This year, we finally got our p11 knockout mice and were able to conduct the behavioral experiments (Specific Aim 1-3). Here, we will present two sets of new results: first, a control data set that included data from control mice; second, an experimental data set that included data from experimental mice, which received pharmacological treatment (e.g., mice received corticosterone injection) and foot shock exposure. We found the latency to find platform of knockout mice was shorter than that of non-p11 knockout (wild type) mice during the first three training days, although both of their latencies were the same on the final day of training and probe test. This data indicate that p11 knockout in the mice might enhanced learning. We also found that corticosterone resulted in significant decreases in the time in quadrant and number of island crossing in both p11 knockout and wild type control, suggesting that corticosterone induced impairment of memory retrieval, which independent the p11 expression. The ongoing final experiments will allow us to accomplish all of our proposed aims to understand the possible molecular mechanism of p11 in memory retrieval, a molecule associated with PTSD, a devastating disorder, especially in military service members.

关键词：创伤后应激障碍；行为；皮质类固醇制剂

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The overall objectives of our work on human ovarian carcinoma cells are to determine the mechanisms whereby hyaluronan-CD44-CD147 interactions influence malignant cell behavior and therapy resistance, and to apply our findings to the improvement of therapy, in malignant ovarian carcinoma. In this grant period we have shown that small hyaluronan oligosaccharides, which have previously been shown to antagonize hyaluronan-receptor interactions, sensitize cisplatin-resistant human ovarian carcinoma cells to cisplatin treatment in a mouse xenograft model, as well as in cell culture. Hyaluronan oligosaccharide- decorated nanoparticles containing chemotherapeutic agents are in preparation for maximizing these effects. We have also shown that siRNAs against the hyaluronan receptor, CD44, and the regulator of hyaluronan synthesis, CD147, sensitize cisplatin-resistant ovarian carcinoma cells to cisplatin in cell culture. Nanoparticles containing these siRNAs are in preparation for use in vivo.

关键词：化疗药物；卵巢肿瘤细胞（生物学）

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The Six1 homeoprotein encodes a transcription factor that is critical during embryonic development. Six1 expression is normally limited to embryogenesis, however is found to be overexpressed in human breast cancers. Using cell culture and mouse models, we have previously shown that Six1 not only promotes proliferation and survival, contributing to tumorigenesis, but also upregulates the TGF pathway, brings about an EMT-like transformation, increases the cancer stem cell population, aand promotesmetastasis. To further investigate the mechanism by which Six1 mediates the switch in TGF signaling, we performed a miRNA microarray screen and identified a cluster of miRNAs, the miR106b-25 cluster, that is upregulated in response to Six1 overexpression. The miR106b-25 cluster consists of three miRNAs, miR-106b, miR-93, and miR-25, which reside together in the intron of the MCM7 gene. Importantly, overexpression and knockdown experiments demonstrate that Six1 regulates all three miRNAs within the cluster. Interestingly, these miRNA have previously been implicated in the impairment of TGF -mediated growth suppression through repression of the cell cycle inhibitor, p21, and pro-apoptotic factor, Bim. These data suggest that Six1-induced upregulation of these miRNA may mediate the switch in TGF signaling from tumor suppressive to tumor promotional. Surprinsingly, bioinformatic analysis revealed that the miR106b-25 cluster may also contribute to the activation of TGF signaling through repression of the TGF signaling inhibitor, Smad7, which mediates the degradation of T RI. Indeed, we now report that overexpression of the miR106b-25 cluster results in repression of the Smad7 3 UTR, with concominant upregulation of T RI.

关键词：乳腺癌；核糖核酸；体内分析

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It has been suggested that PHSCN inhibits metastatic invasion by forming a covalent, disulfide bond with a cysteine residue on the beta1 ( 1) subunit of alpha5 beta1 ( 5 1) integrin1. However, these studies were performed with purified 51 integrin, which also produces evidence of covalent bond formation with the 5 subunit (tandem mass spectroscopy data not shown). Hence, the specificity of the reported interaction between PHSCN and the 1 subunit1 is suspect. Moreover, the cysteine rich 1 subunit can heterodimerize with 12 distinct alpha integrin subunits2, forming integrins that function in many pathways. In contrast, the 5 subunit interacts uniquely with the 1 subunit2 to induce invasion and support adhesion3-5; hence it is a much more desirable target.

关键词：乳腺癌；转移；共价键；半胱氨酸

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A retrospective statistical analysis of data obtained from the Janus Program at Argonne National Laboratory was conducted. We assessed the cancerous and non-cancerous tissue toxicities induced by low dose rate fractionated gamma or neutron irradiation and the way in which gender modulates their accumulation. The statistical analysis was done of the data from a study done on mice irradiated with either 2-40 cGy of Janus reactor fission neutrons or 100-600 cGy of 60 Cobalt gamma rays, given in 60 fractions. Dose rates varied between 0.002 0.034 cGy/min for neutrons or 0.083 0.5 cGy/min for gamma rays.

关键词：毒性；组织（生物学）；积累；癌

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This project was motivated by the continuing need to improve ambient air quality. As of December 2012, more than 74 million Americans live in areas that violate the National Ambient Air Quality Standard for fine particulate matter (or PM2.5). Organic aerosol often contributes between 30 and 60% of ambient fine particulate matter. However, the sources of ambient organic aerosols are not well understood and state-of-the-art chemical transport models often underpredict the measured organic aerosol concentrations by a factor of 2 or more. Better understanding of the sources of organic aerosols may be needed for the development of effective control strategies. This report describes results from a three-phase test program that characterized the emissions from on-road gasoline vehicles, on-road diesel vehicles, and small off-road engines. The overarching goal of the project was to investigate the atmospheric transformations of mobile source emissions to better quantify their contribution to ambient PM levels in other words to link tailpipe to ambient. This was done by characterizing the tailpipe emissions from in-use sources and by investigating the atmospheric evolution of the emissions using dilution tunnels and smog chambers.

关键词：气溶胶；空气质量；柴油燃料；排放控制

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Antimicrobial resistance is one of our most serious health threats. Infections from resistant bacteria are now too common, and some pathogens have even become resistant to multiple types or classes of antibiotics (antimicrobials used to treat bacterial infections). The loss of effective antibiotics will undermine our ability to fight infectious diseases and manage the infectious complications common in vulnerable patients undergoing chemotherapy for cancer, dialysis for renal failure, and surgery, especially organ transplantation, for which the ability to treat secondary infections is crucial.

关键词：抗生素耐药性；传染病；卫生威胁

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Platinum compounds display clinical activity against a wide variety of solid tumors; however, resistance to these agents is a major limitation in cancer therapy. Reduced platinum uptake and increased platinum export are examples of resistance mechanisms that limit the extent of DNA damage. Here, we report the discovery and characterization of the role of ATP11B, a P-type ATPase membrane protein, in cisplatin resistance. We found that ATP11B expression was correlated with higher tumor grade in human ovarian cancer samples and with cisplatin resistance in human ovarian cancer cell lines. ATP11B gene silencing restored the sensitivity of ovarian cancer cell lines to cisplatin in vitro. Combined therapy of cisplatin and ATP11B-targeted siRNA significantly decreased cancer growth in mice bearing ovarian tumors derived from cisplatin-sensitive and -resistant cells. In vitro mechanistic studies on cellular platinum content and cisplatin efflux kinetics indicated that ATP11B enhances the export of cisplatin from cells. The colocalization of ATP11B with fluorescent cisplatin and with vesicular trafficking proteins, such as syntaxin- 6 (STX6) and vesicular-associated membrane protein 4 (VAMP4), strongly suggests that ATP11B contributes to secretory vesicular transport of cisplatin from Golgi to plasma membrane. In conclusion, inhibition of ATP11B expression could serve as a therapeutic strategy to overcome cisplatin resistance.

关键词：药品；卵巢癌；铂化合物；脱氧核糖核酸

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This issue of Research Showcase features articles on two successful research efforts, one on quiet pavements and the other on the benefits of prismatic sign sheeting, and an article on university transportation center participation in Florida.

关键词：佛罗里达州；降噪；棱柱片材

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Prostate cancer is dependent on androgens and the androgen receptor (AR) for disease initiation, maintenance, and progression. Through work by our group and others, it has been shown that there is significant crosstalk between AR and the cell cycle machinery. Most importantly for our study, AR has been shown to induce the G1 to S phase transition in part via regulation of cyclin D1. Cyclin D1 serves as a rheostat to temper the pro-proliferative signaling of AR by directly binding to the receptor and inhibiting it s activity, thus inducing cell cycle arrest. As such, the AR-cyclin D1 crosstalk axis may serve to control the proliferative capacity of prostate cancer cells, and potentially alter the therapeutic efficacy of anti-cancer drugs. The data presented herein will demonstrate that cyclin D1 status does not impinge on the biological outcome in vitro of taxane-based therapy.

关键词：前列腺癌；治疗；雄激素；容量（数量）

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