Biography: 

Prior to joining the Arizona Cancer Center and the University of Arizona College of Medicine, Dr. Ablin served consecutively as Director, Scientific Investigation at Tetragenex Pharmaceuticals, Inc. (Park Ridge, NJ), and Director, Immunobiology Unit, Department of Urology and Research Associate Professor of Urology, State University of New York at Stony Brook School of Medicine. He is President of the Robert Benjamin Ablin Foundation for Cancer Research, founded in memory of his father, since 1979. Dr. Ablin received his Ph.D. in Microbiology from the State University of New York at Buffalo in 1967, following which he continued his training in immunology as a United States Public Health Service Postdoctoral Fellow at the Medical School under the late renowned Distinguished Professor Ernest Witebsky. Dr. Ablin recently received the degree of D.Sc., honoris causa, from Lake Forest College, his undergraduate alma mater.

Dr. Ablin discovered prostate-specific antigen (PSA) in 1970, for which he was a nominee for the Lasker Award in 1997. His discovery of PSA led to the development of the PSA test. A pioneer of cryosurgery and the concept of “cryoimmunotherapy” for the treatment of cancer, Dr. Ablin has extensive experience in cancer research, particularly in the study of the development and metastasis of cancer. A member of Phi Beta Kappa and various professional societies, including the American Association for Cancer Research, the American Association of Immunologists, the British Association of Surgical Oncology, the New York Academy of Sciences, and Sigma Xi, he was a founding member and Vice President (1977-80) of the American College of Cryosurgery and served as President (1977-80) of the International Society of Cryosurgery, who named him Honorary Life-Time President in 1980. Dr. Ablin is a Diplomat of the American Board of Clinical Immunology and Allergy and certified by the American Academy of Microbiology in Public Health and Medical Laboratory Microbiology. Cited in several biographical references, including American Men and Women of Science, Who's Who of Emerging Leaders in America and Who's Who in the World, he has been an invited speaker at numerous national and international scientific meetings and has contributed numerous articles to professional journals and texts. Dr. Ablin is co-editor of the book series Cancer Metastasis - Biology and Treatment and serves on the editorial board of several journals, including Clinical and Diagnostic Laboratory Immunology , Current Opinion in Oncology , Experimental Biology and Medicine , International Journal of Oncology and UroOncology .

Summary of Research Activity:

Studies are directed toward: a) ascertaining the role of the inter- and/or intratumoural microenvironment (milieu) in contributing to the development and progression of cancer; b) the differentiation of latent (indolent) cancer from one that is aggrressive and clinically important and should be treated and c) development of response criteria (biological markers) to evaluate the effectiveness of new therapeutic regimens and/or agents for cancer.

Selected Publications: 

• Ablin RJ. An appreciation and realization of the concept of cryoimmunology, p.136.  In Onik GM, Rubinsky B, Watson G and Ablin RJ. (Eds.): Percutaneous Prostate Cryoablation. Quality Medical Publishing, Inc., St. Louis, 1995.
• Ablin RJ. A retrospective and prospective overview of prostate-specific antigen. J. Cancer Res. Clin. Oncol.,  123 :583, 1997.
• Zaviacic M and Ablin RJ. The female prostate and prostate-specific antigen.  Immunohistochemical localization, implications of this prostate marker in women and reasons for using the term "prostate" in the human female.  Histol. Histopathol., 15 :131, 2000.
• Jiang WG, Ablin RJ, Douglas-Jones A and Mansel RE. Expression of transglutaminases in human breast cancer and their possible clinical significance. Oncol. Rep., 10 :2039, 2003.
• Szabo KA, Ablin RJ and Singh G. Matrix metalloproteinases and the immune response. Clin. Appl. Immunol. Rev., 4 :295, 2004.

Collaborative Research: 

• Wen G. Jiang, M.B., B.Ch., M.D., Metastasis & Angiogenesis Research Group, Department of Surgery, Wales College of Medicine, Cardiff University, Cardiff, United Kingdom: Role of select macromolecules in breast and prostate cancer.
• Mukta M. Webber, Ph.D., Departments of Zoology and Medicine, Michigan State University, East Lansing, Michigan: Chemoprevention and treatment of prostate cancer.
• Milan Zaviacic, M.D., Ph.D., D.Sc., Institute of Pathology, Comenius University School of Medicine, Bratislava, Slovakia: Human female prostate.

Biography: 

Summary of Research Activity:

Mechanism of Antigenic Variation in Giardia lamblia and control of VSP expression - G. lamblia trophozoites undergo antigenic variation of a major surface antigen (VSPs). This antigenic variation may explain the chronicity of Giardia infections as well as the ability of trophozoites to infect the intestines of multiple different mammals. The focus of my laboratory has been to determine the molecular mechanism by which antigenic variation occurs and how VSP expression is controlled.

The Genetics of Giardia lamblia - Giardia trophozoites are fairly unique in their possession of two nuclei, which are equivalent by all criteria that have been examined to date. Current evidence from my laboratory and others suggests that the trophozoites are tetraploid, each made up of two diploid nuclei, and that they reproduce asexually. We have developed a DNA:DNA fluorescence in situ hybridization (FISH) to examine similarities and differences between the nuclei.

Giardia genome project - As part of a multi-center project funded by the NIH, we are determining the sequence of the Giardia genome. Our work has included analysis of the vsp genes, RNA polymerase genes, and the histone modification enzymes (acetylase, deacetylase, methylase, and kinase). This work will also help us to develop a better molecular classification system for Giardia.

Mechanism of Antigenic Variation in Giardia lamblia and control of VSP expression - G. lamblia trophozoites undergo antigenic variation of a major surface antigen (VSPs). This antigenic variation may explain the chronicity of Giardia infections as well as the ability of trophozoites to infect the intestines of multiple different mammals. The focus of my laboratory has been to determine the molecular mechanism by which antigenic variation occurs and how VSP expression is controlled.

The Genetics of Giardia lamblia - Giardia trophozoites are fairly unique in their possession of two nuclei, which are equivalent by all criteria that have been examined to date. Current evidence from my laboratory and others suggests that the trophozoites are tetraploid, each made up of two diploid nuclei, and that they reproduce asexually. We have developed a DNA:DNA fluorescence in situ hybridization (FISH) to examine similarities and differences between the nuclei.

Giardia genome project - As part of a multi-center project funded by the NIH, we are determining the sequence of the Giardia genome. Our work has included analysis of the vsp genes, RNA polymerase genes, and the histone modification enzymes (acetylase, deacetylase, methylase, and kinase). This work will also help us to develop a better molecular classification system for Giardia.

Selected Publications: 

• Adam, R., Hunter, G., DiTomasso, J., Comerci, Jr., G. Mucormycosis: Emerging Prominence of Cutaneous Infections. Clinical Infectious Diseases 19:67-76, 1994.

• Strasser, M.D., Kennedy, R.J., Adam, R.D. Rhinocerebral Mucormycosis with Cavernous Sinus Involvement: Successful Medical Therapy with Amphotericin B Lipid Complex. Arch. Intern. Med, 156:337-339, 1996.

• Adam, R.D. The Biology of Giardia lamblia. Clinical Microbiology Reviews, 14:447-475, 2001.

• Yu, L., C.W. Birky, Jr., and R.D. Adam. The Two Nuclei of Giardia each have Complete Copies of the Genome and are Partitioned Equationally at Cytokinesis, in press, Eukaryotic Cell.

• Seshadri, V., A.G. McArthur, H.G. Morrison, M.L. Sogin, and R.D. Adam. Giardia lamblia RNA polymerase II: Amanitin-Resistant Transcription, in preparation.

Collaborative Research: 

Biography: 

B.A .: University of Dublin , Trinity College , Dublin , Ireland 1978
Ph.D. : University of Michigan , Ann Arbor , MI 1984
Postdoctoral : University of Edinburgh , Edinburgh , Scotland 1985
Massachusetts Institute of Technology, Cambridge , MA 1986-88
Genentech, Incorporated, South San Francisco , CA 1988-90

Faculty Positions:

1990-96 Assistant Professor,Department of Molecular and Cellular Biology,University of Arizona , Tucson , AZ.

1996-8/01 Associate Professor,Department of Molecular and Cellular Biology, University of Arizona , Tucson , AZ

10/00-7/02 Lecturer School of Biological Sciences University of Sussex , UK

1/03-5/04 Associate Lecturer,Chichester College and University College , Chichester W. Sussex, UK

8/04- Assistant Professor, Northern Arizona University Flagstaff , AZ

Summary of Research Activity:

The overall goal of our work is to understand how environmental exposure and genetic factors influence the risk of genomic instability in cancer. During cancer development, chromosomes undergo breakages that lead to rearrangements, which are often unstable and consequently result in further breakage and rearrangements. Such events lead to translocations, deletions, inversions etc, and may result in altered gene products and/or changes in gene expression. This, in turn, can affect growth control, and consequently lead to cancer.

The mechanisms by which these events occur are not well understood. We are particularly interested in events that occur at specific sites in the genome. Dr. Ted Weinert's lab at the University of Arizona has established a system for studying events that occur at particular sites in chromosomes of yeast. His lab is studying what features make such sites particularly susceptible to instability. In collaboration with his lab, we are using this system to learn (i) what gene products are important in stabilizing the genome, and (ii) what environmental factors may influence instability. Several gene products are already known from work in the Weinert lab – for example, some of the check-point genes, as well as some of the genes involved in DNA replication. We are using a genetic screen to identify additional genes that, when either mutant or overexpressed, increase genomic instability. These genes will then be analyzed to identify gene products that are normally required to help stabilize the genome. Ultimately, we plan to extend these observations to human cells by determining whether human orthologs of genes identified in yeast cause DNA rearrangements in human cells that are relevant to cancer.

To address the role of environmental factors in genomic instability, we are first asking whether uranium and arsenic increase the levels of instability in yeast. We are particularly interested in arsenic and uranium as, on the Navajo reservation near Northern Arizona University , these are present at elevated levels in the well-water. An abnormally high incidence of various cancers has been reported on the reservation, and it has been suggested that this may be at least partly due to the high levels of arsenic and uranium. We are examining the effects of arsenic and uranium, either alone or in combination, on genomic instability in yeast. In addition, we are testing whether synergisitc effects are seen when arsenic, uranium or both are combined with mutant or overexpressed genes that affect genomic instability. Eventually, we plan to extend these studies to human cells.

Selected Publications: 

Adams , A.E.M. , D. Botstein, and D.G. Drubin. 1989. A yeast actin-binding protein is encoded by SAC6, a gene found by suppression of an actin mutation. Science 243: 231-233.

Adams , A.E.M. , D. Botstein, and D.G. Drubin. 1991. Yeast fimbrin is required in vivo for actin organization and morphogenesis. Nature 354: 404-408.

Honts, J.E., T.S. Sandrock, S.M. Brower, J.L. O'Dell, and A.E.M. Adams . 1994. Actin mutations that show suppression with fimbrin mutations identify a likely fimbrin-binding site on actin. J. Cell Biol. 126:413-422.

Brower, S.M., J.E. Honts, and A.E.M. Adams . 1995. Genetic analysis of the fimbrin-actin binding interaction in Saccharomyces cerevisiae. Genetics 140:91-101.

Sandrock, T.M., J.L. O'Dell, and A.E.M. Adams . 1997. Allele-specific suppression by formation of new protein-protein interactions. Genetics . 147:1635-42.

Sandrock., T.M., S.M. Brower, K.A. Toenjes, and A.E.M. Adams . 1999. Suppressor analysis of fimbrin (Sac6p) overexpression in yeast . Genetics 151: 1287-97.

Whitacre, J.L., D. A. Davis, K.A. Toenjes, S.M. Brower, and A.E.M. Adams . 2001. Generation of an isogenic collection of yeast actin mutants and identification of three interrelated phenotypes. Genetics . 157(2):533-43.

Kandl, K.A., R. Munshi, Ortiz P.A., Andersen, G.R., Kinzy, T.G., and A.E.M. Adams 2002. Identification of a role for actin in translational fidelity in yeast. Molecular Genet. Genomics. 268 (1) 10-18

Collaborative Research: 

Weinert, T.A. AZCC. Using yeast to understand genomic instability in cancer

Dixon , K. UA. Extending studies of yeast genes involved in genomic instability to studies of their orthologs in mammalian cells.

Biography: 

Summary of Research Activity:

Pediatric AIDS is one of the fastest growing aspects of the AIDS pandemic in the United States and worldwide, as a greater number of women in the childbearing age group are infected with HIV-1. Infants born to mothers infected with HIV-1 are at risk of acquiring HIV-1 infection and subsequently developing AIDS. The World Health Organization (WHO) estimates that by the year 2000, 10 million children will have been born HIV infected.

Mother-to-infant transmission of HIV-1 mainly occurs perinatally at an estimated rate of more than 30 percent. In addition, AIDS-related or unrelated cancers can influence HIV-1 transmission and infection in mothers and infants. However, the molecular mechanisms of maternal transmission of HIV-1 are not known, which makes it difficult to define strategies for prevention and treatment of HIV-1 infection in children.

Genetic studies from my laboratory suggested that a minor subtype of maternal virus from the genetically heterogeneous virus population was transmitted to the infant. The minor HIV-1 genotype predominates initially as a homogeneous population in the infant and then becomes diverse as the infant grows older. Moreover, we don't understand the molecular and biological properties of the HIV-1 that is transmitted from mother to infant.

Our hypothesis is that specific molecular and biological properties of HIV-1 are critical determinants of perinatal transmission. A better characterized HIV-1 transmitted from mother to infant will contribute to the understanding of the molecular mechanisms involved in maternal transmission of HIV-1. Furthermore, the elucidation of the viral determinants involved in maternal transmission may allow AIDS researchers to develop methods to prevent mother-to-infant transmission by means of perinatal interventions, such as gene therapy, immunotherapy, antiviral therapy, and a preventive vaccine.

Selected Publications: 

• Ahmad N, Baroudy BM, Baker RC, Chappey C. Genetic analysis of human immunodeficiency virus type 1 envelope V3 region isolates from mothers and infants after perinatal transmission. J Virol 69:1001-1012, 1995.

• Yedavalli VRK, Chappey C, Matala E, Ahmand N. Conservation of an intact vif gene of human immunodeficiency virus type 1 during maternal-fetal transmission. J Virol 72:1092-1102, 1998.

• Yedavalli VRK, Chappey C, and Ahmad N. Maintenance of an intact human immunodeficiency virus type 1 vpr gene following mother-to-infant transmission. J Virol 72:6937-6943, 1998.

Collaborative Research: 

• Ziad M. Shehab, M.D., Department of Pediatrics, College of Medicine.

• Dominick DeLuca, Ph.D., Department of Microbiology and Immunology, College of Medicine.

• Neil Ampel, M.D., Department of Medicine and V.A. Medical Center, Tucson, Arizona.

• Colombe Chappey, Ph.D., NCBI, NLM, National Institutes of Health, Bethesda, Maryland.

Biography: 

Summary of Research Activity:

In collaboration with other faculty members in the Prostate Cancer Research Group, I have been conducting clinically based integrative research in men afflicted with prostate cancer since the early 1980s. My main areas of current interest and of previous accomplishments include the following:

• Studies into using serum PSA levels for the case finding and screening for prostate cancer.
• Studies of the characteristics and clinical correlations of several serum PSA assays.
• Phase I, II, and III studies of sustained release LHRH agonists and the anti-androgen bicalutamide.
• Neoadjuvant and adjuvant approaches for prostate cancer primary therapy.
• Prostate cancer prevention trials.
• Phase I, II, and III studies of new therapies for hormone refractory prostate cancer.
• Studies into the effectiveness of palliative interventions in prostate cancer.
• New approaches in men with micrometastatic prostate cancer.

Selected Publications: 

• Ahmann FR, Citrin DL, DeHaan HA, Guinan P, Jordan VC, Kreis W, Scott M, Trump DL. Zoladex: a sustained release monthly LHRH analogue for the treatment of advanced prostate cancer. JCO 5:912-917, 1987.
• Catalona WJ, Richie JP, Ahmann FR, Hudson MA, Scardino PT, Flanigan RC, DeKernion JB, Ratliff TL, Kavoussi LR, Dalkin BL, Waters WB, MacFarlane MT, Southwick PC. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multi-center clinical trial of 6,630 men. J of Urology 151:1283-1290, 1994.
• Dalkin BL, Ahmann FR, Nagle R, Johnson CS. Randomized study of neoadjuvant testicular androgen ablation therapy before radical prostatectomy in men with clinically localized prostate cancer. J of Urology 155:1357-1360, 1996.

Collaborative Research: 

• Bruce Dalkin, M.D., Associate Professor of Surgery, Chief, Division of Urology.
• Ray Nagle, M.D., Ph.D., Professor of Pathology, Chief, Immunopathology.
• Evan Hersh, M.D., Professor of Medicine, Chief of Immunobiologic Research.

Biography: 

Summary of Research Activity:

Selected Publications: 

Collaborative Research: 

Biography: 

Summary of Research Activity:

After training at the NCI serving on the faculty and at the University of California, San Francisco, he moved in 1975 from UCSF to the University of Arizona Cancer Center, where he served as Director of the Cancer Prevention and Control Program from 1989 to 2005. The hallmark of his research career has been to take promising anticancer and chemopreventive agents, such as a -difluoromethylornithine (DFMO), ursodeoxycholic acid, selenium and sulindac sulfone from basic studies of their pharmacology all the way to the clinic. He has been continuously funded as PI of Program Project grants in colon (CCPPP) and skin cancer prevention since the 1980's. Four areas of his research are:

1. Retinoids in cancer treatment and prevention. Dr. Alberts' group has conducted landmark basic and clinical studies of retinoids (References #'s 65, 79, 94, 124, 129, 130, 163, 168). In a 2,297 patient trial (# 293), they reported that retinol is effective in preventing squamous cell skin cancer. Dr. Alberts helped demonstrate that topically applied all-trans-retinoic acid leads to regression of cervical intraepithelial neoplasia III (moderate dysplasia) (#'s 84, 135, 242). In a recent dose-finding trial of oral Vitamin A in participants with sun-damaged skin, he reported both efficacy and mechanism of action (# 399).

2. Biomarkers of skin carcinogenesis. Dr. Alberts helped to develop a panel of biomarkers for skin carcinogenesis, including proliferating cell nuclear antigen (PCNA), p53, polyamine levels and apoptosis (#'s 290, 324, 359). The biomarkers have been key to subsequent therapeutic trials, such as the demonstration that topical DFMO can prevent formation of actinic keratoses and reverse sun-related DNA damage (# 340). Dr. Alberts' group has developed topically administered chemopreventive agents that can be incorporated into sunscreens (#s 340, 362, 370). In a recent collaboration with Dr. Jeffrey Trent and others, reported in Nature (# 334), gene expression profiles were used develop a novel and clinically relevant taxonomy of malignant melanomas. Dr. Alberts' group has established VEGFR expression in pigmented moles as a biomarker that can differentiate dysplastic from benign nevi (# 434).

3. Prevention of colon cancer. Dr. Alberts has been a pioneer in the use of adenoma recurrence as a surrogate endpoint for preventing colon cancer in large population-based studies. Phase I and II studies of wheat bran fiber (WBF) preceded his negative phase III randomized study of WBF dietary supplementation (#'s 190, 184, 254, 261, 267, 271, 285, 287). The final results of a phase III randomized study of ursodeoxycholic acid (UDCA) for preventing adenoma recurrence in 1,285 randomized participants followed for three years after initial polypectomy revealed a 39% reduction in the recurrence of highly dysplastic polyps (i.e., the ones most likely to advance to invasive colorectal cancers) (#s 301, 420). The rationale for this study came partly from a phase I study demonstrating that UDCA could “washout” deoxycholic acid in fecal water (# 402). Enrollment began in 2002 for a phase III study of celecoxib and selenium, individually and together, to prevent adenoma recurrence in 1,600 patients. Previously, Dr. Alberts helped to oversee the Arizona Cancer Center phase III trial of selenium in 1,302 resected non-melanoma skin cancer patients. A secondary analysis of this trial documented a selenium-associated 56% reduction in risk of colon cancer incidence and a nearly 70% reduction in prostate cancer risk, which led to the 32,000 male SELECT phase III trial (# 278).

In another secondary analysis, a higher intake of Ca 2+ reduced by 45% the rate of adenoma recurrence in the WBF study (# 360). High-dose WBF supplementation failed to reduce secondary bile acid levels in fecal water in patients with resected colon adenomas; this finding may underlie the relative inactivity of WBF as a polyp prevention agent (# 372). A secondary analysis of the WBF trial data in combination with the NCI's high fiber vegetables and fruit phase III polyp prevention trial suggests that male polyp patients (but not female) may benefit from a high fiber diet to prevent polyp recurrence (# 5). Clinically vital new information concerning characteristics of incident adenomas that predict recurrence was also reported ( #s 318, 346).

4. Nuclear karyometric analysis as a biomarker of early neoplasia. In a series of recent papers published in collaboration with Dr. Peter Bartels in the Optical Science Center at the University of Arizona, Dr. Alberts has reported that subtle karyometric features of nuclear chromatin texture and spatial distribution denote very early neoplastic changes in skin, endometrium, ovary, cervix, colon, bladder and breast (#s 299, 352, 344, 347, 392, 357, 364, 380, 392, 393, 398, 408, 410, 421, 425). These statistically significant findings are of potentially great importance because they arise when the early neoplastic and normal cells are otherwise completely indistinguishable by all conventional histological criteria. The nuclear karyometric approach is beginning to have a major impact on identification of individuals at high risk for cancer and as a sensitive biomarker of response to chemopreventive agents (#s 393, 398).

Dr. Alberts has served as the Principal Investigator on NCI's phase I contracts for chemopreventive agent phase I/II clinical trials since the Task Orders were first competed in the early 1990s. His research group, headed by Dr. Sherry Chow, Associate Professor of Pharmacy, was recently awarded a five-year Phase I/II Chemopreventive Agent Consortium agreement worth $7.5 million. He has been the principal investigator on both T32 and R25T Cancer Prevention and Control Training Grants (2002-2010) and has served as a thesis advisor for more than 15 doctoral degree candidates and a major mentor for 17 post-doctoral fellows, including Drs. Gary Goodman (Chair of the Chemoprevention Subcommittee in the Southwest Oncology Group), Scott Lippman (Chair, Department of Thoracic and Head and Neck Cancer, University of Texas – M.D. Anderson Cancer Center), Dr. William Dalton (Director, Lee Moffitt Cancer Center, Tampa) and Dr. Robert T. Dorr (Director of the Developmental Therapeutics Program, Arizona Cancer Center).

Dr. Alberts has made numerous contributions beyond his own research to advancing the cause of cancer prevention. He has served as the Chair of the FDA's Oncologic Drug Advisory Committee (1982-1984), was a member of the NCI's Board of Scientific Advisors (1997-2006), is Co-Editor-in-Chief of Cancer Epidemiology, Biomarkers and Prevention (2002-2007), and Chairs the Cancer Prevention and Control Committee in the Gynecologic Oncology Group (1995-present). He received the American Society of Clinical Oncology ACS Cancer Prevention Award in 1999, the American Association for Cancer Research Joseph Burchenal Eighth Annual Award for Excellence in Clinical Research in 2003 and the American Society of Preventive Oncology Distinguished Career Award in 2003. In 2004, Dr. Alberts received the third annual AACR-Cancer Research and Prevention Foundation Award for Excellence in Cancer Prevention Research which is given annually to a scientist residing in any country in the world for his or her seminal contributions to the field of cancer prevention. Research must have had not only a major impact on the field, but must also have stimulated new directions in this important area. In conclusion, Dr. David Alberts is without question one of the world leaders in the field of cancer prevention research.

Selected Publications: 

Bartels PH, Ranger-Moore J, Stratton MS, Bozzo, P, Einspahr J, Liu Y, Thompson D, Alberts DS: Statistical analysis of chemopreventive efficacy of vitamin A in sun-exposed, normal skin. Analyt Quant Cytol Histol 24:185-197, 2002.
Alberts DS, Dorr RT, Einspahr JG, Aickin M, Saboda K, Xu MJ, Peng YM, Goldman R, Foote JA, Warneke JA, Salasche S, Roe DJ, Bowden GT: Chemoprevention of human actinic keratoses by topical 2-(difuoromethyl-dl-ornithine. Cancer Epidemiol Biomarkers Prev 9:1281-1286, 2000.
Alberts DS, Martínez E, Roe D, Guillen-Rodriguez MS, Marshall J, van Leeuwen B, Reid M, Ritenbaugh C, Vargas P, Bhattacharyya AB, Earnest D, Sampliner R, and the Phoenix Colon Cancer Prevention Physicians' Network. Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal adenomas. NEJM, Vol. 342:1156-1162, April 20, 2000.

Collaborative Research: 

Peter Bartels, Ph.D., Optical Sciences: nuclear chromatin texture analysis of precancerous lesions in the breast, colon, endometrium, ovary, prostate and skin.
Janine G. Einspahr, Ph.D.: immunohistochemical biomarkers in colon, breast, endometrium, cervix, and prostate intraepithelial neoplasias and cancers.
G. Timothy Bowden, Ph.D., Radiation Oncology: UV carcinogenesis in animals and humans.
Eugene Gerner, Ph.D., Radiation Oncology: colon carcinogenesis and chemoprevention in animal models.
Robert T. Dorr, Ph.D., Department of Pharmacology: development of topical chemoprevention agents.
Jeffrey Trent, Ph.D., President of T-GEN (Translational Genomics Research Institute), Phoenix: chemopreventive agents that hit specific molecular targets in non-melanoma and melanoma skin cancers.
Dennis Ahnen, M.D., University of Colorado Cancer Center: molecular colon carcinogenesis.
Stanley Hamilton, M.D., University of Texas, M.D. Anderson Cancer Center: molecular colon carcinogenesis.
Jean Pierre Issa, Ph.D., University of Texas, M.D. Anderson Cancer Center: gene methylation in colon adenomas and cancers and colonic mucosa.
Gerald Salen, Ph.D., University of New Jersey Medical and Dental School: fecal bile acids and colon carcinogenesis.
Xiao Xu, Ph.D., University of Texas, M.D. Anderson Cancer Center: retinoid receptors in human skin.
Steven P. Stratton, Ph.D., Department of Medicine: phase I studies of chemopreventive agents.
Sherry Chow, Ph.D.: phase I and II studies of chemopreventive agents
Zigang Dong, Ph.D., Hormel Institute, University of Minnesota: mechanisms of UVA-induced skin cancer in mice and humans.

Biography: 

Summary of Research Activity:

Selected Publications: 

Collaborative Research: 

Biography: 

Summary of Research Activity:

Selected Publications: 

Collaborative Research: 

Biography: 
Terry Badger has worked at the University of Arizona College of Nursing since 1986. She came to UA after completing her PhD from The University of Texas, Austin.   Her research interests focus on psychosocial issues in cancer. She is currently testing a telephone counseling intervention with women with breast cancer and their partners.

Summary of Research Activity:

Ongoing Research Support

Badger (PI)                                                                     2003-2005
NINR, NIH
1 R15NR008001-01A1
Telephone Intervention:  Rural Women w/Cancer & Partners
The purpose of this study is to test the effectiveness of the telephone interpersonal counseling intervention
compared to an exercise intervention and control group on symptom management (depressive symptoms and fatigue) and quality of life in rural women with breast cancer and their partners

Selected Publications: 

Badger, T.A., Segrin, C., Meek, P., Lopez, A.M. & Bonham, E.  (2004).  Responders and nonresponders to a telephone interpersonal counseling intervention in women with breast cancer.  Journal of Psychosocial Oncology, 13 (supplemental), S40 .

Badger, T.A., Segrin, C., Meek, P., Lopez, A.M. & Bonham, E.  (2004).  A case study of telephone interpersonal counseling with a woman with breast cancer and her partner. Journal of Psychosocial Oncology, 13 (supplemental), S59-60 .

Badger, T.A., Segrin, C., Meek, P., Lopez, A.M., & Bonham, C. (i2004). A case study of telephone interpersonal counseling with women with breast cancer and their partners.  Oncology Nursing Forum, 31 (5), 997-1003.

Badger, T.A., Gelenberg, A., & Berren, M. (2004).  Consultative intervention to improve outcomes of high utilizers in a public mental health system. Perspectives of Psychiatric Care, 40, 53-69.

Badger, T.A., Segrin, C., Meek, P., Lopez, A.M., Bonham, E. & Sieger, A.  (2005). Telephone interpersonal counseling with women with breast cancer: Symptom management and quality of life.  Oncology Nursing Forum, 32 (2), 273-279.

Bennett, G. & Badger, T.A. (2005).  Depression in men with prostate cancer: A Review. Oncology Nursing Forum, 32 (3), 545-556.

Badger, T.A., Segrin, C., Meek, P., Lopez, A.M., & Bonham, E. (in press)  Profiles of women with breast cancer: Who responds to a telephone interpersonal counseling intervention? Journal of Psychosocial Oncology.

Segrin, C., Badger, T.A., Meek, P., Sieger, A.  & Lopez, A.M. (In press). Interpersonal Well Being and Mental Health Among Male Partners of Women with Breast Cancer. Issues in Mental Health Nursing

Segrin, C., Badger, T.A., Meek, P., Lopez, A.M., Bonham, E., & Sieger, A.  (in press) Dyadic interdependence on affect and quality of life trajectories among women with breast cancer and their partners.  Journal of Social and Personal Relationships.

Collaborative Research: 

Biography: 

Summary of Research Activity:

Selected Publications: 

Collaborative Research: 

Biography: 

Summary of Research Activity:

Selected Publications: 

Collaborative Research: 

Biography: 

Summary of Research Activity:

Selected Publications: 

Collaborative Research: 

Biography: 

Summary of Research Activity:

Selected Publications: 

Collaborative Research: 

Biography: 

Summary of Research Activity:

My research is directed at the development of knowledge-guided procedures in diagnostic histopathology in two major areas: the implementation of a fully autonomous machine vision system for the evaluation of histo-pathologic sections, and the design of diagnostic decision support systems for histopathology.

The machine vision system allows automated detection and delineation of regions of histologic abnormality in a section; automated scene segmentation followed by histometric and karyometric diagnostic clue extraction; and determination of a numeric, statistically secured progression index for a lesion. This system has been implemented for the processing of colonic lesions, prostatic intraepithelial neoplastic lesions (PIN), malignant lesions of the prostate, breast lesions, and non-melanoma lesions of the skin.

The diagnostic decision support systems are based on inference networks augmented by automated reasoning for process control. These systems have been applied to the assessment of fine needle aspirate specimens from the breast, sections of PIN lesions and malignant prostatic lesions, and benign proliferating lesions of the breast. The systems also are used in the development of decision procedures in automated primary screening devices for cervical cancer.

Selected Publications: 

• Bartels PH, Gahm T, Thompson D. Automated microscopy in diagnostic histopathology: from image processing to automated reasoning. International Journal of Image Systems and Technology 8:214-223, 1997.
• Bartels PH, Thompson D, Montironi R. Knowledge-based image analysis in the precursors of prostatic adenocarcinoma. Eur Urology 30:234-242, 1996.
• Bartels PH, Thompson D, Weber JE. Diagnostic and prognostic decision support systems. Pathologica 87:115-130, 1995.

Collaborative Research: 

• R. Montironi, M.D., Dept. of Pathology, University of Ancona, Italy: quantitative histopathologic assessment of prostatic lesions.
• G.M. Mariuzzi, M.D., Dept. of Pathology, University of Verona, Italy: benign proliferative lesions of the breast.
• P. Hamilton, Ph.D., Dept. of Pathology, Queens University, Belfast, U.K.: decision support systems in histopathology.
• J. Sloan, M.D., Dept. of Pathology, Queens University, Belfast, U.K.: quantitative assessment of adenomatous colonic lesions.
• W. Abmayr, Ph.D., Dept. of Informatics, University of Munich, Germany: inference networks in diagnostic decision support systems.

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At least 90 percent of colorectal cancer deaths can be attributed to lifestyle factors, including diet and smoking, and are potentially preventable. A high-fat diet is a likely major cause of colon cancer. Bile acids are produced by the body to aid in digestion of fats and are known to be promoters of colon cancer. Cells that are excessively damaged by bile acids undergo a controlled process of cell death referred to as apoptosis. This process is beneficial to the body because it removes cells with unrepaired DNA damages; such damaged cells, when allowed to survive, tend to mutate and give rise to cancer. While we and others have found that colonic cancer cells are defective in apoptosis, we also found that the normal-appearing, flat colonic tissue of individuals in high-risk groups is deficient in its ability to undergo apoptosis as well. This appears to be a precancerous change in these high-risk individuals.

We have found that bile acid treatment of cells induces changes in the levels of proteins involved in the cell's response to stress. These protein changes may reflect an effort by the cell to protect itself against damages that otherwise would cause apoptosis, or they may be part of the pathway of apoptosis itself. The apoptosis-resistant cells that are found in normal-appearing colonic tissue of high-risk individuals would be expected to differ from apoptosis-competent cells in the expression of these stress proteins. Since the expression of these specific proteins can be measured accurately and specifically using an automated staining system and computerized imaging program in routinely prepared biopsy specimens, we hypothesize that they should prove useful as biomarkers for colon cancer risk.

We have chosen seven specific genes that we expect may have an altered level of expression in cells resistant to apoptosis. We have shown that each of these gene products is induced by bile acids. The seven gene products to be examined are GRP78 and Hsp70 (chaperone proteins responsive to protein unfolding); NFkB and c-fos (responsive to oxidative stress); GADD153 and PARP (responsive to DNA damage); and iNOS (elevated in colon cancers). A major goal of our research is to test the feasibility of using altered patterns of expression of these genes as a practical biomarker for assessing colon cancer risk. We also expect our research to significantly increase our understanding of the early stages of colon carcinogenesis before gross lesions are detectable.

Selected Publications: 

• Bernstein C, Bernstein H, Garewal H, Dinning P, Jabi R, Sampliner RE, McCuskey MK, Panda M, Roe D, L'Heureux L, Payne CM. A bile acid-induced apoptosis assay for colon cancer risk, and associated quality control studies. Cancer Res 59:2353-2357, 1999.
• Washo-Stultz D, Hoglen N, Bernstein H, Bernstein C, Payne CM. Role of nitric oxide and peroxynitrite in bile salt-induced apoptosis: relevance to colon carcinogenesis. Nutrition and Cancer 35:193-202, 1999.
• Crowley CL, Payne CM, Bernstein H, Bernstein C, Roe D. The NAD* precursors, incotinic acid and nicotinamide protect cells against deoxycholate induced apoptosis, increase levels of glyceraldehyde-3-phosphate dehydro-genase and decrease constitutive levels of activated NF-kB and GRP78. Cell Death Diff. 7:314-326, 2000.

Collaborative Research: 

• Claire Payne, Ph.D., Microbiology and Immunology: resistance to bile acid induced apoptosis
• Carol Bernstein, Ph.D., Microbiology and Immunology: resistance to bile acid induced apoptosis
• Harinder Garewal, M.D., Ph.D., Medicine: resistance to bile acid induced apoptosis
• Richard Sampliner, M.D., Medicine: resistance to bile acid induced apoptosis

Biography: 

Summary of Research Activity:

• Our laboratory provides comparative pathology support for the characterization of rodent models of cancer, with an emphasis on genetically-modified murine models of gastrointestinal cancer.

Selected Publications: 
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• Gerner EW, Ignatenko NA, Besselsen DG . (2003). Preclinical Models for Chemoprevention of Colon Cancer. Recent Results in Cancer Research 163: 58-71.

• Boivin GP, Washington K, Yang K, Ward JM, Pretlow TP, Russell R, Besselsen DG , Godfrey VL, Doetschman T, Dove WF, Pitot HC, Groden J, Coffey RJ. (2003). Pathology of mouse models of intestinal cancer: Consensus report and recommendations. Gastroenterol. 124:762-777.
• two genetically altered rodent models of gastrointestinal carcinogenesis involves deregulation of polyamine synthesis. In: COST 917: Biogenically Active Amines in Food, volume III, Polyamines, the Gut and Cancer (Milovic V and Stein J, eds), Office for Official Publications of the European Communities, Luxembourg .
  
• Wu RS, Kobie JJ, Besselsen DG , Font TC, Mack VD, McEarchern JA, Akporiaye ET. (2001). Comparative analysis of IFN- g , B7.1 and antisense TGF-ß gene transfer on the tumorigenicity of a poorly immunogenic metastatic mammary carcinoma. Canc. Immunol. Immunotherapy 50:229-240.
  
• McEarchern JA, Kobie JJ, Mack V, Wu RS, Meade-Tollin L, Arteaga CL, Dumont N, Besselsen D , Seftor E, Hendrix MJ, Katsanis E, Akporiaye ET. (2001). Invasion and metastasis of a mammary tumor involves TGF- b
  signaling. Inter. J. Canc. 91(1):76-82.
  
• McEarchern JA, Besselsen DG , Akporiaye ET. (1999). Interferon- g and Antisense TGF- b Transgenes Synergize to Enhance the Immunogenicity of a Murine Mammary Carcinoma. Canc. Immunol. Immunotherapy 48:63-70.

Collaborative Research: 

• Emmanuel Akporiaye, Ph.D. Microbiology & Immunology
• Eugene Gerner, Ph.D. Radiation Oncology
• Natalia Ignatenko, Ph.D. Radiation Oncology
• Peter Lance, M.D. Medicine
• Jesse Martinez, Ph.D. Radiation Oncology
• Claire Payne, Ph.D. Microbiology & Immunology
• Mark Nelson, Ph.D. Pathology

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Developmental regulation of the cell cycle; DNA replication; Drosophila as a cancer model.

Our lab is interested in understanding how cell cycle events (such as DNA replication, chromosome segregation and cell growth and cytokinesis) are controlled and modified by development. In multicellular organisms, the ordered events leading to cell proliferation are developmentally constrained or modified so as to be coordinated with important steps in tissue formation. Without these constraints, tissues would fail to grow appropriately, fail to fully develop, and possibly become refractory to anti-proliferative signals. Despite the fundamental role development plays in modifying cell cycle control, there is little known about the factors that coordinate cell cycle events with the spatial and temporal constraints of development. In many human cancers, these constraints have been lost and cells undergo unchecked proliferation. We would like to understand how tissue specific cell cycles are regulated, and thus shed light on how tissue specific tumors arise in humans.

Although we are interested in many aspects of the cell division cycle, our current studies are focused on the control of DNA replication in the Drosophila ovary. Ovarian follicle cells undergo two striking developmentally controlled cell cycle modifications. First, the follicle cells undergo three endo cycles (repeated rounds of DNA replication in the absence of mitosis and cytokinesis ). Second, in response to unknown developmental signals these cells synchronously initiate a gene amplification event that continues to increase the copy number of four different loci. These four sites re-initiate replication while all other genomic replication origins are inactive. Thus, this system will allow us to answer fundamental questions about DNA replication and how it is differentially controlled during development. We have discovered that the Drosophila homolog of the human retinoblastoma tumor suppressor (pRB) is involved in controlling both endo cycles and gene amplification. However, we do not know what developmental factors regulate the fly pRB pathway and instruct cells to shut off DNA replication. We are using a combination of genetic, biochemical, and cell biological techniques to answer these questions. We are also developing genomic and proteomic technologies to address this fundamental problem in biology. In the future, we plan to use Drosophila as a tool for large scale drug screening projects in order to identify novel compounds that can potentially be used for cancer therapy.

Selected Publications: 

Bosco, G., and J.E. Haber. 1998. Chromosome break induced DNA replication leads to non-reciprocal translocations and telomere capture. Genetics 150: 1037-1047.

Royzman, I., R.J. Austin, G. Bosco, S.P. Bell, and T.L. Orr-Weaver. 1999. ORC localization in Drosophila follicle cells and the effects of mutations in dE2F and dDP. Genes and Development 13: 827-840.

Orr-Weaver, T.L., I. Royzman, and G. Bosco. 2000. Regulation of replication initiation during the development of Drosophila. In: Cell Division and the Replicon (Fangman, W., T. Kashimoto, M. Kohiyama, and C. Coath, Eds.). Human Frontier Sciences Program, Workshop IX, 112-120.

Lee, L.A., L.K. Elfring, G. Bosco, and T.L. Orr-Weaver. 2001. A genetic screen for suppressors and enhancers of the PAN GU cell cycle kinase identifies Cyclin B as a critical target . Genetics 158: 1545-1556.

Bosco, G., W. Du, and T.L. Orr-Weaver. 2001. DNA replication control through interaction of E2F-RB and the Origin Recognition Complex. Nature Cell Biology 3: 289-295.

Bosco, G., and T.L. Orr-Weaver. 2002. Cell cycle control during Drosophila oogenesis and early embryogenesis. In: Regulation of Gene Expression at the Beginning of Animal Development (DePamphilis, M.L., Ed.). Elsevier Science.

Royzman, I., A. Hayashi-Hagihara, K.J. Dej, G. Bosco, J.Y. Lee, and T.L. Orr-Weaver. 2002. The E2F cell cycle regulator is required for Drosophila nurse cell DNA replication and apoptosis. Mechanisms of Development 119: 225-237.

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Biography: 

College
University of Maryland ; B.A. Biological Sciences; 5/75

Medical
University of Maryland School of Medicine; M.D. 5/79

Internship
Stanford University Medical Center ; 7/79 to 7/80

Residency
Stanford University Medical Center ; 7/80 to 7/81

Fellowship
Stanford University Medical Center ; (Surgical Pathology) 7/81 to 7/82

Research Fellowship
Stanford University Medical Center ; 7/82 to 7/84

Management
Loyola College of Maryland ; M.B.A., Business Administration; 5/91

Summary of Research Activity:

Dr. Bostwick is the President and Medical Director of Bostwick Laboratories. He is internationally renowned with more than two decades of experience and interest in prostate cancer, bladder cancer, and urologic diseases . He was formerly a Professor of Pathology and Urology at the Mayo Clinic (1991-1999), and left in June 1999 to found Bostwick Laboratories and join the clinical faculty of the University of Virginia , Charlottesville . Dr. Bostwick has partnered with White Plains Hospital Center to offer expert second opinion. In 2005, the Richmond , Virginia Chamber of Commerce recognized Bostwick Laboratories as the fastest growing enterprise in the area for the last five years (number one ranking in “Rising 25” competition).

Dr. Bostwick has authored thirteen books, more than 25 book chapters, and more than 400 papers. His textbook, Urologic Surgical Pathology , (WB Saunders, 1997) is the best selling book in Uropathology. Dr. Bostwick published more papers with the keywords “prostate cancer” in the past decade (1990-2000) than any other investigator (independent MedLine review, 2001). He is also the most sought-after pathologist for second opinions in prostate pathology.

Dr. Bostwick serves as an advisor to the American Cancer Society, the National Cancer Institute Task force on Prognostic Factors in Prostate Cancer, and the Cancer Committee of the College of American Pathologists . He is also on the editorial board of ten journals, and is Founding Editor (1991-1997) of the Journal of Urologic Pathology. He is past President of the International Society of Urological Pathology. His most recent book the American Cancer Society's "Complete Guide to Prostate Cancer" is currently a best-seller.

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Biography: 

Ohio Wesleyan University , BA Chemistry, Cum Laude, 1967

University of Wisconsin , Ph.D. Experimental Oncology, 1974

Summary of Research Activity:

My research involves studies of gene alterations that occur during multistage development of cancers. We also are studying the functional role of these gene changes in the development of cancers. Through these basic studies, we are collaborating with clinical scientists to develop new strategies for the chemoprevention of human cancer.

A major focus of our research is on a class of proto-oncogenes that encode for transcription factors of the jun and fos families. These encoded proteins bind to each other (i.e., Jun-Jun or Jun-Fos dimers) to form a transcription factor complex called "activator complex 1" or AP-1. AP-1 is known to bind and transactivate genes that are involved in cell growth and tumor cell invasion. It has been shown that repeated, transient activation of AP-1 plays a role in tumor promotion. Our laboratory has obtained evidence that sustained AP-1 activity plays a role in the maintenance of the malignant phenotype. In the case of tumor promotion, repeated activation of AP-1 may lead to sustained cell proliferation, and constitutive AP-1 activity in malignant cells could lead to invasive and metastatic phenotypes.

Our studies of AP-1 in tumor promotion and progression are carried out in a mouse skin model of multistage carcinogenesis. We have been investigating mechanisms whereby the skin tumor-promoting agent, okadaic acid, a phosphatase inhibitor, mediates AP-1 activation in mouse keratinocytes. We found that the okadaic acid increase in AP-1 DNA binding was through increased expression of JunB, JunD, and FosB. This increase in expression was, in part, through transcriptional activation of the jun and fos genes. We are studying the transcriptional regulation of the junB by okadaic acid. We also have demonstrated that AP-1- mediated transcriptional activation is through altered phosphorylation of JunD and FosB proteins.

In a collaborative effort, we have been investigating UVB-induced signal transduction in mouse and human keratinocytes leading to AP-1 activation and enhanced expression of cyclo-oxygenase-2 gene (COX-2). We have demonstrated that UVB-induced AP-1 activation is mediated through increased binding of JunD and c-Fos to AP-1 consensus DNA sequence. We found that UVB mediates AP-1 activation and COX-2 expression through two signaling pathways, p38 MAP kinase and PI-3 kinase. We also have found that certain natural products, perillyl alcohol and epigallocatechin-gallate, block UVB-induced signaling pathways leading to AP-1 activation and COX-2 expression. These agents have been shown to inhibit UVB-induced mouse skin carcinogenesis and will be tested in human clinical trials for chemopreventive activity. We have investigated UVA induced anti-apoptotic signaling involving the Bcl-X L protein in keratinocytes. We found that UVA induces the stabilization of the Bcl-X L mRNA through the 3'UTR and ARE sites within this region of the mRNA.

Finally, in a collaborative effort, we have been investigating paracrine regulation of the matrix metallo-proteinase (MMP), matrilysin, in human prostate tumor cells. We have demonstrated that interleukin-1 and fibroblast growth factor can transcriptionally up-regulate the expression of matrilysin in prostate tumor cells. We are also investigating the cleavage of certain laminin proteins (i.e. laminins 5 and 10) located in the prostate by the trans-membrane MMP, MT1-MMP, which is overexpressed in prostate cancer. We have found that cleavage of both laminins by MT1-MMP enhances the migration of prostate carcinoma cells.

Selected Publications: 

Bowden GT. Prevention of non-melanoma skin cancer by targeting ultraviolet-b-light signaling. Nature Reviews Cancer , 4:23-35, 2004.

Bachelor MA and Bowden GT . Ultraviolet A-induced modulation of Bcl-X L by p38 MAPK in human keratinocytes. Journal of Biological Chemistry , 279:4142658-68, 2004.

Bachelor MA, Cooper SJ, Sikorski ET, Bowden GT . Inhibition of p38 MAPK and PI3-kinase decreases UVB-induced AP-1 and COX-2 in a SKH-1 hairless mouse model. Molecular Cancer Research , 3(2):90-99, 2005.

Bair EL, Chen M-L, McDaniel K, Sekiguchi K, Cress AE, Nagle RB, Bowden GT . Membrane-type-1 matrix metalloprotease cleaves laminin-10 and promotes prostate cancer cell migration. Neoplasia , in press, 2005.

Collaborative Research: 

• Zigang Dong, Ph.D., Hormel Institute, University of Minnesota, Austin, Minnesota: UVB signal transduction.
• David S. Alberts, M.D., Internal Medicine: chemoprevention of human skin cancer.
• Raymond Nagle, M.D., Ph.D., Pathology: matrix metalloproteinases and human prostate cancer.
• Anne E. Cress, Ph.D., Cell Biology and Anatomy: matrix metalloproteinases, integrins and human prostate cancer

Biography: 

Summary of Research Activity:

My laboratory's research objective is to elucidate relationships between oxidative stress and disease processes, particularly cancer. Specifically, we are investigating the regulation of apoptosis by the redox state of the cell. Cellular redox state is determined by the sum of prooxidants (e.g., the levels of reactive oxygen species) and antioxidants (e.g., proteins like catalase and small molecules like vitamin E) in the cell. Cancer cells have frequently undergone changes consistent with an altered ability to handle oxidative stress. Genetic differences in proteins that protect cells against oxidative stress have been associated with an increased risk of cancer. Epidemiological studies suggest that a diet rich in fruits and vegetables confers a lower risk of cancer. One idea is that the high antioxidants content of fruits and vegetables is protective, although definitive studies to prove this have not yet been conducted. Another untested idea is that cancer patients should avoid taking antioxidant supplements while undergoing chemotherapy, as the antioxidants may oppose the action of the anticancer drugs. Based on our research with model systems for lymphoma, breast and skin cancer, we have accumulated evidence that a cell's ability to handle oxidative stress does influence its susceptibility to apoptosis. Lymphocytes that have acquired resistance to oxidative stress simultaneously acquire resistance to glucocorticoid-induced apoptosis. The basic metabolism of the resistant cells is also fundamentally altered. These findings clearly have implications for the development and treatment of cancer. They potentially have a broader impact, since dysregulation of apoptosis and cellular redox state are common to other major diseases. We are now working towards determining the mechanism by which an altered cellular redox state contributes to the control of apoptotic signaling and identifying molecules that sense oxidative stress, are involved in the mechanism of apoptosis and may be dysfunctional in cancer cells. Using gene expression and tissue arrays from lymphoma patient samples, we are investigating whether the expression of antioxidant enzymes predicts response to therapy. Understanding how key processes like apoptosis can be affected by resistance to oxidative stress will make an important contribution towards teasing out key relationships between genetics, diet, control of oxidative stress and effective cancer prevention and treatment.

Selected Publications: 

Butts, B.D., Kwei, K.A., Bowden, G.T. and Briehl, M.M. (2003) Elevated basal reactive oxygen species and phospho-Akt in murine keratinocytes resistant to ultraviolet B-induced apoptosis. Mol. Carcinog. 37 :149-157

Tome, M.E., Lutz, N.W. and Briehl, M.M. (2003) Overexpression of catalase or Bcl-2 delays or prevents alterations in phospholipid metabolism during glucocorticoid-induced apoptosis in WEHI7.2 cells. Biochim Biophys Acta 1642 :149-162

Efferth, T., Briehl, M.M. and Tome, M.E. Role of antioxidative genes for the activity of artesunate against tumor cells. Int. J. Oncol. 23:1231-1235, 2003.

Butts, B.D., Tran, N.L. and Briehl, M.M. (2004) Identification of a functional peroxisome proliferator activated receptor response element in the 3' untranslated region of the human bcl-2 gene. Int. J. Oncol. 24:1305-1310

Tome, M.E., Lutz, N.W. and Briehl, M.M. (2004) Overexpression of catalase or Bcl-2 alters glucose and energy metabolism concomitant with dexamethasone resistance. Biochim Biophys Acta 1693:57-72

Efferth, T., Rauh, R., Kahl, S., Tomicic, M., Böchzelt, H., Tome, M.E., Briehl, M.M., Bauer, R. and Kaina, B. (2005) Molecular modes of action of cantharidin in tumor cells. Biochem. Pharmacol. 69:811-818

Tome, M.E., Briehl, M.M. and Lutz, N.W. (2005) Increasing the antioxidant defense in WEHI7.2 cells results in a more tumor-like metabolic profile. Int. J. Mol. Med. 15:497-501

Tome, M.E., Johnson, D.B.F., Rimsza, L.M., Roberts, R.A., Grogan, T.M., Miller, T.P., Oberley, L.W., Briehl, M.M. (2005) A redox signature score identifies diffuse large B-cell lymphoma patients with a poor prognosis. Blood (in press)

Collaborative Research: 

Tom Grogan, M.D. and Lisa Rimsza, M.D., Department of Pathology, Expression of antioxidant enzymes as a predictor of treatment response in lymphoma and leukemia

Jeanne Pemberton, Ph.D., Department of Chemistry, and Jani Ingram, Ph.D., Northern Arizona University, Department of Chemistry, Potentially carcinogenic uranium species on Navajo lands

Biography: 

Summary of Research Activity:

• My research centers on the identification of genes disrupted in several mammalian mutations that affect melanocytes. The identification of these genes can yield vital information on the normal function of melanocytes. Moreover, under-standing the normal biology of melanocytes helps us to better understand aberrations of melanocyte growth, such as melanoma.

  Our research efforts include the analysis of the mouse pink-eyed dilution locus, p, located on chromosome 7. Mutations of this locus are defined by hypopigmentation, ranging from a minor diminution in coat color (with dark eyes) to near white (with pink eyes). The hypopigmentation results from a reduction of eumelanin in the melanocytes, where its action is autonomous. We have cloned the mouse p gene and its human homologue, P, located on chromosome 15q11-13 in a region associated with three human genetic diseases: oculocutaneous albinism type II (OCA2), Prader-Willi syndrome and Angelman syndrome. Another major area of research concerns another gene-affecting pigmentation located on chromosome 10q24-25, mutations of which lead to Hermansky-Pudlak syndrome (HPS). Recently, we identified and cloned this gene and its mouse homologue, encoded by the ep (pale ear) locus on mouse chromosome 19.

  Oculocutaneous albinism (OCA) is a heterogeneous genetic disorder characterized by hypopigmentation of the hair, skin, and eyes and is associated with the ocular features of nystagmus, reduced visual acuity, and misrouting of the optic fibers at the chiasm. OCA is classified into two major types, known as tyrosinase-negative OCA (OCA1) and tyrosinase-positive OCA (OCA2). Both forms of albinism are associated with a high risk for developing skin cancers. OCA1 results from mutations of the tyrosinase gene on human chromosome 11q. OCA2 results from mutations of the P gene on chromosome 15q.

  OCA2 is the most common form of albinism, especially among African Americans and Africans. We have found that a single mutant allele (missing exon 7) of the P gene accounts for a large percentage of mutant alleles found in African Americans (50 percent), Cameroon (66 percent), and Zimbabwe (96 percent). These data, along with other independent studies, suggest that this particular mutation arose (once) in Africa about 3,000 to 4,000 years ago.

  The high frequency of OCA2 in Africa has profound consequences in terms of the burden of skin cancer. About 80 percent of Africans with OCA2 develop skin cancer, primarily squamous cell carcinoma, but some basal cell carcinomas are also detected. Curiously, only a handful of melanomas have been documented among African OCA2 individuals. The death rate among these Africans with OCA2 who develop skin cancer is almost 80 percent. Recently, we have found another equatorial population with a high frequency of OCA2 in Indonesia. Surprisingly, these Indonesian OCA2 individuals rarely develop skin cancers (one reported basal cell carcinoma case in 25 years following approximately 150 albinos), despite the equivalence of sun exposure with the African OCA2 population. We are currently trying to understand this difference in skin cancer susceptibility.

Selected Publications: 

• Oetting WS, Brilliant MH, King RA. The clinical spectrum of albinism in humans. Molecular Medicine Today 2:330-335, 1996.
• Gardner JM, Wildenberg SC, Keiper NM, Novak EK, Rusiniak ME, Swank, RT, Puri N, Finger JN, Hagiwara N, Lehman AL, Gales TL, Bayer ME, King RA, Brilliant, MH. The mouse pale ear (ep) mutation is the homologue of human Hermansky-Pudlak Syndrome (HPS). Proc Natl Acad Sci USA 94:9238-9243, 1997.
• Lehman AL, Nakatsu Y, Ching A, Bronson RT, Oakey RJ, Keiper-Hyrnko N, Finger JN, Durham-Pierre D, Horton DB, Newton JM, Lyon MF, Brilliant MH. A very large protein with diverse functional motifs is deficient in rjs (runty, jerky, sterile) mice. Proc Natl Acad Sci USA 95:9436-9441, 1998.
• Orlow SJ, Brilliant MH. The pink-eyed dilution locus controls the biogenesis of melanosomes and levels of melanosomal proteins in the eye. Exp Eye Res 68:147-54, 1999.

Collaborative Research: 

Biography: 

Summary of Research Activity:

Selected Publications: 

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Biography: 

Summary of Research Activity:

Selected Publications: 

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Biography: 

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Selected Publications: 

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Biography: 

• NCI Post-Doctoral Fellowship, Thomas Jefferson University , 2001
• Ph.D., Molecular and Cellular Biophysics,
  University at Buffalo/Roswell Park Cancer Inst., 1998
• B.A., Biological Sciences, University College at Buffalo , 1994

Summary of Research Activity:

Current research interests in our laboratory focus on improving tumor radiation response through the use of biological response modifiers that alter tumor cell function, metabolism, cytokine stimulation and prostaglandin production, and affect aspects of tumor development, growth and treatment response. These modifiers include pharmaceutical drugs that are designed to specifically target tumors, bioactive nutritional components such as bioflavonoids, and compounds that regulate tumor glucose metabolism.

Selected Publications: 

• Evans, S.S., Wang, W.C., Bain, M.D., Burd, R., Ostberg, J.R., and Repasky, E.A. Fever-range hyperthermia dynamically regulates lymphocyte delivery to high endothelial venules. Blood, 97: 2727-2733, 2001. 
• Burd, R., Wachsberger, P.R., Biaglow, J.E., Wahl, M.L., Lee, I. , and Leeper, D.B. Absence of Crabtree effect in human melanoma cells adapted to growth at low pH: reversal by respiratory inhibitors. Cancer Res., 61: 5630-5635, 2001.
• Wachsberger, P.R., Burd, R., Wahl, M.L., and Leeper, D.B. Betulinic acid sensitization of low pH adapted human melanoma cells to hyperthermia. Int. J Hyperthermia, 18: 153-164, 2002.
• Wahl, M.L., Owen, J.A., Burd, R., Herlands, R.A., Nogami, S.S., Rodeck, U., Berd, D., Leeper, D.B., and Owen, C.S. Regulation of intracellular pH in human melanoma: potential therapeutic implications. Mol. Cancer Ther., 1: 617-628, 2002.       
• Burd, R., Lavorgna, S.N., Daskalakis, C., Wachsberger, P.R., Wahl, M.L., Biaglow, J.E., Stevens, C.W., and Leeper, D.B. Tumor oxygenation and acidification are increased in melanoma xenografts after exposure to hyperglycemia and meta-iodo-benzylguanidine. Radiat. Res ., 159: 328-335, 2003.
• Wachsberger, P.R., Burd, R., Bhala, A., Bobyock, S.B., Wahl, M.L., Owen, C.S., Rifat, S.B., and Leeper, D.B. Quercetin sensitizes cells in a tumour-like low pH environment to hyperthermia. Int. J Hyperthermia, 19: 507-519, 2003.
• Coss, R.A., Leeper, D.B., Storck, C.W., Burd, R.M., Wachsberger, P.R., and Dicker, A.P. The epidermal growth factor receptor inhibitor gefitinib (Iressa, ZD 1839) sensitizes human melanoma cells to hyperthermia. Int. J. Radiat. Oncol. Biol. Phys., 57: S352, 2003.
• Wachsberger, P., Burd, R., and Dicker, A.P. Tumor response to ionizing radiation combined with antiangiogenesis or vascular targeting agents: exploring mechanisms of interaction. Clin. Cancer Res., 9: 1957-1971, 2003.
• Lee, I., Glickson, J.D., Dewhirst, M.W., Leeper, D.B., Burd, R., Poptani, H., Nadal, L., McKenna, W.G., and Biaglow, J.E. Effect of mild hyperglycemia +/- meta-iodo-benzylguanidine on the radiation response of R3230 Ac tumors. Adv. Exp. Med. Biol., 530:177-186: 177-186, 2003.
• Pritchard, M.T., Ostberg, J.R., Evans, S.S., Burd, R., Kraybill, W., Bull, J.M., and Repasky, E.A. Protocols for simulating the thermal component of fever: preclinical and clinical experience. Methods, 32: 54-62, 2004.
•  Lanza-Jacoby, S., Miller, S., Flynn, J.T., Lavorgna, S., Dicker, A.P., and Burd, R. Selective Cyclooxygenase (COX)-2 inhibitor improves the radiation response in a mammary tumor cell-line, NMF 11.2 , derived from HER-2/neu mice.  Mol. Cancer Thera. Mol Cancer Ther. 3:417-24, 2004.
• Wachsberger, P., Burd, R. and Dicker, A.P.   Improving Tumor Response to Radiotherapy By Targeting Angiogenesis Signaling Pathways. Hematology/Oncology Clinics of North America, in press 2004.
•  Burd, R., Lavorgna, S.N., Daskalakis, C., Wachsberger, and Dicker, A.P. Tumor oxygenation and radiation response are increased by taxotere and hyperoxic breathing."  Submitt to Clinical Cancer Research June 2004.
• Wachsberger, P., Burd, R., Marrero, N., Ryan, A. and Dicker, A.P . Role of tumor hypoxia and NO in U87 glioblastoma radioresistance to the vascular targeting agent, ZD6126. Manuscript prepared.  Accepted with revision, Clinical Cancer Research.

Collaborative Research: 

Our lab is very active in exploring the use of novel drugs in combination with radiation therapy, with the goal of rapid translation into the clinic.  This goal is pursued through the use of in vitro, ex vivo, human tumor xenografts and animal models that faithfully recapitulate the complex biology of invasive human cancer and its precursors. This is necessary for the discovery and development of novel targeted therapeutic strategies with a high probability of success in treating cancer. We currently have numerous collaborations with investigators and pharmaceutical companies to test their compounds in combination with radiation therapy. We have various tumor models available and can measure a variety of parameters of tumor response. Investigators or pharmaceutical companies interested in testing their drugs in combination with radiation are welcome to contact our laboratory.

Biography: 

Jeffery L. Burgess is Division Director and an Associate Professor of Environmental and Occupational Health at the University of Arizona Mel and Enid Zuckerman College of Public Health. He received his medical degree at the University of Washington. Doctor Burgess also holds the Master of Science degree in Toxicology and Industrial Hygiene from the University of Arizona and the Master of Public Health degree in Occupational and Environmental Health from the University of Washington. Dr. Burgess is American Board of Medical Specialties Certified in Emergency Medicine, Medical Toxicology and Occupational and Environmental Medicine.

Summary of Research Activity:

His research interests include respiratory toxicology in firefighters and smoke inhalation victims, reduction of mining-related injuries and exposures, environmental arsenic exposure and hazardous materials exposures including methamphetamine laboratories. Dr. Burgess is the Principal Investigator for the NIH/Fogarty International Center-funded International Program for Mining Health and Safety as well as for research projects evaluating smoke exposure and arsenic exposure.

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Dr. Campesino is with the University of Arizona 's Center for Frontier Medicine in Biofeld Science, funded through the National Center for Complementary and Alternative Medicine, National Institutes of Health. She is a Psychiatric Nurse Practitioner and was Predoctoral Clinical Fellow with the American Nurses Association Ethnic Minority Fellowship Program from 1998-2003. Dr. Campesino's research interests include spirituality in traumatic bereavement; end of life and palliative care; Latino health; and cultural competency in healthcare education and delivery.

Dr. Campesino developed the Latino Spiritual Perspective Scale, which is currently undergoing validation testing. She is exploring the role of culture and cultural identification in the expression of spiritual beliefs and practices among Latinos, and how spirituality relates to quality of life. She is interested in expanding her program of research to explore spirituality in bereavement and dying among Latino cancer patients.

Related to cultural competency in healthcare delivery, Dr. Campesino is submitting a grant to the National Cancer Institute to examine minority cancer patients' perceptions of and experiences with racial/ethnic discrimination in healthcare settings.

Selected Publications: 

• Campesino Flenniken, M. (1997). Psychotropic prescriptive patterns among nurse practitioners in primary care settings. Journal of the American Academy of Nurse Practitioners, 9 (3), 117-121

• Campesino, M. (2002). Commentary: Problematic issues in cross cultural comparisons. Journal of Professional Nursing, 18 (6), 343-45.

• Campesino, M. (2004). From memorialization to rehumanization: Mourning rituals in Mexican American gang-related funerals. Manuscript submitted for publication. Campesino, M. (2004). Homicide bereavement: Reflections on the therapeutic relationship in trauma research. Manuscript submitted for publication.

• Campesino, M. & Schwartz, G.E. (2004). The Latino spiritual perspective scale: An emerging measure of spirituality among U.S. Latinos. Manuscript submitted for publication.

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Websites
http://www.biochem.arizona.edu/dept/ppl/Profiles/Canfield.htm
http://www.nativecancer.org

Assistant: Beth Cloud - 626-0260
Contact for grant information: Marilyn Guengerich - 792-4815

Summary of Research Activity:

Previous work in my laboratory focused on carotenoid metabolism in the mother-infant dyad and in the biological actions of oxidation products of ß-carotene. Our studies of mothers and infants in Central America showed that b -carotene in breastmilk improves the vitamin A status of infants as well as the health of both mothers and infants.  From these studies, we concluded that b -carotene fortification of foods or supplementation of lactating mothers with b -carotene could be an important public health strategy to impact vitamin A deficiency worldwide.   We have also recently shown that oxidation products of b -carotene strongly arrest growth, DNA synthesis and cholesterol synthesis in cancer cells.  One product has been identified and purified.  In addition, we identified and synthesized two new retinoic acid endoperoxides that strongly inhibit the growth of cancer cells.   Experiments are in progress to investigate the mechanism of action of these compounds.

My current research centers on cancer in Native Americans and my primary responsibility is direction and oversight of the Native American Cancer Research Partnership (NACRP) . This partnership is jointly administered between Northern Arizona University (NAU) and the Arizona Cancer Center (AZCC) and is comprised of three interdependent Cores: Research, Education and Outreach.  

Increased rates of cancer following the advent of uranium mining on Reservation lands has led to widespread concern among Native peoples about the relationship of mining to cancer.  In response to these concerns, our initial research focused on identification of the biological species of uranium in Reservation water, the molecular interactions of uranium with biological molecules and the effects of uranium on cell division.  Recently our work has expanded to include the study of folding and assembly of the P53 tetramer and the effects of chromo-some instability on gene expression.  Approximately 20 Native American students are currently working on research projects in our lab-oratories. Details of these projects and their relevance to cancer among Native Americans may be found at our website, www.nativecancer.org.

Community participation is essential to the development and sustainability of our educational and research programs. Our Outreach Core is comprised of Native American people chosen from NACRP faculty, staff and community leaders and is responsible for facilitating the exchange of information between NACRP and the community. Through our Outreach Core, NACRP students and faculty work closely with community leaders to ensure that our projects and programs are responsive to community needs.  Tribal government and community perspectives are heard in meetings with tribal departments of health and education and in community forums. During the course of their research projects, NACRP students and faculty visit communities to discuss their progress and the relevance of their findings to the community.

Working closely with American Indian Studies and Public Health at both universities, our Education Core has developed a four year curriculum for students in health care professions that integrates Native and academic research cultures. Currently approximately 40 Native American students participate per year.  The curriculum is available on our website, www.nativecancer.org.  Courses are offered jointly from NAU and U of A via the Telemedicine Network.

Selected Publications: 

1. Douglas L. Taren, Burris Duncan, Kamal Shrestha, Natayani Shrestha, Denise Genaro-Wolf, Rosemary L. Schleicher, Christine M. Pfieffer, Anne L. Sowell, John Greivenkamp, and Louise M. Canfield . (2004) The Night Vis ion Threshold Test is a Better Predictor of Low Serum Vitamin A Concentration then Self-Reported Night Blindness in Pregnant Urban Nepalese Women. J. Nutr. 134: 2573-2578.
2. E. M. Kithsiri Wijeratne, Thomas J. Turbyville, † Zhongge Zhang, Donna Bigelow, Leland S. Pierson, III, Hans D. VanEtten, , Luke Whitesell, Louise M. Canfield , and A. A. Leslie Gunatilaka , (2003) Cytotoxic Constituents of Aspergillus terreus from the Rhizosphere of Opuntia versicolor of the Sonoran Desert J. Nat Prods  66:1566-73
3. Douglas L. Taren, Burris Duncan, Kamal Shrestha, Narayani Shrestha, Denise Genaro-Wolf, Rosemary Schleisher, Michelle Pfeiffer, Anne Sowell, John Greivenkamp, and Louise Canfield , The Night Vision Threshold Test and Not Reported Night Blindness is Associated with Serum Retinol Concentrations in Urban Nepalese Pregnant Women, J. Nutr. 2004
4. Canfield LM , Clandinin MT, Davies, DP, Fernandez MC, Jackson J, Gibson R, Goldman WJ, Pramuk K, Reyes H, Sablan B, Sonobe T, Xu B. Multinational Study of Major Breast Milk Carotenoids of Healthy Mothers, Eur J. Nutr, 42: 133-141 (2003).

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Dr. Chambers received her BS and MD degrees from Brown University. She completed her residency in Obstetrics and Gynecology as well as a fellowship in Gynecologic Oncology at Yale University. She remained at Yale as a member of the faculty until 2004. During her tenure at Yale, she was Director of the Gynecologic Oncology fellowship program and, until recently, was the only woman professor in Obstetrics and Gynecology. Throughout her career, Dr. Chambers has served on many national and regional committees, grant review panels and study sections. She is an examiner for the American Board of Obstetricians and Gynecologists and has served as President of the New England Association of Gynecologic Oncologists. She has authored over 80 peer reviewed publications and chapters.

Dr. Chambers is one of the few gynecologic oncologist physician-scientists in the country, active as both a researcher and clinical gynecologic oncologist, evaluating oncology patients at the Arizona Cancer Center, an affiliate of the University Medical Center, University Physicians, Inc., and the University of Arizona. Her research laboratory, which is funded by both the National Cancer Institute and Department of Defense, is devoted to understanding the molecular basis for breast and ovarian cancer invasion and metastasis.

Dr. Chambers recently moved to Tucson, Arizona to become Director of the newly-created Division of Women's Cancers at the Arizona Cancer Center. Her current role is to develop a comprehensive Women's Cancers program, encompassing both research and clinical practice in the areas of breast and gynecologic cancers. Her multidisciplinary division is comprised of gynecologic oncologists, surgical oncologists, medical oncologists, radiation oncologists, and translational and basic science researchers. Collectively, these experts seek to deliver exemplary, cutting-edge care to women throughout the Southwest who either have cancer or are at risk for developing this disease. Now, with the help of Christine and Lute Olson, it is likely that her vision will be realized.

Summary of Research Activity:

•  CSF-1 and its role in neoplastic progression of breast and ovarian cancer.

•  Androgens and neoplastic transformation of normal ovarian surface epithelium.

•  The c-fms proto-oncogene and breast cancer invasiveness.

Selected Publications: 

Chambers SK , Kacinski BM, Ivins CM, Carcangiu ML. Overexpression of epithelial CSF-1 and CSF-1 receptor: a poor prognostic factor in epithelial ovarian cancer; contrasted to a protective effect of stromal CSF-1. Clin Cancer Res. 1997;3:999-1007.

Chambers SK, Chambers JT, Schwartz PE , Kohorn EI, Lorber MI, Handschumacher RE, Pizzorno G. Pharmacokinetic and phase I trial of intraperitoneal carboplatin and cyclosporine A in refractory gynecologic cancer patients. J Clin Oncol. 1997;15:1945-1952.

Chambers SK , Ivins CM, Kacinski BM, Hochberg RB. An unexpected effect of glucocorticoids on stimulation of c-fms proto-oncogene expression in choriocarcinoma cells expressing little glucocorticoid receptor. Am J Obstet Gynecol. 2004;190:974-85.

Tangir J, Bonafe N, Gilmore-Hebert M, Chambers SK . SGK-1, a potential regulator of c-fms related breast cancer aggressiveness. Clin Exp Metastasis. 2004;21:477-483.

Toy EP, Bonafe N, Savlu A, Zeiss C, Zheng W, Flick M, Chambers SK . Correlation of tumor phenotype with c-fms proto-oncogene expression in an in vivo intraperitoneal model for experimental human breast cancer metastasis. Clin Exp Metastasis. 2005;22(1):1-9.

Bonafe N, Gilmore-Hebert M, Folk NL, Azoudi M, Zhou Y, Chambers SK . Gyceraldehyde-3-Phosphate dehydrogenase binds to the AU-rich 3 ¢ untranslated region of colony-stimulating factor-1 messenger RNA in human ovarian cancer cells: possible role in colony-stimulating factor-1 posttranscriptional regulation and tumor phenotype. Cancer Res. 2005 May 1;65(9):3762-3771.

Chambers SK . Systematic lymphadenectomy in advanced epithelial ovarian cancer: two decades of uncertainty resolved. J Natl Cancer Ins. 2005; 97(8):548-549.

Collaborative Research: 

Collaborative work with Roy R. Parker, PhD, Regents Professor and Howard Hughes Investigator, Molecular and Cell Biology, University of Arizona, Joan A. Steitz, PhD, Sterling Professor of Molecular Biophysics and Biochemistry, Yale University, and Imed Gallouzi, PhD, Assistant Professor, Biochemistry, McGill University on post-transcriptional gene regulation, 3' UTR RNA binding proteins.

Collaborative work with Wenxin Zheng, MD, Professor of Pathology, Director of Molecular Pathology, now at University of Arizona, on the molecular pathogenesis of uterine papillary serous carcinoma, and on the hormonal etiology of ovarian cancer. 

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My research interests have been focused on two major areas: 1) risk factors of cancers, such as obesity, high bone density, ethnicity, aging, hormone levels, and dietary factors; 2) effects of cancer diagnosis and treatment on body composition and risk of osteoporotic fractures. In the "Ethnicity, Body Composition, Bone Mineral Density, and Breast Cancer “ study, newly diagnosed postmenopausal breast cancer patients who were either Hispanic or non-Hispanic whites were recruited to investigate ethnic differences in body composition and risk of osteoporosis, and the association between breast cancer and osteoporosis. Bone mineral density is measured on all the participants using a dual-energy x-ray absorptiometer. Blood and urine samples are collected for studying biomarkers and hormonal factors associated with breast cancer and osteoporosis.

Collaborating with Dr. Maskarinec at the Cancer Research Center of Hawaii and other colleagues at the Arizona Cancer Center , we are investigating the association of high bone density and high mammographic density, an indicator of increased risk of breast cancer. Both bone mineral density and breast density are targets of certain hormones, such as estrogen. Life-long estrogen exposure has been suggested to be the major link between bone mineral density and risk of breast cancer, which has been investigated in our research. Studying the association of breast cancer and bone mineral density will not only contribute to our understanding of the etiology of breast cancer, but also may lead to development of non- or minimal-invasive methods to identify populations or individuals with high risk of breast cancer in cancer prevention and control. In addition, we are investigating the effect of body composition on mammographic density assessments, and the association of growth factors with mammographic density.

Citrate and tea consumption is an important aspect of the Mediterranean diet. Dr. Iman Hakim and I are engaging in a pilot study to assess whether citrate and tea consumption can alter risk of breast cancer and risk of osteoporosis among Tucson participants of the Women's Health Initiative study. Effect modification of citrate and tea consumption on the relationship between bone mineral density and risk of breast cancer will be examined.

In the study among prostate cancer patients treated with androgen depletion therapy (ADT), it is found that these patients had significant higher risk for obesity and osteoporosis in comparison to men without a history of any cancer. Similarly, the study with the participants in the Women's Health Initiative also indicated that breast cancer survivors have increased risk for osteoporotic fractures. These evidences from my research support a comprehensive approach in cancer management to reduce comorbidity in the large and growing population of cancer survivors.

Selected Publications: 

• Morimoto LM; White E; Chen Z ; Chlebowski RT, Hays J, Kuller L, Lopez AM, Manson J, Margolis KL, Muti PC, Stefanick, ML; McTiernan A. Obesity, body size, and risk of postmenopausal breast cancer: the Women's Health Initiative (United States). Cancer Causes & Control 2002;13:741-751.
• Chen Z, Maricic M, Nguyen P, Ahmann FR, Bruhn R, Dalkin BL. Low Bone density and high percentage of body fat among men who were treated with androgen deprivation therapy for prostate carcinoma. Cancer 2002;95:2136-44.
• LaCroix A, Cauley J, Pettinger M, Hisa J, Bauer D, McGowan J, Chen Z , Lewis C, McNeeley SG, Maureen Pasaro, Jackson R. Statin use, osteoporotic fracture and level of bone density in postmenopausal women, results from the Women's Health Initiative Observational Study. Annals of Internal Medicine 2003; 139:97-104.
• Chen Z , Pettinger MB, Ritenbaugh C, LaCroix AZ, Robbins J, Caan BJ, Barad DH, Hakim IA. Habitual Tea Consumption and Risk of Osteoporosis -- A Prospective Study in the Women's Health Initiative Observational Cohort. American Journal of Epidemiology 2003, 158:772-81.
• Cauley JA, Robbins J, Chen Z , Cummings SR, Jackson R, LaCroix A, LeBoff M, Lewis CE, McGowan J, Neuner J, Pettinger M, Stefanick ML, Wactawski-Wende J, Watts N. Estrogen Plus Progestin Reduces The Risk of Fracture: Expanded Analyses Of Fracture And Bone Mineral Density. The Women's Health Initiative Randomized Controlled Trial. JAMA 2003, 290:1729-1738.
• Chen Z, Staten LK, Maskarinec G, Arendell L, Bruhn R, Marshall J. The relationship between mammographic density and body composition --- Results from a cross-sectional study among Hispanic and non-Hispanic White women. International Journal of Body Composition Research 2004,2 (1): 23-29.
• Chen Z, Stini WA, Marshall JR, Martinez M E, Guillén-Rodríguez J M, Roe D, Alberts D S. Wheat Bran Fiber Supplementation and Bone Loss among Participants in a Colon Cancer Prevention Trial. Nutrition 2004, 20:747-751
• Chen Z, Kooperberg C, Pettinger MB , Bassford T, Cauley JA, LaCroix AZ , Lewis CE, Kipersztok S, Borne MC, Jackson RD. Validity of Self-Report for Fractures among a Postmenopausal Multiethnic Cohort. Menopause 2004, 11(3): 264-274.
• Chen Z , Maricic M, Bassford TL, Ritenbaugh C, Lopez AM, Leboff MS, Gass M, Barad DH. Increased Fracture Risk among Breast Cancer Survivors-Results from the Women's Health Initiative (Achieve of Internal Medicine: accepted for publication, September, 2004).
• Chlebowski RT, Chen Z , Anderson G, Rohan T, Aragaki A, Land D, Dolan NC , Paskett ED, McTiernan A, Hubbell FA, Adams-Campbell LL, Prentice R. Ethnicity and breast cancer: factors influencing differences in incidence and outcome (Journal of National Cancer Institute, accepted for publication, 2004). 

• Wampler NS , Chen Z , Jacobsen C , Henderson JA, Barbara V. Howard BV , Rossouw JE. Bone mineral density of American Indian and Alaska Native women: Results from the Women's Health Initiative Study (Menopause, accepted for publication, 2004).

Collaborative Research: 

• Gartraud Maskarinec, M.D., Ph.D., Associate Researcher, Cancer Research Center of Hawaii, University of Hawaii ; Jim Marshall, Ph.D., Professor; Lisa Staten, Ph.D., Research Assistant Professor: Mammographic density patterns, bone mineral density and breast cancer among Hispanic and Anglo postmenopausal women.

• Gartraud Maskarinec, M.D., Ph.D., Associate Researcher, Cancer Research Center of Hawaii, University of Hawaii; Cyndi Thomson, Ph.D., Assistant Professor, Arizona Cancer Center: Association of mammographic density and bone mineral density.
• Iman Hakim, M.D., Ph.D., Associate Professor of Public Health, Arizona Cancer Center : Some aspects of Mediterranean diet in relation to risk of chronic diseases among postmenopausal women.

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1. The Problem
   The rapidly expanding medical knowledge base can make it difficult for researchers and physicians to stay abreast of the most recent developments. Much of this new information is available through online medical databases, such as the Nation Library of Medicine's Medline or the National Cancer Institute's CANCERLIT database. However, before including bibliographic information in their databases, these institutions use the slow, labor intensive, and sometimes inconsistent practice of human indexing, which can significantly delay access to vital information. In addition, the MeSH terms applied by human indexers are often unfamiliar to users.

   The Artificial Intelligence Lab at the University of Arizona has developed computer-generated indexing techniques to overcome the problems of human indexing. Tools also have been developed to improve recall and precision beyond what is available through simple keyword searching. These tools may be used to supplement traditional MeSH searches or searches using the UMLS Metathesaurus. Similar techniques have been applied successfully to other domains, including the geosciences, digital libraries, group systems comments, and law enforcement.

   AI Solutions
   The AI Lab currently is funded by the National Cancer Institute (NCI) to explore methods to improve medical information access. NCI has provided the AI Lab with a testbed of CANCERLIT documents for conducting our research. NCI's CANCERLIT database contains abstracts from 200 core journals, proceeding reports, theses, and a few select monographs. Our testbed contains the last five years of the CANCERLIT collections, from January 1992 to the present, totaling more than 624,000 abstracts. This mini-collection is updated every two months.

   AI techniques identify grammatically correct noun phrases within the abstracts to serve as terms for document indexing and retrieval. These techniques could become an alternative to human indexing in the future, decreasing the time between publication and database availability. In addition, the AI Lab has generated an automatic thesaurus or concept space to facilitate searching. A concept space is a ranked list of 40 terms that co-occur within the collection. It provides users with the terms that appear in the documents and can be used to suggest alternative search terms or phrases to refine a keyword search. It also may suggest associations that warrant further exploration.

   We have incorporated two Java-based graphical applications as access tools. The Graphical Thesaurus provides users with a visual representation of the associations seen in the concept space for the top ten co-occurring terms. The Visual Categorizers makes a large set of retrieved documents more manageable by dividing it into computer-assigned categories and displaying the categories as regions on a map. This allows users to visualize the conceptual relationships within a large document set.

   Currently, we are at the alpha release for the various CANCERLIT retrieval tools. We are beginning user studies and feedback solicitation to assist us in making necessary design changes. We appreciate the assistance we have received from the Arizona Cancer Center. You can access our five-year CANCERLIT collection and search tools at http://ai.bpa.arizona.edu/CancerLit

Selected Publications: 

• Chen H, Martinez J, Ng TD, Schatz BR. (1997). A Concept Space Approach to Addressing the Vocabulary Problem in \par Scientific Information Retrieval: An Experiment on the Worm Community System. Journal of the American Society for Information Science 48(1):17-31
• Schatz B and Chen H. (1996). Building Large-Scale Digital Libraries. IEEE Computer, Special Issue on "Building Large-scale Digital Libraries," 29(5):22-27.
• Chen H, Schatz BR, Ng TD, Martinez JP, Kirchhoff AJ, Lin C, A Parallel Computing Approach to Creating Engineering Concept Spaces for Semantic Retrieval: The Illinois Digital Library Initiative Project, IEEE Transactions on Pattern Analysis and Machine Intelligence, Special Section on Digital Libraries: Representation and Retrieval, 18(8):771-782.

Collaborative Research: 

• Bruce Schatz, Ph.D., Directory of the Digital Library Research Program, University of Illinois at Urbana-Champaign.
• Susan Hubbard, Director of the International Cancer Information Center, National Cancer Institute, Bethesda, MD.

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Taipei Medical College, BS Pharmacy, 1983

State University of New York at Buffalo, Ph.D. Pharmeceutics, 1989

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Palmer C, Coe K & Wadley R. On tools and traditions. Current Anthropology, 46(3): 459-60. Reply by John McCabb, Current Anthropology, 46(3): 460-464, 2005

Coe K., Aiken, N., & Palmer, C. The role of traditional children's stories in evolution. Entelechy, on line journal. http://www.entelechyjournal.com/ , 2005.

Coe K & Palmer C. Human categories and health: the power of the concept of ethnicity. D. Alberts and L. Hess (eds). Fundamentals of Cancer Prevention. Chapter 4, pp. 85-104. Berlin : Springer, 2005.

Coe K & Lopez AM. Ovarian cancer prevention. D. Alberts and L. Hess (eds). Fundamentals of Cancer Prevention. Chapter 9, 349-362. Berlin : Springer, 2005.

Aiken N & Coe K. Promoting human cooperation: art and the ties that bind. Bulletin of Psychology and the Arts, 5(1): 5-20, 2004.

Coe K. The Epidemiology of Ovarian Cancer: Reproductive Factors and Environmental Chemical Exposure. P. Hoyer (ed.). Ovarian Toxicology . Chapter 10, pp. 171-201. Taylor and Francis Books. Routledge, 2004.

Coe K, Attakai A, Papenfuss M, Martin L, Nuvayestewa L & Giuliano A. Traditionalism and its relationship to disease risk and protective behaviors of women living on the Hopi reservation. Health Care for Women International 25(5):291-410, 2004.

Tilman L, Myers S, Castro G, Gladding S, Coe K, Carman D, Chilian R, Begay E, Lobell M. Lymphocytic infiltrates associated with aggressive breast cancers in Native American women. Published Abstract #3561, ASCO, 39 th Annual Meeting, May, 2003.

Coe K. T he Ancestress Hypothesis : Rutgers University Press, 2003.

Coe K. An essay on the origins of altruism and compassion. Paper presented at the Conference on Religious and Scientific Approaches to Altruism. Villanova University , May 2003 and published at http://www.metanexus.net/conference2003/paperpresenters.html .

Coe K, Wilson C, Eisenberg M, Attakai A, Lobell M. Creating the environment for a University and Indian Health Service community partnership.Cancer, Supplement (in press).

Coe K. The words of our ancestors: kinship, tradition, and moral codes. World Cultures (in press).

Flinn MV, Alexander RD & Coe K. Runaway social selection: the special case of human cognition, reciprocity, and culture. In: The evolution of mind, S.W. Gangestad & J.A. Simpson (Eds.).  New York : Guilford Press (in press)

Coe K, Aiken N & Palmer C. Once upon a time: ancestors and the evolutionary significance of stories. Anthropological Forum (in press).

Palmer C, Steadman L & Coe K. More Kin: An evolutionary benefit of marriage. Structure and Dynamics; Explorations in Anthopological Sciences (in press).

Palmer C, Steadman L, Cassady C, Coe K. Taking the “magic” out of magic: belief and behavior in the anthropological study of religion. Religion (in review).

Palmer C, Wright , Wright , Cassidy, VanPool, Coe . The many manipulations of Morty Mouse. Testing predictions about the evolutionary role of children's stories. Journal of Anthropological Research (in review).

Coe K. Morality to law: the role of kinship and tradition. Book Chapter Altruism and Biology (in review).

Coe K, Attakai A, Papenfuss M, Martin L, Nuvayestewa L & Giuliano A. Predictors of pap test use among women living on the Hopi reservation. Health Care for Women International (in press).

Coe K & Ezell K. Tonic remedies: cross-cultural characteristics and classification , Encyclopedia of Herbal Medicine (in review).

Hunter J & Coe K. The roles and characteristics of effective community health workers: empowering Hispanic women along the US-Mexico border. J. Community Health (in review).

Soliman AS , Wilson C, Sadegh-Nobari T, Lantz PM, Bernsteon A, Coe K. Access to care among American Indian cancer patients in Arizona . Public Health Reports (submitted).

Castro F & Coe K. Elemental of Cultural Traditionalism as Risk and Protective Factors: An Integrative Mixed-Methods Analysis (submitted).

Collaborative Research: 

1 UO1 CA114696 Coe (PI)
NIH - 7/1/05-4/30/10
Southwest American Indian Collaborative Network (SAICN)
The aim of this grant, which is housed at the Inter Tribal Council of Arizona, is to develop an organizational infrastructure for comprehensive cancer care, community-based, participatory research, and community-based activities in cancer education.
Role: PI

HD/NIH RFA-MD-02-003 Rosales (PI) - 9/28/02-9/27/07
Excellence in Partnerships for Community Outreach, Research on Health Disparities
The major goals of this project are to develop a Center of Health Disparities among American Indians and Hispanics focusing on diabetes and substance abuse. The objectives are to increase the number of under-represented minority master’s and PhDs interested in working in minority health disparities areas; increase the awareness of minority health disparities and cultural competence of faculty, increase information on health disparities to American Indian reservations.
Role: Co PI subcontract, Director of Outreach

R Harris (PI, UA), C Begay (PI, NAU) - 6/01/05-5/31/06
Pilot project off NAU-UA Cancer Partnership Grant (Canfield).
Hopi Women’s Health Program Proposal for Applied Research on Cancer
Role: Co-PI, UA

2P30CA023074-26 Alberts (PI)
NIH/NCI - 1/03-6/30/08
Cancer Center Support Grant (CCSG) / Special Populations Shared Service (SPSS)
The Cancer Center Support Grant is a 5 year renewal of the core grant of the Arizona Cancer Center which
funds the basic, translational/clinical, and cancer prevention and control research programs. One of the
twenty shared services that support these programs is the Special Populations Shared Service. The goal
of the Special Populations Shared Service is to provide resources and capacity building –technical
assistant and training – to Arizona Cancer Center researchers working with Special Populations.
Role: Co Director Shared Service

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Dr. Cranmer grew up in Southern California.  After completing undergraduate studies in Biochemistry at Harvard University, he obtained a Master of Science degree in parasitology from the University of Liverpool/Liverpool School of Topical Medicine in England.  Thereafter, he enrolled in the Medical Scientist Training Program at the University of California, San Diego.  While there, Dr. Cranmer was supported by a Life and Health Insurance Medical Research Fund scholarship.  His graduate research was in the area of viral immunology, with an emphasis on the design of experimental vaccines.  After receiving his M.D. and Ph.D in Biology in 1998, Dr. Cranmer completed a residency in internal medicine at the Mayo Clinic in Rochester, Minnesota.  He then came to the Arizona Cancer Center at the University of Arizona to complete fellowship training in medical oncology.

It was at the Arizona Cancer Center that Dr. Cranmer began his collaboration with Dr. Evan Hersh in the Melanoma Program.  After completion of his training in 2003, Dr. Cranmer remained at the Arizona Cancer Center as a faculty member.  He works closely with Dr. Hersh in treating patients with malignant melanoma.    Dr. Cranmer is also developing interdisciplinary collaborations in the management of sarcomas, an area in which he has developed a strong interest.  Dr. Cranmer also treats patients with general hematologic and oncologic disorders, attends hospital in-patients, and provides outside consultation in clinical drug development, malignant melanoma and sarcoma management. 

Summary of Research Activity:

Dr. Cranmer has strong clinical and basic research programs.  He is primary investigator on a number of research protocols in malignant melanoma and is developing protocols for patients with sarcomas.  He also has a strong interest in the biology of brain metastasis in melanoma, a significant clinical problem. 

Dr. Cranmer collaborates closely with Dr. Katrina Trevor, Ph.D. in basic research and basic science investigations.  His two areas of focus are biology of brain metastasis in melanoma and the pathogenesis of synovial sarcoma. 

Selected Publications: 

Ebbinghaus, S., Rubin, E., Hersh, E., Cranmer, L.D., Bonate, P.L., Fram, R.J., Jekunen, A., Weitman, S., and Hammond, L.A.  A Phase I Study of Dolastatin-15 Analogue Tasidotin (ILX651) Administered Intravenously Daily for 5 Consecutive Days Every 3 Weeks in Patients with Advanced Solid Tumors. (2005) Clin Cancer Res 11(21) 7807-7816.

Cranmer, L.D., Bandlamuri S., Trevor K., and Hersh E.  Rodent models of brain metastasis in melanoma. (2005) Melanoma Res 5:325-356.

Ebbinghaus, S., Rubin, E., Hersh, E., Cranmer, LD, Marsh, S., Bonate, P., Van Dijk, S., Fram, R., and Jekunen, A. A phase I study of ILX-651 administered intravenously daily for five days every three weeks in patients with advanced solid tumors. Proceedings American Society of Clinical Oncology  (2003). 22: page 129, 2003 (abstr 517).

Cranmer, LD, Warrington, K., and Ytterberg, S. 61-year-old man with dyspnea and bilateral foot drop.  Mayo Clinic Proceedings. (2002) 77(4):363-366.

Morello, C.S., Cranmer, LD,  and Spector, D.H. Suppresion of murine cytomegalovirus (MCMV) infection with a DNA vaccine encoding MCMV M84 (a homolog of human cytomaglovirus pp65).  Journal of Virology (2000) 74(8): 3696-3708.

Gonzalez-Armas, J.C., Morello, C.S., Cranmer, LD and Spector, D.H. DNA immunization confers protection against murine cytomegalovirus infection.  Journal of Virology (1996)70(11):7921-7928.

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My research interest is to understand the regulation of normal and cancer cell responses to environmental signals. The response of cells to extracellular signals is one determinant of epithelial cancer progression and is a major avenue to exploit for new therapeutic and diagnostic purposes. The following major areas of research are investigated in my laboratory. 

1) The response of cells to adhesive signals via integrin cell surface molecules. The integrins are major cell surface molecules that are responsible for the signaling of environmental changes to cells within a tissue environment. One specific integrin, a6b1, is a laminin receptor and is persistently expressed in progressing epithelial cancers and in metastatic lesions. Our current work is to understand the contribution of variant forms of the alpha 6 integrin to cancer progression and to develop ligand mimetics. During the course of this work, we have discovered a novel form of the a6b1 integrin expressed on tumor cells and have identified lead peptides that may prove useful in modifying tumor cell progression. Alternatively, these agents may be useful for specific targeting of tumor cells for diagnostic and therapeutic purposes.

2) The response of human cells to the extracellular matrix protein, laminin. We recently purified two forms of laminin called laminin 5 and laminin 10. These proteins are the ligands for the integrins a6b4 and a6b1, respectively, and act as powerful signaling molecules to direct cellular responses. Our current working hypothesis is that these ligands and their fragments promote cell migration and distinct cellular transcription responses. We currently are using DNA microarray technology to determine whether specific laminin forms and fragments will trigger specific patterns of gene activation. These ligands also are being tested for their ability to promote attachment and spreading characteristics of human microvessel endothelial cells for use in human graft material.

3) The response of cells to damaging agents. In particular, we have studied the signaling responses of normal and tumor cells to ionizing radiation and chemotherapeutic agents. During the course of this work, we have discovered a novel form of drug resistance that is dependent upon the cytoskeleton and cellular adhesion.

Selected Publications: 

• Davis TL, Rabinovitz I, Futscher BW, Cress AE. Identification of a novel structural variant of the a6 integrin. J. Biol. Chem., 276:(28)26099-26106, 2001.

• DeRoock IB, Pennington ME, Sroka TC, Lam KS, Bowden GT, Bair El, Cress AE.  Synthetic peptides inhibit adhesion of human tumor cells to extracellular matrix proteins.  Cancer Research, 61:3308-3318, 2001.

• Schmelz M, Cress AE, Scott KM, Burger F, Cui H, Sallam S, McDaniel K, Dalkin BL, Nagle RB.  Different phenotypes in human prostate cancer: a6 or a3 integrin in cell-extracellular adhesion sites.  Neoplasia, 4(2):243-254, 2002.

• Whitacre DC, Chahuan S, Davis TD, Cress AE, Miesfeld RL. Androgen-induction of in vitro prostate cell differentiation, Cell Growth and Differentiation, 13(1):1-11, 2002

• Davis TL, Buerger F and Cress AE.  Differential regulation of a novel variant of the a6 integrin, a6p. Cell Growth and Differentiation, 13:107-133, 2002.

Collaborative Research: 

• G. Timothy Bowden, Ph.D., Radiation Oncology

• Molly Kulesz-Martin, Ph.D., Oregon Health and Science University

• Kit Lam, M.D., Ph.D., University of California, Davis

• Roger Miesfeld, Ph.D., Biochemistry and Molecular Biophysics

• Raymond B. Nagle, M.D., Ph.D., Pathology

• J. Thomas Parsons, Ph.D., University of Virginia Health Sciences Center

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Our laboratory continues its 20-year N.I.D.A. collaborative biodistribution research program by characterizing the specific cellular mechanisms involved in delivering peptide-based drugs across the blood-brain barrier to the C.N.S. We recently have discovered specific peptide drug transporters that can be targeted to enhance delivery. We also are studying the effect of hypoxia/aglycemia on endothelial cell permeability and protein cytoarchitecture at the blood-brain barrier with a newly funded program from N.I.N.D.S. We recently have shown that short-term hypoxia/aglycemia leads to significant endothelial cell protein structural alterations and permeability, which can be reversed by specific calcium channel antagonists. This work has significant consequences to the field of stroke research. Additionally, we have shown that acute versus chronic nicotine exposure leads to permeabilizing of the blood-brain barrier and alterations in protein cytoarchitecture. This is the basis of an Arizona Disease Control Research Commission (ADCRC) contract.

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My area of interest in research is related to surgical oncology and particularly to mechanisms of tumor metastases. I have focused primarily on pancreatic cancer and thyroid cancer. In pancreatic cancer, the group which I led did seminal work in demonstrating that pancreatic cancers have a high rate of early micrometastases even in apparent clinical stage I tumors. We were able to demonstrate this by both immunohistochemistry and PCR dependent methods. This work led to further studies looking at the affects of adjuvant chemoradiation in patients with micrometastases. It also led to ongoing work examining the role of the immune system in tumor defense. We currently have a mouse model which we are using to study the effects of immunization of Kras peptides.

Work related to thyroid cancer has focused on cellular properties associated with metastases. We have looked at the cytoskeleton, integrins, other cell surface extracellular matrix receptors and tumor proteases. We have shown in the cultured cell models that metastatic are highly aggressive tumor cells have altered actin architecture, decreased ECM receptors and increased tumor proteases. We are now focusing on translating these findings into studies that may help diagnose indeterminate follicular neoplasms. A further outgrowth of this work is a study which would employ micro array technology to examine the properties of thyroid neoplasms.

A new effort at the University of Arizona in research has been to work with colleagues in the Arizona Cancer Center on a phase II clinical trail on anaplastic thyroid cancer. We have learned recently that we will be the lead institution in a multi-center study through the auspices of the American College of Surgeons Oncology Group to look at the effect of a two-drug regimen of paclitaxel and SCH66336 (farnesyl transferase inhibitor) on anaplastic thyroid cancer.

Selected Publications: 

• Demeure MJ. Endocrine Tumors of the Pancreas. In: Steel, GD, Phillips TL, Chabner BA (eds.) Endocrine Tumors . BC Decker Inc. 2003.
• Grippo PJ, Demeure MJ, Sandgren EP. Preinvasive Ductal Pancreatic Neoplasia Induced by Acinar Cell Targeting of Mutant Kras in Transgenic Mice. Cancer Research. 63(9):2016-9, 2003. (cover story)
• Neeleman SD, Demeure MJ. Non-functioning Islet Cell Carcinoma of the Pancreas. In: Ettinger DS (ed.). Endocrine Tumors, Chap. 3, p355-360, Current Science, 2002.
• Ahrendt, SA, Komorowski RK, Demeure MJ, Wilson SD, Pitt HA. Cystic Pancreatic Neuroendocrine Tumors: Is Preoperative Diagnosis Possible? J Gastroinestinal Surg. 6: 66-74, 2002.
• Goldblatt MI, Duelge J, Erickson BA, Ritch PS, Demeure MJ, Wilson SD, Pitt, HA. Gemcitabine Increases Toxicity without Altering Pancreatic Cancer Survival. Gastroenterology 120: 483, 2001.
• Keene SA and Demeure MJ. The Clinical Significance of Micrometastases and Molecular Metastases. Surgery 129(1): 1-5, 2001.
• Brown HB, Ahrendt SA, Komorowski RA, Doffek K, Wilson SD, Demeure MJ. Immunohistochemistry and Molecular Detection of Nodal Micrometastases in Pancreatic Cancer. J Surg Res. 95:141-146, 2001.

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•  PhD, The University of Arizona , 1994

•  MS, The University of Arizona , 1992

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•  Optical engineering. Micro-optical imaging systems for applications in life sciences and health sciences.  Design of multispectral and hyperspectral imaging systems for remote-sensing and biomedical applications.

•  High-speed spectral imaging.

•  Processing and analysis of high-dimensional spectral data; spectral subpixel analysis.

•  Design and fabrication of visible and infrared diffractive optics, including specialized dispersive elements.

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This laboratory investigates the pharmacology of new anticancer agents and chemopreventive agents, including: 1)mechanisms of action; 2)antitumor effects in human tumor cells in vitro and in small animal (rodent) models; 3)pharmacokinetic disposition of new agents in animals and in human clinical trials; and 4)toxicologic effects of these agents in vitro and in vivo. New antitumor agents under study include a series of redox-active derivatives of 2-cyanoaziridine that were derived from an original imminopyrolidone compound called imexon. Imexon has been shown to have unique activity in the B-cell bone marrow disease, multiple myeloma. Unique features of imexon include the lack of myelosuppression and a novel mechanism of action involving binding to thiols and perturbation of redox systems in the cell leading to apoptosis. Mitochondrial thiols appear to be selectively targeted by the agents in this series, many of which have broader antitumor activity than the parent compound, imexon.

A second group of compounds are DNA-binding drugs derived from anthracenes (more than 100 synthesized) or from mitomycin C. The anthracenes, which intercalate into DNA and impair topoisomerase II enzymes, have shown activity in breast cancer. The mitosene derivatives, which cross-link DNA, have activity in melanomas and other solid tumors. Molecular structure-activity relationships have been developed for each series of agents, which are targeted to tumors refractory to existing classes of antitumor agents.

Chemopreventive drugs under development include the green tea derivative, EGCG, which is a potent antioxidant polyphenolic agent found in green tea. This agent was shown to be well tolerated when applied topically to mice receiving simulated solar exposure. It also has favorable topical pharmacokinetics: stable in a cream base and able to penetrate into skin but not be absorbed through the skin, thereby preventing systemic toxicity to the liver seen with an injectable drug. Another topical antioxidant under development to prevent skin cancer is the creosote bush derivative NDGA, which has been shown to prevent DNA synthesis in tumor cells by a mechanism currently being investigated.

Mechanism of action studies performed in the laboratory include assessments of covalent and non-covalent DNA binding, inhibition of topoisomerase enzyme systems, and perturbation of cellular redox defense systems such as the glutathione-based transferase, reducatse and peroxidase enzymes. Disruption of the mitochondrial membrane potential also is investigated as a triggering event for apoptotic cell death from anticancer agents.

Clinical pharmacokinetic studies of anticancer drugs are investigated using high-performance liquid chromato-graphy and other analytical methods to quantitate anticancer drug levels in the plasma of patients treated with refractory cancers. These studies include the analysis of the impact of resistance-modulating agents of anthracycline drug disposition in patients with hema-tologic malignancies. Modulators such as cyclosporin A and its D-analog, valspodar (PSC-833), have been shown to significantly reduce the clearance of daunorubicin and i's metabolite, daunorubicinol, in patients with resistant acute myeloid leukemias. Other drugs that are assayed in clinical specimens include the alkylating agents melphalan and mitomycin C; the anthracyclines daunorubicin, doxorubicin, and mitoxantrone; and in bone marrow transplant patients, the topoisomerase II inhibitor etoposide.

Selected Publications: 

• Chow H-H S, Cai Y, Alberts DS, Hakim I, Dorr RT, Shahi F, Crowell JA, Yang CS, Hara Y.  Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E¹. Cancer Epidemiology, Biomarkers & Prevention 10: 53-58, 2001.

• Taylor CT, Dorr RT, Fanta P, Hersh EM, Salmon SE: A phase I and pharmacodynamic evaluation of  polyethylene glycol-cojugated L-asparaginase in patients with advanced solid tumors. Cancer Chemother Pharmacol 47: 83-88, 2001.

• Dorr RT, Karanes C, Spier C, Grogan T, Greer J, Moore J, Weinberger J, Schiller G, Pearce T, Litchman M, Dalton W, Roe D, List AF: Phase I/II Study of the P-Glycoprotein Modulator PSC 833 (Valspodar) in Patients with Acute Myeloid Leukemia. J Clin Onc 19(6): 1589-1599, 2001.

• Dvorakova K, Payne CM, Tome M, Briehl M, McClure T, Dorr RT. Induction of oxidative stress and apoptosis in myeloma cells by imexon. Biochem Pharmacol, in press 2/2000.
• Xing C, Wu P, Skibo EB, Dorr RT. Design of cancer-specific antitumor agents based on aziridinylcyclopent [b]indoloquinolones. Journal of Medicinal Chemistry 43(3):457-466, 2000.

Collaborative Research: 

• Victor Hruby, Ph.D., Chemistry: synthesis formulation and testing synthetic opiates for cancer pain, and for superpotent synthetic melanotropic peptides for skin tanning and skin cancer prevention.
• G. Robert Pettit, Ph.D, Chemistry, Arizona State University: preclinical development of natural-product based antitumor agents from marine and plant sources.
• Laurence Hurley, Ph.D., College of Pharmacy: preclinical pharmacology and toxicology of novel DNA minor groove binding agents for cancer therapy.
• Edward Skibo, Ph.D., Arizona State University: preclinical screening and mechanism of action studies (DNA-binding) for azamitosene-based antitumor agents for solid tumors.
• David Alberts, M.D., Medicine and Pharmacology: formulation and preclinical pharmacology of skin and colon cancer prevention agents.
• Alan List, M.D., Medicine and head of Bone Marrow Transplantation Program: pharmacokinetic interactions of anticancer agents with resistance modulating agents.

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Tomislav Dragovich, M.D., Ph.D., Assistant Professor of Medicine, joined University of Arizona after receiving his pharmacology training at the University of Illinois and his medical oncology training at the University of Chicago. Dr. Dragovich's research interest focuses on developing novel treatment approaches for patients with gastrointestinal malignancies (gastric, esophageal, pancreatic, hepatobiliary and colorectal cancers). Dr. Dragovich serves as a Director of the Clinical Core for the Gastrointestinal Cancer SPORE (Specialized Program of Research Excellence) that was awarded to the Arizona Cancer Center in 2002.

The ongoing clinical research protocols include: evaluation of COX-2 inhibitors (celecoxib) as anticancer therapy in patients with colorectal and pancreatic malignancies, evaluation of Thioredoxin-1 inhibitor (PX-12) in patients with advanced GI malignancies, investigations of receptor tyrosine kinase inhibitors (EGFR, PDGFR) as anticancer therapeutics, and trials of novel chemotherapeutic agents in patients with pancreatic, colorectal and hepatobiliary cancer.

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My major research interest is focused on the role of bile acids and gastric acids in the development of Barrett's esophagus and esophageal adenocarcinoma. We study signaling pathways induced by bile acids and gastric acids in esophageal cell lines as well as in human biopsies with major focus on anti-apoptotic signaling pathways, such as JAK-STAT and NF-kB pathways.

Selected Publications: 

Bernstein H, Payne CM, Kunke K, Crowley-Weber CL, Waltmire CN, Dvorakova K , Holubec H, Bernstein C, Vaillancourt RR, Raynes DA, Guerriero V, Garewal H. 2004 May. A proteomic study of resistance to deoxycholate-induced apoptosis. Carcinogenesis 25:681-92.

Dvorakova K , Payne CM, Ramsey L, Holubec H, Sampliner R, Dominguez J, Dvorak B, Bernstein H, Bernstein C, Prasad A, Fass R, Cui H, Garewal H. 2004 Mar. Increased expression and secretion of interleukin-6 in patients with Barrett's esophagus. Clin Cancer Res 10:2020-8.

Payne CM, Waltmire CN, Crowley C, Crowley-Weber CL, Dvorakova K , Bernstein H, Bernstein C, Holubec H, Garewal H. 2003 Nov. Caspase-6 mediated cleavage of guanylate cyclase alpha 1 during deoxycholate-induced apoptosis: protective role of the nitric oxide signaling module. Cell Biol Toxicol 19:373-92.

Crowley-Weber CL, Dvorakova K , Crowley C, Bernstein H, Bernstein C, Garewal H, Payne CM. 2003 Mar. Nicotine increases oxidative stress, activates NF-kappaB and GRP78, induces apoptosis and sensitizes cells to genotoxic/xenobiotic stresses by a multiple stress inducer, deoxycholate: relevance to colon carcinogenesis. Chem Biol Interact 145:53-66.

Dvorak B, Halpern MD, Holubec H, Dvorakova K , Dominguez JA, Williams CS, Meza YG, Kozakova H, McCuskey RS. 2003 Mar. Maternal milk reduces severity of necrotizing enterocolitis and increases intestinal IL-10 in a neonatal rat model. Pediatr Res 53:426-33.

Halpern MD, Dominguez JA, Dvorakova K , Holubec H, Williams CS, Meza YG, Ruth MC, Dvorak B. 2003 Jan. Ileal cytokine dysregulation in experimental necrotizing enterocolitis is reduced by epidermal growth factor. J Pediatr Gastroenterol Nutr 36:126-33.

Crowley-Weber CL, Payne CM, Gleason-Guzman M, Watts GS, Futscher B, Waltmire CN, Crowley C, Dvorakova K , Bernstein C, Craven M, Garewal H, Bernstein H. 2002 Dec. Development and molecular characterization of HCT-116 cell lines resistant to the tumor promoter and multiple stress-inducer, deoxycholate. Carcinogenesis 23:2063-80.

Dvorakova K , Payne CM, Landowski TH, Tome ME, Halperin DS, Dorr RT. 2002 Nov. Imexon activates an intrinsic apoptosis pathway in RPMI8226 myeloma cells. Anticancer Drugs 13:1031-42.

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My research involves creating mouse models of human genetic disease, including ones related to cancer. In order to do this, my laboratory provides the facilities for the transgenic core of the Cancer Center Grant and provides advice and/or guidance to a number of investigators. I recently have returned from a sabbatical leave at the University of Cambridge in the laboratories of Dr. Martin Evans (the discoverer of embryonic stem cells) and Dr. Nabeel Affara (the discover of the gene that we wish to knock out). During this sabbatical, I gained experience with construct design and manipulation, embryonic stem cell culture and maintenance, and modes of introducing embryonic stem cells into embryos. We now have successfully made embryonic stem cell chimeric mice. Thus, we are ready to introduce knockout technology to further our goals of providing animal models of genetic disease.

Another interest of our laboratory is the use of such animal models to study gene therapy. We currently are using an animal model of Niemann-Pick C (a spontaneous mutation in this case) for studies of gene therapy targeted to the liver. We plan on extending these studies to target the central nervous system, initially with adenovirus vectors and perhaps later with lentivirus vectors. Expertise garnered from these studies may be of use to the investigators interested in gene therapy of cancer.

Selected Publications: 

• Erickson RP, Kessler S, Kremling H, Sen GC. Species variation in the testicular angiotensin converting enzyme promoter studied in transgenic mice. Mol Reprod Dev 44:324-331, 1996.
• Erickson RP. Mouse models of human genetic disease: Which mouse is more like a man? BioEssays 18:993-998, 1996.
• Kessler SP, Rowe TM, Blendy JA, Erickson RP, Sen GC. A cyclic AMP response element in the angiotensin-converting enzyme gene and the transcription factor CREM are required for transcription of the mRNA for the testicular isozyme. J Biol Chem 273:9971-9975, 1998.

Collaborative Research: 

• Garth Powis, D. Phil., Arizona Cancer Center: the development of a thioredoxin knockout controlled by tetracycline and/or tissue-specific promoters.
• Charlene A. McQueen, Ph.D., Pharmacology and Toxicology: genetic modifications of N-acetyltransferase and DNA-adduct formation.

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