The goal of this project is to determine the underlying synaptic dysfunction in Tuberous Sclerosis Complex (TSC). Scope: TSC is a multi-system genetic disorder with central nervous system dysfunction as a defining factor. The most common clinical features are mental retardation, epilepsy, autism, anxiety and mood disorders. Fragile X syndrome (FXS), another form of inherited mental retardation and autism, shares many of the same molecular and clinical features. Much of the pathophysiology in FXS can be ameliorated through modulation of Group 1 metabotropic glutamate receptors (mGluRs). Since both disorders share key features suggests that they may also share common pathogenic mechanisms. Therefore, determined whether altered synaptic protein synthesis, plasticity and hippocampal-dependent behavior could be ameliorated through modulation of mGluR s in a mouse model of TSC. Major findings: Unlike in FXS where negative modulation of mGluR s has proven beneficial, we found that augmenting mGluR function either genetically or through application of an mGluR5 positive allosteric modulator (PAM) ameliorates several of the synaptic and hippocampal-dependent behavioral deficits observed in a mouse model of TSC. Significance: These results suggest that modulation of mGluR activity with PAMs may be a therapeutic intervention for several of the deficits observed in TSC.

关键词：解剖模型;中枢神经系统;临床医学;障碍;脆性x综合征;谷氨酸;干预;长期抑郁,心理能力;Metabotropic谷氨酸受体;积极变构调制器,雷帕霉素;受体网站(生理学);缺陷;突触,突触蛋白质合成;治疗;结核病;结节性硬化症复杂

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The overall objective of our synergistic team was to develop and apply a novel NMR-compatible model of human prostate cancer (PCa) to identify new hyperpolarized molecular imaging biomarkers for improved clinical management of PCa. We demonstrated that thin, precision-cut prostate tissue slice cultures (TSCs) could be maintained in an NMR-compatible bioreactor and that hyperpolarized 13C spectroscopy could be employed to study real-time metabolism of normal and malignant tissues. The similarity of metabolism in TSCs compared to humans validates this new preclinical model and for the first time provides a representative experimental model that could be widely adopted by others to improve imaging modalities for prostate cancer. Our results suggest that hyperpolarized 13C lactate may serve as a biomarker of prostate cancer.

关键词：生物标志物;临床医学;文化;人类;图像;乳酸;代谢;模型;分子;前列腺癌,前列腺;光谱;合作;组织(生物学)

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The conceptualization of three-dimensional (3D) images within the human brain is a difficult task requmng extensive use of the brain's working memory. In the medical education community, this problem is particularly prevalent due to the complex 3D structures inherent in human anatomy. One potential solution to this problem is to present medical content in three dimensions rather than 2/2.5 dimensions. In doing so, the trainee would no longer be burdened with the additional cognitive load imposed during conversion of a 2/2.5D representation to a 3D representation within working memory. A unique technological solution to achieve this uses holography to present the medical content. Holography allows the user to view fully parallax, auto- stereoscopic 3D images. Within this research effort, static, full-color holograms were created depicting medical content. A study was conducted involving two groups of students presented with medical content in either a traditional format via textbook handouts or through holography. Cognitive load analysis was performed to determine if a difference in cognitive effort was experienced while using holography. A usability study was conducted to evaluate hologram performance and collect user experience metrics during the trial. This paper will discuss in detail the results of the experiment including the cognitive load analysis, the usability evaluation, performance trends, and lessons learned.

关键词：大脑;认知;教育;全息图,全息术;教训;医务人员;医学;内存设备;军事训练;视差电脑;静力学

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Our objective is to create a multi-institutional tissue microarray resource from radical prostatectomy samples with detailed clinical information and follow-up and rigorous casecohort design for use as a platform for validating tissue biomarkers of prognosis. In addition, we have proposed testing a series of biomarkers of prognosis and a set of biomarkers that correlate with Gleason Score. We have made significant progress over the past year. Having completed construction of the tissue microarrays and finalized standard procedures for tissue microarray storage, sectioning and shipping, we have now stained scanned, gridded and read TMAs for several biomarkers. We havenow changed to the Leica scanner and PathXL image analysis software suite for some of the biomarkers and have also used the Aperio system for others. Pathologists have read compete sets of TMAs for H & E, High Molecular Weight Keratin, ERG, SPKINK1, Ki67 (MIB1), Survivin and PTEN FISH and we have correlated staining results with clinical outcome. We also have made significant progress in testing TACOMA, an automated TMA scoring algorithm. We have completed staining of the TMAs for . Over the next year we will complete refinements of the infrastructure, complete pathologic review of the p27 and MUC1 biomarkers, and stain and evaluate several additional biomarkers which have received approval. We will complete statistical analysis for all of the completed biomarkers (and others evaluated over the next year) and plan to publish papers for each of the biomarkers over the next year. We wil also carry out outcome analysis for a panel of the biomarkers soon.

关键词：临床医学,计算机程序;建设;变色;图像处理;标志;医学研究;分子量;病理学家;平台;前列腺癌;资源;示踪研究,验证

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Findings reported herein detail our progress on the development of prostate cancer cell line reagents, which are critical to our proposed studies of micro RNA-mediated regulation of the MKK4 protein. Since our last progress report we have focused on studies in Specific Aim 1, Major Task 2, subtask 1d and 1e. Specifically, building on our previous findings, we now have determined the growth kinetics and metastatic site preference of CWR22Rv1-luc2 cells after intracardiac injection using both IVIS imaging and histology. We have also made significant progress in our efforts to develop bone-seeking cell lines from CWR22Rv1-luc2 cells. Thus far, our effort to develop bone-seeking sublines of the CWR22Rv1 cell line is on track. To be frank, the work in progressing at a faster pace and with cleaner results that we expected. Thus, we are in an excellent position to address the work proposed for YR5 of our EWOF.

关键词：癌症细胞（生物学）;注射（医学）;动力学;转移

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The recent development of fluorescently tagged deoxyglucose analog (2-NBDG) has attracted the attention of researchers and clinicians alike for its potential use as a tool in detecting cancer. Although the use of 2-NBDG imaging for cancer diagnosis has been explored in several other organ sites prior to this project, the potential applications of this technique to early lung cancer detection had not been explored. The objective of this study was to monitor both qualitatively and quantitatively 2-NBDG uptake in lung cancer cells and normal cells using fluorescence imaging techniques. Initial results were promising, and this work represents an important first step towards establishing the use of 2-NBDG as a contrast modality for applications in early lung cancer diagnosis.

关键词：支气管炎;诊断(医学),荧光,荧光标记脱氧葡萄糖模拟(2-NBDG);肺癌;光学仪器

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Large, osseous segmental defects do not heal well and are a major clinical problem. Our research is based upon the hypothesis that healing of such defects is sensitive to the mechanical environment, particularly the axial stiffness; in particular, we postulate that healing will be accelerated by first fixing the defect under conditions of low axial stiffness and then increasing the stiffness once bone begins to form. We call this reverse dynamization . A rat model was developed in which a critical size, femoral, diaphyseal defect was surgically created, treated with BMP-2 and stabilized with a custom-designed external fixator whose stiffness could be altered while still attached to a living animal. Three different axial stiffnesses were tested: low (114 N/mm), medium (185 N/mm) and high (254 N/mm). Pilot studies showed that, under non-dynamized conditions, low stiffness fixation provided the best outcome. Reverse dynamization was explored with low stiffness fixation for the first 14 days, during which time bone began to form in the defect, followed by high stiffness fixation for the remaining 6 weeks of the experiment. Reverse dynamization had a dramatic effect on healing, leading to accelerated bridging and advanced remodeling of the newly formed bone. After 8 weeks the strength of the healed bone under reverse dynamization was considerably enhanced, suggesting an early return to normal mechanical properties. Experiments to test this empirically are underway, but could not be completed in time for this report. Another possibility, that reverse dynamization could reduce the need for BMP-2, was tested empirically but this did not appear to be the case. Reverse dynamization accelerated and improved the healing of a defect treated with an effective dose of BMP-2 but was unable to initiate healing in a defect treated with an inactive dose of BMP-2.

关键词：骨头;临床医学;缺陷(材料);剂量;环境;治疗;可逆

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In accordance with the Federal Highway Administration (FHWA) 'Interim Guidance Update on Mobile Source Air Toxic Analysis in NEPA Documents (September 30, 2009),' transportation projects subject to the National Environmental Policy Act (NEPA) must include an analysis of mobile source air toxics (MSATs). MSATs are air pollutants emitted by mobile sources that can cause serious health effects. Of a group of 93 MSAT compounds, the U.S. Environmental Protection Agency (USEPA) has identified seven compounds with significant contributions from mobile sources that are among the national and regional-scale cancer risk drivers from their 1999 National Air Toxics Assessment (NATA). These seven compounds consist of acrolein, benzene, 1,3-butadiene, diesel particulate matter plus diesel exhaust organic gases (diesel PM), formaldehyde, naphthalene, and polycyclic organic matter. FHWA classifies these seven compounds as the 'priority MSATs,' recognizing that this list is subject to change. The objectives of this project are to: (1) propose a 'screening' protocol that will facilitate the decision making process regarding which projects warrant MSAT assessment; (2) develop procedures (in consultation with regulatory agencies) for conducting qualitative and quantitative analyses of the seven priority MSATs in NYSDOT NEPA and SEQRA environmental documents; and (3) identify feasible MSAT mitigation measures for NYSDOT capital improvement projects and facilities. The work involves 10 separate tasks, including a guidance document for conducting MSAT assessments for projects that fall within NEPA/SEQRA.

关键词：空气质量;空气毒物;评估;癌;排放;环境影响;健康风险;气象;移动源排放;

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Our objective is to utilize de identified database constructed from the world-wide Military Electronic medical record for datasets (constructed for clinical purposes and not research) specific to patients with Crohn's disease (CD) and acute pancreatitis (AP). Using the collected data we will develop Bayesian Network (BN) models to predict outcomes in CD and AP (death, surgeries, hospitalizations, etc). Once our model is developed we hope to apply our model at an outside institution, specifically University of Pittsburgh Medical Center (UPMC) who will be conducting a similar experiment, testing our model on their EMR.

关键词：临床医学;消化系统;健康;传染病;医疗服务

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In previous studies we have demonstrated that the ovarian cancer antigen CA125 specifically binds to certain sunsets of immune cell. Based on these observations we have hypothesized that proteomic and transciptomic analysis of immune cells from ovarian cancer patients will result in the identification of specific biomarkers in the immune cells. The current proposal will further investigate this hypothesis by conducting in-depth proteomic analysis of immune cells from cancer patients and healthy blood donors. Studies conducted have resulted in development of streamlined protocols for proteomic analysis of human immune cells. Proteomic analysis of human NK cells has been completed. In addition to proteomic analysis we have also compared the transcriptome of immune cells from ovarian cancer patients and healthy donors and have identified approximately 1600 genes that are differentially expressed in the patient samples. On-going research is focused on validating the proteomic and transcriptome data and demonstrating changes immune cells in response to cancer antigens.

关键词：抗原;生物标志物;细胞(生物学);捐助者(医学);免疫;卵巢癌;蛋白质组分析;蛋白质组学

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