on fresh and frozen serum and differing HIV sub- types have been conducted in both the research and field environments. Testing has been compared to reference technology for calculation of operating characteristics. Conclusion: Rapid HIV-1 testing technology is an evolving field subject to market demands. Several tests exist that support warfighter use in the field. However, these tests should still be utilized in the context of the medical risk decision making process. DTIC Blood; Military Operations; Serums; Viruses 20050173139 Naval Medical Research Inst., Portsmouth, VA USA Improving Management of Pediatric Patients with Attention- Deficit/ Hyperactivity Disorder at Naval Medical Center Portsmouth Caron, Roger; Apr. 2004; 38 pp.; In English; Original contains color illustrations Report No.(s): AD-A432228; No Copyright; Avail: Defense Technical Information Center (DTIC) The purpose of this research is to determine if the selection of a primary care or psychiatrist provider, is significantly different between direct care and network providers, given similar diagnosis of attention-deficit hyperactivity disorder (ADHD) in children between the age of 5 and 17. The Chi-square statistical analysis is used to determine the extent of the relationship. Results of the test revealed a statistical significance given a Chi-square value of 365.84, 90, 1 and a critical value of 6.63. The explanation for beneficiary selection of psychiatric specialists vice their primary care provider was found to be dependant on current rules not requiring a referral for mental health care coupled with no out of pocket expense for care. The application of best business practices is explored to reduce this trend. The implementation of ADHD clinical path guidelines, marketing strategies and utilization of current pharmacy programs are recommended. DTIC Medical Services; Mental Health; Military Operations; Patients 20050173140 Duke Univ., Durham, NC USA Analysis of the Link Between Acquired Expression of a Master Switch Gene of Osteoblast Differentiation by Breast Cancer and Bone Metastasis Wang, Xiao-Fan; Aug. 2004; 10 pp.; In English Contract(s)/Grant(s): DAMD17-03-1-0600 Report No.(s): AD-A432229; No Copyright; Avail: CASI; A02, Hardcopy Bone metastasis of breast cancer is a major cause of death among breast cancer patients. However, we still know relatively little about why many breast cancers metastasize to the bone. To develop better treatments of bone -metastasis of breast cancer, we need to understand how breast cancer cells acquire the abilities to move to the bone, survive in the new environment, and flourish as metastatic tumors. We postulate that one potential mechanism by which breast cancer cells may acquire such abilities is their acquired expression of bone specific proteins that are known to be involved in mediating the activities of the bone-forming cells in the bone tissue, the - osteoblasts. In this study, we attempted to address the critical question of whether the expression of a master gene for the development of bone-forming osteoblast cells, CBFAl, by the breast cancer cells leads to bone metastasis in an established animal model system. To do this, we manipulated the expression of this gene in established human breast cancer cell lines and planned to -monitor the ability of those cancer cells to grow in the bone as metastases. A positive finding from such studies will pave the way for the development of potential therapeutic agents for the treatment of this horrifying disease. DTIC Bones; Breast; Cancer; Mammary Glands; Metastasis; Osteoblasts; Switches 20050173141 Naval Postgraduate School, Monterey, CA USA Using Web-Based Interactive Multimedia to Supplement Traditional Teaching Methods: A Pilot Program for Medical Training of Non-Medical Personnel Gellman, Gregg W.; Mar. 2005; 166 pp.; In English; Original contains color illustrations Report No.(s): AD-A432230; No Copyright; Avail: Defense Technical Information Center (DTIC) This thesis proposes that it is possible to create an adjunct to traditional instructor-led training that will reduce training time and costs and at the same time improve performance using commercial off-the shelf (COTS) software. Motivated by the lessons learned following the attack on the USS Cole on October 12, 2000 in which 17 sailors were killed and 42 were wounded, we created a simulator using readily available software in minimal time with zero funding and tested it against small sample sizes of eventual recipients of the training. The simulator, as part of a blended learning solution, was shown to be as 175 effective as traditional instructor-based learning but was conceived at a fraction of the cost and with a significant reduction in total training time. Both of these factors are increasingly being valued in today’s reality of increased operational tempo and reduced resources. DTIC Computer Programs; Education; Medical Personnel; Medical Services; Multimedia; Pilot Training 20050173142 Duke Univ., Durham, NC USA A Functional Genomics Approach to Identify Novel Breast Cancer Gene Targets in Yeast Bennett, Craig; May 2004; 39 pp.; In English Contract(s)/Grant(s): DAMD17-03-1-0232 Report No.(s): AD-A432231; No Copyright; Avail: CASI; A03, Hardcopy We are using the yeast Saccharomyces cerevisiae to identify new cancer gene targets that interact with the tumor suppressor Brcal. Expression of Ercal in diploid WT yeast leads to prolonged Gi arrest and lethality. We identified from a collection of ionizing radiation (IR) -sensitive yeast deletion strains or from a pool of 4%46 genetically tagged deletion strains, 34 that rescue Brcal-induced lethality. Two IR resistance genes that rescue Brcal-induced lethality are the transcription factors CCR4 and DHHl. These are checkpoint genes required for cell cycle progression in Gl and S phases following DNA damage. Consistent with a role in radiation resistance, Dhhlp and its highly conserved human ortholog DDX6 were found to physically interact with Brcal in yeast and human cells. Another transcription factor (YAF9) was IR sensitive and rescued Brcal-induced lethality when deleted. This deletion strain and 19 others were subsequently isolated from the deletion strain pool. Most of these deletions (75%) were IR sensitive and hypersensitive to the toxin zymocin which appears to induce DSB damage by inhibiting transcription. Furthermore, most (85%) of these genes are highly conserved suggesting that the hunan orthologs may interact with Brcal to maintain genomic stability and suppress the onset of breast cancer. DTIC Breast; Cancer; Genome; Mammary Glands; Targets; Yeast 20050173143 Ohio State Univ., Columbus, OH USA Development of Dual Acting Inhibitors for Breast Cancer Li, Pui-Kai; Nov. 2004; 17 pp.; In English Contract(s)/Grant(s): DAMD17-00-1-0238 Report No.(s): AD-A432232; No Copyright; Avail: CASI; A03, Hardcopy Purpose: To design dual acting inhibitors that can block the enzyme estrone sulfatase and act as antiestrogens. Scope: The design and%synthesis of 30 dual inhibitors are proposed. The inhibitors contain 4 different structural core. The synthesized inhibitors will be tested on their ability to inhibit the enzyme estrone sulfatase and also their abilities to inhibit the growth of breast cancer cells stimulated by estrone suffate. In addition, selected inhibitors will be tested in vivo using NMU-induced mammary tumors inrats: Major findings: All thirty of the proposed inhibitors have been synthesized. The inhibitors have been tested for their ability to inhibit estrone sulfatase activity of rat liver microsomes at 20 %M concentrations and in the presence of 20 %M of substrate estrone sulfate. All the inhibitors tested so far are more potent thanour lead compound Tamoxifen sulfamate. Raloxifene sulfamate (inhibitor 30) is still the most potent compound among the 30 inhibitors we have synthesized. It inhibits more than 95% of the sulfatase activity at 20 %M concentration. It is by far the most potent dual inhibitor we have ever obtained. We have selected inhibitor 30 as one of the compounds for in vivo study using NMU-induced mammary tumors in rats. We have synthesized 4 grims of the compound needed for the study. Unfortunately, ten percent of compound 30 degraded unexpectedly Which delay ourin vivo studies. The proposed in vivo study is delayed awaiting the synthesis 9f more compound 30. DTIC Breast; Cancer; Inhibitors; Mammary Glands 20050173145 Naval Postgraduate School, Monterey, CA USA Agent-Based Simulation of Disease Spread Aboard Ship Gutierrez, Louis M.; Mar. 2005; 65 pp.; In English; Original contains color illustrations Report No.(s): AD-A432234; No Copyright; Avail: Defense Technical Information Center (DTIC) Extreme examples like the Spanish Flu pandemic of 1918 make clear the devastating impact that communicable diseases can have on military readiness. It is highly desirable to have models and tools that can be used to evaluate the course of a disease over time. These tools can help assess the effectiveness of strategies employed to contain the outbreak such as 176 constraining movement, wearing protective gloves or masks, closing high traffic areas, etc. Armed with these tools, a medical practitioner can better assess the right course of action in a time critical situation. The primary difficulty with creating models and simulations for this purpose is that disease spread depends upon the details of human behavior and environmental variables which are not accounted for in current mathematical models. The likelihood that a particular individual will catch a given disease depends upon such specifics as where he works, whom he interacts with, where he sleeps, what he eats, his habits of personal hygiene, etc. It is hypothesized that a software disease simulation can combine agents that mimic human behavior, a ship specific environment, and disease specific attributes to more accurately model the spread of disease aboard ship than a mathematical model. DTIC Computerized Simulation; Diseases; Infectious Diseases; Maintainability; Military Operations; Ships; Simulation 20050173148 Texas Univ., Arlington, TX USA Non-Invasive Monitoring of Breast Tumor Oxygenation: A Key to Tumor Therapy Planning and Tumor Prognosis Liu, Hanli; Sep. 2004; 202 pp.; In English Contract(s)/Grant(s): DAMD17-00-1-0459 Report No.(s): AD-A432239; No Copyright; Avail: CASI; A10, Hardcopy The overall goal of this research project is to develop and evaluate a new approach to monitoring of oxygenated hemoglobin concentration (HbO2) of breast tumors under respiratory interventions using near infrared (NIR) spectroscopy and imaging techniques. The aims have included (1) to evaluate a single-channel, dual wavelength, NIR, frequency-domain oximeter and the algorithms for obtaining tumor HbO2 against tumor PO2 measured by 19F magnetic resonance imaging (MRI), (2) to modify the single-channel system into a 3-channel NIR system, (3) to investigate heterogeneity of HbO2 in breast tumors using the 3-channel NIR system, and (4) to study the influence of three interventions on HbO2 and PO2 of the breast tumors. We have accomplished all of the proposed aims and compared the optical method with concurrent measurements of tumor oxygen tension using oxygen needle electrodes, fiber optic needle systems (FOXY), and 19F MRI. Overall, we conclude that NIR techniques could be a useful non-invasive monitoring tool for breast tumor oxygenation, which is a key to breast tumor therapy planning and tumor prognosis. Furthermore, the need for NIR imaging is obvious and is our current research development in order to fully characterize static and dynamic heterogeneity of breast tumor vasculature under therapeutic interventions. DTIC Breast; Cancer; Mammary Glands; Prognosis; Therapy; Tumors 20050173153 Army Medical Research Inst. of Infectious Diseases, Fort Detrick, MD USA Quorum Sensing: A Transcriptional Regulatory System Involved in the Pathogenicity of Burkholderia mallei Ulrich, Ricky L.; DeShazer, David; Hines, Harry B.; Jeddeloh, Jeffrey A.; Nov. 2004; 9 pp.; In English; Original contains color illustrations Contract(s)/Grant(s): Proj-02-4-5X-026 Report No.(s): AD-A432255; No Copyright; Avail: Defense Technical Information Center (DTIC) Numerous gram-negative bacterial pathogens regulate virulence factor expression by using a cell density mechanism termed quorum sensing (QS). An in silico analysis of the Burkholderia mallei ATCC 23344 genome revealed that it encodes at least two luxI and four luxR homologues. Using mass spectrometry, we showed that wild-type B. mallei produces the signaling molecules N-octanoyl-homoserine lactone and N-decanoyl-homoserine lactone. To determine if QS is involved in the virulence of B. mallei, we generated mutations in each putative luxIR homologue and tested the pathogenicities of the derivative strains in aerosol BALB/c mouse and intraperitoneal hamster models. Disruption of the B. mallei QS alleles, especially in RJ16 (bmaII) and RJ17 (bmaI3), which are luxI mutants, significantly reduced virulence, as indicated by the survival of mice who were aerosolized with 10 to the 4th power CFU (10 50% lethal doses). For the B. mallei transcriptional regulator mutants (luxR homologues), mutation of the bmaR5 allele resulted in the most pronounced decrease in virulence, with 100% of the challenged animals surviving a dose of 10 LD50s. DTIC Detection; Mass Spectroscopy; Pathogenesis; Regulations; Virulence 20050173155 Tripler Army Medical Center, Honolulu, HI USA Cost-Benefit Analysis of Radiation Therapy Services at Tripler Army Medical Center Diehl, Diane S.; Sep. 2004; 71 pp.; In English; Original contains color illustrations Report No.(s): AD-A432257; No Copyright; Avail: Defense Technical Information Center (DTIC) 177 The purpose of this analysis was to examine the costs and benefits associated with continuance of ‘in-house’ radiation therapy services to eligible beneficiaries at Tripler Army Medical Center (TAMC), as opposed to purchasing services. In determining the optimal solution for TAMC, three models were developed and used to project, for FY04 through FY10, a financial analysis using historical data. The analysis indicated purchasing radiation therapy services, i.e., outsourcing this care would produce a cost avoidance of $442,683 to $604, 619, depending upon model comparison. However, the financial data alone is insufficient to determine the optimal solution. Qualitative factors were analyzed using a relative values decision matrix. Evaluation criteria consisted of cost, access, perceived quality, measurable quality, and political views. These criteria were ranked and weighted. A threats, opportunities, weaknesses, and strengths matrix was then used to establish the strategic direction. Based on the results of this analysis, it is recommended that TAMC continue to provide radiation therapy services in-house and enhance those services through purchase of intensity-modulated radiation therapy technology. DTIC Chemotherapy; Cost Analysis; Cost Effectiveness; Medical Services; Military Operations; Radiation Therapy 20050173170 Great Plains Regional Medical Command, Fort Sam Houston, TX USA A Feasibility Study on the Implementation of Teleophthalmology in the Medical Treatment Facilities in the Great Plains Regional Medical Command Dixon, Margaret L.; Jun. 2004; 99 pp.; In English; Original contains color illustrations Report No.(s): AD-A432280; No Copyright; Avail: Defense Technical Information Center (DTIC) With the ever increasing costs of health care today finding, testing, and, if found workable, utilizing a new technology is an absolute must. Teleophthalmology is just such a technology. This service will greatly benefit the present and growing diabetic population. One of the major complications of diabetes is diabetic retinopathy, which eventually causes blindness. The effects of diabetic retinopathy can be limited if early and effective treatment is provided. The key to early intervention is an annual eye exam. The compliance rate for annual eye exams for Great Plains Regional Medical Command is less than the 90% required to meet HEDIS as well as our own Clinical Practice Guideline metric. Teleophthalmology is a way to meet the needs of the patient for an eye exam without a second visit to the hospital. Utilizing a digital ophthalmic camera allows the patient’s pupils to be dilated, the films obtained and sent for review by an ophthalmologist during their routine primary care visit. This decreases the hassle factor for the patient, it frees up ophthalmology clinic visits held for routine diabetic eye exams, and best utilizes the limited number of ophthalmology providers available in the region. DTIC Eye (Anatomy); Feasibility; Great Plains Corridor (North America); Ophthalmology 20050173175 RAND Corp., Santa Monica, CA USA Determinants of Dispensing Location in the TRICARE Senior Pharmacy Program Malkin, Jesse D.; Joyce, Geoffrey; Pace, Jennifer; Croghan, Thomas; Jan. 2005; 94 pp.; In English Contract(s)/Grant(s): DASW01-C-01-0004 Report No.(s): AD-A432290; No Copyright; Avail: CASI; A05, Hardcopy The MHS serves approximately 8.6 million eligible beneficiaries, including active-duty military personnel and their family members (dependents), retired military personnel and their dependents, and surviving dependents of deceased military personnel. TRICARE, the program that administers health care for the DoD, includes a pharmacy benefit that provides coverage for virtually all U.S. Food and Drug Administration (FDA) approved prescription medications. Prior to fiscal year (FY) 2001, elderly military retirees and their dependents who wished to use their military benefits to fill a prescription could do so only at a MTF outpatient pharmacy; However, some drugs that were frequently prescribed by civilian providers were not always available at MTFs because of formulary restrictions. As of FY 2001, DoD introduced a new program for elderly military retirees and their dependents, entitled TRICARE Senior Rx (TSRx). TSRx beneficiaries can now fill their prescriptions at any of four points of service: (1) outpatient pharmacies at MTFs; (2) the TRICARE Mail Order Pharmacy (TMOP), 3 currently administered by Express Scripts Inc.; (3) retail pharmacies contracted by regional TRICARE contractors (referred to as ‘network’ pharmacies); and (4) non-network retail pharmacies. The TMOP dispenses drugs for chronic conditions. Although it cannot dispense a few drugs, such as atorvastatin, without proof of medical necessity the overwhelming majority of drugs for chronic conditions are available. Retail pharmacies have completely open formularies: TRICARE reimburses them for all prescriptions except those specifically excluded from TRICARE coverage. DTIC Dispensers; Health; Medical Services; Military Operations; Pharmacology; Position (Location) 178 20050173176 RAND Corp., Santa Monica, CA USA Pharmacy Use and Costs in Employer-Provided Health Plans. Insights for TRICARE Benefit Design from the Private Sector Joyce, Geoggrey; Malkin, Jesse D.; Pace, Jennifer; Jan. 2005; 94 pp.; In English Contract(s)/Grant(s): DASW01-C-01-0004 Report No.(s): AD-A432298; No Copyright; Avail: CASI; A05, Hardcopy The military health system (MHS) has approximately 8.6 million eligible beneficiaries, including active-duty military personnel and their family members, retired military personnel and their family members, and surviving family members of deceased military personnel. In 2002, the Department of Defense (DoD) spent about $3 billion on outpatient pharmacy benefits. Like the private health care sector, the MHS has experienced a rapid growth in pharmaceutical expenditures. At the request of DoD, the RAND Corporation has undertaken two studies designed to help DoD shape their pharmacy benefit policy to control costs. The U.S. Congress has identified the TRICARE pharmacy benefit as an area for reform. Section 701 of the National Defense Authorization Act for Fiscal Year 2000 requires the Secretary of Defense to establish an effective, efficient, and integrated pharmacy benefits program. As part of a program redesign effort, which will result in the establishment of a Uniform Formulary (UF), the DoD is considering moving from a two-tiered copayment system to a three-tiered copayment system, which will increase the copayment for some classes and brands of medications. It is hoped that this move will give providers (acting in the interest of their patients) an incentive to prescribe lower-tier, less-costly options. To assist the DoD in assessing the potential implications of this policy change, RAND used an existing data resource to examine how beneficiaries with private drug coverage responded to similar changes in pharmacy benefits. The findings from this analysis, presented in this report, can inform the DoD of the potential costs and benefits of adopting the proposed Uniform Formulary. DTIC Costs; Health; Medical Services; Military Operations; Pharmacology 20050173208 Blanchfield Army Community Hospital, Fort Campbell, KY USA Investing in the Future by Learning from the Past: Developing a Survey Tool to Gather Feedback from Deployed Army Forward Surgical Team Morton, Richard; Jun. 2004; 64 pp.; In English; Original contains color illustrations Report No.(s): AD-A432379; No Copyright; Avail: Defense Technical Information Center (DTIC) The purpose of this Graduate Management Project (GMP) was to develop a validated survey instrument to gather crucial feedback from deployed Forward Surgical Teams (EST) for use by the Army Medical Department Center and School (AMEDD C&S) in the developmental evolution of the Program of Instruction (POI) for the Army Trauma Training Center (ATTC), currently operating out of Ryder Trauma Center, Miami, Florida. Three critical processes or phases were used to assure validity in the initial design of this tool. After a thorough literature review, an initial template was developed with assistance from the Executive Officer (XO) and another instructor assisted in staffing this tool through the ATTC. The second phase was to have the Survey Administrator, AMEDD C&S, automate and modify the survey to comply with Center and School training feedback objectives and the Army Surgeon General’s Balanced Scorecard. Finally, the tool went through a second audit conducted by the ATTC and was piloted for content through the 801st FST at Fort Campbell. The objective of developing a solid instrument for the ATTC was completed during the course of this project. Ultimately, utilizing this tool to gather feedback will be essential to evaluate the Army’s current trauma training program and enhancing the quality of care we deliver on the battlefield. DTIC Deployment; Feedback; Learning; Surgery; Surveys 20050173214 Delaware Univ., Newark, DE USA Mucin (MUC1) Expression and Function in Prostate Cancer Cells Carson, Daniel D.; Mar. 2004; 24 pp.; In English Contract(s)/Grant(s): DAMD17-00-1-0525 Report No.(s): AD-A432401; No Copyright; Avail: CASI; A03, Hardcopy Mucin glycoproteins are highly expressed by many tumors, reduce normal cell-cell and cell-extracellular matrix adhesion and protect cancer cells from attack by the immune system. Mucin expression not only increases, but also changes from a restricted pattern of apical expression to a general distribution over the entire cell surface. In this regard, conversion of prostate epithelium from a highly-organized, growth-controlled phenotype to a highly proliferative, metastatic phenotype is associated with loss of cell polarity. Very few studies been performed on mucin expression by prostate cancer cells. MUC1 is a large molecular weight, type I transmembrane mucin glycoprotein expressed by normal and malignant prostate epithelium. High 179 level cell surface expression, reported immunosupressive activities of its released ectodomain, and antiadhesive properties all contribute to this mucin’s ability to protect and promote tumor cell growth and survival. Recent observations using human breast cancer cell lines indicate that MUC1 can associate with the intracellular signal transducing molecules, beta-catenin and GRB-2. Recent studies from the PI’s lab demonstrate that cytokines, including interferon-gamma, markedly stimulate MUC1 gene expression. Primary prostate tumors are often found in the vicinity of cytokine producing cells, and commonly metastasize to bone marrow, a rich source of these same cytokines. DTIC Cancer; Prostate Gland; Proteins 20050173216 University of Southern California, Los Angeles, CA USA Development of Quantum Dot Probes for Near-Infrared Fluorescence Imaging of Breast Cancer Angiogenesis Chen, Xiaoyuan; Sep. 2004; 23 pp.; In English Contract(s)/Grant(s): DAMD17-03-1-0752 Report No.(s): AD-A432403; No Copyright; Avail: CASI; A03, Hardcopy The overall objective of this proposal is to develop cyclic RGD peptide conjugated biocompatible quantum dot nanoparticles for near-infrared fluorescence imaging of breast cancer angiogenesis. The two hypotheses to be tested are that: 1) the integrin alpha(v)beta(3) antagonist, when conjugated with semiconductor nanocrystals, will not change the fluorescent properties of the QDs significantly; and 2) the QD-based breast cancer angiogenesis probes are specific enough to recognize the integrin receptor and bright enough for effective detection in preclinical animal models. Specific Aim 1: to prepare water-soluble QD-RGD conjugates and characterize the probes in vitro. Specific Aim 2: to assess the tumor targeting efficacy of QD-RGD in breast cancer model. Major Findings: Although biocompatible quantum dots in theory is superior to organic dyes for long-term, multi-target and highly sensitive imaging, however, the current surface coating techniques do not offer enough stability of QDs in biological medium. On the other hand, NIR fluorescent dyes labeled RGD peptides demonstrated highly sensitive and semi-quantitative NIR fluorescence images for tumor detection in preclinical xenograft models. This non-invasive optical imaging approach provides the opportunity for rapid and cost-effective studies before more costly radionuclide-based imaging studies. DTIC Angiogenesis; Breast; Cancer; Fluorescence; Images; Imaging Techniques; Mammary Glands; Quantum Dots 20050173217 New South Wales Univ., Sydney, Australia The Role of p53 Mutations in Metastasis of Prostate Cancer to Bone Russell, Pamela J.; Blair, Julie M.; Kingsley, Elizabeth A.; Szymanska, Barbara; Perryman, Lara; Jackson, Paul; Dec. 2004; 89 pp.; In English Contract(s)/Grant(s): DAMD17-02-1-0108 Report No.(s): AD-A432404; No Copyright; Avail: CASI; A05, Hardcopy The spread of prostate cancer (CaP) to bone causes morbidity and death, yet interactions between CaP cells and bone are poorly understood. To test if specific mutations of the tumor suppressor gene, p53, that occur in CaP cause disease progression, we generated cell lines from the human LNCaP cell line that stably express normal or mutant p53. Purpose: To test whether p53 mutations affect establishment/growth of experimentally-induced CaP in the bone. Score: LNCaP cell lines were tested in tissue culture for factors that alter normal bone remodeling and angiogenesis and were implanted in immuno-incompetent mice to analyze their ability to form tumors and to spread to the bone. Results/ Progress: p53-mutant CaP cells modulated osteoclastogenesis and affected osteoblast proliferation; different p53 mutations showed differentiation stage-dependent effects. Osteoblasts also stimulated the growth of p53 mutant CaP cells, suggesting that osteoblast-CaP interactions lead to new bone formation and allow CaP to establish in bone. When implanted in mice, some p53 mutant CaP cells inhibited angiogenesis, and were cytotoxic to bone marrow derived endothelial cells in vitro. We aim to identify the molecules responsible for these effects. Significance: Further studies will explain how specific mutations of p53 found in patients impact on progression, and could allow development of new therapeutic strategies. DTIC Bones; Cancer; Metastasis; Mutations; Prostate Gland; Tissue Culturing 20050173221 Dana Farber Cancer Inst., Boston, MA USA Functional Study of the Human BRCA2 Tumor Suppressor Xia, Bing; Livingston, David M.; Aug. 2004; 11 pp.; In English Contract(s)/Grant(s): DAMD17-02-1-0360 Report No.(s): AD-A432411; No Copyright; Avail: CASI; A03, Hardcopy 180 My research is focused on the BRCA2 protein, whose mutations have been implicated in the development of breast, ovarian, male breast, prostate, pancreatic cancers and Fanconi anemia. It is intended to elucidate some of the biological functions of BRCA2 and/or regulation of its in vivo function through generation/utilization of new reagents and identification of new BRCA2 interacting proteins. During this second year of grant support, I was able to identify a completely novel protein, named CLB2 in this study, as a major physiological partner of BRCA2. I discovered that CLB2 is a chromatin bound protein and is required for BRCA2’s chromatin binding. In light of these findings, it is attempting to speculate that disruption of CLB2 function would lead to significant impairment of BRCA2’s tumor suppressor function realized at least in a large part through its DNA recombination/repair activity which presumably requires its docking to the chromatin. DTIC Breast; Cancer; Mammary Glands; Mutations; Ovaries; Proteins; Suppressors; Tumors 20050173222 California Univ., Irvine, CA USA Functional Analysis of LIM Domain Proteins and Co-Factors in Breast Cancer Wang, Ning; Andersen, Bogi; Oct. 2004; 28 pp.; In English Contract(s)/Grant(s): DAMD17-01-1-0183 Report No.(s): AD-A432413; No Copyright; Avail: CASI; A03, Hardcopy We identified a novel transcription factor, LMO4, which is highly expressed in breast epithelial cells during mid- pregnancy when these cells are proliferating and invading the stroma. Since previous members of the LIM only (LMO) gene family are oncogenes, we hypothesized that LMO4 may play roles in mammary gland development and cancer. We have now shown that expression of LMO4 correlates with proliferation, and in transgenic mice we shrewd that dominant-negative LMO4 inhibits lobuloalveolar development, demonstrating that LMO4 plays roles in proliferation and/or invasion of breast epithelial cells. Because these cellular features are associated with breast carcinogenesis and because LMO4 is overexpressed in a subset of breast cancers, our studies implicate LMO4 as a possible oncogene in breast cancer. In addition, we found that the LMO4 gene is activated by the Her2/Neu receptor in breast cancer cells, providing further linkage to breast cancer. In biochemical assays we showed that LMO4 may act by associating with the GATA3 transcription factor, also expressed in mammary epithelial cells. We have also created stable breast cancer cell lines in which we can induce expression of LMO4 and Clim2. With this method, we have identified several target genes of LMO4, one of which is Bone Morphogenic Protein 7 (BMP-7) , which can affect survival of breast cancer cells by regulating apoptosis. In summary, we have defined a role for a new gene, LMO4, in mammary epithelial cell proliferation in normal development and in breast cancer cells, DTIC Breast; Cancer; Functional Analysis; Mammary Glands; Proteins 20050173225 Ontario Cancer Inst., Toronto, Ontario Canada Analysis of Preneoplasia Associated with Progression to Prostatic Cancer Yoshimoto, Maisa; Squire, Jeremy; Mar. 2005; 101 pp.; In English Contract(s)/Grant(s): DAMD17-03-1-0154 Report No.(s): AD-A432418; No Copyright; Avail: CASI; A06, Hardcopy PURPOSE: To examine the topographical variation in expression levels of genes associated with prostate cancer, telomere dysfunction and/or chromosomal instability. SCOPE: To show that telomere erosion observed in prostatic epithelium may involve DNA damage response/repair pathways at the onset of preneoplasia (HPIN) and cancer in me n. MAJ0R FINDINGS: Our working hypothesis is that cells that undergo telomere loss as part of the normal aging process in the prostate are more susceptible to undergo chromosome end-fusion thus triggering genomic instability. Our initial progress showed that loss of telomere length occurred in preneoplastic HPIN lesions that were located close to small, localized microfoci of newly diagnosed prostate cancer. We have optimized whole genome and RNA amplification techniques and shown that there is high fidelity and reproducibility of dissected amplified PCR product. RESULTS: The first phase of gene expression profiling in HPIN, and cancer foci using repair/damage response array has been successfully performed. We are developing topographical maps of telomere bass, genomic instability and concomitant changes in gene expression. SIGNIFICANCE: These results will form the first direct link between telomere-dependent alteration, DNA repair and damage response signaling in prostate cancer. DTIC Cancer; Chromosomes; Deoxyribonucleic Acid; Prostate Gland 181 20050173226 Royal Prince Alfred Hospital, Camperdown, Australia Epigenetic Inheritance of Breast Cancer Clark, Susan J.; Sep. 2004; 20 pp.; In English Contract(s)/Grant(s): DAMD17-03-1-0642 Report No.(s): AD-A432420; No Copyright; Avail: CASI; A03, Hardcopy Hypermethylation of tumor suppressor genes is only thought to occur in the somatic cell in sporadic tumors. However, we propose that methylation of the promoter of tumor suppressor genes, such as BRCA1, may also occur in the germ-line. Germ-line inheritance of this epigenetic silent state would therefore contribute to familial breast cancer. In this study we aimed to address if methylation of the tumor suppressor gene BRCA1 is inherited through the germ-line and is associated with the hereditary breast cancer. We developed a high-throughput sensitive real-time methylation assay that allowed us to screen for BRCA1 methylated DNA. We used this assay to screen for BRCA1 methylation from DNA isolated from archival blood and biopsy samples of women that have a family history of breast cancer but have no defined BRCA1 or BRCA2 mutations. DTIC Breast; Cancer; Mammary Glands; Methylation 20050173230 Roswell Park Memorial Inst., Buffalo, NY USA CTL-Tumor Cell Interaction: The Generation of Molecular Probes of Monitoring the HLA-A*0201-HER-2/neu Peptide Complex Campoli, Michael R.; Mar. 2005; 132 pp.; In English Contract(s)/Grant(s): W81XWH-04-1-0372 Report No.(s): AD-A432429; No Copyright; Avail: CASI; A07, Hardcopy The overall goal of this project is to probe the CTL - tumor cell interaction by generating scFv probes that are able to recognize the HLA-A*0201-HER-2/neu369-377 peptide complex. In the 12 month period covered by this report, I have successfully generated HLA-A*0201-HER-2/neu369-377 complexes, and have isolated two scFv fragment clones that recognize this complex. In addition, I have started to analyze the expression levels of antigen processing machinery (APM) components, HLA class I antigens and beta2m in several breast carcinoma cell lines. This analysis takes advantage of the availability of a wide panel of mAb to these antigens that several investigators in our laboratory, including myself, have developed and characterized. Collectively, the results we have obtained strongly support our future analysis to correlate the expression levels of APM components, HLA class I antigens, beta2m and HER-2/neu with the levels of HLA-A*0201-HER- 2/neu369-377 complexes on breast carcinoma cells and lesions. The information derived from these studies is expected to contribute to our knowledge of the variables that influence the levels of HLA class I antigen-TAA derived peptide complex expression on breast carcinoma cells. DTIC Antigens; Breast; Cancer; Cells (Biology); Mammary Glands; Peptides; Tumors 20050173232 Pittsburgh Univ., Pittsburgh, PA USA Hormonal Determinants of Mammographic Density Simpson, Jennifer K.; Modugno, Francesmary; Weissfeld, Joel L.; Kuller, Lewis; Vogel, Victor; Costantino, Joseph P.; Aug. 2004; 13 pp.; In English Contract(s)/Grant(s): DAMD17-02-1-0553 Report No.(s): AD-A432434; No Copyright; Avail: CASI; A03, Hardcopy Hormone Replacement Therapy (HRT) has been shown to increase breast cancer risk as well as to increase breast density. Breast density, a reflection of the histologic composition of the breast, is one factor shown to affect mammographic sensitivity and specificity, and it is predictive of breast cancer risk. Thus, the use of HRT, through its effect on breast density, may compromise the well-established reduction in mortality gained by mammographic screening. However, not all women on HRT will experience an increase in breast density. We propose a novel hypothesis to explain in part the individual variability in breast density seen among women on HRT: differences in breast density are associated with differences in estrogen metabolism, and this association may be attenuated by individual factors such as body mass index and HRT regimen. Our work and the work of others provide compelling evidence to support this hypothesis. To date 50 cases and 180 healthy postmenopausal women have been enrolled in this study. DTIC Breast; Cancer; Determinants; Hormones; Mammary Glands 182 20050173235 Hawaii Univ., Honolulu, HI USA Genetic Plymorphisms, Estrogens, and Breast Density Maskarinec, Gertraud; Jan. 2005; 48 pp.; In English Contract(s)/Grant(s): DAMD17-00-1-0281 Report No.(s): AD-A432441; No Copyright; Avail: CASI; A03, Hardcopy This study investigated the association between genetic polymorphisms in hormone producing and metabolizing enzymes and several markers of breast cancer risk among women of different ethnic background. The specific aims were to analyze the relation of breast density and estrogen levels in urine and serum with the presence of variant alleles in CYP17, COMT, CYP1A1, CYP1A2, and CYP1B1, to describe ethnic differences in urinary excretion levels of estrogen, and to explore the association of breast density with estrogen levels. Mammograms for 328 women were assessed for breast density using a computer-assisted method. The genes were analyzed for polymorphisms using PCR/RFLP methods and estrogens and their metabolites were measured by radioimmunoassay. We found that women carrying the COMT and CYP1A2 variant alleles had lower mammographic densities than women carrying the common alleles. The CYP1A2 C allele was also significantly associated with lower serum estradiol levels and a lower 2OHE1/ 16alpha-OHE1 ratio. Total urinary hormone excretion, androgens, 2-OHE1, and the 2/16alpha-OHE1 ratio were significantly lower in women of Asian ancestry than in Caucasians, but breast density was higher among women of Asian ancestry due to their relatively small breast size. Estrogens and their metabolites measured in the urine of premenopausal women were not associated with mammographic densities. However, contrary to the initial hypothesis, the 2-OHE1/16alpha-OHE1 ratio was directly related with mammographic densities. DTIC Breast; Cancer; Enzymes; Estrogens; Genetics; Mammary Glands; Polymorphism 20050173236 Fox Chase Cancer Center, Philadelphia, PA USA Hierarchical Nonlinear Mixed Effect Modeling: Defining Post-radiation Therapy Relapse in Prostate Cancer Patients Hanlon, Alexandra L.; Jul. 2004; 107 pp.; In English Contract(s)/Grant(s): DAMD17-01-1-0056 Report No.(s): AD-A432448; No Copyright; Avail: CASI; A06, Hardcopy The research accomplished and described here validates and extends a model to classify prostate cancer patients according to disease relapse following definitive radiation therapy. The original model was developed within a hierarchical nonlinear mixed effect modeling framework with likelihood based estimation incorporating the EM algorithm. The model was tested statistically using a subset of 35 patients with relatively homogenous tumor and treatment characteristics. The research described in this report successfully applied the methodology to a larger population of men (\g600 patients) representing all stages of disease via the modeling of covariates, including tumor differentiation, stage, and pre-treatment PSA. The success of the modeling was dependent upon a Bayesian framework with Markov chain Monte Carlo methodology for estimating mixture distribution parameters. Poor mixing and slow convergence were encountered and required various re- parameterizations and creative initialization techniques. The analysis includes an assessment of predictors of post-nadir rise, as salvage therapy strategies are often designed around the rate of increase in PSA levels post-nadir, as well as an analysis of predictors of initial decline and its relationship to outcome. The modeling was compared to biochemical classification using a clinical definition of relapse and also to clinical results as obtained from imaging and/or biopsy. DTIC Cancer; Nonlinearity; Patients; Prostate Gland; Radiation Therapy 20050173237 California Univ., Berkeley, CA USA Non-Invasive Imaging of In Vivo Breast Cancer Tissue Utilizing Metabolically Incorporated Unnatural Sugars Bertozzi, Carolyn R.; Aug. 2004; 9 pp.; In English Contract(s)/Grant(s): DAMD17-03-1-0548 Report No.(s): AD-A432449; No Copyright; Avail: CASI; A02, Hardcopy Cancer cells have long been known to express glycosylation patterns that are different from those found on normal cells from the same tissue. Many tumor-specific carbohydrate antigens possess the monosaccharide sialic acid, and as a consequence, many tumor cells express high levels of sialic acid compared to normal cells. Thus, any agent that targets sialic acid specifically could be used for tumor targeting. Preliminary work on this project has shown that unnatural sialic acids can be introduced onto tumor cells metabolically by feeding the cells unnatural analogs of their biosynthetic precursors. The unnatural analogs can include reactive functional groups capable of covalent reaction with exogenous probes. For example, an azide-functionalized analog of Nacetylmannosamine is converted by tumor cells to the corresponding sialic acid, and the azide can be covalently reacted on the cell surface with triarylphosphine probes in vivo. The objective of this project is to 183 [...]... website: www.usminstitute.org DTIC Command and Control; Decision Making; Medical Services; United States 20050173 247 Kansas Univ Center for Research, Inc., Lawrence, KS USA Synthesis of Cryptophycin Affinity Labels and Tubulin Labeling Yang, Kyounglang; Georg, AGunda I.; May 20 04; 18 pp.; In English Contract(s)/Grant(s): DAMD17-02-1- 043 4 Report No.(s): AD-A43 247 1; No Copyright; Avail: CASI; A03, Hardcopy... Relief and Emergency Medical Services Project (DREAMS TM): science, Triage and Treatment (STAT) Casscells, S W.; Oct 20 04; 119 pp.; In English Contract(s)/Grant(s): DAMD17-01-2-0 047 Report No.(s): AD-A43 249 8; No Copyright; Avail: CASI; A06, Hardcopy Science, Triage, and Treatment:STAT is the component of DREAMS (Disaster Relief and Emergency Medical Services) that is developing new ways to diagnose and. .. Medicine; Mammary Glands 20050173275 Baylor Coll of Medicine, Houston, TX USA Identification of Signaling Proteins the Modulate Androgen Receptor Activity Songyang, Zhou; Nov 20 04; 8 pp.; In English Contract(s)/Grant(s): DAMD17-01-1-0022 Report No.(s): AD-A432 546 ; No Copyright; Avail: CASI; A02, Hardcopy Androgens and the androgen receptor (AR) play a critical role in the development and progression of... peer-reviewed journals (listed in APPENDIX 4) DTIC Breast; Cancer; Clinical Medicine; Education; Mammary Glands; Medical Science 20050173 240 Hutchinson (Fred) Cancer Research Center, Seattle, WA USA Regulation and Function of the Ipl1/Aurora Kinase Kotwaliwale, Chitra; Biggins, Sue; May 20 04; 10 pp.; In English Contract(s)/Grant(s): DAMD17-02-1-0385 Report No.(s): AD-A43 245 4; No Copyright; Avail: CASI; A02,... detection and diagnosis of cancer Longer-term applications include targeted anti-cancer drugs and vaccines DTIC Breast; Cancer; Imaging Techniques; In Vivo Methods and Tests; Mammary Glands; Sugars 20050173238 Yale Univ., New Haven, CT USA Predoctoral Training Program in Breast Cancer Research Stern, David F.; Aug 20 04; 18 pp.; In English Contract(s)/Grant(s): DAMD17-99-1- 946 1 Report No.(s): AD-A43 245 1;... occurred first, while controlling for influential covariates and temporal changes In comparison with Gulf War veterans (n = 45 5 ,46 5), personnel deployed to Southwest Asia after the Gulf War (n = 249 , 047 ) were at a slight increased risk of hospitalization (hazard ratio = 1.05; 95% confidence interval: 1.02,1 08) However, personnel deployed to Bosnia (n = 44 , 341 ) were at decreased risk for any cause hospitalization... Feb 20 04; 58 pp.; In English; Original contains color illustrations Report No.(s): AD-A4327 24; No Copyright; Avail: Defense Technical Information Center (DTIC) This study identified personnel, equipment, facilities, evacuation, time, and patient acuity variables within the Department of Defense Central and European Commands as they pertained to the development of a Separate Table of Distribution and Allowances... ERbB2 low; 3) ER-alpha-positive, no ErbB2; 4) ER-negative, ErbB2 high; 5) ER- negative, ErbB2 low; and 6) ER-negative, no ErbB2 will be tested for AKT (AKT1, AKT2, AKT3), ErbB (EGFR, ErbB2, ErbB3, and ErbB4) and ER-a expression and activity We have received 26 tumors and their surrounding normal tissue Paraffin sections were prepared from most of these tissues and the sections were immunostained with... Nancy E.; Mar 2005; 21 pp.; In English Contract(s)/Grant(s): W81XWH- 04- 1- 040 3 Report No.(s): AD-A43 246 9; No Copyright; Avail: CASI; A03, Hardcopy The U.S Medicine Institute for Health Studies, a nonprofit entity devoted toward enhancing communication among federal agencies and between federal agencies and the private sector, conducts forums and smaller roundtable discussions at which high-level officials... Kendra, Kari L.; Sep 20 04; 20 pp.; In English; Original contains color illustrations Contract(s)/Grant(s): DAMD17-03-1-0750 Report No.(s): AD-A432 547 ; No Copyright; Avail: Defense Technical Information Center (DTIC) The purpose of this study was to evaluate the combined impact of surgery and immunomodulation with low dose cytoxan and GM-CSF on the development of dendritic cells and the activation of . Patients Hanlon, Alexandra L.; Jul. 20 04; 107 pp.; In English Contract(s)/Grant(s): DAMD17-01-1-0056 Report No.(s): AD-A43 244 8; No Copyright; Avail: CASI; A06, Hardcopy The research accomplished and described. DAMD17-01-1-0022 Report No.(s): AD-A432 546 ; No Copyright; Avail: CASI; A02, Hardcopy Androgens and the androgen receptor (AR) play a critical role in the development and progression of prostate cancers. The. USA Genetic Plymorphisms, Estrogens, and Breast Density Maskarinec, Gertraud; Jan. 2005; 48 pp.; In English Contract(s)/Grant(s): DAMD17-00-1-0281 Report No.(s): AD-A43 244 1; No Copyright; Avail: CASI; A03,