This study aims to characterize a cohort of type 2 diabetes patients in rural North Dakota clinics, with a goal of identifying ways to improve individual patient care while at the same time meeting required treatment targets. This cross-sectional study analyzed type 2 diabetes patients (n=208) managed by six primary care providers working in four clinics affiliated with one health care system. Demographic, anthropomorphic and behavioral information was extracted from electronic medical records, as well as laboratory results, disease outcomes and medical services provided. The extreme tertiles of patients in best and worst glycemic control were compared.

关键词：糖尿病；临床医学；患者；医疗诊所

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Heparanase (HPR1) is an endoglycosidase that specifically degrades heparan sulfate proteoglycans, a main constituent on the cell surface and in the extracellular matrix and basement membrane. The role of heparanase in breast cancer tumorigenesis remains unclear. In particular, whether HPR1 enzymatic activity is required for its stimulatory effect on tumor growth and initiation are not fully understood. Here we report that the C-terminus of HPR1, which lacks the enzymatic activity, was able to accelerate breast cancer formation in a somatic breast cancer mouse model since mice infected with RCAS- Neu virus plus RCAS-8C (a vector encoding the C terminus of HPR1), developed breast cancer faster than that infected with RCAS-Neu plus RCAS-GFP control virus. Our results suggest that HPR1 may promote tumor growth independent of its enzymatic activity.

关键词：乳腺癌；肿瘤细胞（生物学）；乳腺增生病

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The purpose of our research proposal is to determine how the deletion of Tsc1 and mTOR dysregulation affects thalamus development and function. An addition goal of our research was to use our conditional gene deletion system to test the ability of the mTOR inhibitor rapamycin to ameliorate neurological phenotypes depending upon the time and duration of treatment. During this research period, we further advanced our novel genetic approach to control Tsc1 gene deletion concomitant with cell lineage tracing and biochemical analysis to better understand the developmental aspects of Tuberous Sclerosis. A major set of findings is that we identified cellular, molecular, circuitry, and behavioral changes that occur during development and are specific to distinct temporal roles of Tsc1 and the mTOR pathway. Specifically, we showed that early embryonic deletion of Tsc1 resulted in mTOR dysregulation within 48 hours and this dysregulation persisted throughout the life of the mice; this is the first report of the kinetics of mTOR dysregulation. In addition, we showed that neural circuits that connect the thalamus and cerebral cortex are disrupted by early or late deletion of Tsc1 and that the neural circuit abnormality is first observed at the end of embryogenesis (five days after mTOR dysregultion). Thus, specific phenotypes emerge rapidly and others appear over a more prolonged developmental window. We then used biochemistry to show that proteins involved in synaptic architecture are altered by the early deletion of Tsc1. Finally, we show that behavioral alterations are strongly associated with the time of Tsc1 function. We initiated studies to address our additional and have begun delineate the most effective method and dose of rapamycin that can support development while at the same time effectively suppressing the mTOR pathway.

关键词：脑；疾病；丘脑;畸形；行为；生物化学

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MicroRNAs are non-coding small RNAs that exert their silencing functions at the posttranscriptional level; they play a fundamental role in regulation of diverse cellular pathways. In addition to microRNAs, the cell also expresses abundantly other non-coding RNAs such as long non-coding RNAs (>200 bases) (lncRNAs), which could account for 4-9% of transcripts in human genome. In this application we proposed to test whether lncRNAs are dysregulated in prostate cancer. We demonstrated that lncRNA GAS5 is a direct target for miR-21. Furthermore, GAS5 can also suppress miR-21. In addition to GAS5, we identified that PCGEM1 is upregulated in prostate cancer, and it interacted with androgen receptor (AR). More importantly, both AR and PCGEM1 were co-localized in prostate cancer cells as well as in the clinical specimens, especially in high grade prostate tumors, suggesting that their interaction may contribute to aggressiveness of prostate cancer and castration resistance. Together, our study suggests that lncRNAs are important players in prostate cancer biology, and further characterization of these lncRNAs will provide a better understanding of prostate cancer biology. As a result, lncRNAs may serve as biomarkers for prostate cancer.

关键词：前列腺癌；雄激素；细胞（生物学）

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This is a basic research project designed to understand the role of mechanically sensitive excitatory ion channels (MSC) in the pathology of chronic pain, and the use of a small pepti de inhibitor of these channels called GsMTx4 to treatment peripheral pain. Our first goal is to develop an in vitro assay using single neurons to study the properties of MSCs and to determine the affinity of GsMTx4 and muta nt analogs for neuronal MSCs. We have learned to prepare dorsal root ganglion neurons (DRG) from mouse spinal cord and have determined the types of MSCs expressed and the frequency of their occurrence in the cell-attached and outside-out patch assay. We have also designed a second assay for MSC activity by pressing on DRG with a precision controlled motion glass probe while measuring whole cell currents as a independent measure of the MSC activity. Stress on the internal cytoskeleton may play a critical role in the activation of MSCs on the surface and so we will measure stress changes in the proteins that make up the cytoskeleton of DRGs using a new FRET based stress probe we have made which can be inserted into the sequence of cytoskeletal proteins to report stress. We have tried to reproduce the published findings of others showing GsMTx4 analgesic activity in whole animals by treating inflamed tissue in mice, but were unable to do so. However, we have learned new information about the pharmaco kinetics of GsMTx4 that will be used to redesign the study.

关键词：神经节；动力学；疼痛；激活

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Since this application was written, it has become increasingly appreciated that NF B activation can either promote cancer cell death or cancer cell survival the outcome being dependent on the context of parallel biological processes. Notably, the presence of tumor suppressors influences the outcome. Our bioinformatic approach to define a cancer promoting NF B gene activation signature is proving to be well suited for accounting for the varied and opposing roles of NF B activation. Specifically, our prostate cancer specific work has identified absence of a unique set of tumor suppressors which leads to cancer cell survival and ultimately lethal prostate cancer. Notably, PTEN was not one of these tumor suppressors. It is also now appreciated that indiscriminate inhibition of NF B activation may be problematic as this may block the anti-cancer effect of NF B activation. As such the increased understanding of NF B activation s context dependency adds further support for the work we are doing. In year one and two of the project we have found elevated cytokines and presence of T. Vaginalis at time of diagnosis of prostate cancer are not associated with higher grade disease nor risk of relapse after prostatectomy. We have also identified a 31 tumor gene signature which correlates with relapse with lethal disease post prostatectomy in our training set. We have also used the 31 gene signature and publically available data-bases to computationally create a refined network of cancer promoting NF B gene activation. This network is now being used to (i) further inform selection of genes to test in multiple independent data sets for association with lethal disease; (ii) inform and increase power for identification of new SNPs in GWAS datasets associated with lethal outcome, and (iii) help to interpret the mechanisms of action of genes associated with lethal disease identified separately in the tumor gene expression profiling and SNP analyses.

关键词：基因；前列腺癌；生物细胞（生物学）

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Overexpression of EGFR is frequently linked to more aggressive tumor behavior, including increased proliferation, metastasis, and therapeutic resistance. Here, we identified a molecular linkage between IKK and EGFR signaling in breast cancer cells. Inhibition of IKKs activity elevates EGFR tyrosine phosphorylation. In addition, IKK forms a specific interaction with EGFR in Golgi apparatus and catalyzes EGFR S1026 phosphorylation. We found that EGFR S1026A possess a stronger tumorgenesis phenotype compare with wild type EGFR suggesting a negative regulation of IKK in EGFR signaling. In agreement with an earlier finding where conditional ablation of IKK in the mice keratinocytes elevates the autocrine loop of EGFR, our results further provide a potent role of IKK kinase activity in preservation of EGFR activity.

关键词：乳腺癌；肿瘤细胞（生物学）；炎症

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The proposed study, targeting the kinase independent pro-survival function of EGFR in prostate cancer, is to investigate the molecular mechanism of EGFR-SGLT1 interaction and test the possibility of use interfering peptides to disrupt the EGFR-SGLT1 interaction for therapeutic purpose, and in parallel to profile the expression status of EGFR/SGLT1 in prostate cancer tissues. Outcomes from this study may lead to find novel strategies for EGFR targeted therapy for prostate cancer. To date, we have successfully constructed expression plasmids for 12 type of truncated EGFR, which are the key tools to map the interaction domains between EGFR and SGLT1, and we have successfully developed/characterized a polycolonal antibody against human SGLT1 for immunihistochemical staining of human prosate tissues.

关键词：表皮；前列腺癌；受体位点（生理学）

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Cyanide is a deadly poison which may be ingested or inhaled and can cause severe incapacitation or death. The diagnosis of cyanide exposure is critical to speed treatment and reduce harm. The development of a diagnostic sensor device and the identification and analysis of novel biomarkers of cyanide exposure are the major objectives of this research. Since the onset of toxic outcome from cyanide exposure is very fast, a rapid and portable sensor for the detection of cyanide exposure was developed and tested. The sensor utilized a cyanide-selective fluorescent reaction as the core chemical reaction with micro-diffusion sample preparation (previously reported). Second- and third-generation cyanide sensors were developed and the latest version is currently undergoing laboratory testing. Multiple novel markers of cyanide exposure were also identified as having potential advantages to cyanide and thiocyanate, and methods of analysis for these markers were developed or are in the process of being developed. Specifically, 2-amino-2-thiozoline-4-carboxylic acid (ATCA), alpha-ketoglutarate, and a cyanide-glutathione adduct were investigated. Toxicokinetic models were obtained through analysis of the plasma concentrations of ATCA, cyanide, and thiocyanate, analyzed from cyanide-exposed rats (previously reported), rabbits (reported in 2012), and swine, to assess the utility of ATCA as a bio-marker for cyanide exposure.

关键词：血；氰化物；食入（生理学）；唾液

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We have investigated whether and how autoimmune complex (AIC) in SLE (lupus) can induce T helper (Th) cell polarizing cytokines including IL-27 and IL-1 , leading to enhanced Th cell responses. We have measured IL-27 gene and protein expression by healthy human monocytes g Istimulated with autoimmune complex containing anti-dsDNA and snRNP antibodies using qPCR and ELISA, respectively. However, levels of IL-27 produced from the stimulated monocytes were relatively low compared to those of the pro-inflammatory cytokine IL-1 . IL-1 promotes of the development of Th17 cells that is increased in lupus patients. Increased IL-1 expression was found in the target tissues of lupus patients although the mechanism for these findings is unknown. It is conceivable that a combination of IL-27 and IL-1 can promote the development of Th17 cells with the capacity to produce IL-10, a notion in accordance with our original hypothesis. We have reported that AIC containing dsDNA and U1-snRNP activate human monocytes dependently of anti-dsDNA and U1-snRNP antibodies, respectively, leading to the production of cytokines including IL-1 . This phenomenon was dependent on the activation of Toll-like receptor and NLRP3 inflammasome pathways. We also found that IL-27 can suppress IL-17 production in human CD4+ T cells and that such suppression is enhanced in patients with SLE. This finding suggests a potential therapeutic implication of exogenous IL- 27 in patients with SLE.

关键词：自身免疫性疾病细胞（生物学）；细胞因子；T淋巴细胞

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