The primary objective of our Early Investigator Synergistic Idea Award is to establish a driver prioritization pipeline to functionally evaluate lung cancer genomics data to identify somatic driver aberrations, which beyond the handful of well-characterized genes like oncogenic KRAS, contribute to lung cancer progression. As outlined in our Annual Report, we have successfully constructed the necessary gene libraries for the screens outlined in our proposal (Aim 1), and we have optimized and initiated the proposed in vitro and in vivo screens (Aim 2). We have already identified several robust drivers of cell invasion, and we are on task to complete all screens in year two of this project as planned. Finally, we are putting into place the necessary tools for mechanistic studies of lead candidate genes (Aim 3) that includes our development of a novel isogenic human bronchial epithelial cell system that permits regulatable expression of the KRAS oncogene. We have made several technical improvements to our overall work plan and view this first year as a highly successful start to this project and further screening of lung cancer genomics data that will extend past the life of this particular award.

关键词：分析;细胞基因图书馆;基因;基因;高通量屏幕;喀斯特癌基因;肺腺癌;肺癌;转移;吞吐量

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The most significant finding of this research study during this period is the validation of resistance to fluid shear stress as a biomarker of prostate cancer cells. This initial finding has been published. Additional efforts have been undertaken to detect this biomarker in circulating tumor cells from blood samples from prostate cancer patients. This involves the development of methods to achieve this goal.

关键词：生物物理学;血液细胞(生物学);循环前列腺癌细胞;流体剪应力阻力;标志;肿瘤;前列腺癌,前列腺;采样;验证

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Prior research has established an association between deployment and family violence, with insufficient evidence to identify when such violence occurs in relation to deployment and identification of mental illness in ADSM. This project will use: (1) longitudinal models to capture the temporal relationships between deployment, mental illness and family violence and (2) qualitative techniques to allow military stakeholders to evaluate Stage 1 findings and inform future interventions. This year we assembled our experts, obtained human subjects approvals, and acquired datasets. We now have our finalized cohort for our study period of interest. Our programmer is working intensively to clean the datasets so that we can link deployment/UIC/MOS records to substantiated reports of family abuse and medical claims data. Once this is done, we will move forward with formal data analyses and begin to answer our research questions. The last 3 months have been filled with progress and momentum, and we look forward to sharing results from our analyses in the upcoming months.

关键词：军队人员;数据处理;部署;家庭暴力;向前;卫生服务研究;疾病;医学;智力;精神疾病

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We combine fly genetics with haploid ES cell mutagenesis and in vivo mouse genetics to functionally characterize human candidate breast cancer genes. Using mouse genetics we have progressed in defining the role of RANKL/RANK in breast cancer. Moreover, we have first results that deletion of RANK might affect the development of BRCA1-mutant breast cancer. If correct this might lead to first cancer prevention trials in BRCA1 carriers using RANKL blockade. Using Drosophila modeling of Ras-driven transformation, we performed a near-genome wide screen for genes that control tumor progression. Using this system we have functionally identified multiple novel cancer genes that also play a role in breast cancer, e.g. the surface receptor TSPAN6 or the chromatin modulator EPC1. Finally, we have progressed in generating a haploid ES cell library for all researchers and have already generated more than 27000 murine ES cell clones targeting more than 10000 different genes. These integrations are repairable and each clone carries a genetic barcode, essential to perform future synthetic lethal experiments or to uncover resistance to defined drugs. Thus, we have successfully initiated all proposed aims with the vision to provide rapid functional annotation of breast cancer genes and, in case or RANKL/RANK, to provide the essential rationale for clinical prevention trials.

关键词：乳腺癌;染色质;临床研究;克隆;控制;果蝇;基因;基因;体内分析;抑制;杀伤力;转移;模型;调节器;突变;肿瘤;预防;预防医学;等级次序统计;耐药性;感觉器官;表面;目标;转换

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No abstract available.

关键词：航空航天医学;模拟;生物动力学;骨骼成像技术;长期太空飞行;脊髓损伤

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The purpose of this award is to help the principle investigator (PI) transition into a long term career in breast cancer imaging research through both training and independent research. While the focus of this project has shifted more towards the independent research, the clinical training component continues to include the observation of an NIH funded, multi-center breast imaging trial (data from which will be used in the research portion of this grant), time spent with radiologists specializing in breast imaging, and attendance at clinical research and case conferences. The research portion of this project is to develop computer-based analysis software that will extract physical parameters from a new method of ultrasound imaging (subharmonic imaging) to improve breast lesion characterization. These algorithms have also been applied to an existing contrast enhanced ultrasound dataset from murine xenografts to determine their relationship with immunohistochemical angiogenic marker expression (which may be useful as a potential tool for monitoring treatment response). Currently, mammography leads to an unacceptably high rate of false positive findings. Thus, the ultimate goal of this research is to develop subharmonic ultrasound image (SHI) processing algorithms to improve the classification of breast lesions.

关键词：算法;乳腺癌;临床医学;计算机辅助诊断;图像;损伤;乳腺;乳房x光检查;肿瘤;观察;患者;物理性质,放射科医生;反应;外科移植;座谈会;超声波成像

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The purpose of this study is to establish the safety and clinical efficacy of in home, web based psychosocial treatments for depression. This is a necessary step prior to the large scale dissemination of home based telemental healthcare programs for active duty Service Members, Veterans, and their families. Randomized controlled trials, such as this study, are the gold standard method of investigating the effects and comparisons of specific treatment options. As such, this study has the direct potential to inform and improve current strategies targeting the healthcare needs of our Service Members and Veterans. No current findings to report to date.

关键词：现役;行为;行为激活;临床医学;控制;抑郁;分布;医疗设备;医疗服务;军事人员;随机变量;安全;社会心理学;策略;目标;远程健康

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This grant prepares DANA (Defense Automated Neurobehavioral Assessment), the next-generation neurocognitive assessment tool (NCAT), for transition into operational military use. DANA is a clinical decision support tool developed for and funded by the Department of Defense (DOD) for use in field and clinical settings. The effort is organized around two foci science and transition. The science concentrates on CONUS-based studies such as testing DANA in clinical drug, fatigue/alertness, concussion and/or depression protocols. The second thrust, transition, includes obtaining FDA clearance for DANA (DOD has determined it is a medical device), and positioning DANA to be operationally deployed into the military.

关键词：行为;药品;疲劳;医药;神经病学;转变

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The identification of brain metastatic breast cancer (BMBC) mechanisms responsible for brain metastasis is imperative to develop new therapies. The relevance of heparanase (HPSE) in cancer invasion and metastasis has been establishe. Heparanase is the only known functional endoglycosidase in mammals and degrades heparan sulfate (HS), the main polysaccharide component of growth factor-binding proteoglycans. The therapeutic disruption of heparanase/HS function provides the opportunity to block multiple signaling pathways which are crucial for tumor cell adhesion, survival, and growth within the target organ microenvironment. Our hypothesis is that heparanase represents a novel target for the development of therapies for BMBC treatment. We propose aims to determine HPSE regulation by MiR-1258 in BMBC and to Identify novel functions of SST0001 as synergies with lapatinib and/or miR-1258 in BMBC cell and animal models. We will address HPSE regulation at three levels: the first is to identify how heparanase is modulated translationally by miR-1258; the second is to study the efficacy of SST0001, a small-molecule glycol-split heparinoid, regulating post-translational HPSE activity; the third is to investigate synergies of the heparanase inhibitor SST0001 and lapatinib, and assess whether heparanase promotes the pathogenesis of BMBC by selectively foster resistance to lapatinib.

关键词：大脑;乳腺癌;假设;转移;器官(解剖);硫酸盐;治疗

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Previously, we completed the molecular/ biochemical characterization of several shortlisted candidate gene fusions from the transcriptome sequencing of over 70 previously validated samples. From these studies, we identified two rare but recurrent gene fusions in breast cancer cell lines and tissues involving the MAST and Notch genes. Both of these fusion genes are potentially targetable and patients harboring MAST or Notch fusions may benefit from MAST or Notch inhibitors. We also describe a novel study of cancer-specific pseudogenes, including those in breast cancer. Most recently, through our clinical sequencing initiative, we discovered a series of activating mutations in the estrogen receptor (ESR1) in breast cancer patients. These activating mutations in ESR1 are a key mechanism in acquired endocrine resistance in breast cancer therapy. Overall, these discoveries made over the funding period contribute towards the understanding of the molecular and genetic etiology of breast cancer that will advance the development of targeted therapies.

关键词：生物化学;乳腺癌;临床医学;雌激素;病因;基因;基因;乳腺;分子;治疗

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