Composite Tissue Allotransplantation (CTA) offers an alternative reconstructive strategy for complicated musculoskeletal injuries incurred during modern warfare where functional outcomes after multipe conventional reconstructions are suboptimal. Broader clinical application of CTA, however, continues to be hampered by requirement for long-term multi-drug immunosuppression to prevent graft rejection. Furthermore, unlike in solid organs, clinical success is dictated not only by graft acceptance, but also by functional outcome. Our study proposes a novel cell-based therapy utilizing mesenchymal stem cells (MSC) that can augment nerve regeneration while minimizing the need for immunosuppression. After transition from University of Pittsburgh to Johns Hopkins University, we optimized our isolation and culture protocol for MSCs. Immunophenotypic and functional characterization of cultured cells demonstrated potent immunomodulatory effects of MSCs in vitro. Preliminary functional outcome analysis using Catwalk showed convergent data with similar loss and return of function among groups. Similarly, compound muscle action potentials at early time points showed small non-significant increases in amplitude in experimental groups. In contrast, normalized gastrocnemius weights showed increased muscle weight in only the systemic injection group. Overall, we continue to monitor both functional and histological outcomes. Consistent with existing literature on nerve regeneration, we expect to observe more evident differences among groups with increased data over the longer term.

关键词：免疫抑制;肌肉骨骼系统;神经干细胞;组织(生物学)

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Epidemiological evidence has demonstrated an inverse association between serum vitamin D levels and sunlight exposure to prostate cancer incidence. In addition, serum androgen levels and biologically available testosterone decrease significantly in elder men while the incidence rate of prostate cancer increases. These findings lead to the hypothesis that androgen- and vitamin D-mediated signaling events may act together to inhibit prostate tumor initiation and/or development. Using concurrent microarray analyses, we demonstrated that testosterone and 1,25(OH)2D3 co-operate to regulate mRNA and miRNA expression, including some well-defined oncogenes and tumor suppressor genes. Pheno typically, this results in G0/G1 cell cycle arrest and increased neutral lipid accumulation in LNCaP cells, as a consequence of repression of various cell cycle regulators and the up-regulation of PPAR alpha; respectively. This suggests that the cross talk between T and 1,25(OH)2D3 induces cell cycle arrest and promotes cell differentiation in LNCaP cells. It is important ton ote that co-treatment of LNCaP cells with testosterone, 1, 25(OH)2D3 and other standard therapeutics, including bicalutamide, docetaxel and TRAIL did not affect the potencies of these treatments, though there were no synergistic effects either. This suggests that androgen andvitamin D supplementation slow disease progression without affecting the efficacy of standard therapies for prostate cancer. Further analysis is still required to elucidate the underlying mechanisms of T and 1,25(OH)2D3 to modulate key mRNA and miRNA and their significance in prostate tumorigenesis and therapeutic interventions.

关键词：前列腺癌;雄激素;流行病学;增长(生理学);肿瘤

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Prostate cancer (PCa) is one of the most common malignancies in men, and is a complex disease in its development and response to therapy. Loss of tumor suppressors genes is a frequent initiating event that is irreversible, whereas tumor promotion and progression are susceptible to modulation, which provides a rationale for therapeutic intervention. Tumor promotion is highly regulated by the interaction between initiated cells and their microenviroment and inflammation is a frequent and important tumor promoter. However, despite the strong evidence for an inflammatory component to the pathology of PCa, the process of inflammation and the related signaling pathways are largely unknown. Therefore, a better understanding of the molecular mechanisms that govern the inflammatory response and its impact on PCa progression is of paramount importance in developing novel therapies for PCa. Here we report the identification of a novel network between tumor suppressors: Par-4, PKCzeta and PTEN and the characterization of the inflammatory response unleashed upon their loss. Importantly, our results also demonstrate that inflammation is not only secondarily associated to carcinogenesis but it is an important contributing factor in tumor promotion.

关键词：炎症、前列腺癌疾病;炸药发起者;基因

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关键词：抗体;乳腺癌;免疫;辐射效应;可行性研究

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This randomized, single blind study extends recruitment to an additional active duty site (Womack Army Medical Center at Ft Bragg) in support of a previously funded clinical trial to evaluate the efficacy of virtual reality exposure therapy (VRET) and prolonged exposure therapy (PE) with a waitlist (WL) group in the treatment of posttraumatic stress disorder (PTSD) in active duty (AD) Soldiers with combat-related trauma. During the first year, the study team developed the infrastructure to implement the trial including personnel recruitment, hiring, and initial training, process development to identify, screen, and enroll participants, and research protocol development and approval by IRB’s. During the second year hiring of clinical staff and training of the study team was completed. Recruitment and enrollment commenced.

关键词：创伤后应激障碍;现役陆军人员;接触(生理学);医疗服务

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This program has undertaken the study of the discoidin domain 2 (DDR2) tyrosine kinase as a potential therapeutic target in squamous cell lung cancer. We identified mutations in the DDR2 gene in a cohort of 290 individuals with this type of lung cancer and showed that these mutations are oncogenic when expressed in cell lines. Importantly, we showed that DDR2- driven cellular transformation sensitizes cancer cells to treatment with tyrosine kinase inhibitors which target DDR2, namely dasatinib. We have generated cellular and animals models to study DDR2, have studied the mechanisms by which DDR2 transforms cells and have worked to develop more selective inhibitors of DDR2 as well as identify mechanisms of cellular resistance to dasatinib therapy. This work has led to a publication in Cancer Discovery and has been presented at several scientific meetings including AACR and IASLC. Dasatinib is now being studied in the clinic as a DDR2 inhibitor in a national phase II trial for patients with squamous cell lung cancer, a disease for which no targeted agents are approved at this time.

关键词：(生物学);肺癌;细胞门诊诊所;治疗;酪氨酸

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Breast cancer refers to a variety of types that each derive from distinct causes and merit different treatments. It is crucial to develop new classes of molecules that target heretofore unexplored cellular mechanisms, so that tumors not responsive to current treatments might be responsive to new routes of therapy. We are exploring a previously under-appreciated avenue that can lead to precise identification of breast cancer sub-types to improve treatment options and identify new therapeutic targets. The genetic code is decoded by transfer RNA (tRNA). We discovered that breast tumors have high levels of tRNA and tRNA over-expression has an aberrant pattern suggesting that tumors use tRNA over-expression to mis-regulate the synthesis of some crucial proteins. Further, we found that a specific tRNAis an on cogene in breast cells suggesting that tRNA over-expression could even originate the development of breast cancer. We are identifying the mis-regulation targets of tRNA over- expression in breast cancer to serve as biomarkers and establishing the potential of targeting tRNA as a new route for breast cancer treatment.

关键词：乳腺癌;基因;核醣核酸酸;异常;编码;细胞学

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Counterinsurgency (COIN) has become the cornerstone of the military s strategy to combat terrorist threats. COIN operations are complex and often expose soldiers to unfamiliar stressors as they fight the enemy while developing and maintaining rapport with the local populace. Utilizing a retrospective record review protocol, we examined 282 mental health files of soldiers assigned to a brigade combat team that operated from a large forward operating base in Iraq during the counterinsurgency campaign. Most reported sleep disturbance, depression, anxiety, irritability, and conflict with supervisors related to either operational stress, exposure to direct combat, or home front concerns. Most received brief individual supportive therapy or attended solution-focused group counseling emphasizing life skills training, post-traumatic stress treatment, women s support, or relationship skills. Psychopharmacologic treatment was an essential adjunct to the counseling program. Results indicate that supporting a COIN deployment requires a comprehensive mental health program that can respond to a wide range of mental health problems.

关键词：镇压叛乱;心理健康;阿富汗冲突;军队人员

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The overall objective of this project is to develop targeted therapy tools directed against the breast cancer vasculature. We aim to bypass many obstacles in the field by developing a treatment based on the targeting of tumor blood vessels with T cells bearing chimeric immune receptors (CIRs). We have constructed and tested first generation CIR lentiviral vectors targeting hTEM1, which were derived from a panel of scFvs of varying affinity. These constructs signal through CD3 but can be augmented by the addition of costimulatory molecules (CD28 and 4-1BB). In vitro, only T cells bearing the scFv78 CIR were activated upon co-culture with recombinant hTEM1 protein. However, no activation was observed when scFv78 CIR bearing T cells were co- cultured with cells expressing hTEM1 on the surface. Additional strategies, including hinge elongation and the utilization of loadable CIR bearing T cells, also failed to elicit a response against the hTEM1 bearing target cells. We engineered a new yeast-display scFv library from patients with ovarian cancer to isolate a second generation of anti-TEM1 scFvs. We validated a panel of multivalent antibodies for binding to recombinant proteins by ELISA assays. We have generated CIRs against PSMA using scFv (PZ1) and T cells bearing PZ1 and CD28 produce a robust polyfunctional repertoire of cytokines. A tumor vascular mouse model expressing human TEM1 was developed and PET imaging with (124I)-MORAb-004 indicated TEM1-specific accumulation of antibody. We have established optimized HSV-tk as extra safety and tracer for PET imaging.

关键词：乳腺癌;疾病载体;T淋巴细胞;解剖模型

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Initially prostate cancer development is driven by the male hormone androgen through the androgen receptor, however, in some patients androgen receptor becomes dysfunctional at late stages of tumorigenesis. Early knowledge of the androgen receptor dysfunctions, what would make prostate tumors refractory to routine androgen ablation therapy, should help in patient stratification for other emerging therapeutic strategies. We proposed a novel approach for evaluating potential dysfunctions of the androgen receptor by measuring the expression of a functionally relevant panel of genes. This approach is direct and can be easily addressed from human prostate cancer tissues (surgery or diagnostic biopsy specimens) at early stages of the disease. Within the first reporting period we have designed, tested and completed the quality control of specific proves and primers evaluating the androgen dose and time kinetics of endogenously expressed PSA/KLK3. PMEPA1, NKX3.1, ODC11, AMD1 and TMPRSS2-ERG genes in VCaP cell culture model. Preliminary evaluation of an initial number of whole-mounted sections of RP specimens with prostate cancer by the Immunohistochemical assessment of AR, ERG, NKX3.1, and PSA proteins indicated reduced expression of ARP genes in a subset of th4e cases. The proposed research we will provide a quantitative index of AR dysfunction for enhancing disease prognostic characteristics to improve accuracy and to stratify patients for specific therapeutic approaches at early stages of prostate cancer treatment.

关键词：前列腺癌;消融;精度;雄激素;活检

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