ARIZONA BIOMEDICAL RESEARCH COMMISSION ANNUAL REPORT 2006-2007 Janet Napolitano, Governor David Landrith, M.P.A., Chairman COMMISSION MEMBERS General Public David Landrith, M.P.A. David Jerman, M.B.A. Gregorio M. Garcia, J.D. Medical Community Colleen Brophy, M.D. Barbara Wuebbels, R.N., M.S. Eve Shapiro, M.D. Scientific Community Manuel Modiano, M.D. Thomas "Lon" Owen, Ph.D. Joan Rankin Shapiro, Ph.D. Staff Executive Director: Dawn C. Schroeder, D.D.S., M.A. Deputy Director: James Matthews, M.P.A. Executive Staff Assistant: Damika D. Brock Accountant II: Ismene Quintanilla Program Project Specialist II: Daniel J. Powell Administrative Assistant: Cecelia Tosie 15 South 15th Street, Suite 103A Phoenix, Arizona 85007 Telephone: 602.542.1028 Fax: 602.542.6380 January 2008 TABLE OF CONTENTS Message from the Chairman v The Commission Members vii General Public vii Medical Community .ix Scientific Research Community xi Summary of 2006-2007 Commission Activities xiii Section A: Continuing Contracts, Medical Research, Year Three, FY 2007 1 Section B: Continuing Contracts, Medical Research, Year Two, FY 2007 15 Section C: Continuing Contracts, Medical Research, Year One, FY 2007 .35 Section D: New Contract Awards, FY 2007 .55 Section E: Indices 83 Principal Investigator 85 Subject 87 III David Landrith M.P.A. Message from the Chairman Fiscal Year 2007 was a year of increasing activity in both basic research and translational research. The Arizona Biomedical Research Commission continued its pivotal role in advancing biosciences in Arizona. The Commission awarded twenty-eight new scientific research contracts this year. There will be a total of seventy-five research projects under contract with the Commission beginning in FY2008. The Annual Report contains abstracts of all the projects along with information on funding levels and institutional involvement. The abstracts demonstrate the wide breadth of inquiry being undertaken by Arizona investigators. Commission contract awards enabled many Arizona researchers to prove their investigative concepts and go on to obtain additional funding at the national level. The Commission through its statutory authority continues its technology transfer efforts. Translational research expanded through continuing contracts addressing Parkinson's disease, Alzheimer's disease, cancer, bioengineering, bioimaging, and innovative approaches to research in Native American communities. The Commission sponsored AzTransNet (Arizona Translational Research Network) conducted workshops and meetings focused on tissue issues, intellectual property, business practices, institutional review boards, and clinical research practices. v The Commission worked with The Flinn Foundation sponsoring symposia, convening meetings, and advancing the promise of the Arizona Bioscience Roadmap. The Commission in concert with the Arizona Board of Regems was actively involved in supporting the development of the Arizona application to the National Institutes of Health Clinical and Translational Science Award. The final award decision is to be made in 2008. The Annual Report is prepared and submitted in January of each year to the Governor, the President of the Senate, and the Speaker of the House of Representatives. It is the hope of the all the members of the Arizona Biomedical Research Commission that encouraging both new researchers and large scale multi-institutional!multidisciplinary investigations will advance scientific discovery in the search for better health and lives of all Arizonans. VI The Commission Members Nine Commissioners guide the work of the Arizona Disease Control Research Commission. They are appointed by the Governor and confirmed by the Senate. The Commission is divided into three communities-General Public, Medical and Scientific Research. Each community is represented by three Commissioners appointed for three-year terms. Generally, the terms of three members expire each year; Commissioners may be reappointed. The Chairman and Commissioners who served during 2005-2006 are presented below. General Public Gregorio M Garcia, Esq. Shughart, Thomson & Kilroy, P.e. Commissioner Garcia received his undergraduate and graduate degrees from Arizona State University. He holds a Juris Doctorate and Master of Business Administration. He is currently pursuing a Master of Laws (LL.M.) in Biotechnology and Genomics. Commissioner Garcia is an attorney and practices with the firm of Shughart, Thomson & Kilroy, P.e. He sits on the board of directors for Arizona's largest legal aid law firm, Community Legal Services, and has held leadership positions within the State Bar ofArizona and other legal organizations. Commissioner Garcia was appointed by Governor Napolitano in 2006. VB David Jerman, M.BA. Administrative Director Arizona Alzheimer's Research Center and Arizona Alzheimer's Disease Institute Commissioner Jerman received his undergraduate accounting and Masters of Business Administration in finance degrees from the University of Utah. He has extensive experience in the pharmaceutical industry and in technology transfer issues. Commissioner Jerman is the Administrative Director of the Arizona Alzheimer's Disease Institute located within Banner Healthcare system. The Arizona Alzheimer's Research Center is a statewide research consortium composed ofASU, UA, TGen, Banner, Mayo Clinic Scottsdale, Sun Health Research Institute, and Barrow Neurological Institute. Commissioner Jerman is also Chairman of the Board of Directors of Frontier Scientific Incorporated. Jerman was appointed by Governor Napolitano in 2005. David Landrith, M.PA. Vice President of Policy and Political Affairs, Arizona Medical Association Commissioner Landrith is the Vice President of Policy and Political Affairs at the Arizona Medical Association. His undergraduate studies were in political science at Arizona State University. He received a Masters of Public Administration degree at Harvard University and accomplished summer studies at Oxford. Commissioner Landrith is the Chairman of the Board ofArizona Health-e Connection and serves on the steering committee of The Arizona Partnership for Immunization. He has served as co-chairman of the ASU Dean's Advisory Council, a member of the Arizona Town Hall Board of Directors, member of the ST. Vincent De Paul Free Medical and Dental Clinic Endowment Committee, Director of the Arizona Bioethics Network, and Past Chairman and Executive Secretary of the Arizona Council of Governments Directors' Association. He has received the Partnership Award from the Arizona Chapter of the American Academy of Pediatrics, and the Presidential Award for the Arizona State Association of Physician's Assistants. Commissioner Landrith was appointed by Governor Napolitano in 2004. Vlll Medical Community GoHeen Brophy, M.D. Chief of Vascular Surgery Carl T. Hayden VAMC Dr. Brophy is a vascular surgeon, scientist, and entrepreneur. She is currently Research Professor of Kinesiology at the Center for Metabolic Biology, Adjunct Professor of Bioengineering, and Adjunct Professor of Cellular and Molecular Biology, Arizona State University; Chief ofVascular Surgery at the Carl 1: Hayden VA Medical Center in Phoenix; and a Clinical Professor of Surgery at the University ofArizona. Brophy received both her B.S. and M.D. from the University of Utah. She was a surgical resident at Yale University and a vascular fellow at Harvard University. She has received the National Institutes of Health (NIH) National Research Service Award; the American College of Surgeons Faculty Fellowship Award; the SVS/ISCVS Lifeline Foundation Award; the Clinician Scientist Award from the American Heart Association and the Von Leibig Foundation Award for EarlyCareer Academic Surgeons, for her investigative research. She has been continuously supported by the NIH and VA (Merit Award) for over 15 years. She has over 70 publications in peer reviewed journals and has edited a textbook in vascular surgery. Dr. Brophyhas served on the Executive Councils for the Association of Academic Surgery, Society of University Surgeons, and the Lifeline Foundation Board of Directors. She is an associate editor for the Journal of Surgical Research and has served on the editorial board of Surgery. She served as an active member of the Bioengineering, Biotechnology, and Surgical Sciences (BTSS) and the Cardiovascular Devices (SBTS) study sections of the NIH. She is currently serving on the Executive Committee of the Surgical Research Committee of the American College of Surgeons and was recently appointed Chair of this committee. Dr. Brophy is the Chair of the Young Surgical Investigators course for the American College of Surgeons. She has been Chair of the Committee on Women's Issues for the Society for Vascular Surgery. She was appointed in 2002 and 2006 by Governor Napolitano. IX Eve Shapiro, M.D., M.P.H. Orange Grove Pediatrics Commissioner Shapiro received her undergraduate degree from Brandeis University and her M.D. from SUNY Upstate Medical Center in1976. She did a pediatric residency at Strong Memorial Hospital in Rochester, N.Y. and Montefiore Hospital, Bronx, N.Y. She completed an adolescent medicine fellowship at Mt. Sinai Hospital in NY in 1982. She received an MPH from the University of Arizona in 2001. Dr. Shapiro is a pediatrician in private practice in Tucson, specializing in adolescent medicine. She has been involved in legislative and voter initiatives to increase access to care for the uninsured and improve health care funding. She is on the boards of the Pima County Medical Society, Arizona Medical Association and Pima County Pediatric Association and has been on the executive committee of the Arizona chapter of the American Academy of Pediatrics. She was appointed to the commission in 2006 by Governor Napolitano to compete the term of Gary Krahenbuhl. Barbara Wuebbels, R.N., M.S. Director of Clinical Education BioMarin Corporation Commissioner Wuebbels received her Bachelor of Science in Nursing from St. Louis University, her Master of Science in Business Administration from the University of Phoenix, and her Master of Science in Adult Health Nursing from Arizona State University. Prior to joining BioMarin, she served as Director of Clinical Education at Medicis Pharmaceutical Corporation, as research coordinator at Maricopa Medical Center, and as Director of Clinical Affairs at Vivra Health Advantage in Brentwood, Tennessee. Commissioner Wuebbels has presented at various national conferences and she has published on nursing research, spinal cord stimulation, and wound care in the long term care setting. Wuebbels was appointed by Commissioner Napolitano in 2006. x Scientific Research Community Manuel Modiano, M.D. Arizona Oncology Associates Commissioner Modiano obtained his Bachelor ofScience degree from Colegio Collumbia in Mexico City. He received his M.D. with high honors from the Universidad Nacional Autonoma de Mexico. He completed post graduate education at the University ofWisconsin, Mount Sinai Medical Center, and the University ofArizona -Arizona Cancer Center. Commissioner Modiano has published numerous peer reviewed articles and has served as Principal Investigator in numerous clinical research studies. Dr. Modiano is Director of Research for Arizona Oncology Associates, Medical Director of the Arizona Clinical Research Center, Past Chief of Hematology and Oncology and Past-President of the Medical Staff at Carondelet St. Mary's Hospital and Medical Center, and Past President of the Arizona Clinical Oncology Society. He was appointed by Governor Napolitano in 2006. r Lon Owen, Ph.D. Professor of Medical Anatomy and Physiology Northern Arizona University Commissioner Owen received his B.A. in Zoology from the University of California, a Master's Degree in Biology from California State University at Sacramento, and his Ph.D. in Physiology from U.c. Davis. He was an NIH Postdoctoral Fellow at Michigan State University and Visiting Associate Professor in the Pharmacology Department of the University ofArizona College ofMedicine. He is a member of the American Physiological Society and has chaired the Research Committees of the American Heart Association at both the Arizona Affiliate and Southwestern Regional levels. His publications are in the areas ofcardiovascular, aging, and environmental physiology. He has taught physiology and pathology at Northern Arizona University since 1974. He is a member of the Translational Genomics Research Institute Board of Directors. Commissioner Owen was appointed to the Commission by Governor Hull in 1998 and 2001. His term expired in 2004, and he was reappointed by Governor Napolitano in 2006. Xl Joan Rankin Shapiro, Ph.D. St. Joseph's Hospital and Medical Center Commissioner Joan Rankin Shapiro is a human geneticist who received her M.D., Ph.D. from Cornell University Medical College in 1979. Her initial research was in human birth defects at Rockefeller University. She began her cancer career at Memorial Sloan-Kettering Cancer Center, New York. In September, 1989, she relocated to the Barrow Neurological Institute (BNI) of St. Joseph's Hospital and Medical Center, Phoenix, Arizona, where she became the Director of NeuroOncology Research. Her research involved the characterization of genetic abnormalities associated with central nervous system malignancies. Since 1979 her grant awards have totaled more than fourteen million dollars. In November 2007 she received a Life Time Achievement Award from the Society of Neuro-Oncology for her contribution to the field. She served thirteen years as an NIH Reviewer on Pathology A and on Experimental Therapeutics study sections. In 2001 Dr. Shapiro retired from the laboratory and has assumed the role as VP., Research and Development at St. Joseph's Hospital and Medical Center. She is the Past President of the National Organization Women in Cancer Research. Dr. Shapiro has also retained a strong commitment to community education. She has developed and continues to teach numerous school enrichment programs. In conjunction with the American Academy of Neurology, she conducted K-12th grade neuroscience enrichment training workshops for physicians and scientists. She is the past Chairman of the National Neuroscience prize for high school students. She remains at St. Joseph's Hospital and Medical Center as a Consultant for research activities. She was appointed by Governor Napolitano. Xli Summary of2006-2007 Commission Activities The Commission administered 72 contracts worth over $6 million with medical researchers in Arizona. The Commission continued its commitment to individual investigators, investigator collaborations, and expansion into translational research. 21 new contracts and $2.2 million were directed toward assisting individual investigators in developing proof of their research concepts, collecting preliminary data, and in continued support of translational research. Inter-institutional collaborators have formed working relationships to better address more complex research problems. A special effort is being made to ensure the success of TGen. The Translational Genomics Research Institute receives $5,000,000 per year for a period of five years plus a $500,000 annual award for a period of ten years. Section headings in this report list each program and whether the project is in its first, second, or third year of funding. Research abstracts outlining the progress made during the year are contained in SectionsA-C. Citations for scientific publications and abstracts arising out of the research are also listed. Section D provides information on new contracts awarded beginning July 2007 (FY2008). Over 1,000 Requests for Proposals (RFPs) for 2006-2007 awards were mailed to potential applicants in September 2006. The amount of funding available for new unrestricted medical research was approximately $2.0 million. In response to the RFp, the Commission received 113 unrestricted medical research proposals. ABRC Projects Submitted/Accepted FY 2007 Institution Arizona State University Northern Arizona University University of Arizona Sun Health Research Institute Barrow's Neurological Institute Mayo Clinic Others Submitted Accepted 12 3 5 2 73 17 1 4 3 12 Amount 25 40 23 250,000 88,606 1,196,321 50,000 13 4 60 299,973 110,279 15 o o 33 33 100 1 00 7 Percent of Total $ Percent Accepted o $ 3 5 In November and December the medical research proposals received were sent to a panel of national and international scientific and medical experts for peer review and evaluation. The Commission received the proposal evaluations prepared by more than 170 out-of-state peer reviewers. Three reviews were sought for each proposal. In the spring and summer of2006 the Commission selected 28 proposals for funding. During 2006-2007 the ABRC managed a total of72 basic research contracts. XIII ABRC Total New and Continuing Project Contracts 2007 Institution Award Arizona State University Northern Arizona University University of Arizona Sun Health Research Institute Barrow's Neurological Institute TGen Mayo Clinic Others % of Total Awarded 11 6 8 4 41 56 7 10 3 3 4 5 7 2 2 3 In May of 2007 the Commission awarded 21 new research contracts for a total of $1,999,440. The contracts were effective on July 1, 2007. Progress on these projects will be reported in the next Commission Annual Report. ABRC Projects Submitted! Accepted FY 2008 Institution Arizona State University Northern Arizona University University of Arizona Sun Health Research Institute Barrow's Neurological Institute Translational Genomics Institute Others Submitted Accepted 24 2 76 6 10 6 3 1 14 o 5 Percent Accepted 12.5 50 18.4 17 10 17 o Amount $ 350,000 300,000 999,440 150,000 50,000 150,000 o Percent of Total $ 18 15 50 7 3 7 o The Commission remains committed to making the results ofscientific discovery more readily available to health care providers. The Commission currently has 15 translational research projects underway. The Commission has sponsored workshops and symposia examining translational issues such as the appropriate treatment of biospecimens. Institutional barriers are being addressed by the Commission sponsored Arizona Translational Resource Network (AzTransNet). Workshops, model documents, and consulting services relating to Institutional Review Boards, collaborative agreements, intellectual property contracts, and clinical trial networks have been developed and delivered by AzTransNet. The Commission is confident that that these translational projects will result in more rapid deployment of medical therapies to Arizonans. XIV Number of All Projects That Are Basic Science, Translational, or Clinical Research Basic Science Research: Scientific knowledge of basic life processes. studies that increase Translational Research: Medical research that attempts to more directly connect basic research to patient care. Clinical Research: The study of drugs, biologics, or devices in human subjects with the intent to discover potential effects and/or determine safely or usefulness. Funding of All Projects That Are Basic Science, Translational, or Clinical Research Section A Continuing Contracts Medical Research Year Three FY 2007 University of Arizona Award Amount FY05: $172,841 Burris Duncan, M.D. Acupuncture as Complementary Therapy for Cerebral Palsy The conclusion of this collaborative investigation between the Department of Pediatrics at the University of Arizona and the Beijing Children's Hospital has resulted in a number of very interesting findings that may have far reaching implications for children with cerebral palsy not only for those born in Arizona, but wherever they may live. • • • • • • The feasibility of initiating and completing a trans-cultural study involving investigators on three continents was confirmed. The project was able to assess a combined east-west intensely administered therapeutic approach (physical, occupational, and hydro-therapies plus acupuncture) for a condition where the results are less than satisfactory when the standard-of-care used in the u.s. is administered. One hundred and sixteen children were enrolled in the study with 83 completing the 28-week trial and 8 more completing at least 12 weeks of the trial, making this one of the largest investigations ever conducted by u.s. researchers assessing therapeutic interventions for cerebral palsy. Preliminary analysis of the first 76 children who completed the trial clearly shows that the combined east-west package of the care when initiated early and intensely is far superior to any report published in the western medical literature regardless of the intervention, including invasive surgical procedures. Although not conclusive, it appears that acupuncture does playa positive role in the improvement seen in these children. The project has generated one letter to the editor Oournal of the American Medical Association); two articles submitted for publication; three abstracts submitted to the Society Acupuncture Research recently held in Baltimore, one accepted for oral presentation and one accepted as a poster presentation; three research projects submitted to foundations or governmental agencies in China; a project to be submitted to the United Cerebral Foundation in the U.S. with committed financial assistance from the Tucson Medical Center, and a large research proposal to be submitted to the National Institutes of Health to continue this investigation that the ABRC had the vision to fund. The NIH grant will involve 240 children and will include an exploratory phase using imaging techniques to determine if any structural/functional changes occur in the brain as a result of these therapies. Caspi 0, Duncan B, Han T, Zou L. MRI Findings and Cerebral Palsy. JAMA 297:466,2007. Wu Y, Jin Z, Li K, Han T, Zheng H, Caspi 0, et al. Ya-wei Acupoint-specific fMRI Patterns in Child Brains. Journal of Alternative & Complimentary Medicine. Submitted for publication. Caspi 0, Zou L, Han 1"; Duncan B. Ethical and Methodological Challenges in Conducting International Acupuncture Research. Society for Acupuncture Research. Presentation Nov. 2007. 3 Robert P. Erickson, M.D. University of Arizona Award Amount FY05: $131,535 Identification of Genes Involved in Lymphedema by Single Nucleotide Polytnorphism Mapping During the year we extended the clinical base for studies on the genetic causes of lymphedema. We were able to identifY a five generation family with most of the members in the Phoenix area. We preformed physical examinations and obtained DNA from twenty-two members of this family. In addition, we used the most sensitive method of delineating and characterizing the lymphatics of patients, lymphangioscintograms, on several members of the family. This allows us to compare the specific kind of lymphatic abnormality particular to this family to the kind of abnormality in other families. We also added more individuals, more DNA samples, and lymphangioscintograms in three other Arizona families. The refined linkage analyses on chromosome 3 were performed but the data have not yet been analyzed (due to illness/pregnaneyltermination ofkey personnel at the Translational Genomics Institute). Brent Gendleman 5AM Solutions Award Amount FY05: $100,000 5AM Illumine SAM Illumine TM is a web-based data management system that elevates collaborative clinical research. Easy access to real-time study status; organized data views for collaborators, regulators, sponsors and grantors; and clinical and genomic data integration are all benefits to multi-disciplinary investigators. We have deployed the supporting infrastructure at the state of the art facility in downtown Phoenix and have launched the first global study. Led by Dr. Michael Berens, this study involves 15 research partners from Asia, Europe and North America submitting brain cancer tumors in paraffin block and the accompanying clinical annotation from each subject. TGen will assemble tissue microarrays from these samples and redistribute slides back from staining. All the data, including the tracking and staining, is managed by the system. The software will adopt several new diverse studies in FY 2006, add features and provide the first open-source enterprise clinical research system to Arizona investigators. xxxxxxxxx~~xxxxx~x~xxxxxx~~xxxx~xxxx~xx 4 Eric J. Guilbeau, Ph.D. Arizona State University Award Amount FY05: $50,000 Biosensor for Measurement of Breath Acetone This research is aimed at developing a novel, inexpensive and easy to use sensor that can be used by individuals with diabetes to monitor their breath acetone concentration. The sensor works by measuring the heat that is generated when acetone reacts with another chemical on the surface of a very sensitive temperature measuring device called a thermopile. The research is significant because a large number of individuals in the U.S. suffer from type 2 diabetes. Individuals with type 2 diabetes are susceptible to a condition called diabetic ketoacidosis (DKA). Under this condition high amounts of acetone is released into the blood stream and unless corrected, the individual may die. During the past year, we succeeded in fabricating a prototype of the sensor and using it to measure acetone concentrations comparable to those in the breath of individuals with diabetes. Mathematical models were also developed that confirm the experimental sensor response and the theoretical basis for the sensor's operation. Ahmad L, Dodt S, Guilbeau E. The Development of a Non-invasive Breath Ketone Biosensor for Obesity Management. Abstract, Biomedical Engineering Society, Philadelphia, October 2004. Leslie Gunatilaka, Ph.D. University of Arizona Award Amount FY05: $164,500 Discovery of Novel Anticancer and Anti-infective Drugs from Endophytic Fungi of Desert Plants The overall goal of this inter-institutional and multi-investigator collaborative project is to discover novel anticancer and anti-infective drugs from endophytic fungi (fungi that live in the intercellular spaces) of desert plants. During the course of the first year of this project over 100 endophytic fungi have been cultured, extracts prepared, and screened for their potential anti-cancer and anti-HIV activity. Anticancer activity was evaluated in NCI-H460 (non-small cell lung) and PC-3M (prostate) cancer cell lines, and target oriented in vitro bioassays for activation of heat shock response and for the inhibition of the migration of metastatic cancer cell line, PC-3M. Prior to testing of fungal extracts for anti-HIV activity in virus infected T cells, they were evaluated in A30.1 lymphocyte cell line for their toxicity towards this cell line. Fourteen extracts were selected and these are currently being evaluated in anti-HIV assay. Bioactivity-guided fractionation of an extract active in cell migration inhibition assay yielded a small cyclic peptide identified as lateritin. If extracts active in above assays contain compounds that can inhibit the growth of solid tumors such as lung, breast, colon and prostate cancers, and/or are capable of inhibiting the human immune deficiency virus (HIV), our results will have an impact on the health of Arizona's population. 5 Cherry L. Herald, Ph.D. Arizona State University Award Amount FY05: $164,500 Preclinical Development of Three Anticancer Drugs Of the 200 or more diseases diagnosed as cancer, head and neck cancer is the focus of this research project. There is an urgent need for the discovery and development of new and effective anticancer drugs for human treatment of these diseases. Based on the ASU-CCR anticancer and vascular targeting agent combretastatin A-4 phosphate now advancing in human clinical trials for anaplastic thyroid and head and neck cancers, we have synthesized new structural modifications with promising anticancer activity. Tyrostatin prodrug and stilstatins 2 and 3 are being further developed and synthesized in sufficient quantity for continued early preclinical development leading towards human clinical trials. Pinney K, Jelinek C, Edvardsen K, Chaplin D , and Pettit G. The Discovery and Development of the Combretastatins: Emphasis on combretastatin A-4 (CA4). Anticancer Agents from Natural Products, Cragg, Kingston and Newman eds. CRC Press, Taylor & Francis, Boca Raton, FL, 2005. Pinney K, Jelinek C, Edvardsen K, Chaplin D , and Pettit G. Combretastatin A-I (CAl). Anticancer Agents from Natural Products, Cragg, Kingston and Newman eds. CRC Press, Taylor & Francis, Boca Raton, FL, 23-46, 2005. Monk K, Siles R, Hadimani M, Mugabe B, Ackley J, Studerus S, Edvardsen: K, Trawick M, Garner C, Pettit G, Pinney K. Design, Synthesis and Biological Evaluation of Combretastatin Nitrogencontaining Derivatives as Inhibitors of Tubulin Assembly and Vascular Disrupting Agents. BioOrg. Med. Chern. 14: 3231-34, 2006. xx~xxxxxxxxxxxxxxxxxxxxxxxxxxxx~~~x~xxx~xx 6 Arizona State University Award Amount FY07: $50,000 Steven Hoffman, Ph.D. Autoantibodies in CNS Lupus The overall goal of this project has been to understand how mental disorders can occur in the autoimmune disease, systemic lupus erythematosus. Significant progress has been made by showing that there are correlations between brain-reactive autoantibodies (BRAA) and behavior in mouse models ofautoimmune disease. We have also shown that there is evidence for increased blood-brain barrier (BBB) permeability, through elevated MHC class I levels, as a mechanism to allow access of these autoantibodies into the brain. Furthermore, we are showing how these BBB permeability changes can occur involving the neuropeptide substance P. We have also made good progress toward developing a phage-display technique to identifY the molecular specificity of autoantibodies reactive with brain and producing immortalized cell lines of some of the BRAA. These advances are instrumental in allowing us to develop diagnostic and therapeutic techniques in the future for these diseases. Laurence Hurley, Ph.D. University of Arizona Award Amount FY05: $49,746 Targeting the Silencer Element in the PDGF-A Promoter to Suppress Gene Expression We have identified a signaling pathway that is important in the survival of pancreatic cancer cells. In this pathway the key molecular switch involves an unusual DNA structure and an enzyme that remodels the DNA to activate this signaling pathway. Through this proposal we will gain molecular details of the switching mechanism and how we can externally control this process to inactivate it and selectively kill cancer cells. In the first year of funding we have gained insight into the structure of the switch and shown that a number of small molecules bind selectively to this switch. This is the first milestone in ultimately achieving the development of a drug to treat pancreatic cancer through this mechanism. Qin Y, Rezler E, Gokhale V; Sun D, Hurley L. Characterization of the G-quadruplexes in the Duplex Nuclease Hypersensitive Element of the PDGF-A Promoter and Modulation of PDGF-A Promoter Activity by TMPyP4. Nucleic Acids Res. In press. 7 Tamara King, Ph.D. University of Arizona Award Amount FY05: $164,500 Model of Bone Metastasis Pain and Phenotype We have successfully characterized a new murine model of bone cancer pain in which breast cancer cells are injected and sealed into the femur. This model of bone cancer pain is novel in that 1) it models bone cancer pain from breast cancer, and 2) it models bone cancer pain from mixed osteoblastic!osteolytic reactions within the femur. This model will allow analysis of potential differences in mechanisms underlying bone metastasis pain between pure osteolytic reactions as modeled with the osteosarcoma cells or the human prostate cell lines, and mixed osteolytic!osteoblastic as observed in this new breast cancer cell line. This model of bone cancer induced pain using breast cancer cells may lead to novel pain management treatments for women suffering from bone pain due to breast cancer metastases. We also demonstrated that noproxen (i.e. Aleve) reduced sarcoma-induced bone loss and attenuated pain behavior in this osteolytic bone cancer. Douglas Lake, Ph.D. University of Arizona Award Amount FY05: $39,600 Dendritic Cells and Immunity of Valley Fever In the first year of funding we have evaluated and characterized the phenotype and function of human dendritic cells (DC) when exposed to Coccidioides spherule lysate (T27K) and to heat-inactivated spherules. While T27K does not mature DC, MPL is a sub-optimal maturation agent as determined by phenotype and functional analysis. We have chosen to move forward with the spherules, as they stimulate lymphocytes from healthy donors who have previously had Valley Fever and are taken up by immature DC prior to maturation of DC. We demonstrated that DC engulf fluorescently labeled spherules and also become mature during or immediately after this process. Endocytosis of spherules by DC suggest they are functionally endoeytic prior to maturation by spherules. It also suggests that these DC are capable of processing and presenting antigen to T cells. The nature of this presentation demands investigation as it sets the stage for how an individual will immunologically respond against the fungus-protective or non-protective. We will embark upon the nature ofT cell activation in the next 2 years of funding. Dionne S, Podany A, Ruiz Y, Ampel N, Galgiani J, Lake D. Spherules Derived from Coccidioides posadasii Promote Human Dendritic Cell Maturation and Activation. Infection and Immunity. April: 2415-22, 2006. xxxxxxxxxx~xx~~x~xxxx~x~~xxx~xxx~x~xx 8 Dianne Lorton, Ph.D. Sun Health Research Institute Award Amount FY05: $50,000 Sodium Narcistatin in Treatment of Rheumatoid Arthritis Narciclasine, an isocarbostyrils, is an active component of Narcissus species and is reported to have anti-inflammatory properties and to significantly reduce the soft tissue swelling of arthritic joints in an adjuvant-induced arthritis (AA) rat model for rheumatoid arthritis (RA). In this series of studies we demonstrated 1) that sodium narcistatin, a pro-drug of narciclasine, was the most effective of three potential anti-proliferative drugs for treating the inflammation and bone loss that characterizes RA, 2) the most effective dose range for the narcistatin in preventing inflammation and bone loss, 3) assessed narcistatin's bone marrow, cardiac, kidney and liver toxicity, 4) completed preliminary screens of secondary immune organ cytokine and immune cell profiles for potential mechanisms of action, and 5) completed a head to head comparison of the narcistatin with the current gold standard RA treatments, anti-TNF-a and methotrexate for efficacy and toxicity. These studies support narcistatin is a safe and effective candidate for use in RA treatment. Schaller L, Meldoy J, Pettit G, Lorton D. Sodium Narcistatin Reduces Inflamation and Bone Destruction of Arthritic Joints in a Rat Adjuvant-induced Arthritis Model. J. Rheumatol. Emmanuelle Meuillet, Ph.D. University of Arizona Award Amount FY05: $50,000 Novel Inhibitors of Akt as Anticancer Drugs Inhibiting the signaling pathways that promote cancer cell survival offers a rational and attractive way of selectively inhibiting cancer growth. We have chosen to target one of the key players in the process of tumor growth, the protein Akt. This protein is an attractive target for the development of drugs to promote death specifically in cancer cells and to increase their sensitivity to cancer drugs. We have adopted a novel approach to interfering with Akt signaling and will design, synthesize and test inhibitors ofAkt for their antitumor activity. We have identified a novel lead compound and made analogues of it in order to make them more bio-available and more soluble, in other words, to make better drugs. The goal of the work is to identifY a lead compound for development as a cancer drug. xxxxxxxx~xxxx~xxxx.:~~:~co~,.xxxxxxxxxxxxxxxxxxxxxxx 9 University of Arizona Award Amount FY05: $50,000 Marek Jan Romanowski, Ph.D. Contrast Agents for Optical Coherence Tomography The overall goal of this project is to develop a new class of contrast agents for cancer research. The proposed contrast agent will be used in conjunction with optical coherence tomography (OCT), a biomedical imaging technique for visualization ofliving tissues. We seek to develop this contrast agent by forming dense arrays of gold nanoparticles on the surface of liposome, a biocompatible sphere of diameter ca. 100nm. In Year 3 of this project we successfully generated and characterized liposomesupported gold nanoshells, a new class of structures strongly interacting with light in the near-infrared spectral range in a tunable manner. These plasmon resonant structures are supported on biodegradable soft template appropriate for applications in vivo. We demonstrated optical tunability of these structures, their biodegradation, and safe use in animal models of cancer. Troutman T, Barton J, Romanowski M. Optical Coherence Tomography with Plasmon Resonant Nanorods of Gold. Optics Letters. 32-11: 1438-40. Troutman T, Barton J, Romanowski M. Gold-coated Liposomes - Biodegradable Plasmonic Nanostructures. Submitted to Nano Letters. August 2007. XXX"XX"XXXX"XXX"XX"XXXXXXXXXXXXXXXXXXXXX"XXXXXX"XXXXXXXXX 10 Joyce A. Schroeder, Ph.D. University of Arizona Award Amount FY05: $49,718 Molecular Therapeutic Targeting of MUClIp-catenin Interactions in Invasive Breast Carcinoma Breast cancer is the third leading cause of cancer-related deaths in Arizona. The majority of these patients die when breast cancer spreads from the breast to distant sites in the body (metastasis). While current chemotherapeutic treatments are making small gains against this devastating disease, the need for a treatment that targets a large number of patients is needed. We have identified a molecular event that occurs in a high percentage of transformed cells, but not in normal, non-cancerous cells. Specifically, the tumor antigen MUCI becomes highly expressed (greater than 90% of patients analyzed have increased MUCllevels) and interacts in a novel way with the adhesion protein ~-catenin and oncogene EGFR during breast cancer growth and metastasis. Experimental evidence indicates that by preventing this interaction, breast cancer cells lose the ability to progress. We have developed a targeted anticancer therapy that inhibits the growth and spread of metastatic breast cancer cells while having no side-effects on normal tissue. We have discovered that this drug significantly inhibits breast cancer growth and spread in relevant mouse models. We are very hopeful that this drug will have similar strong efficacy in treating breast cancer patients, and we will soon be applying for funding to perform clinical trials. .x.x.x~.x~.x~.x.x.x.x.x~~.x~.x.x~.x~.x.x.x.x.x~.x.x.x.x~.x.x.x.x.x 11 Arizona State University Award Amount FY05: $121,369 Michael R. Sierks, Ph.D. Morphology Specific Antibodies for Treating Parkinson's We have shown that scFv fragments directed toward a-synuclein can alter a-synuclein folding and toxicity in vivo. Here we have developed the protocols needed to generate and image a-synuclein morphologies, to isolate morphology specific scFv's, to characterize binding and specificity of the scFv's, and to improve affinity of the isolated scFv's. We have also demonstrated that scFv's expressed intracellularly as intrabodies can provide protection against a-synuclein induced toxicity. We have shown that the scFvs can label specific folded morphologies of a-synuclein in vivo in cell culture models and the morphology specific scFvs can also label specific protein morphologies in brain tissue samples obtained from human PD patients. These results hold great promise for developing a potential therapeutic for Parkinson's Disease. Barkhordarian H, Emadi S, Sierks M. Isolating Recombinant Antibodies Against Specific Protein Morphologies Using Atomic Force Microscopy and Phage Display Technologies. PEDS. 19: 497-502, 2006. Emadi S, Barkhordarian H, Wang M, Sierks M. Isolation of a Human Single Chain Antibody Fragment Against Oligomeric Alpha-synuclein That Inhibits Aggregation and Prevents Alpha-Synucelin Induced Toxicity. J Mol BioI. 368: 1132-44, 2007. Zhou C, Emadi S, Sierks M, Messer A. A Human Anti-alpha-synuclein Intrabody Interferes with Pathogenic Cellular Effects of Overexpressed Synuclein. Molecular Therapy. 10: 1023-31,2004. Shlyakhtenko L, Yuan B, Emadi S, Lyubchenko Y, Sierks M. Single Molecule Selection and Recovery of Structure Specific Antibodies Using Atomic Force Microscopy. Nanomedicine. 2007. In press. xxx~~xxxxxx~~xxxxxx~~~~x~~x~xxxx~~xx 12 Steven P. Stratton, Ph.D. University of Arizona Award Amount FY05: $164,366 Phase II Trial of Topical Perillyl Alcohol in Sun Damaged Skin Skin cancer is by far the most common cancer (with more than 1.3 million new cases expected in 2003 in the U.S.), and is a tremendous public health problem, especially in Arizona and the southwestern United States where sun exposure is high. As reported by the Southeastern Arizona Skin Cancer Registry, rates of nonmelanoma skin cancer in Arizona are among the highest in the world and are 4-6 fold higher than in the general US population. Incidence rates for melanoma, the most deadly form of skin cancer, are rising faster than almost any other cancer. Topically administered chemopreventive drugs that actually stop or reverse the growth of precancerous lesions in the skin may reduce this burden. Perillyl alcohol is a molecule found in the essential oils of lavendin, peppermint, spearmint, cherries, celery seeds, and other edible plants. We have shown that pure perillyl alcohol effectively reduces the incidence of skin tumors when applied topically to the skin in preclinical models of both melanoma and nonmelanoma skin cancers. We have recently performed a Phase I clinical trial ofa cream formulation of topical perillyl alcohol developed by our group. Results of this study indicate that this formulation is safe when applied twice daily for 30 days. Further clinical testing is now warranted to determine if perillyl alcohol applied directly to sun-damaged skin can reverse such damage. The objective of this research is to perform a randomized, placebo-controlled, double-blind, Phase 2a dose-finding clinical trial of topical perillyl alcohol in subjects with moderately to severely sun-damaged skin. The hypothesis being tested is that topical perillyl alcohol, when applied twice daily for three months, can successfully reverse sun damage in skin in a dose-dependent manner as evidenced by histopathologic normalization. As secondary endpoints, we will also determine if topical perillyl alcohol can significantly alter previouslystudied surrogate endpoint biomarkers of neoplastic changes, including optical coherence tomography (OCT) of skin; as well as p53 expression, c-Fos expression, and apoptosis (as measured by expression of activated caspase-3) in skin biopsy tissue. In addition, karyometric analysis of nuclear chromatin patterns in skin biopsy tissue will be measured. Establishment ofvalid biomarkers is vital for demonstrating the activity of this and other drugs in future studies. Safety, tolerance, absorption, and formulation stability will also be monitored. Ancillary studies dependent on performance of this trial (but funded from other sources) will include comparative genomic hybridization analysis of skin biopsy samples for gene copy number changes (in collaboration with the Translational Genomics Research Institute (TGen) in Phoenix, Arizona) and nutritional correlates and dietary assessment. Due to unexpected delays regarding FDA approval of experimental use of topical perillyl alcohol in the proposed clinical trial, this project has been extended while we complete additional preclinical dermal toxicology studies. These studies have been completed (December 2005) and we began enrolling patients beginning in January 2006. The protocol has been approved by the University ofArizona Institutional Review Board (IRB) and enrollment will commence once final FDA approval is granted. ~.x~.x.x.x.x.x~.x.x~~.x.x.x~~~.x.x~.x.x.x.x~.x.x.x~.x.x~.x 13 Timothy L. Vail, Ph.D. Northern Arizona University Award Amount FYOS: $44,992 Paramagnetic nanoparticle Immunoassay for Food Pathogen Detection Recent national outbreaks of food borne illnesses demonstrated a need for rapid, sensitive, and specific methods to test for the presence of disease-causing bacteria in food supplies. Although such tests exist, their sensitivity comes at the cost of increasing the time to get a result. Conversely, rapid assays (less than 10 minutes to result) typically lack sensitivity. Thus, there exists a need for the continued development of highly sensitive and accurate assay technology. This research seeks to further the state of the art of assay technology through the research and development of a prototype rapid assay using nanometer-sized paramagnetic particles onto which fluorescent dyes have been bound. To date, we have demonstrated the ability to create silica-coated paramagnetic nanoparticles with incorporated fluorescent dye (FITC), or quantum dots, through a multi-step process of chemical modification. We have attached a linker protein (avidin) to the surface of the particles and have shown increased stability via chemical cross-linking. Current experiments underway include the incorporation of fluorescent quantum dots as an alternative fluorescent marker. We have initiated a series of prototype immunochromatographic assays to demonstrate the functionality of the nanoparticles. The next steps will include the creation of functional particle that are specific for the causative agent of one type of food poisoning (Listeria monoeytogenes). This system is also being used as a means to create quantitative, rapid assays that are being tested for the detection of endocrine disrupting compounds in wastewater. We have filed a provisional patent with the USPTO on the design of a hand-held, field portable integrated assay and radial cassette reader. The ultimate goal is a miniaturized assay system that will probe for multiple types of disease-causing organisms simultaneously and provide testing results in a very short time. This system is intended to be adaptable to a wide variety of public health, medical, veterinary, and environmental applications. xxxx~x~xxx~xxxxxxx~xxx~xxxxxxxx~~x~~x~x 14 Section B Continuing Contracts Medical Research Year Two FY 2007 xxxxxxxxx~xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 15 Charles H. Adler, M.D., Ph.D. Mayo Clinic Scottsdale Award Amount FY06: $250,000 Arizona Parkinson's Disease Center The overall goals of the APDC are to develop clinical biomarkers for Parkinson's disease and PD with dementia (PDD) as well as find targets for novel treatment strategies. To this end the program is divided into a clinical core (which prospectively examines PD and control subjects enrolled in the brain donation program), a neuropathology core that performs the autopsies and provides CSF and brain tissue to the laboratory scientists, and 4 projects investigating the pathophysiology of PD and PDD. To date> 5,000 clinical evaluations of >1,000 subjects have occurred. In the past year 15 PDf parkinsonism and 15 control subjects came to autopsy. Projects 1 and 2 have found changes in the BDNF and D]-1 proteins, respectively. Project 3 has found dysregulation of multiple sets of genes when comparing brain tissue of control, PD, and PDD cases. Project 4 has developed the methodology for CSF protein analysis. The second year's goals of our program have been met with plans for the next year of funding being on target. Eight papers have been published, four others have been submitted, and five presentations made. Additional funding from the Michael J. Fox Foundation has been obtained. Beach T, Sue L, Walker D, Lue L, Connor D, Caviness], Sabbagh M, Adler C. Marked Microglial Reaction in Normal Aging Human Substrantia Nigra: Correlation with Extraneuronal Neuromelanin Pigment Deposits. Acta Neuropathol. 114(4): 419-24, 2007. Beach T, Adler C, Sue L, Peirce], Bachalakuri], Lue L, Caviness], Conno D, Sabbagh M, Walker D. Reduced Striatal Tyrosine Hydroxylase in Incidental Lewy Body Disease. Acta Neuropathol. In press. Beach T. Sue L, Walker D, Roher A, Lue L, Vedders L, Connor D, Sabbagh M, Rogers]. Sun Health Research Institute Brain Donation Program: Description and Expertise, 1987-2007. Cell & Tissue Banking. In Press. Caviness ], Driver-Dunckley E, Sabbagh M, Connor D, Noble B, Evidente V, Shill H, Adler C. Defining Mild Cognitive Impairment in Parkinson's Disease (PD-MCI). Mov. Disorders. 22:127277,2007. Caviness], Hentz], Evidente V, Driver-Dunckley E, Samanta], Mahant P, Connor D, Sabbagh M, Shihll H, Adler C. Both Early and Late Cognitive Dysfunction Affects the Electroencephalogram in Parkinson's Disease. Parkinsonism and Related Disorders. 13:348-54,2007. Sabbagh M, Lahti T, Connor D, Caviness ], Shill H, Mahant P, Samanta ], Burns R, Evidente V, Driver-Dunckley E, Reisberg B, Bircea S, Adler C. Functional Decline Correlates with Cognitive Impairment in Alzheimer's Disease and Parkinson's Disease. Dementia, Geriatric, Cognitive Disorders. 24:327-34,2007. xxx~xxxxx~xxxx~xxxx~x~~~xxxx~xxxxx~~xx 17 Shill H, Adler C, Sabbagh M, Connor D, Caviness ], Hentz], Beach T. Pathological Findings in Prospectively Ascertained Essential Tremor Subjects. Neurology. In press. Adler C, Grover A, Sabbagh M, Caviness], Connor D, Beach T. Clinical and Pathologic Findings in PD with LRRK2 Mutations: 2 Cases with Mild Cognitive Impairment and Small Amplitude Myoclonus. Mov. Dis. 2l(Suppl 15): S583, 2006. Beach T, Connor D, Sue L, Caviness ], Sabbagh M, Adler C. Motor and Cognitive Findings in Incidental Lewy Body Disease. J. Neuropathol. Exp. Neurol. 66(5): 422, 2007. Leslie v: Boyer, M.D. University of Arizona Award Amount FY06: $150,177 Scorpion Treatment and Imaging of Neurotoxicity Group (STING) Neurotoxicity from scorpion sting is rare, but it may be life-threatening, especially in young children. This study addresses (1) the shortage of an effective treatment severe scorpion neurotoxicity and (2) the lack of a validated clinical assessment tool with which to further new drug development and train emergency providers. The infrastructure for providing experimental antivenom as therapy for significant scorpion stings, established in the last reporting period, was expanded and refined. A total of 16 rural and urban hospitals in Arizona are approved to treat patients and have treated over 250 patients ranging in age from 2 months to 80 years since the start of this study. This successful treatment has meant shorter hospital stays, fewer admissions to the Pediatric and Adult Intensive Care Units and increased safety for children and adults stung and treated in Arizona. xxxxxxx~xxxxx~~xxxxxxxx~xxx~xx~~xxxxxxx~ 18 Danny Brower, Ph.D. University of Arizona Award Amount FY06: $49,995 A Rapid and Inexpensive Screen for Mutations that Sensitize Cells to Cancer Drugs The primary goal has been to develop a system that can identifY specific genetic lesions that sensitize cells to the effects of particular anti-cancer drugs. This system takes advantage of the ease with which individual genes can be neutralized in cells from the fruit fly, Drosophila. To date, we have established procedures for eliminating hundreds of genes, one at a time, and asking if this sensitizes cells to die when a drug is added, and tested the assay using established anti-cancer drugs. We are now proceeding to use the system to test novel compounds that target pathways that potentially promote abnormal cell growth or survival in tumor cells and will attempt to uncover previously unknown drug/ genetic interactions. David J. Duggan, Ph.D. TGEN Award Amount FY06: $50,000 Genetic Basis of Auriculo-condylar Syndrome in 2 Arizona Families At the conclusion of year 1, a disease-causing locus had been localized to chromosome 20. Within the critical region of interest a candidate disease-causing gene, JAG!, was identified. In year 2, the complete coding sequence of this candidate gene JAGI was resequenced. Four novel DNA sequence variants were identified. One of the variants, a T-to-C nucleotide change, segregated with the disease phenotype at least for the 4 affected individuals that were resequenced. Further testing of the identified and putative disease-causing T-to-C change revealed that the base change did not segregate with the disease phenotype when the entire pedigrees from both families were tested. Additionally, genetic markers in the form of microsatellites were subsequently genotyped. These data were integrated with the genome-wide linkage data from the AffYmetrix 10Kstudy (year 1) and the resequencing data (year 2). Haplotype analysis of the combined data revealed that we had successful narrowed the region of interest to a minimum 2.3Mb region flanked by markers rs771943 and 26B-2. In the final year (year 3), we intend to (1) prioritize the candidate genes in this newly defined minimal region of interest, (2) resequence the candidate gene(s), (3) confirm the identification of a putative causative variant in all members of the pedigrees, (4) confirm the identified variant is not an unreported polymorphism, and (5) determine the functional significance of the identified variant(s). Dr. Jason Johnson (UA Med. Sch. 2006) was part of the group that published the hearing finding on individuals from these families (Storm et al. 2005). Dr. Johnson has also presented three oral presentations and or posters at national and international meetings on this subject matter. xxx~xxx~xx~xx~xxxxxxxx~xx~o~xxxxxxx~x~xx~ 19 University of Arizona Award Amount FY06: $153,922 Katerina Dvorak, Ph.D. Barrett's Esophagus Esophageal Adenocarcinoma and Apoptosis About 10% of patients with chronic heartburn have Barrett's esophagus (BE), a premalignant condition associated with a 30-fold increased risk for the development of esophageal cancer (EC). The major focus of our studies is to identify molecular pathways that are responsible for the development of BE and for the progression from BE to EC. Bile acids and gastric acid are two major components of refluxate. We found that the combination of gastric acid and bile acids induce oxidative stress and DNA damage leading to increased mutations, activation of anti~apoptotic pathways and an increase in cells with damaged DNA. We used several different experimental approaches on tissue samples and cell lines obtained from normal, BE and EA patients. The results from these studies resulted in new NCI/NIH funding (Specialized Program of Research Excellence), presentation at national and international meetings, and publications in high ranking journals. Dvorak K, Payne C, Chavarria M, Ramsey L, Dvorakova A, et al. Bile Acids in Combination with Low pH Induce Oxidative Stress and Oxidative DNA Damage: Relevance to the Pathogenesis of Barrett's Oesophagus. Gut. 56: 763-71, 2006. Dvorak K, Chavarria M, Papyne C, Ramsey L, Crowle-Weber C, Dvorakova K, et al. Activation of the Interleukin-6/Signal Transducers and Activators of Transcription 3 Antiapoptotic Pathway in Esophageal Cells by Bile Acids and Low pH: Relevance to Barrett's Esophagus. Clin. Cancer Res. In press. Dvorak K, Garewal H. Synergistic Interaction of Low pH and Bile Acids. OESO Congress Book, Guili ed. In press. Dvorak K, Garewal H. How Might GERD Promote Carcinogenesis in Barrett's Esophagus? OESO Congress Book. Guili ed. In press. Dvorak K. Are Genetic Alterations Observed in Non-dysplastic Barrett's Epithelium? OESO Congress Book. Guili ed. In press. Dvorak K, Bernstein H, Payne C, Bernstein C, Garewal H. Bile Acid Induction ofApoptosis in Relation to Gastrointestinal Cancer. Bile Acids: Toxicology and Bioactivity, Jenkins and Hardie eds. RSC Publishing. xxxxxx~xxxx~~xxx~xxxxxxx~xxxx~xx~xxxxxxxx 20 Scot W Ebbinghaus, M.D. University of Ariwna Award Amount f-<:xx~xxxxx 89 o 28 opioid p 28 pam parietal area Parkinson's Disease PDGF-A perillyl alcohol phospholoid imaging probes polyposis 60 12, 17, 59 7 13 37 57 R 38 respiratory muscles S 30 scaffolds, biomimetic scorpion sting spinal cord injury state estimation stem cells sulfonium-salt supranuclear palsy syndrome, auriculo-condylar systemic lupus erythematosus 18 30 60 80 49 63 19 7,46 T 5,8,27,57,71 T cell thermoregulation translational control Tribal community participation trichloroethylene tumor cells, circulating 49 80 26 75 54 U 21 umbilical cord blood cells V 27 vaccine technology valley fever VEGF transcription visual fixation 8, 69 32 63 W 4 web-based data management systems Withaferin A 66 xxxxxxxxxxxxxx~xxx~xxxx~x~x~xx~x~x~~x~ 90