in toxicity studies. [NIH] 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] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [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] Endoscopy: Endoscopic examination, therapy or surgery performed on interior parts of the body. [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-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxin: Toxin from cell walls of bacteria. [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] Enterohepatic: Of or involving the intestine and liver. [EU] Enterohepatic Circulation: Recycling through liver by excretion in bile, reabsorption from intestines into portal circulation, passage back into liver, and re-excretion in bile. [NIH] Enteropeptidase: A specialized proteolytic enzyme secreted by intestinal cells. It converts trypsinogen into its active form trypsin by removing the N-terminal peptide. EC 3.4.21.9. [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,

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or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Environmental Pollutants: Substances which pollute the environment. Use environmental pollutants in general or for which there is no specific heading. [NIH]

for

Environmental tobacco smoke: ETS. Smoke that comes from the burning of a tobacco product and smoke that is exhaled by smokers (second-hand smoke). Inhaling ETS is called involuntary or passive smoking. [NIH] Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [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] Epidemiologic Studies: Studies designed to examine associations, commonly, hypothesized causal relations. They are usually concerned with identifying or measuring the effects of risk factors or exposures. The common types of analytic study are case-control studies, cohort studies, and cross-sectional studies. [NIH] 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] Epidermal growth factor receptor: EGFR. The protein found on the surface of some cells and to which epidermal growth factor binds, causing the cells to divide. It is found at abnormally high levels on the surface of many types of cancer cells, so these cells may divide excessively in the presence of epidermal growth factor. Also known as ErbB1 or HER1. [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] Epidermoid carcinoma: A type of cancer in which the cells are flat and look like fish scales. Also called squamous cell carcinoma. [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] Epirubicin: An anthracycline antibiotic which is the 4’-epi-isomer of doxorubicin. The compound exerts its antitumor effects by interference with the synthesis and function of DNA. Clinical studies indicate activity in breast cancer, non-Hodgkin’s lymphomas, ovarian cancer, soft-tissue sarcomas, pancreatic cancer, gastric cancer, small-cell lung cancer and acute leukemia. It is equal in activity to doxorubicin but exhibits less acute toxicities and less

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cardiotoxicity. [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] Erectile: The inability to get or maintain an erection for satisfactory sexual intercourse. Also called impotence. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Escalation: Progressive use of more harmful drugs. [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] Estrogen: One of the two female sex hormones. [NIH] Estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. [NIH]

Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [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] 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] Excrete: To get rid of waste from the body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] Expiration: The act of breathing out, or expelling air from the lungs. [EU] 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]

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Eye Color: Color of the iris. [NIH] 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] Farnesyl: Enzyme which adds 15 carbon atoms to the Ras precursor protein. [NIH] Fat: Total lipids including phospholipids. [NIH] Fathers: Male parents, human or animal. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [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 and animal limb regeneration. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] 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] Flavopiridol: Belongs to the family of anticancer drugs called flavinols. [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] 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]

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Forearm: The part between the elbow and the wrist. [NIH] Frameshift: A type of mutation which causes out-of-phase transcription of the base sequence; such mutations arise from the addition or delection of nucleotide(s) in numbers other than 3 or multiples of 3. [NIH] Frameshift Mutation: A type of mutation in which a number of nucleotides not divisible by three is deleted from or inserted into a coding sequence, thereby causing an alteration in the reading frame of the entire sequence downstream of the mutation. These mutations may be induced by certain types of mutagens or may occur spontaneously. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [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] Gangrene: Death and putrefaction of tissue usually due to a loss of blood supply. [NIH] 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] Gemcitabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [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 Amplification: A selective increase in the number of copies of a gene coding for a specific protein without a proportional increase in other genes. It occurs naturally via the excision of a copy of the repeating sequence from the chromosome and its extrachromosomal replication in a plasmid, or via the production of an RNA transcript of the entire repeating sequence of ribosomal RNA followed by the reverse transcription of the molecule to produce an additional copy of the original DNA sequence. Laboratory techniques have been introduced for inducing disproportional replication by unequal crossing over, uptake of DNA from lysed cells, or generation of extrachromosomal sequences from rolling circle replication. [NIH] Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Expression Profiling: The determination of the pattern of genes expressed i.e., transcribed, under specific circumstances or in a specific cell. [NIH] Gene Products, rev: Trans-acting nuclear proteins whose functional expression are required for HIV viral replication. Specifically, the rev gene products are required for processing and translation of the HIV gag and env mRNAs, and thus rev regulates the expression of the

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viral structural proteins. rev can also regulate viral regulatory proteins. A cis-acting antirepression sequence (CAR) in env, also known as the rev-responsive element (RRE), is responsive to the rev gene product. rev is short for regulator of virion. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Genes, env: DNA sequences that form the coding region for the viral envelope (env) proteins in retroviruses. The env genes contain a cis-acting RNA target sequence for the rev protein (= gene products, rev), termed the rev-responsive element (RRE). [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 Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event. [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] Genetic transcription: The process by which the genetic information encoded in the gene, represented as a linear sequence of deoxyribonucleotides, is copied into an exactly complementary sequence of ribonucleotides known as messenger RNA. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genistein: An isoflavonoid derived from soy products. It inhibits protein-tyrosine kinase and topoisomerase-ii (dna topoisomerase (atp-hydrolysing)) activity and is used as an antineoplastic and antitumor agent. Experimentally, it has been shown to induce G2 phase arrest in human and murine cell lines. [NIH] Genital: Pertaining to the genitalia. [EU] Genitourinary: Pertaining to the genital and urinary organs; urogenital; urinosexual. [EU] 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] Geriatric: Pertaining to the treatment of the aged. [EU] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Germline mutation: A gene change in the body’s reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; germline mutations are passed on from parents to offspring. Also called hereditary mutation. [NIH] Gland: An organ that produces and releases one or more substances for use in the body.

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Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glioblastoma: A malignant form of astrocytoma histologically characterized by pleomorphism of cells, nuclear atypia, microhemorrhage, and necrosis. They may arise in any region of the central nervous system, with a predilection for the cerebral hemispheres, basal ganglia, and commissural pathways. Clinical presentation most frequently occurs in the fifth or sixth decade of life with focal neurologic signs or seizures. [NIH] Glioblastoma multiforme: A type of brain tumor that forms from glial (supportive) tissue of the brain. It grows very quickly and has cells that look very different from normal cells. Also called grade IV astrocytoma. [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] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [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]

Glutathione Transferase: A transferase that catalyzes the addition of aliphatic, aromatic, or heterocyclic radicals as well as epoxides and arene oxides to glutathione. Addition takes place at the sulfur atom. It also catalyzes the reduction of polyol nitrate by glutathione to polyol and nitrite. EC 2.5.1.18. [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] Glycogen: A sugar stored in the liver and muscles. It releases glucose into the blood when cells need it for energy. Glycogen is the chief source of stored fuel in the body. [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] Glycoside: Any compound that contains a carbohydrate molecule (sugar), particularly any such natural product in plants, convertible, by hydrolytic cleavage, into sugar and a nonsugar component (aglycone), and named specifically for the sugar contained, as glucoside (glucose), pentoside (pentose), fructoside (fructose) etc. [EU] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] Glycosylation: The chemical or biochemical addition of carbohydrate or glycosyl groups to other chemicals, especially peptides or proteins. Glycosyl transferases are used in this biochemical reaction. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH]

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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] Grading: A system for classifying cancer cells in terms of how abnormal they appear when examined under a microscope. The objective of a grading system is to provide information about the probable growth rate of the tumor and its tendency to spread. The systems used to grade tumors vary with each type of cancer. Grading plays a role in treatment decisions. [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] 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] Gram-positive: Retaining the stain or resisting decolorization by alcohol in Gram’s method of staining, a primary characteristic of bacteria whose cell wall is composed of a thick layer of peptidologlycan with attached teichoic acids. [EU] Granule: A small pill made from sucrose. [EU] Granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes. [NIH] 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] Grasses: A large family, Gramineae, of narrow-leaved herbaceous monocots. Many grasses produce highly allergenic pollens and are hosts to cattle parasites and toxic fungi. [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] Guanine: One of the four DNA bases. [NIH] 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] Haematuria: Blood in the urine. [EU] Hair Color: Color of hair or fur. [NIH] Hair Dyes: Dyes used as cosmetics to change hair color either permanently or temporarily. [NIH]

Hairy cell leukemia: A type of chronic leukemia in which the abnormal white blood cells appear to be covered with tiny hairs when viewed under a microscope. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody

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response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Hematuria: Presence of blood in the urine. [NIH] Hemochromatosis: A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the liver. Also called iron overload disease. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into 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 of 9 percent or more. [NIH] Hemoglobin A: Normal adult human hemoglobin. The globin moiety consists of two alpha and two beta chains. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemophilia: Refers to a group of hereditary disorders in which affected individuals fail to make enough of certain proteins needed to form blood clots. [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]

Hepatoma: A liver tumor. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Hereditary mutation: A gene change in the body’s reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; hereditary mutations are passed on from parents to offspring. Also called germline mutation. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Hernia: Protrusion of a loop or knuckle of an organ or tissue through an abnormal opening. [NIH]

Heterodimer: Zippered pair of nonidentical proteins. [NIH]

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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]

Heterozygote: An individual having different alleles at one or more loci in homologous chromosome segments. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Histone Deacetylase: Hydrolyzes N-acetyl groups on histones. [NIH] Histones: Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] 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] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormonal therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called hormone therapy or endocrine therapy. [NIH] 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] 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] Hydrogel: A network of cross-linked hydrophilic macromolecules used in biomedical applications. [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] Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophilic: Readily absorbing moisture; hygroscopic; having strongly polar groups that readily interact with water. [EU] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a

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hydrophobic colloid. [EU] 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 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] Hyperreflexia: Exaggeration of reflexes. [EU] 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] Hyperthermia: A type of treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anticancer drugs. [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] Hypodermic: Applied or administered beneath the skin. [EU] Hypoxic: Having too little oxygen. [NIH] Ibuprofen: A nonsteroidal anti-inflammatory agent with analgesic properties used in the therapy of rheumatism and arthritis. [NIH] Ileal: Related to the ileum, the lowest end of the small intestine. [NIH] Ileum: The lower end of the small intestine. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [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] Immunocompetence: The ability of lymphoid cells to mount a humoral or cellular immune response when challenged by antigen. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunogenetics: A branch of genetics which deals with the genetic basis of the immune response. [NIH]

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Immunoglobulins: Glycoproteins present in the blood (antibodies) and in other tissue. They are classified by structure and activity into five classes (IgA, IgD, IgE, IgG, IgM). [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] Immunosuppressant: An agent capable of suppressing immune responses. [EU] 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] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a 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] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infant, Newborn: An infant during the first month after birth. [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.

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[EU]

Infiltrating cancer: Cancer that has spread beyond the layer of tissue in which it developed and is growing into surrounding, healthy tissues. Also called invasive cancer. [NIH] Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] 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] Informed Consent: Voluntary authorization, given to the physician by the patient, with full comprehension of the risks involved, for diagnostic or investigative procedures and medical and surgical treatment. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Insecticides: Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. [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] Instillation: . [EU] 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] Interindividual: Occurring between two or more individuals. [EU] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [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] 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] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU]

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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] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intravenous: IV. Into a vein. [NIH] Intravenous pyelography: IVP. X-ray study of the kidneys, ureters, and bladder. The x-rays are taken after a dye is injected into a blood vessel. The dye is concentrated in the urine, which outlines the kidneys, ureters, and bladder on the x-rays. [NIH] Intravesical: Within the bladder. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] 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]

Invasive cancer: Cancer that has spread beyond the layer of tissue in which it developed and is growing into surrounding, healthy tissues. Also called infiltrating cancer. [NIH] Involuntary: Reaction occurring without intention or volition. [NIH] Ionization: 1. Any process by which a neutral atom gains or loses electrons, thus acquiring a net charge, as the dissociation of a substance in solution into ions or ion production by the passage of radioactive particles. 2. Iontophoresis. [EU] 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] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isoflavones: 3-Phenylchromones. Isomeric form of flavones in which the benzene group is attached to the 3 position of the benzopyran ring instead of the 2 position. [NIH] Isoprenoids: Molecule that might anchor G protein to the cell membrane as it is hydrophobic. [NIH] Isothiocyanates: Organic compounds with the general formula R-NCS. [NIH] IVP: Intravenous pyelogram or intravenous pyelography (in-tra-VEE-nus PYE-el-o-gram or

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pye-LAH-gra-fee). A series of x-rays of the kidneys, ureters, and bladder. The x-rays are taken after a dye is injected into a blood vessel. The dye is concentrated in the urine, which outlines the kidneys, ureters, and bladder on the x-rays. [NIH] Karyotype: The characteristic chromosome complement of an individual, race, or species as defined by their number, size, shape, etc. [NIH] Kava: Dried rhizome and roots of Piper methysticum, a shrub native to Oceania and known for its anti-anxiety and sedative properties. Heavy usage results in some adverse effects. It contains alkaloids, lactones, kawain, methysticin, mucilage, starch, and yangonin. Kava is also the name of the pungent beverage prepared from the plant’s roots. [NIH] Ketoprofen: An ibuprofen-type anti-inflammatory analgesic and antipyretic. It is used in the treatment of rheumatoid arthritis and osteoarthritis. [NIH] Kidney Cortex: The outer zone of the kidney, beneath the capsule, consisting of kidney glomerulus; kidney tubules, distal; and kidney tubules, proximal. [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 Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH] Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body’s electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [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] 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] Latency: The period of apparent inactivity between the time when a stimulus is presented and the moment a response occurs. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Laxative: An agent that acts to promote evacuation of the bowel; a cathartic or purgative. [EU]

Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [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] Leukemia: Cancer of blood-forming tissue. [NIH] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [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] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Light microscope: A microscope (device to magnify small objects) in which objects are lit directly by white light. [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] Linkage Disequilibrium: Nonrandom association of linked genes. This is the tendency of the alleles of two separate but already linked loci to be found together more frequently than would be expected by chance alone. [NIH] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] 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]

Lipoxygenase Inhibitors: Compounds or agents that combine with lipoxygenase and thereby prevent its substrate-enzyme combination with arachidonic acid and the formation of the eicosanoid products hydroxyeicosatetraenoic acid and various leukotrienes. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [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] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside

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diameter) and used in transferring microorganisms. [NIH] Loss of Heterozygosity: The loss of one allele at a specific locus, caused by a deletion mutation; or loss of a chromosome from a chromosome pair. It is detected when heterozygous markers for a locus appear monomorphic because one of the alleles was deleted. When this occurs at a tumor suppressor gene locus where one of the alleles is already abnormal, it can result in neoplastic transformation. [NIH] Lycopene: A red pigment found in tomatoes and some fruits. [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] Lymphocytes: White blood cells formed in the body’s lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each); those with characteristics of neither major class are called null cells. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU] Macronutrients: Nutrients in the diet that are the key sources of energy, namely protein, fat, and carbohydrates. [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] Macrophage Colony-Stimulating Factor: A mononuclear phagocyte colony-stimulating factor synthesized by mesenchymal cells. The compound stimulates the survival, proliferation, and differentiation of hematopoietic cells of the monocyte-macrophage series. M-CSF is a disulfide-bonded glycoprotein dimer with a MW of 70 kDa. It binds to a specific high affinity receptor (receptor, macrophage colony-stimulating factor). [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy 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] Malabsorption: Impaired intestinal absorption of nutrients. [EU] 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

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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]

Mammography: Radiographic examination of the breast. [NIH] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Meat: The edible portions of any animal used for food including domestic mammals (the major ones being cattle, swine, and sheep) along with poultry, fish, shellfish, and game. [NIH]

Median Nerve: A major nerve of the upper extremity. In humans, the fibers of the median nerve originate in the lower cervical and upper thoracic spinal cord (usually C6 to T1), travel via the brachial plexus, and supply sensory and motor innervation to parts of the forearm and hand. [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] Medical oncologist: A doctor who specializes in diagnosing and treating cancer using chemotherapy, hormonal therapy, and biological therapy. A medical oncologist often serves as the main caretaker of someone who has cancer and coordinates treatment provided by other specialists. [NIH] Medical Oncology: A subspecialty of internal medicine concerned with the study of neoplasms. [NIH] Medical Records: Recording of pertinent information concerning patient’s illness or illnesses. [NIH] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Megaloblastic: A large abnormal red blood cell appearing in the blood in pernicious anaemia. [EU] 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] 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] Melanosis: Disorders of increased melanin pigmentation that develop without preceding inflammatory disease. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and

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intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [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] Menopause: Permanent cessation of menstruation. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [NIH]

Mephenytoin: An anticonvulsant effective in tonic-clonic epilepsy. It may cause blood dyscrasias. [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] Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metallothionein: A low-molecular-weight (approx. 10 kD) protein occurring in the cytoplasm of kidney cortex and liver. It is rich in cysteinyl residues and contains no aromatic amino acids. Metallothionein shows high affinity for bivalent heavy metals. [NIH] 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] Metastasize: To spread from one part of the body to another. When cancer cells metastasize and form secondary tumors, the cells in the metastatic tumor are like those in the original (primary) tumor. [NIH] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Metastatic cancer: Cancer that has spread from the place in which it started to other parts of the body. [NIH] Methotrexate: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of dihydrofolate reductase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [NIH] Micelles: Electrically charged colloidal particles or ions consisting of oriented molecules; aggregates of a number of molecules held loosely together by secondary bonds. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular

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animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Micronutrients: Essential dietary elements or organic compounds that are required in only small quantities for normal physiologic processes to occur. [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] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microspheres: Small uniformly-sized spherical particles frequently radioisotopes or various reagents acting as tags or markers. [NIH]

labeled

with

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] Miscarriage: Spontaneous expulsion of the products of pregnancy before the middle of the second trimester. [NIH] Mistletoe lectin: A substance that comes from the mistletoe plant, and that is being studied as a treatment for cancer. A lectin is a complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] 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] Mitomycin: An antineoplastic antibiotic produced by Streptomyces caespitosus. It acts as a bi- or trifunctional alkylating agent causing cross-linking of DNA and inhibition of DNA synthesis. [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] Mitotic inhibitors: Drugs that kill cancer cells by interfering with cell division (mitostis). [NIH]

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] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the 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]

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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] Monosomy: The condition in which one chromosome of a pair is missing. In a normally diploid cell it is represented symbolically as 2N-1. [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] 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] Mucolytic: Destroying or dissolving mucin; an agent that so acts : a mucopolysaccharide or glycoprotein, the chief constituent of mucus. [EU] Multicenter study: A clinical trial that is carried out at more than one medical institution. [NIH]

Multidrug resistance: Adaptation of tumor cells to anticancer drugs in ways that make the drugs less effective. [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] 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] Musculature: The muscular apparatus of the body, or of any part of it. [EU] 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] Mutagen: Any agent, such as X-rays, gamma rays, mustard gas, TCDD, that can cause abnormal mutation in living cells; having the power to cause mutations. [NIH] Mutagenic: Inducing genetic mutation. [EU] Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary arteriosclerosis), to obstruction by a thrombus (coronary thrombosis), or less commonly, to diffuse narrowing of arterioles and other small vessels

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within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (myocardial infarction). [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [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] 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] Neonatal: Pertaining to the first four weeks after birth. [EU] Neonatal period: The first 4 weeks after birth. [NIH] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Nephropathy: Disease of the kidneys. [EU] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers 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] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neurogenic: Loss of bladder control caused by damage to the nerves controlling the bladder. [NIH] Neurologic: Having to do with nerves or the nervous system. [NIH] 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] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neurophysiology: The scientific discipline concerned with the physiology of the nervous system. [NIH] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light

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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] Neutrophils: Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. [NIH] Nickel: A trace element with the atomic symbol Ni, atomic number 28, and atomic weight 58.69. It is a cofactor of the enzyme urease. [NIH] Nicotine: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. [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] Nitrosamines: A class of compounds that contain a -NH2 and a -NO radical. Many members of this group have carcinogenic and mutagenic properties. [NIH] Node-negative: Cancer that has not spread to the lymph nodes. [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 Envelope: The membrane system of the cell nucleus that surrounds the nucleoplasm. It consists of two concentric membranes separated by the perinuclear space. The structures of the envelope where it opens to the cytoplasm are called the nuclear pores (nuclear pore). [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] 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

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form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nurse Practitioners: Nurses who are specially trained to assume an expanded role in providing medical care under the supervision of a physician. [NIH] Occult: Obscure; concealed from observation, difficult to understand. [EU] Occupational Exposure: The exposure to potentially harmful chemical, physical, or biological agents that occurs as a result of one’s occupation. [NIH] Odds Ratio: The ratio of two odds. The exposure-odds ratio for case control data is the ratio of the odds in favor of exposure among cases to the odds in favor of exposure among noncases. The disease-odds ratio for a cohort or cross section is the ratio of the odds in favor of disease among the exposed to the odds in favor of disease among the unexposed. The prevalence-odds ratio refers to an odds ratio derived cross-sectionally from studies of prevalent cases. [NIH] Ofloxacin: An orally administered broad-spectrum quinolone antibacterial drug active against most gram-negative and gram-positive bacteria. [NIH] Oligosaccharides: Carbohydrates consisting of between two and ten monosaccharides connected by either an alpha- or beta-glycosidic link. They are found throughout nature in both the free and bound form. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [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] Oncologist: A doctor who specializes in treating cancer. Some oncologists specialize in a particular type of cancer treatment. For example, a radiation oncologist specializes in treating cancer with radiation. [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] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [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]

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Osteogenic sarcoma: A malignant tumor of the bone. Also called osteosarcoma. [NIH] Osteosarcoma: A cancer of the bone that affects primarily children and adolescents. Also called osteogenic sarcoma. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [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] Overall survival: The percentage of subjects in a study who have survived for a defined period of time. Usually reported as time since diagnosis or treatment. Often called the survival rate. [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]

Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxidative Phosphorylation: Electron transfer through the cytochrome system liberating free energy which is transformed into high-energy phosphate bonds. [NIH] 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] Oxygenase: Enzyme which breaks down heme, the iron-containing oxygen-carrying constituent of the red blood cells. [NIH] P53 gene: A tumor suppressor gene that normally inhibits the growth of tumors. This gene is altered in many types of cancer. [NIH] 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] 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] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Papilla: A small nipple-shaped elevation. [NIH] Papillary: Pertaining to or resembling papilla, or nipple. [EU] Papillary tumor: A tumor shaped like a small mushroom, with its stem attached to the

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epithelial layer (inner lining) of an organ. [NIH] Papilloma: A benign epithelial neoplasm which may arise from the skin, mucous membranes or glandular ducts. [NIH] Parasite: An animal or a plant that lives on or in an organism of another species and gets at least some of its nutrition from that other organism. [NIH] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Particle: A tiny mass of material. [EU] Paternity: Establishing the father relationship of a man and a child. [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 Advocacy: Promotion and protection of the rights of patients, frequently through a legal process. [NIH] PDQ: Physician Data Query. PDQ is an online database developed and maintained by the National Cancer Institute. Designed to make the most current, credible, and accurate cancer information available to health professionals and the public, PDQ contains peer-reviewed summaries on cancer treatment, screening, prevention, genetics, and supportive care; a registry of cancer clinical trials from around the world; and directories of physicians, professionals who provide genetics services, and organizations that provide cancer care. Most of this information is available on the CancerNet Web site, and more specific information about PDQ can be found at http://cancernet.nci.nih.gov/pdq.html. [NIH] Pelvic: Pertaining to the pelvis. [EU] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] 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] Peptide Library: A collection of cloned peptides, or chemically synthesized peptides, frequently consisting of all possible combinations of amino acids making up an n-amino acid peptide. [NIH] Perineural: Around a nerve or group of nerves. [NIH] Perioperative: Around the time of surgery; usually lasts from the time of going into the hospital or doctor’s office for surgery until the time the patient goes home. [NIH] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Vascular Disease: Disease in the large blood vessels of the arms, legs, and feet. People who have had diabetes for a long time may get this because major blood vessels in their arms, legs, and feet are blocked and these limbs do not receive enough blood. The signs of PVD are aching pains in the arms, legs, and feet (especially when walking) and foot sores that heal slowly. Although people with diabetes cannot always avoid PVD, doctors say they

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have a better chance of avoiding it if they take good care of their feet, do not smoke, and keep both their blood pressure and diabetes under good control. [NIH] Peroxidase: A hemeprotein from leukocytes. Deficiency of this enzyme leads to a hereditary disorder coupled with disseminated moniliasis. It catalyzes the conversion of a donor and peroxide to an oxidized donor and water. EC 1.11.1.7. [NIH] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Pesticides: Chemicals used to destroy pests of any sort. The concept includes fungicides (industrial fungicides), insecticides, rodenticides, etc. [NIH] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [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] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [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] Phosphorylase: An enzyme of the transferase class that catalyzes the phosphorylysis of a terminal alpha-1,4-glycosidic bond at the non-reducing end of a glycogen molecule, releasing a glucose 1-phosphate residue. Phosphorylase should be qualified by the natural substance acted upon. EC 2.4.1.1. [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photodynamic therapy: Treatment with drugs that become active when exposed to light. These drugs kill cancer cells. [NIH] Photosensitizer: A drug used in photodynamic therapy. When absorbed by cancer cells and exposed to light, the drug becomes active and kills the cancer cells. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [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] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH]

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Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [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] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [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] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [NIH] Plastids: Self-replicating cytoplasmic organelles of plant and algal cells that contain pigments and may synthesize and accumulate various substances. Plastids are used in phylogenetic studies. [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] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Ploidy: The number of sets of chromosomes in a cell or an organism. For example, haploid means one set and diploid means two sets. [NIH] Pneumoconiosis: Condition characterized by permanent deposition of substantial amounts of particulate matter in the lungs, usually of occupational or environmental origin, and by the tissue reaction to its presence. [NIH] Pneumonia: Inflammation of the lungs. [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] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [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 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]

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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] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] 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] Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH] 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] Postoperative: After surgery. [NIH] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Potentiates: 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] Precancerous: A term used to describe a condition that may (or is likely to) become cancer. Also called premalignant. [NIH] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Predictive factor: A situation or condition that may increase a person’s risk of developing a certain disease or disorder. [NIH] Predisposition: A latent susceptibility to disease which may be activated under certain

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conditions, as by stress. [EU] Premalignant: A term used to describe a condition that may (or is likely to) become cancer. Also called precancerous. [NIH] Premenopausal: Refers to the time before menopause. Menopause is the time of life when a women’s menstrual periods stop permanently; also called “change of life.” [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Preoperative: Preceding an operation. [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] Primary tumor: The original tumor. [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] Prognostic factor: A situation or condition, or a characteristic of a patient, that can be used to estimate the chance of recovery from a disease, or the chance of the disease recurring (coming back). [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] Promotor: In an operon, a nucleotide sequence located at the operator end which contains all the signals for the correct initiation of genetic transcription by the RNA polymerase holoenzyme and determines the maximal rate of RNA synthesis. [NIH] Promyelocytic leukemia: A type of acute myeloid leukemia, a quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. [NIH]

Prone: Having the front portion of the body downwards. [NIH] Prospective Studies: Observation of a population for a sufficient number of persons over a sufficient number of years to generate incidence or mortality rates subsequent to the selection of the study group. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] 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

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upon the rectum. [NIH] Prostate gland: A gland in the male reproductive system just below the bladder. It surrounds part of the urethra, the canal that empties the bladder, and produces a fluid that forms part of semen. [NIH] Prostatectomy: Complete or partial surgical removal of the prostate. Three primary approaches are commonly employed: suprapubic - removal through an incision above the pubis and through the urinary bladder; retropubic - as for suprapubic but without entering the urinary bladder; and transurethral (transurethral resection of prostate). [NIH] Prostate-Specific Antigen: Kallikrein-like serine proteinase produced by epithelial cells of both benign and malignant prostate tissue. It is an important marker for the diagnosis of prostate cancer. EC 3.4.21.77. [NIH] Prostatic Hyperplasia: Enlargement or overgrowth of the prostate gland as a result of an increase in the number of its constituent cells. [NIH] Prostatic Intraepithelial Neoplasia: A premalignant change arising in the prostatic epithelium, regarded as the most important and most likely precursor of prostatic adenocarcinoma. The neoplasia takes the form of an intra-acinar or ductal proliferation of secretory cells with unequivocal nuclear anaplasia, which corresponds to nuclear grade 2 and 3 invasive prostate cancer. [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 Isoforms: Different forms of a protein that may be produced from different genes, or from the same gene by alternative splicing. [NIH] Protein Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein. EC 2.7.1.37. [NIH] Protein p53: Nuclear phosphoprotein encoded by the p53 gene whose normal function is to control cell proliferation. A mutant or absent p53 protein has been found in leukemia, osteosarcoma, lung cancer, and colorectal cancer. [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] Protein-Tyrosine Kinase: An enzyme that catalyzes the phosphorylation of tyrosine residues in proteins with ATP or other nucleotides as phosphate donors. EC 2.7.1.112. [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] Proteome: The protein complement of an organism coded for by its genome. [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

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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] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [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] 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 Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [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] Putrefaction: The process of decomposition of animal and vegetable matter by living organisms. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Quality of Health Care: The levels of excellence which characterize the health service or health care provided based on accepted standards of quality. [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

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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] Radical cystectomy: Surgery to remove the bladder as well as nearby tissues and organs. [NIH]

Radioactive: Giving off radiation. [NIH] Radioactivity: The quality of emitting or the emission of corpuscular or electromagnetic radiations consequent to nuclear disintegration, a natural property of all chemical elements of atomic number above 83, and possible of induction in all other known elements. [EU] 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] 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] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [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] Random Allocation: A process involving chance used in therapeutic trials or other research endeavor for allocating experimental subjects, human or animal, between treatment and control groups, or among treatment groups. It may also apply to experiments on inanimate objects. [NIH] Randomization: Also called random allocation. Is allocation of individuals to groups, e.g., for experimental and control regimens, by chance. Within the limits of chance variation, random allocation should make the control and experimental groups similar at the start of an investigation and ensure that personal judgment and prejudices of the investigator do not influence allocation. [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] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that

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the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient’s choice to be in a randomized trial. [NIH] 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] 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] Rectal: By or having to do with the rectum. The rectum is the last 8 to 10 inches of the large intestine and ends at the anus. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recur: To occur again. Recurrence is the return of cancer, at the same site as the original (primary) tumor or in another location, after the tumor had disappeared. [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] Reflux: The term used when liquid backs up into the esophagus from the stomach. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [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] Regional lymph node: In oncology, a lymph node that drains lymph from the region around a tumor. [NIH] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Relative risk: The ratio of the incidence rate of a disease among individuals exposed to a

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specific risk factor to the incidence rate among unexposed individuals; synonymous with risk ratio. Alternatively, the ratio of the cumulative incidence rate in the exposed to the cumulative incidence rate in the unexposed (cumulative incidence ratio). The term relative risk has also been used synonymously with odds ratio. This is because the odds ratio and relative risk approach each other if the disease is rare ( 5 percent of population) and the number of subjects is large. [NIH] Reliability: Used technically, in a statistical sense, of consistency of a test with itself, i. e. the extent to which we can assume that it will yield the same result if repeated a second time. [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 cell cancer: Cancer that develops in the lining of the renal tubules, which filter the blood and produce urine. [NIH] Renal cell carcinoma: A type of kidney cancer. [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] Reproductive cells: Egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes. [NIH] Research Support: Financial support of research activities. [NIH] Resected: Surgical removal of part of an organ. [NIH] Resection: Removal of tissue or part or all of an organ by surgery. [NIH] Residual Volume: The volume of air remaining in the lungs at the end of a maximal expiration. Common abbreviation is RV. [NIH] 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] 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 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] Retinoblastoma Protein: Product of the retinoblastoma tumor suppressor gene. It is a nuclear phosphoprotein hypothesized to normally act as an inhibitor of cell proliferation. Rb protein is absent in retinoblastoma cell lines. It also has been shown to form complexes with

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the adenovirus E1A protein, the SV40 T antigen, and the human papilloma virus E7 protein. [NIH]

Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Retropubic: A potential space between the urinary bladder and the symphisis and body of the pubis. [NIH] Retrospective: Looking back at events that have already taken place. [NIH] Retrospective study: A study that looks backward in time, usually using medical records and interviews with patients who already have or had a disease. [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] 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] Ribonucleic acid: RNA. One of the two nucleic acids found in all cells. The other is deoxyribonucleic acid (DNA). Ribonucleic acid transfers genetic information from DNA to proteins produced by the cell. [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] Risk patient: Patient who is at risk, because of his/her behaviour or because of the type of person he/she is. [EU] Rod: A reception for vision, located in the retina. [NIH] Rodenticides: Substances used to destroy or inhibit the action of rats, mice, or other rodents. [NIH]

Rubber: A high-molecular-weight polymeric elastomer derived from the milk juice (latex) of Hevea brasiliensis and other trees. It is a substance that can be stretched at room temperature to atleast twice its original length and after releasing the stress, retractrapidly, and recover its original dimensions fully. Synthetic rubber is made from many different chemicals, including styrene, acrylonitrile, ethylene, propylene, and isoprene. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Sarcoma: A connective tissue neoplasm formed by proliferation of mesodermal cells; it is usually highly malignant. [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]

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Scatter: The extent to which relative success and failure are divergently manifested in qualitatively different tests. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [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] 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] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [EU] Sediment: A precipitate, especially one that is formed spontaneously. [EU] Sedimentation: The act of causing the deposit of sediment, especially by the use of a centrifugal machine. [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] Sensitization: 1. Administration of antigen to induce a primary immune response; priming; immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in the presence of homologous antigen, the first stage of a complement fixation test. [EU] Sentinel lymph node: The first lymph node that cancer is likely to spread to from the primary tumor. Cancer cells may appear first in the sentinel node before spreading to other lymph nodes. [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]

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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] 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] Sex Ratio: The number of males per 100 females. [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] Skin Pigmentation: Coloration of the skin. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smallpox: A generalized virus infection with a vesicular rash. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Sneezing: Sudden, forceful, involuntary expulsion of air from the nose and mouth caused by irritation to the mucous membranes of the upper respiratory tract. [NIH]

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Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Social Work: The use of community resources, individual case work, or group work to promote the adaptive capacities of individuals in relation to their social and economic environments. It includes social service agencies. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [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] 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 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] 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] 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] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Sprains and Strains: A collective term for muscle and ligament injuries without dislocation

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or fracture. A sprain is a joint injury in which some of the fibers of a supporting ligament are ruptured but the continuity of the ligament remains intact. A strain is an overstretching or overexertion of some part of the musculature. [NIH] Squamous: Scaly, or platelike. [EU] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cells: Flat cells that look like fish scales under a microscope. These cells cover internal and external surfaces of the body. [NIH] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Standardize: To compare with or conform to a standard; to establish standards. [EU] 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] Stillbirth: The birth of a dead fetus or baby. [NIH] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [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] Stool: The waste matter discharged in a bowel movement; feces. [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] Stress incontinence: An involuntary loss of urine that occurs at the same time that internal abdominal pressure is increased, such as with laughing, sneezing, coughing, or physical activity. [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] Styrene: A colorless, toxic liquid with a strong aromatic odor. It is used to make rubbers, polymers and copolymers, and polystyrene plastics. [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

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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] 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] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Sulindac: A sulfinylindene derivative whose sulfinyl moiety is converted in vivo to an active anti-inflammatory analgesic that undergoes enterohepatic circulation to maintain constant blood levels without causing gastrointestinal side effects. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1. [NIH] Supportive care: Treatment given to prevent, control, or relieve complications and side effects and to improve the comfort and quality of life of people who have cancer. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Survival Rate: The proportion of survivors in a group, e.g., of patients, studied and followed over a period, or the proportion of persons in a specified group alive at the beginning of a time interval who survive to the end of the interval. It is often studied using life table methods. [NIH] Symphysis: A secondary cartilaginous joint. [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 Transmission: The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific synaptic receptors. These activated receptors modulate ion channels and/or secondmessenger systems to influence the postsynaptic cell. Electrical transmission is less common in the nervous system, and, as in other tissues, is mediated by gap junctions. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systemic therapy: Treatment that uses substances that travel through the bloodstream,

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reaching and affecting cells all over the body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Taxanes: Anticancer drugs that inhibit cancer cell growth by stopping cell division. Also called antimitotic or antimicrotubule agents or mitotic inhibitors. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [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] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [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] 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] Thanatophoric Dysplasia: A severe form of neonatal dwarfism with very short limbs. All cases have died at birth or in the neonatal period. [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] 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] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and

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serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

Thrombosis: The formation or presence of a blood clot inside a blood vessel. [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] Thyroid Hormones: Hormones secreted by the thyroid gland. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Polypeptide Antigen: Serological tumor marker composed of a molecular complex of cytokeratins 8, 18, and 19. It is used in the diagnosis and staging of bronchogenic carcinoma. [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] Tomograph: An X-ray apparatus; an instrument that produces a relatively sharp image of a thin layer of the object, all other layers being blurred by predetermined relative motion of the roentgen tube, film, and subject. [NIH] 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] Tonic: 1. Producing and restoring the normal tone. 2. Characterized by continuous tension. 3. A term formerly used for a class of medicinal preparations believed to have the power of restoring normal tone to tissue. [EU] Topical: On the surface of the body. [NIH] 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] Toxicokinetics: Study of the absorption, distribution, metabolism, and excretion of test substances. [NIH] 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] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH]

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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] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme “donor:acceptor group transferase”. (Enzyme Nomenclature, 1992) EC 2. [NIH] Transitional cell carcinoma: A type of cancer that develops in the lining of the bladder, ureter, or renal pelvis. [NIH] Translating: Conversion from one language to another language. [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] 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] Transurethral: Performed through the urethra. [EU] Transurethral resection: Surgery performed with a special instrument inserted through the urethra. Also called TUR. [NIH] Transurethral Resection of Prostate: Resection of the prostate using a cystoscope passed through the urethra. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Treatment Failure: A measure of the quality of health care by assessment of unsuccessful results of management and procedures used in combating disease, in individual cases or series. [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]

Trees: Woody, usually tall, perennial higher plants (Angiosperms, Gymnosperms, and some Pterophyta) having usually a main stem and numerous branches. [NIH] Tretinoin: An important regulator of gene expression, particularly during growth and development and in neoplasms. Retinoic acid derived from maternal vitamin A is essential for normal gene expression during embryonic development and either a deficiency or an

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excess can be teratogenic. It is also a topical dermatologic agent which is used in the treatment of psoriasis, acne vulgaris, and several other skin diseases. It has also been approved for use in promyelocytic leukemia. [NIH] Trinucleotide Repeat Expansion: DNA region comprised of a variable number of repetitive, contiguous trinucleotide sequences. The presence of these regions is associated with diseases such as Fragile X Syndrome and myotonic dystrophy. Many chromosome fragile sites (chromosome fragility) contain expanded trinucleotide repeats. [NIH] Trinucleotide Repeats: Microsatellite repeats consisting of three nucleotides dispersed in the euchromatic arms of chromosomes. [NIH] Trisomy: The possession of a third chromosome of any one type in an otherwise diploid cell. [NIH]

Trypsin: A serine endopeptidase that is formed from trypsinogen in the pancreas. It is converted into its active form by enteropeptidase in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4. [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] 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] 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 model: A type of animal model which can be 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] 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 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] Typhimurium: Microbial assay which measures his-his+ reversion by chemicals which cause base substitutions or frameshift mutations in the genome of this organism. [NIH] 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] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Ultraviolet radiation: Invisible rays that are part of the energy that comes from the sun. UV radiation can damage the skin and cause melanoma and other types of skin cancer. UV radiation that reaches the earth’s surface is made up of two types of rays, called UVA and

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UVB rays. UVB rays are more likely than UVA rays to cause sunburn, but UVA rays pass deeper into the skin. Scientists have long thought that UVB radiation can cause melanoma and other types of skin cancer. They now think that UVA radiation also may add to skin damage that can lead to skin cancer and cause premature aging. For this reason, skin specialists recommend that people use sunscreens that reflect, absorb, or scatter both kinds of UV radiation. [NIH] Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] Urease: An enzyme that catalyzes the conversion of urea and water to carbon dioxide and ammonia. EC 3.5.1.5. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Ureters: Tubes that carry urine from the kidneys to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [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] Urinary tract infection: An illness caused by harmful bacteria growing in the urinary tract. [NIH]

Urinate: To release urine from the bladder to the outside. [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] Urogenital: Pertaining to the urinary and genital apparatus; genitourinary. [EU] Urogenital Diseases: Diseases of the urogenital tract. [NIH] Urography: Radiography of any part of the urinary tract. [NIH] Urokinase: A drug that dissolves blood clots or prevents them from forming. [NIH] Urologic Diseases: Diseases of the urinary tract in both male and female. It does not include the male genitalia for which urogenital diseases is used for general discussions of diseases of both the urinary tract and the genitalia. [NIH] Urologic oncologist: A doctor who specializes in treating cancers of the urinary system. [NIH]

Urologist: A doctor who specializes in diseases of the urinary organs in females and the urinary and sex organs in males. [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] Vaccination: Administration of vaccines to stimulate the host’s immune response. This includes any preparation intended for active immunological prophylaxis. [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] Vaccinia: The cutaneous and occasional systemic reactions associated with vaccination

Dictionary 293

using smallpox (variola) vaccine. [NIH] Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Valine: A branched-chain essential amino acid that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway. [NIH]

Variola: A generalized virus infection with a vesicular rash. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [NIH] Vasodilators: Any nerve or agent which induces dilatation of the 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] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vesicoureteral: An abnormal condition in which urine backs up into the ureters, and occasionally into the kidneys, raising the risk of infection. [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] Vinca Alkaloids: A class of alkaloids from the genus of apocyanaceous woody herbs including periwinkles. They are some of the most useful antineoplastic agents. [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] 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] Virulent: A virus or bacteriophage capable only of lytic growth, as opposed to temperate phages establishing the lysogenic response. [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] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used

294

Bladder Cancer

together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [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]

Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH] Wound Healing: Restoration of integrity to traumatized tissue. [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] Zebrafish: A species of North American fishes of the family Cyprinidae. They are used in embryological studies and to study the effects of certain chemicals on development. [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]

295

INDEX 1 1-phosphate, 296 3 3-dimensional, 186, 218, 241 A Abdomen, 3, 241, 267, 280, 283, 294, 295, 310, 311, 319 Abdominal, 294, 311 Aberrant, 28, 45, 103 Ablation, 51, 65, 83 Acanthosis Nigricans, 10, 12 Acceptor, 283, 293, 315 Acetylcholine, 255, 290, 291 Acetylcysteine, 55 Acid, 244, 247, 269, 272, 292 Acne, 316 Acne Vulgaris, 316 Acoustic, 148 Acrylonitrile, 306 Actin, 81 Acute leukemia, 267 Acute myeloid leukemia, 299 Adaptability, 253, 254 Adduct, 50, 150 Adenine, 180, 242, 302 Adenocarcinoma, 43, 72, 300 Adenosine, 181, 242, 248, 252, 296 Adenosine Triphosphate, 181, 242, 248, 296 Adenovirus, 74, 99, 111, 113, 123, 150, 214, 305 Adhesives, 241 Adipocytes, 259 Adjuvant, 24, 59, 79, 116, 135, 149, 159, 173 Administration, iv, 21, 32, 34, 39, 72, 75, 79, 215, 216, 223, 307, 318 Adrenal Medulla, 267 Adrenergic, 264, 267 Adverse Effect, 85, 281, 308 Aerobic, 288 Affinity, 83, 242, 243, 283, 284, 287, 309 Agar, 257, 296 Age Groups, 25, 40 Aged, 80 and Over, 243 Agonist, 291 Agonists, 82 Alanine, 9 Alcohol Drinking, 115 Alertness, 251

Algorithms, 250 Alkaline, 79, 244, 252, 293 Alkaline Phosphatase, 79 Alkaloid, 291 Alleles, 44, 200, 275, 283, 284 Allergen, 307 Allergic Rhinitis, 251 Allogeneic, 273 Alopecia, 260 Alpha Particles, 243, 302 Alpha-1, 196, 200, 264, 296 Alternative medicine, 258 Alternative Splicing, 79, 300 Amino Acid Sequence, 245, 268, 271 Amino acids, 9, 10, 182, 186, 193, 244, 256, 271, 287, 295, 298, 300, 306, 308, 312, 315, 317 Amino Acids, 9, 10, 182, 186, 193, 244, 256, 271, 287, 295, 298, 300, 306, 308, 312, 315, 317 Aminolevulinic Acid, 118 Ammonia, 317 Amnion, 244 Amniotic Fluid, 209, 212, 244 Amplification, 81, 167 Ampulla, 265 Amygdala, 248, 313 Amygdalin, 148 Anaemia, 285 Anaesthesia, 278 Anal, 266, 269 Analgesic, 277, 281, 312 Analgesics, 133 Analogous, 315 Anaphylatoxins, 258 Anaplasia, 300 Anatomical, 255, 278, 307 Anemia, 194, 196, 199, 205, 226, 251, 256, 269 Anesthetics, 267 Aneuploidy, 193 Angiogenesis Factor, 40, 159 Angiogenesis inhibitor, 245 Animal model, 25, 34, 37, 47, 66, 78, 316 Anions, 281, 312 Annealing, 297 Anode, 245 Anomalies, 313 Antagonism, 252

296

Bladder Cancer

Anterior chamber, 281 Anthracycline, 262, 267 Antibacterial, 292, 310 Antibiotic, 33, 245, 251, 262, 264, 267, 288, 295, 310 Antibiotics, 245 Antibodies, 24, 27, 37, 62, 63, 171, 172, 246, 274, 277, 278, 288, 296, 302 Antibody, 38, 62, 148, 170, 242, 245, 246, 257, 274, 276, 278, 279, 281, 285, 288, 302, 303, 308, 310, 320 Antibody therapy, 62 Anticarcinogenic, 72 Anticoagulant, 300 Anticonvulsant, 286 Antigen, 24, 38, 54, 55, 62, 96, 166, 170, 171, 242, 245, 246, 257, 276, 277, 278, 279, 285, 305, 307 Antigen-Antibody Complex, 246, 257 Antigens, 38, 62, 63, 171, 246, 273, 277, 280, 310 Anti-infective, 276 Anti-inflammatory, 133, 253, 272, 277, 281, 312 Anti-Inflammatory Agents, 253 Antimetabolite, 287 Antimicrobial, 92 Antimitotic, 312 Antimony, 25 Antineoplastic, 56, 252, 260, 271, 287, 288, 297, 319 Antineoplastic Agents, 319 Antioxidant, 80, 247, 293 Antipyretic, 281 Antiviral, 241, 279 Anuria, 282 Anus, 244, 257, 304 Anxiety, 281 Apoptosis, 12, 13, 15, 17, 18, 19, 21, 33, 34, 35, 55, 56, 69, 75, 83, 103, 104, 108, 124, 129, 150, 151, 152, 157, 162, 181, 190, 253, 261 Aqueous, 56, 248, 261, 276 Arachidonic Acid, 283 Archaea, 247, 287 Arginine, 9, 10, 244, 275, 291, 316 Arsenicals, 26 Arterial, 92, 115, 155, 277, 300, 312 Arteries, 247, 250, 260, 289 Arteriolar, 251 Arterioles, 250, 289 Arteriosus, 301

Artery, 247, 301, 306 Articular, 293 Ascorbic Acid, 277 Aseptic, 310 Assay, 27, 36, 59, 73, 75, 87, 96, 99, 100, 133, 257, 317 Astigmatism, 304 Astringents, 286 Astrocytes, 247 Astrocytoma, 272 Asymptomatic, 97 Ataxia, 226, 247, 313 Atrophy, 225, 226 Atypical, 205 Autoimmune disease, 248 Autoimmune Diseases, 248 Autoimmunity, 62 B Bacillus, 96, 103, 105, 116, 130, 170 Bacteria, 28, 48, 111, 180, 187, 192, 245, 246, 247, 259, 265, 268, 273, 287, 297, 303, 310, 314, 315, 318 Bacterium, 259 Barbiturates, 302 Basal cell carcinoma, 45 Basal cells, 248 Basal Ganglia, 247, 248, 272 Basal Ganglia Diseases, 247 Base, 11, 14, 16, 17, 20, 59, 180, 181, 184, 186, 190, 191, 192, 193, 216, 217, 242, 248, 252, 261, 262, 269, 271, 282, 313, 317 Base Sequence, 191, 269, 271 Basement Membrane, 252, 268 Basophils, 273 Benign, 22, 83, 249, 274, 290, 294, 300, 303 Benign prostatic hyperplasia, 83 Benzo(a)pyrene, 35 Beta Rays, 265 Beta-Glucosidase, 148 Bewilderment, 259 Bilateral, 39, 117 Bile, 249, 266, 276, 283 Bile Acids, 249 Bile Acids and Salts, 249 Bioassays, 83 Biochemical, 24, 34, 71, 75, 196, 243, 246, 249, 273, 282, 288, 293, 308 Biological Markers, 72 Biological response modifier, 249, 279 Biological therapy, 274, 285 Biological Transport, 263

Index 297

Biomarkers, 24, 26, 27, 28, 30, 33, 34, 35, 39, 42, 45, 49, 50, 54, 56, 58, 64, 70, 84, 85, 106, 127 Biopsy, 29, 66, 88, 238 Biosynthesis, 308 Biotechnology, 217 Biotransformation, 63 Bivalent, 287 Blastocyst, 258 Blood Coagulation, 250, 252, 314 Blood Coagulation Factors, 250 Blood Glucose, 275 Blood Platelets, 308 Blood pressure, 199, 252, 277, 288, 295, 309 Blood urea, 282 Blood vessel, 7, 83, 202, 245, 250, 252, 254, 255, 265, 280, 281, 284, 286, 295, 309, 311, 313, 314, 318, 319 Blood Vessels, 7, 83, 203, 245, 252, 254, 255, 265, 284, 286, 295, 309, 313, 318, 319 Blot, 26 Body Fluids, 250, 309, 316 Body Mass Index, 102 Bone Marrow, 216, 242, 257, 271, 277, 284, 299, 309, 311 Bone Marrow Cells, 257 Boron, 251, 260 Boron Neutron Capture Therapy, 251 Bowel, 244, 280, 282, 311 Bowel Movement, 311 Brachial, 285 Brachial Plexus, 285 Brachytherapy, 280, 281, 302, 320 Bradykinin, 291 Brain Hypoxia, 313 Brain metastases, 147 Brain Neoplasms, 313 Broad-spectrum, 292 Bronchi, 43, 267, 315 Buccal, 85, 209, 212, 251 Budesonide, 35 C Cadmium, 61, 85, 251 Cadmium Compounds, 251 Cadmium Poisoning, 251 Caffeine, 44, 251, 302 Calcium, 71, 252, 257, 308 Callus, 265 Canonical, 103 Capillary, 251, 319 Capillary Permeability, 251 Carbohydrate, 27, 273, 298

Carbohydrates, 252, 253, 284 Carbon Dioxide, 269, 305, 317 Carboplatin, 117, 151, 153 Carcinogen, 31, 33, 45, 56, 71, 80, 84, 121, 242, 249, 289 Carcinogenesis, 26, 30, 33, 34, 38, 41, 45, 52, 54, 55, 56, 58, 68, 72, 254 Carcinogenic, 25, 27, 46, 48, 49, 55, 279, 291, 292, 299, 317 Carcinogenicity, 80 Carcinogens, 23, 25, 30, 32, 35, 42, 43, 52, 80, 84, 165, 255, 292 Carcinoma, 6, 22, 24, 48, 52, 54, 59, 66, 67, 69, 107, 166, 168, 170, 171, 248, 252, 256, 267, 305, 310, 314, 315 Carcinoma in Situ, 66, 69 Cardiac, 66, 251, 260, 267, 289 Cardiotoxicity, 267 Cardiovascular, 219, 283, 308 Cardiovascular disease, 219 Carotene, 305 Carotenoids, 126, 147 Carpal Tunnel Syndrome, 40 Case report, 253 Case series, 92, 253 Case-Control Studies, 24, 32, 93, 266 Caspase, 74, 124 Catheter, 88, 239 Catheters, 278, 280 Cathode, 265 Cations, 281 Caudal, 298 Caudate Nucleus, 248 Causal, 25, 27, 266 Cause of Death, 166, 168, 262 CDC2, 127 Cecum, 282 Celecoxib, 33 Cell Cycle, 17, 23, 33, 56, 60, 61, 70, 112, 113, 148, 190, 256, 260, 268, 301 Cell Death, 13, 15, 18, 74, 76, 190, 247, 268, 290 Cell Differentiation, 308 Cell Division, 4, 10, 13, 14, 15, 16, 18, 182, 189, 191, 203, 204, 225, 248, 253, 254, 261, 268, 274, 285, 288, 296, 307, 312 Cell membrane, 7, 10, 249, 262, 281 Cell motility, 52, 81, 149 Cell proliferation, 31, 34, 35, 55, 70, 82, 119, 157, 300, 305, 308 Cell Respiration, 288, 305 Cell Survival, 15, 274

298

Bladder Cancer

Central Nervous System, 241, 243, 251, 270, 272, 274, 283, 308 Central Nervous System Infections, 274 Centrifugation, 27 Centromere, 183, 185 Cerebellar, 247, 254, 304 Cerebellar Diseases, 247 Cerebellum, 254, 304 Cerebral, 247, 248, 254, 267, 268, 272 Cerebral Cortex, 247, 268 Cerebral hemispheres, 248, 254, 272 Cerebrovascular, 248, 252, 313 Cerebrovascular Disorders, 313 Cerebrum, 254, 316 Cervical, 47, 88, 107, 165, 254, 285 Cervix, 11, 171, 254 Chemoprevention, 30, 33, 34, 35, 57, 133 Chemopreventive, 33, 35, 55, 56, 59, 69, 78, 80 Chemotactic Factors, 258 Chemotherapy, 24, 29, 31, 57, 59, 75, 77, 79, 91, 92, 115, 116, 124, 128, 130, 131, 135, 151, 152, 153, 155, 156, 157, 158, 159, 160, 165, 170, 173, 257, 285 Chiasma, 260 Chin, 286 Cholesterol, 181, 249, 260, 264 Choline, 97, 134, 135 Cholinergic, 291 Chondrocytes, 10, 269 Choroid, 305 Chromatin, 46, 247, 266, 284, 291 Chromium, 85, 255 Chromosomal, 25, 27, 68, 74, 124, 190, 193, 204, 205, 206, 208, 244, 245, 255, 275, 289, 296, 306, 313 Chromosomal Proteins, Non-Histone, 255 Chromosome Aberrations, 30 Chromosome Fragility, 316 Chronic, 25, 28, 30, 225, 241, 255, 263, 266, 274, 279, 281, 282, 297, 301, 311 Chronic Disease, 282 Chronic leukemia, 274 Chronic renal, 297 Cirrhosis, 274 CIS, 79, 256, 270, 271, 305 Cisplatin, 137, 150, 151, 152, 153, 155, 156, 158, 160, 256 Clear cell carcinoma, 262 Clinical Medicine, 218, 298

Clinical trial, 21, 23, 33, 34, 37, 55, 77, 87, 94, 215, 216, 219, 222, 264, 289, 294, 301, 303 Clinical Trials, 23, 33, 55, 87, 94, 215, 216, 219, 222, 294 Clonic, 286 Cloning, 65, 250 Coagulation, 275 Cobalt, 85 Codon, 74, 136, 188, 256, 271 Codon, Terminator, 256 Codons, 256, 271 Coenzyme, 247 Cofactor, 291, 300, 314 Cohort Studies, 120, 266 Collagen, 47, 76, 249, 256, 269, 297, 299 Colloidal, 265, 287 Colon, 40, 47, 71, 157, 166, 197, 225, 257, 282 Colonoscopy, 199 Colony-Stimulating Factor, 257, 273, 284 Colony-Stimulating Factors, 274 Colorectal, 39, 71, 75, 257, 300 Colorectal Cancer, 39, 71, 75, 257, 300 Combination chemotherapy, 151, 159 Combinatorial, 58 Comet Assay, 58 Complement, 37, 62, 244, 257, 258, 271, 281, 308 Complement Activation, 244 Complementary and alternative medicine, 137, 161 Complementary medicine, 137 Complementation, 75 Complete remission, 305 Compliance, 76, 258 Computational Biology, 222, 224 Computed tomography, 173, 258 Computerized axial tomography, 258 Computerized tomography, 258 Concentric, 291 Conception, 189, 268, 309, 310 Concomitant, 45, 65 Cones, 305 Confounding, 25 Confusion, 196, 263, 317 Conjugated, 148, 170, 259, 261, 306 Conjugation, 65, 250 Connective tissue, 173, 247, 251, 256, 259, 269, 270, 284, 286, 306 Connective Tissue, 173, 247, 251, 256, 259, 269, 270, 284, 286, 306

Index 299

Connective Tissue Cells, 259 Consciousness, 244, 262, 263 Constitutional, 30 Constriction, 92, 183, 185, 281, 307 Consultation, 205, 206, 209, 210 Contamination, 24, 85 Contraindications, ii Contralateral, 304 Control group, 303 Conus, 301 Convulsions, 246 Coordination, 40 Cornea, 273, 311 Corneum, 267 Coronary, 40, 166, 252, 260, 289 Coronary Arteriosclerosis, 289 Coronary Disease, 166 Coronary heart disease, 40, 252 Coronary Thrombosis, 289 Coronary Vessels, 260 Corpus, 295 Cortical, 268, 307, 313 Corticosteroids, 272 Cranial, 274 Craniocerebral Trauma, 248, 274, 313 Creatinine, 260, 282 Creatinine clearance, 260 Crenarchaeota, 247 Cricoid Cartilage, 319 Crossing-over, 304 Cross-Sectional Studies, 266 Cruciferous vegetables, 69, 71 Culture Media, 242 Curative, 170, 313 Curcumin, 148 Cutaneous, 39, 318 Cyclic, 252, 274, 291 Cyclin, 127 Cyclins, 70, 260 Cyclophosphamide, 165 Cystectomy, 59, 88, 98, 102, 126, 127, 128, 131, 149, 151, 154, 158, 170, 173, 302 Cysteine, 10, 241, 261, 312 Cysteinyl, 287 Cystine, 261 Cystitis, 48, 76, 86 Cystoscope, 66, 315 Cystoscopy, 66, 105, 106, 168, 230 Cytochrome, 107, 293 Cytogenetics, 38, 306 Cytokine, 45, 55 Cytokines, 67, 83

Cytoplasm, 179, 180, 181, 187, 188, 247, 249, 253, 261, 266, 284, 287, 291, 306 Cytosine, 41, 180, 302 Cytoskeleton, 172, 287 Cytostatic, 289 Cytotoxic, 63, 74, 83, 302, 303, 308 Cytotoxicity, 83, 115, 135, 148, 256 D Data Collection, 38 Daunorubicin, 264 De novo, 190 Deamination, 317 Death Certificates, 199 Defense Mechanisms, 80 Degenerative, 293 Deletion, 167, 192, 247, 283 Dementia, 194 Denaturation, 297 Dendrites, 290 Dendritic, 286 Deoxyribonucleic, 180, 306 Deoxyribonucleic acid, 180, 306 Deoxyribonucleotides, 262, 271 Depolarization, 308 Dermatitis, 40 Dermatology, 22 DES, 42, 244 Detoxification, 56, 80, 84 Deuterium, 276 Diabetes Mellitus, 275 Diagnostic procedure, 164 Dialysate, 263 Dialyzer, 263, 274 Diastole, 263 Diastolic, 277 Diastolic pressure, 277 Diathesis, 158 Diffusion, 154, 250, 279 Digestion, 27, 249, 280, 283, 311, 318 Digestive tract, 309, 310 Dihydrotestosterone, 304 Dilation, 251 Diploid, 245, 258, 288, 296, 297, 316 Direct, iii, 26, 37, 40, 53, 55, 61, 64, 67, 69, 88, 210, 211, 256, 304 Discrimination, 212, 218 Disease Progression, 93, 174 Disease Vectors, 279 Diseases, 22, 221, 230, 233, 235, 236, 248, 254, 313, 318 Dislocation, 310 Disorientation, 259

300

Bladder Cancer

Disparity, 108, 127 Dissection, 128, 131 Dissociation, 242, 280 Dissociative Disorders, 263 Distal, 281 Diuresis, 251 DNA Topoisomerase, 271 DNA Topoisomerase (ATP-Hydrolysing), 271 Docetaxel, 152, 153, 156 Dopamine, 290, 295 Dorsal, 298 Dorsum, 264 Dose-dependent, 70 Double-blind, 130 Doxazosin, 111 Doxorubicin, 29, 150, 152, 155, 156, 158, 267 Drive, 7, 15, 18, 53, 264 Drug Resistance, 264 Drug Tolerance, 314 Duct, 244, 268, 306 Duodenal Ulcer, 108 Duodenum, 249, 264, 265, 311 Dwarfism, 7, 12, 264, 313 Dyes, 49, 249, 291 Dysplasia, 10, 11, 226 Dystrophy, 226 E Edema, 289 Effector, 37, 73, 241, 257 Efficacy, 29, 31, 33, 34, 56, 60, 67, 80, 99, 111, 156, 158, 264, 316 Ejaculation, 307 Elastic, 88 Elastin, 256 Electric shock, 40 Electrolysis, 245 Electrolyte, 282, 309 Electrolytes, 249, 282 Electrons, 246, 248, 265, 280, 281, 293, 302, 303 Electrophoresis, 257 Elementary Particles, 265, 290, 301 Embryo, 7, 189, 190, 191, 200, 244, 250, 253, 265, 278 Embryogenesis, 31, 265 Emulsion, 269 Emulsions, 242 Encapsulated, 283 Endemic, 28, 310 Endogenous, 42, 72, 80, 114

Endorphins, 290 Endoscope, 88, 265 Endoscopic, 66, 170 Endoscopy, 66 Endothelial cell, 82, 269, 314 Endothelial cells, 82, 269, 314 Endothelium, 265, 291 Endothelium, Lymphatic, 265 Endothelium, Vascular, 265 Endothelium-derived, 291 Endotoxin, 317 Endotoxins, 257 End-stage renal, 255, 297 Enkephalins, 290 Enterohepatic, 312 Enterohepatic Circulation, 312 Enteropeptidase, 316 Environmental Exposure, 38, 43, 46, 48, 57, 72, 249, 292 Environmental Health, 25, 221, 222 Environmental Pollutants, 80, 266 Environmental tobacco smoke, 23, 129 Enzymatic, 46, 252, 258, 260, 297, 305 Enzyme, 60, 76, 79, 176, 181, 243, 249, 256, 263, 264, 266, 271, 272, 274, 283, 291, 295, 296, 297, 300, 308, 311, 312, 313, 315, 317, 319, 320 Enzymes, 23, 44, 49, 55, 61, 84, 109, 181, 191, 243, 260, 286, 290, 294, 295, 300, 315 Eosinophils, 273 Epidemic, 310 Epidemiologic Studies, 39, 40, 249 Epidemiological, 28, 31, 33, 42, 45, 57, 58, 84, 94 Epidermal, 57, 149, 160, 266, 267 Epidermal Growth Factor, 57, 149, 160, 266, 267 Epidermal growth factor receptor, 57, 149, 160 Epidermis, 248, 266 Epidermoid carcinoma, 310 Epigastric, 294 Epinephrine, 242, 290, 317 Epirubicin, 99, 151 Epithelial, 30, 49, 51, 52, 55, 59, 63, 78, 171, 242, 249, 252, 266, 267, 294, 300, 318 Epithelial Cells, 30, 55, 59, 78, 266, 267, 300 Epithelium, 55, 170, 171, 173, 248, 265, 281, 300 Erectile, 295 Erection, 267

Index 301

Erythrocytes, 245, 251, 267, 304, 308 Escalation, 170 Esophagus, 39, 107, 171, 304, 311 Essential Tremor, 226 Estrogen, 105, 267 Estrogen receptor, 105 Ether, 247 Ethnic Groups, 39, 205, 208 Etoposide, 79 Eukaryotic Cells, 53, 67, 253, 278, 293, 317 Euryarchaeota, 247 Evacuation, 282 Evoke, 311 Excitation, 290 Excitatory, 272 Excrete, 246, 282 Exhaustion, 245 Exocrine, 294 Exogenous, 40, 128, 250, 265, 268 Exon, 244 Exons, 244, 268 Expiration, 305 Extensor, 301 External radiation, 268 External-beam radiation, 281, 302, 320 Extracellular, 172, 259, 268, 269, 309 Extracellular Matrix, 259, 269 Extracellular Space, 268 Extremity, 285 Eye Color, 191 Eye Infections, 242 F Family Planning, 222 Farnesyl, 33, 35 Fast Neutrons, 290 Fat, 251, 260, 283, 284, 309 Fathers, 200 Fats, 249, 255 Fecal Incontinence, 278 Feces, 311 Fetus, 208, 209, 212, 216, 299, 311, 318 Fibrin, 250, 313 Fibrinogen, 313 Fibroblast Growth Factor, 7, 9, 10, 12, 34 Fibroblasts, 50, 259 Fibrosis, 76, 191, 194, 199, 226, 307 Filtration, 282 Fixation, 269, 308 Flatus, 270 Flavopiridol, 148 Fluorescence, 53, 66, 105, 118, 120, 121, 127, 133, 269

Folate, 269 Fold, 49, 56, 77 Folic Acid, 71, 269 Foramen, 255 Forearm, 250, 285 Fovea, 269 Frameshift, 192, 317 Frameshift Mutation, 192, 317 Free Radicals, 246, 263 Fructose, 273 G Gait, 254 Gait Ataxia, 254 Gallbladder, 241 Gamma Rays, 289, 302, 303 Ganglia, 241, 290 Ganglia, Parasympathetic, 241 Gangrene, 99 Gap Junctions, 312 Gas, 244, 263, 276, 289, 291 Gastric, 157, 266, 267 Gastrin, 276 Gastrointestinal, 251, 267, 283, 308, 311, 312, 316 Gastrointestinal tract, 283, 308, 316 Gemcitabine, 115, 116, 135, 150, 154 Gene Amplification, 81 Gene Expression, 17, 33, 40, 44, 46, 49, 50, 54, 65, 90, 114, 131, 149, 150, 155, 187, 188, 226, 271, 316 Gene Expression Profiling, 65, 114, 155 Gene Products, rev, 271 Gene Therapy, 57, 66, 67, 74, 79, 99, 213, 214, 215, 216, 242, 271 Genes, env, 198 Genetic Code, 292 Genetic Engineering, 250, 256 Genetic Markers, 38, 40, 46, 87 Genetic testing, 167, 202, 206, 207, 208, 209, 210, 211, 212, 213, 218, 297 Genetic transcription, 299, 315 Genetics, 38, 120, 179, 190, 192, 195, 196, 197, 202, 205, 206, 207, 212, 216, 217, 218, 235, 259, 261, 278, 294 Genistein, 149 Genital, 256, 271, 318 Genitourinary, 86, 168, 318 Genomics, 219 Genotype, 20, 39, 44, 115, 295 Geriatric, 77 Germ Cells, 190, 216, 286, 293, 309, 313 Germline mutation, 190, 272, 275

302

Bladder Cancer

Gland, 284, 294, 296, 299, 300, 307, 311, 314 Glioblastoma, 31, 83 Glioblastoma multiforme, 31 Globus Pallidus, 248 Glomerular, 282 Glomerular Filtration Rate, 282 Glucocorticoid, 251 Glucose, 225, 247, 249, 255, 262, 272, 273, 274, 296 Glucose Intolerance, 262 Glutamate, 272 Glutamic Acid, 9, 269, 290, 299 Glutathione Peroxidase, 307 Glutathione Transferase, 56 Glycine, 9, 13, 14, 244, 290, 308 Glycogen, 296 Glycoprotein, 83, 156, 273, 284, 289, 313, 317 Glycosaminoglycan, 60 Glycosaminoglycans, 63 Glycoside, 244 Glycosidic, 292, 296 Governing Board, 298 Government Agencies, 298 Grade, 12, 34, 60, 61, 69, 72, 82, 168, 173, 272, 273, 300 Grading, 44, 95, 273 Graft, 278 Graft Rejection, 278 Grafting, 278 Gram-negative, 292 Gram-positive, 292 Gram-Positive Bacteria, 292 Granule, 306 Granulocyte, 45, 257, 273 Granulocyte Colony-Stimulating Factor, 45, 257 Granulocyte-Macrophage ColonyStimulating Factor, 257 Granulocytes, 257, 273, 274, 282, 308, 319 Grasses, 269, 274 Growth factors, 7, 274 Guanine, 180, 302 Guanylate Cyclase, 291 H Haematuria, 101 Hair Color, 191, 274 Hair Dyes, 49 Hairy cell leukemia, 39 Haploid, 296, 297 Haptens, 242

Hay Fever, 243 Headache, 251, 274 Headache Disorders, 274 Heart attack, 252 Hematopoietic tissue, 251 Hematuria, 133, 230 Hemochromatosis, 209 Hemodialysis, 117, 263, 282 Hemoglobin, 49, 181, 245, 267, 274, 275 Hemoglobinopathies, 271 Hemoglobinuria, 225 Hemophilia, 200 Hemorrhage, 274, 311 Hemostasis, 308 Hepatoma, 168 Hereditary, 39, 40, 75, 122, 179, 180, 190, 200, 206, 272, 275, 295, 305 Hereditary mutation, 190, 272, 275 Heredity, 182, 241, 270, 271 Hernia, 40 Heterodimer, 51, 78 Heterogeneity, 21, 63, 242, 275 Heterozygote, 167 Histamine, 244 Histamine Release, 244 Histology, 62 Histone Deacetylase, 150 Histones, 46, 182, 255, 275 Homeostasis, 52, 80 Homologous, 243, 250, 260, 271, 275, 307, 308, 312 Hormonal, 39, 71, 248, 285 Hormonal therapy, 285 Hormone, 72, 128, 187, 249, 262, 264, 267, 270, 276, 286, 306, 308, 313, 314 Hormone therapy, 276 Hormones, 40, 187, 255, 267, 272, 276, 293, 313 Horny layer, 267 Humoral, 37, 273, 277 Humour, 276 Hybrid, 276 Hybridization, 27, 59, 95, 122, 276 Hydrogel, 52 Hydrogen, 76, 248, 252, 262, 272, 276, 283, 288, 290, 292, 293, 301, 312 Hydrogen Bonding, 292 Hydrogen Peroxide, 76, 272, 283, 312 Hydrolysis, 249, 250, 256, 295, 298, 301, 316 Hydrophilic, 276 Hydrophobic, 276, 281

Index 303

Hydroxylysine, 256 Hydroxyproline, 256, 277 Hyperopia, 304 Hyperplasia, 28, 69, 83 Hyperreflexia, 37 Hypersensitivity, 243, 283, 306, 307 Hypertension, 22, 252, 264 Hypertrophy, 249, 277 Hypodermic, 88 Hypothalamus, 296 Hypotonic Solutions, 288 Hypoxic, 245 I Ibuprofen, 281 Ileal, 104, 114, 116, 118 Ileum, 277 Imidazole, 42 Immune Complex Diseases, 246 Immune response, 37, 55, 62, 100, 242, 246, 248, 273, 274, 277, 278, 307, 311, 318, 319 Immune Sera, 277 Immune system, 37, 246, 248, 249, 277, 278, 283, 284, 295, 318, 319 Immunity, 54, 62, 86, 243, 315 Immunization, 67, 277, 278, 307 Immunocompetence, 176 Immunodeficiency, 225 Immunodiffusion, 243 Immunoelectrophoresis, 243 Immunogenetics, 103 Immunoglobulins, 63 Immunohistochemistry, 26, 27, 36, 49 Immunologic, 254, 277, 303 Immunology, 242 Immunosuppressant, 287 Immunosuppressive, 260, 272, 278 Immunosuppressive therapy, 278 Immunotherapy, 37, 62, 79, 104, 158, 173, 249 Immunotoxins, 302 Impairment, 268, 278, 286 Implant radiation, 280, 281, 302, 320 Implantation, 258 Impotence, 267 In situ, 27, 58, 66, 68, 88, 120, 121, 127, 133 In Situ Hybridization, 58, 68, 120, 127, 133 In vitro, 26, 28, 33, 38, 45, 53, 60, 64, 67, 69, 73, 75, 79, 81, 82, 84, 107, 152, 157, 169, 271, 278 In vivo, 31, 34, 45, 47, 54, 62, 65, 66, 69, 70, 73, 75, 79, 81, 82, 99, 135, 152, 271, 278, 312

Incision, 280, 300 Incontinence, 278, 311 Induction, 24, 37, 52, 55, 56, 113, 302 Infancy, 219 Infant, Newborn, 243 Infection, 28, 48, 55, 67, 79, 86, 169, 249, 254, 273, 277, 279, 284, 290, 295, 306, 309, 311, 318, 319 Infections, 28, 48, 87, 213, 245 Infiltrating cancer, 280 Infiltration, 76, 92 Inflammation, 28, 76, 83, 86, 99, 215, 241, 246, 262, 268, 269, 283 Informed Consent, 28, 40, 209, 213, 218 Ingestion, 46, 251, 297 Inhalation, 43, 297 Initiation, 26, 43, 80, 87, 299, 315 Innervation, 285 Inorganic, 63, 256 Insecticides, 295 Insight, 75 Instillation, 55, 101, 123, 125, 128 Interferon, 24, 105, 279 Interferon-alpha, 279 Interferons, 279 Interindividual, 58 Interleukin-1, 93 Interleukin-2, 280 Interleukin-3, 257 Internal Medicine, 285 Internal radiation, 281, 302, 320 Interstitial, 48, 86, 251, 280, 281, 320 Intestinal, 266, 285 Intestine, 257, 266, 282, 309 Intestines, 241, 266, 270, 280 Intracellular, 73, 172, 252, 279, 286, 291, 303, 307, 308 Intracellular Membranes, 286 Intracranial Hemorrhages, 313 Intracranial Hypertension, 274 Intravenous, 38, 63, 281 Intravenous pyelography, 281 Intravesical, 29, 37, 38, 55, 74, 76, 79, 95, 96, 99, 101, 114, 115, 124, 125, 153, 154, 169, 170, 173 Intrinsic, 242, 248 Invasive, 29, 33, 36, 42, 47, 50, 54, 59, 68, 69, 73, 87, 88, 90, 91, 99, 100, 106, 113, 115, 116, 117, 119, 123, 126, 128, 129, 131, 132, 150, 151, 153, 155, 157, 158, 159, 160, 168, 171, 173, 277, 279, 285, 300 Invasive cancer, 50, 68, 173, 279

304

Bladder Cancer

Involuntary, 248, 266, 267, 309, 311 Ion Channels, 312 Ionization, 42, 280 Ionizing, 76, 243, 266, 303 Ions, 248, 263, 265, 276, 280, 287 Ipsilateral, 304 Iris, 259, 268, 281 Irradiation, 76, 320 Ischemia, 66, 248 Isoflavones, 152 Isoprenoids, 156, 157 Isothiocyanates, 55 Isotonic, 288 IVP, 230 K Kallidin, 251 Karyotype, 184 Kava, 56 Keratolytic, 297 Ketoprofen, 35 Kidney Cortex, 287 Kidney Disease, 226 Kidney Failure, 194, 266, 282 Kidney Failure, Acute, 282 Kidney Failure, Chronic, 282 Kidney Glomerulus, 281 Kidney Transplantation, 282 Kinetic, 280 Kinetics, 112 L Labile, 257 Laminin, 249 Large Intestine, 257, 280, 282, 304, 309 Larynx, 315 Latency, 32, 34 Latent, 58, 298 Laxative, 242, 265 Lectin, 286, 287 Lenses, 304 Lesion, 29, 125, 283, 317 Lethal, 7, 10, 11, 12, 166, 168, 289 Leucocyte, 243, 283 Leukaemia, 156 Leukemia, 27, 39, 225, 241, 255, 264, 271, 274, 299, 300 Leukotrienes, 283 Ligament, 299, 310 Ligaments, 259 Ligands, 65, 158 Ligation, 117 Light microscope, 47 Linkage, 39, 271

Linkage Disequilibrium, 39 Linkages, 274, 275 Lipid, 255, 293 Lipid Peroxidation, 293 Lipophilic, 42 Lipopolysaccharide, 273 Lipoprotein, 273 Liposomal, 23 Liver, 80, 188, 241, 249, 255, 260, 266, 269, 272, 274, 275, 283, 287, 317 Localization, 26, 51, 66, 73, 170, 278 Localized, 55, 71, 168, 265, 269, 279, 296, 317 Locomotion, 296 Longitudinal Studies, 260 Loop, 275, 283 Loss of Heterozygosity, 167 Luxation, 263 Lycopene, 71 Lymph, 98, 100, 128, 131, 152, 173, 254, 265, 276, 284, 291, 304, 308, 311 Lymph node, 98, 100, 128, 131, 152, 173, 254, 284, 291, 304, 308 Lymph nodes, 100, 128, 254, 284, 291, 308 Lymphatic, 101, 279, 284, 286, 309, 310, 314 Lymphatic system, 284, 309, 310, 314 Lymphocytes, 30, 58, 246, 277, 280, 282, 284, 310, 314, 319 Lymphoid, 39, 245, 277, 282, 284 Lymphoma, 27, 225 Lysine, 9, 10, 275, 276, 316 Lytic, 319 M Macronutrients, 155 Macrophage, 190, 257, 280, 284 Macrophage Colony-Stimulating Factor, 257 Magnetic Resonance Imaging, 173 Malabsorption, 225 Malignancy, 48, 66, 79, 88, 168, 241 Malignant, 17, 24, 28, 31, 39, 49, 52, 54, 56, 61, 71, 80, 108, 165, 168, 171, 225, 242, 246, 252, 272, 290, 293, 300, 303, 306, 313 Malignant tumor, 165, 252, 293 Malnutrition, 248, 289 Mammography, 199 Mandible, 255 Manifest, 88 Maximum Tolerated Dose, 264 Meat, 71 Median Nerve, 252, 285

Index 305

Mediate, 48, 70, 72 Mediator, 280, 308 Medical oncologist, 77, 285 Medical Oncology, 24 Medical Records, 199, 212, 306 MEDLINE, 222 Megaloblastic, 269 Meiosis, 189, 250, 312 Melanin, 281, 286, 295, 317 Melanocytes, 286 Melanoma, 17, 24, 30, 39, 46, 55, 165, 225, 317 Melanosis, 241 Melanosomes, 286 Membrane, 24, 51, 70, 78, 171, 180, 243, 244, 253, 258, 262, 263, 268, 273, 286, 291, 293, 298, 305, 308, 315 Membrane Proteins, 51, 78 Membranes, 79, 246, 286, 288, 291, 294, 297, 309, 313 Memory, 262, 286 Meninges, 254 Menopause, 298 Menstruation, 286 Mental, 204, 206, 208, 254, 255, 259, 262, 263, 286, 301, 307, 317 Mental Health, 301 Mental Processes, 263 Mental Retardation, 204, 206, 208 Mephenytoin, 44 Mercury, 85, 286 Mesencephalic, 304 Mesenchymal, 52, 266, 284 Meta-Analysis, 96, 128 Metabolite, 64, 250, 299 Metallothionein, 61 Metaphase, 250 Metastasis, 26, 45, 60, 66, 69, 81, 82, 111, 119, 128, 157, 159, 287 Metastasize, 31, 287, 307 Metastatic, 24, 33, 36, 63, 69, 70, 81, 82, 90, 124, 130, 152, 155, 159, 166, 170, 171, 173, 287, 307 Metastatic cancer, 69 Methotrexate, 137, 150, 151, 152, 153, 155, 156, 158, 175, 177 Micelles, 29 Microbe, 314 Microbiology, 22, 248 Micronutrients, 155 Microorganism, 256, 319 Microscopy, 53, 249

Microtubules, 294 Migration, 70, 81, 82, 125 Miscarriage, 212 Mitochondria, 76, 180, 181, 194, 200, 288, 293 Mitochondrial Swelling, 290 Mitomycin, 99, 114, 115, 116, 135 Mitosis, 189, 246, 247, 253, 288 Mitotic, 264, 268, 312, 319 Mitotic inhibitors, 264, 312 Modeling, 32, 58, 121 Modification, 271, 302 Molecule, 13, 31, 180, 181, 182, 187, 246, 248, 256, 257, 263, 264, 265, 270, 273, 276, 282, 287, 288, 292, 293, 296, 297, 303, 308, 315, 319 Monitor, 34, 61, 78, 96, 260, 291 Monoclonal, 148, 170, 171, 281, 288, 302, 320 Monoclonal antibodies, 170, 171, 288 Monocyte, 284 Monocytes, 280 Mononuclear, 284, 317 Monosomy, 193, 245 Morphological, 79, 265, 286 Morphology, 53, 66, 88, 247 Morula, 250 Mosaicism, 191 Motility, 73, 81, 253, 308 Motion Sickness, 289 Motor Cortex, 304 Movement Disorders, 313 Mucolytic, 241 Mucus, 289 Multicenter study, 130 Multidrug resistance, 107 Muscle Fibers, 289 Muscle Hypotonia, 254 Muscular Atrophy, 226 Musculature, 310 Mustard Gas, 289 Mutagen, 39, 58, 249 Mutagenic, 52, 80, 291 Mutagens, 25, 42, 270 Myocardial infarction, 289 Myocardial Ischemia, 260 Myopia, 304 Myotonic Dystrophy, 203, 226, 316 N Nausea, 317 NCI, 256, 294 Necrosis, 47, 66, 247, 272, 289

306

Bladder Cancer

Neonatal, 313 Neonatal period, 313 Neoplasia, 68, 225, 300 Neoplasm, 294, 306, 317 Neoplasms, 168, 170, 246, 262, 285, 303, 316 Nephropathy, 282 Nervous System, 203, 254, 285, 290, 312 Networks, 22, 54 Neural, 276 Neuroblastoma, 40 Neurodegenerative Diseases, 248 Neurogenic, 37 Neurologic, 272 Neuromuscular, 241 Neuromuscular Junction, 241 Neurons, 268, 270, 291, 312 Neuropathy, 200 Neurophysiology, 37, 262 Neurotransmitter, 241, 242, 251, 272, 290, 308, 311, 312 Neutrons, 243, 281, 290, 302 Neutrophils, 273 Niacin, 316 Nickel, 85 Nicotine, 43 Nitric Oxide, 76, 96, 120, 291 Nitrogen, 76, 243, 260, 269, 282, 316 Nitrosamines, 84 Node-negative, 173 Norepinephrine, 242, 290 Nuclear, 7, 21, 75, 134, 180, 248, 256, 259, 265, 268, 270, 272, 290, 291, 300, 302, 305 Nuclear Envelope, 180, 291 Nuclear Matrix, 134 Nuclear Pore, 291 Nuclear Proteins, 270, 291 Nuclei, 243, 259, 265, 271, 275, 285, 288, 290, 301 Nucleic acid, 27, 167, 172, 248, 261, 271, 276, 278, 291, 302, 306 Nucleic Acid Hybridization, 276 Nucleic Acids, 167, 172, 248, 261, 276, 291, 302, 306 Nucleus, 13, 15, 18, 180, 181, 182, 187, 194, 214, 216, 247, 249, 255, 260, 261, 262, 266, 268, 270, 284, 286, 288, 290, 291, 301, 311, 313 Nurse Practitioners, 209 O Occult, 34, 68, 173 Occupational Exposure, 41, 48, 165

Odds Ratio, 292, 304 Ofloxacin, 130 Oligosaccharides, 121 Oliguria, 282 Oncogene, 12, 14, 69, 171, 225, 292 Oncogenes, 13, 29, 51, 69, 301 Oncogenic, 14, 52, 65, 69, 301 Oncologist, 285, 318 Oncology, 73, 77, 176, 304 Oncolysis, 292 Oncolytic, 112 Operon, 299 Ophthalmology, 269 Opsin, 305 Optic Nerve, 305 Organelles, 179, 180, 254, 261, 286, 297 Organizations, 231, 234 Osmotic, 288 Ossification, 8 Osteoarthritis, 281 Osteogenic sarcoma, 293 Osteosarcoma, 15, 293, 300 Ovaries, 208, 293 Ovary, 71, 166 Overall survival, 60 Ovum, 320 Oxidation, 246, 250, 261, 272, 283, 293 Oxidation-Reduction, 250 Oxidative metabolism, 283 Oxidative Phosphorylation, 181, 182 Oxidative Stress, 28, 48, 50, 64, 293 Oxides, 272, 293 Oxygen Consumption, 305 Oxygenase, 80 P P53 gene, 22, 300 Paclitaxel, 29, 148, 151, 154, 155, 156 Palliative, 313 Pancreas, 72, 166, 241, 250, 274, 294, 316 Pancreatic, 38, 225, 267 Pancreatic cancer, 38, 225, 267 Papilla, 294 Papillary, 33, 69, 91, 168, 173 Papillary tumor, 34, 69 Papilloma, 305 Parasite, 28 Paroxysmal, 225 Partial remission, 305 Particle, 51, 315 Paternity, 209 Pathologic, 59, 128, 173, 247, 250, 260, 277, 301

Index 307

Pathologic Processes, 247 Pathologies, 88 Patient Advocacy, 60 PDQ, 220, 230, 231, 294 Peduncle, 304 Pelvic, 22, 76, 100, 128, 299 Pelvis, 241, 293, 294, 305, 318 Penicillin, 245, 318 Penis, 99 Peptide, 63, 92, 266, 269, 295, 298, 300, 301 Peptide Library, 63 Perennial, 316 Perineural, 101 Perioperative, 131, 157, 158 Peripheral blood, 30, 58, 279 Peripheral Nervous System, 290, 311 Peripheral Vascular Disease, 46 Pernicious, 285 Peroxidase, 76, 110 Peroxide, 295 Pesticides, 39 Phagocyte, 284 Phallic, 269 Pharmacokinetics, 66 Pharmacologic, 245, 314 Phenotype, 15, 39, 52, 83, 166, 249, 258, 295 Phenotypes, 50, 97 Phenylalanine, 317 Phospholipases, 308 Phospholipids, 268 Phosphorus, 252, 296 Phosphorylase, 131 Phosphorylated, 64, 256 Phosphorylation, 64, 81, 181, 260, 300 Photodynamic therapy, 101, 296 Photosensitizer, 147 Physical Examination, 206 Physiologic, 243, 250, 287, 296, 303 Physiology, 79, 86, 249, 290 Pigment, 284, 286 Pigmentation, 286 Pigments, 256, 297, 305 Pilot study, 36, 39, 78, 88, 124 Pituitary Gland, 268 Plants, 243, 255, 265, 272, 273, 282, 288, 314, 316 Plaque, 51 Plasma, 70, 71, 78, 118, 126, 171, 180, 243, 245, 253, 257, 275, 282, 296, 307 Plasma cells, 245 Plasmid, 270

Plasmids, 67, 87 Plastids, 293 Platelet Activation, 309 Platelet Aggregation, 244, 291 Platelets, 291, 297 Pneumoconiosis, 40 Pneumonia, 259 Pneumonitis, 251 Podophyllotoxin, 268 Poisoning, 40, 286, 289 Polycystic, 226 Polymerase, 46, 104, 297, 299 Polymerase Chain Reaction, 104 Polymers, 311 Polymorphic, 50, 167 Polymorphism, 48, 57, 93, 102, 109, 110, 119, 121, 125, 136, 167, 211 Polypeptide, 244, 256, 266, 276, 320 Polyposis, 40, 257 Polysaccharide, 246, 273 Posterior, 165, 244, 247, 264, 281, 294 Postoperative, 128, 149 Postsynaptic, 308, 312 Post-translational, 27 Potentiates, 280 Potentiation, 309 Practicability, 316 Practice Guidelines, 223, 232 Precancerous, 35, 254, 298 Preclinical, 29, 55 Precursor, 61, 255, 264, 266, 268, 273, 295, 299, 300, 316, 317, 318 Predictive factor, 93 Predisposition, 40, 94, 133, 169 Premalignant, 34, 66, 298, 300 Premenopausal, 39 Prenatal, 208, 211, 212, 265 Preoperative, 105, 149 Presynaptic, 290, 312 Prevalence, 23, 28, 49, 195, 292 Primary tumor, 41, 65, 171, 308 Probe, 27, 47, 88 Prodrug, 79 Progeny, 259 Prognostic factor, 6, 119, 129, 137 Progression, 6, 14, 15, 17, 26, 33, 35, 36, 39, 40, 41, 47, 50, 53, 54, 56, 57, 59, 60, 63, 65, 68, 69, 70, 72, 80, 81, 82, 91, 103, 105, 109, 121, 171, 173, 245, 260, 316 Progressive, 22, 194, 255, 262, 282, 289, 290, 293, 297, 317 Projection, 262, 304

308

Bladder Cancer

Proline, 10, 256, 276 Promoter, 54, 67, 69, 72, 102, 107, 126 Promotor, 79 Promyelocytic leukemia, 316 Prone, 194, 203 Prophase, 250, 312 Prophylaxis, 318 Prospective Studies, 71 Prospective study, 36, 60, 128, 155 Prostate, 24, 27, 39, 40, 53, 65, 71, 72, 80, 83, 86, 97, 111, 123, 129, 134, 136, 158, 166, 171, 176, 225, 249, 250, 300, 315, 316 Prostate gland, 300 Prostatectomy, 128 Prostate-Specific Antigen, 171 Prostatic Hyperplasia, 83, 249 Prostatic Intraepithelial Neoplasia, 72 Protein Conformation, 244 Protein Isoforms, 243 Protein Kinases, 70 Protein p53, 18, 19 Protein-Tyrosine Kinase, 271 Proteoglycans, 249 Proteolytic, 243, 257, 266 Proteome, 27 Prothrombin, 313 Protocol, 40, 44, 87, 215 Protons, 243, 276, 280, 302 Proto-Oncogene Proteins, 294 Proto-Oncogene Proteins c-mos, 294 Protozoa, 259, 287 Proximal, 281 Psoriasis, 289, 301, 316 Psychiatric, 249 Psychiatry, 269, 301 Psychic, 286, 307 Psychoanalytic Theory, 269 Psychology, 263 Public Health, 28, 32, 41, 44, 48, 56, 80, 84, 249 Public Policy, 222 Pulmonary, 250, 282, 283 Pulmonary Artery, 250 Pulmonary Edema, 282 Pulse, 288 Pupil, 259 Purgative, 282 Purines, 248, 308 Pustular, 241 Putamen, 248 Putrefaction, 270 Pyrimidines, 248, 308

Q Quality of Health Care, 316 Quality of Life, 41, 112, 170, 312 Quiescent, 52 R Race, 25, 40, 84, 281, 287 Radiation, 58, 65, 76, 97, 153, 154, 165, 170, 241, 266, 268, 269, 270, 277, 278, 280, 281, 292, 302, 303, 317, 320 Radiation oncologist, 292 Radiation therapy, 154, 165, 241, 280, 281, 302, 320 Radical cystectomy, 59, 92, 100, 101, 112, 114, 117, 125, 130, 159 Radioactive, 171, 276, 278, 280, 281, 288, 291, 292, 302, 303, 317, 320 Radioactivity, 171 Radioimmunotherapy, 303 Radiolabeled, 170, 281, 302, 320 Radiological, 132 Radiology, 303 Radiotherapy, 91, 104, 111, 132, 155, 156, 160, 170, 251, 281, 302, 303, 320 Random Allocation, 303 Randomization, 59 Randomized, 34, 59, 96, 118, 128, 130, 137, 149, 150, 154, 264, 303 Randomized clinical trial, 128 Reabsorption, 266 Reactive Oxygen Species, 64, 80, 303 Reagent, 38, 74 Receptor, 7, 8, 9, 10, 12, 36, 45, 51, 70, 72, 73, 82, 92, 93, 104, 106, 110, 111, 113, 150, 197, 246, 267, 284, 303, 308 Receptor, Macrophage ColonyStimulating Factor, 284 Receptors, Serotonin, 308 Recombinant, 55, 67, 319 Recombination, 20, 74, 259, 271 Rectal, 92 Rectum, 71, 246, 257, 270, 278, 282, 299, 304 Recur, 19, 173 Recurrence, 14, 29, 33, 34, 36, 41, 59, 60, 82, 93, 94, 96, 102, 103, 105, 110, 117, 125, 128, 131, 135, 150, 159, 166, 168, 173, 254 Red blood cells, 294 Red Nucleus, 248 Reductase, 56, 287 Refer, 1, 185, 189, 197, 216, 251, 257, 269, 283, 290, 302, 314

Index 309

Reflux, 51 Refraction, 310 Refractory, 80, 148, 153, 154, 173 Regeneration, 269 Regimen, 69, 147, 264 Regional lymph node, 173 Relapse, 24, 71, 81, 158 Relative risk, 32, 304 Reliability, 46 Remission, 304 Renal cell carcinoma, 23 Renal pelvis, 315 Repressor, 292 Reproductive cells, 193, 204, 205, 272, 275 Reproductive system, 300 Research Support, 40 Resected, 27 Resection, 29, 36, 79, 114, 115, 148, 170, 173, 315 Residual Volume, 76 Respiration, 288, 305 Retina, 245, 305, 306 Retinal, 263, 305 Retinoblastoma, 15, 16, 17, 40, 44, 74, 196, 225, 305 Retinoblastoma Protein, 17 Retinoid, 72 Retinol, 305 Retropubic, 300 Retrospective, 157 Retrospective study, 157 Retroviral vector, 271 Retrovirus, 81 Reversion, 317 Rheumatoid, 281 Rheumatoid arthritis, 281 Rhodopsin, 305 Ribonucleic acid, 187, 306 Ribonucleoproteins, 291, 306 Ribose, 46, 242 Ribosome, 188, 315 Rigidity, 296 Risk factor, 4, 22, 25, 28, 30, 39, 44, 48, 49, 56, 58, 71, 72, 165, 266, 299, 304 Risk Factors, 4, 22, 25, 28, 39, 44, 48, 58, 71, 266 Risk patient, 59, 103 Rod, 248 Rodenticides, 295 Rods, 305 Rubber, 165, 241, 306

S Saliva, 306 Salivary, 294, 311 Sarcoma, 12, 40, 293 Satellite, 86, 89 Scatter, 65, 317 Schizophrenia, 200 Sclerosis, 196, 226 Screening, 17, 26, 59, 66, 89, 95, 98, 102, 117, 168, 172, 199, 208, 209, 211, 231, 256, 294 Sebum, 241 Secondary tumor, 287, 307 Secretion, 241, 264, 266, 276, 307, 318 Secretory, 300, 312 Sedative, 281 Sediment, 29, 41, 307 Sedimentation, 254 Segregation, 304 Seizures, 272, 294, 307 Selenium, 25, 45, 71, 133 Sella, 296 Sella Turcica, 296 Semen, 299, 300 Semisynthetic, 268 Senescence, 65, 75 Sensibility, 244 Sensitization, 162 Sensory loss, 313 Sentinel lymph node, 100 Sequencing, 23, 26, 74, 217, 297 Serine, 13, 300, 301, 316 Serotonin, 111, 290, 303, 316 Serous, 265 Serum, 27, 72, 96, 104, 244, 257, 264, 282 Sex Characteristics, 313 Sex Determination, 226 Sex Ratio, 56 Shock, 265, 308, 315 Side effect, 56, 99, 170, 216, 219, 242, 249, 260, 312, 314 Side effects, 56, 99, 170, 216, 219, 249, 312, 314 Signal Transduction, 13, 71, 308 Signs and Symptoms, 4, 9, 202, 203, 208, 304 Skeletal, 7, 10, 11, 12, 264 Skeleton, 241, 309 Skin Pigmentation, 9 Skull, 9, 10, 313 Small intestine, 264, 276, 277, 280, 316 Smallpox, 318

310

Bladder Cancer

Smooth muscle, 244, 251, 259, 311 Sneezing, 311 Social Environment, 302 Social Work, 205 Sodium, 26, 152, 309 Soft tissue, 251, 309 Solid tumor, 45, 77, 170, 245, 264 Soma, 309 Somatic, 4, 10, 13, 16, 18, 19, 27, 191, 193, 194, 205, 265, 276, 286, 288, 313 Somatic cells, 191, 193, 205, 286, 288 Somatic mutations, 4, 10, 13, 16, 18, 19, 194 Spasmogenic, 244 Specialist, 209, 234 Species, 27, 49, 63, 67, 76, 171, 218, 248, 267, 276, 281, 286, 287, 288, 294, 302, 303, 310, 311, 315, 319, 320 Specificity, 23, 36, 63, 66, 79, 80, 83, 102, 242 Spectrum, 23, 39, 65, 251, 260 Sperm, 189, 190, 191, 193, 203, 204, 205, 208, 216, 255, 272, 275, 305, 309 Spermatozoa, 307 Spinal cord, 247, 254, 255, 285, 290 Spinous, 267 Spleen, 284, 310 Sporadic, 38, 57, 75, 305 Sprains and Strains, 40 Squamous, 24, 43, 48, 62, 81, 171, 267, 310 Squamous cell carcinoma, 43, 267 Squamous Cell Carcinoma, 43, 267 Squamous cells, 310 Staging, 44, 66, 91, 95, 105, 116, 130, 131, 132, 134, 173, 314 Standardize, 87 Sterility, 261 Steroids, 272 Stillbirth, 206 Stimulant, 251, 318 Stimulants, 28 Stimulus, 52, 264, 282, 313 Stomach, 107, 241, 267, 270, 276, 289, 304, 309, 310 Stool, 257, 278, 282 Strand, 167, 180, 257, 297 Stress, 46, 80, 86, 289, 298, 306 Stress incontinence, 86 Stroke, 199, 252 Stroma, 49, 50, 60, 281 Stromal, 49 Styrene, 306

Subacute, 279 Subarachnoid, 274 Subclinical, 279, 307 Submandibular, 311 Submaxillary, 266 Subspecies, 310 Substrate, 81, 283 Sulfur, 272 Sulindac, 35 Superoxide, 76, 312 Superoxide Dismutase, 76 Supportive care, 57, 294 Suppression, 54, 74 Survival Rate, 78, 168, 293 Sympathomimetic, 267 Symphysis, 255, 299 Synapse, 242, 312 Synapsis, 312 Synaptic, 290, 291, 308, 312 Synaptic Transmission, 291, 312 Synergistic, 32, 37, 48, 83, 115 System, 25, 31, 34, 41, 42, 46, 47, 53, 61, 62, 80, 88, 158, 161, 170, 223, 225, 226, 227, 229, 231, 257, 273, 278, 284, 291, 292, 293, 308 Systemic, 54, 78, 148, 159, 160, 250, 267, 279, 315, 318 Systemic therapy, 55, 148 Systolic, 277 T Taxanes, 51, 159 Teichoic Acids, 273 Telangiectasia, 226 Telencephalon, 248, 254 Telomerase, 74, 119, 127, 133 Telomere, 58, 74 Temporal, 25, 47 Teratogenic, 316 Testicular, 30 Testis, 96, 313 Testosterone, 304 Thalamic, 247 Thalamic Diseases, 247 Thalamus, 313 Thanatophoric Dysplasia, 10, 12 Theophylline, 302 Therapeutics, 37, 57 Thermal, 263, 290, 297 Thoracic, 285, 319 Threonine, 301, 308 Threshold, 277, 313 Thrombin, 297, 300, 314

Index 311

Thrombocytes, 297 Thrombomodulin, 300 Thrombosis, 300, 311 Thymus, 42, 277, 284, 314 Thyroid, 171, 208, 314, 317 Thyroid Gland, 208, 314 Thyroid Hormones, 314, 317 Thyroxine, 295 Tissue Polypeptide Antigen, 106 Tolerance, 62, 242 Tomograph, 47 Tomography, 66, 97, 98, 258 Tone, 314 Tonic, 286 Topical, 247, 276, 316 Toxic, 18, 48, 63, 74, 85, 180, 246, 259, 261, 262, 266, 274, 277, 290, 291, 297, 307, 311, 314 Toxicity, 33, 46, 55, 64, 80, 104, 125, 130, 171, 215, 265, 286 Toxicology, 222 Toxin, 314 Toxins, 246, 279, 288, 302 Trace element, 25, 251, 255, 256, 291 Trachea, 251, 314 Transcriptase, 100, 104, 119, 306, 313 Transcription Factors, 189 Transduction, 79, 308 Transfection, 26, 55, 61, 76, 148, 250, 271 Transfer Factor, 277 Transferases, 273 Transitional cell carcinoma, 3, 33, 45, 59, 62, 79, 93, 125, 134, 137, 150, 168, 171, 173 Translating, 83 Translation, 36, 53, 55, 57, 77, 83, 187, 188, 270 Translational, 23, 35, 57, 71, 76, 86, 298 Translocation, 40 Transmitter, 241, 285 Transplantation, 255, 277 Transurethral, 29, 91, 103, 116, 118, 173, 300 Transurethral resection, 91, 103, 116, 118, 300 Transurethral Resection of Prostate, 300 Trauma, 290 Treatment Failure, 166 Treatment Outcome, 75 Trees, 306 Tretinoin, 23 Trinucleotide Repeat Expansion, 203

Trinucleotide Repeats, 316 Trisomy, 193, 245 Trypsin, 53, 100, 266, 320 Tryptophan, 256, 308 Tuberous Sclerosis, 226 Tubulin, 287 Tumor marker, 50, 102, 104, 132, 250, 314, 316 Tumor model, 70 Tumor Necrosis Factor, 125, 129 Tumor suppressor gene, 7, 15, 18, 21, 35, 68, 69, 73, 107, 171, 284, 294, 305 Tumorigenic, 74 Tumour, 17, 106, 114, 115, 118, 158, 292 Typhimurium, 67 Tyrosine, 81, 300 U Ubiquitin, 64, 130 Ulcer, 264 Ultraviolet radiation, 191 Uracil, 302 Urea, 76, 317 Urease, 291 Uremia, 95, 282 Ureters, 280, 281, 318, 319 Urethra, 170, 249, 295, 299, 300, 315, 318 Urinary, 27, 28, 33, 34, 35, 42, 48, 51, 59, 60, 68, 78, 82, 86, 93, 100, 104, 106, 112, 113, 117, 118, 121, 126, 127, 131, 132, 152, 155, 165, 168, 170, 171, 173, 232, 261, 271, 278, 292, 300, 305, 317, 318 Urinary tract, 51, 86, 93, 118, 165, 318 Urinary tract infection, 51 Urinate, 4 Urine, 3, 4, 24, 27, 28, 30, 33, 37, 41, 42, 46, 48, 55, 59, 60, 61, 63, 76, 78, 85, 96, 104, 107, 112, 118, 120, 126, 127, 167, 168, 169, 171, 237, 246, 249, 250, 257, 260, 263, 266, 274, 275, 278, 280, 281, 282, 292, 305, 311, 317, 318, 319 Urogenital, 271, 318 Urogenital Diseases, 318 Urography, 98, 118 Urokinase, 106 Urologic Diseases, 22 Urologic oncologist, 86 Urologist, 106 Urothelium, 28, 48, 51, 52, 54, 55, 59, 61, 63, 66, 69, 78, 171 Uterus, 208, 254, 260, 293, 318 V Vaccination, 318

312

Bladder Cancer

Vaccine, 242, 301, 318 Vaccines, 318, 319 Vaccinia, 55 Vacuoles, 293 Vagina, 254, 262 Valine, 14 Variola, 318 Vascular, 65, 85, 101, 104, 119, 279, 291, 314 Vascular endothelial growth factor, 104, 119 Vasoconstriction, 267 Vasodilator, 251 Vasodilators, 291 Vector, 38, 214, 306, 315 Vein, 280, 291, 306 Veins, 250, 260, 319 Venous, 300 Ventricle, 301, 312 Venules, 250 Vertebrae, 310 Vesicoureteral, 51 Vesicular, 309, 318 Veterinary Medicine, 222 Vinblastine, 137, 150, 151, 152, 153, 155, 156, 158 Vinca Alkaloids, 319 Vincristine, 153 Viral, 12, 61, 67, 112, 123, 213, 241, 270, 271, 292, 306, 315, 317 Viral Regulatory Proteins, 270 Viral Structural Proteins, 270 Virion, 271 Virulence, 314

Virulent, 67 Virus, 112, 214, 271, 279, 296, 305, 306, 309, 315, 318, 319 Viruses, 28, 187, 214, 242, 246, 268, 287, 306, 318, 319 Viscera, 309 Viscosity, 241 Vitreous, 305 Vitreous Body, 305 Vitro, 26, 67, 73, 79, 81, 115, 148, 208, 278, 297 Vivo, 47, 63, 65, 66, 69, 70, 73, 79, 81, 278 Volition, 280 W War, 289 Warts, 297 White blood cell, 190, 245, 273, 274, 284, 288, 296 Windpipe, 314 Womb, 318 Wound Healing, 7, 70, 245, 269 X Xenograft, 31, 92, 245, 316 X-ray, 66, 258, 270, 280, 281, 291, 302, 303, 320 X-ray therapy, 281 X-Rays, 270, 280, 281, 291, 302, 303, 320 Y Yeasts, 295, 320 Z Zebrafish, 31 Zygote, 258, 259, 289 Zymogen, 300, 320