Modern breast cancer therapies utilize non-specific approaches to kill or remove cancerous cells, inflicting significant collateral damage to healthy cells. In response to the need for highly targeted detection and destruction of cancerous cells, we propose to implement multi-input genetic circuits that act as cell state classifiers based on mRNA or microRNA expression profiling. The mRNA sensing project is focused on the MCF-7 breast adenocarcinoma cell line. MCF-7 cells overexpress Gata3, NPY1R and TFF1 mRNA relative to healthy cells. Based on our bioinformatics analysis, taking into account the three biomarkers allows for dramatically improved specificity in comparison to targeting single genes. We therefore design a three-input AND gate that triggers a response only when all three biomarkers are expressed above a defined threshold. In second approach we implement transcriptional/post- transcriptional regulatory circuit that senses expression levels of a customizable set of endogenous microRNAs and computes whether to trigger a response if the expression levels match a pre-determined profile of interest. We have created a circuit that computes a complex abstract logic (miR1 AND miR2+3 AND NOT miR4 AND NOTmiR5 AND NOT miR6) and selectively triggers output response in HeLa but not in other cells.

关键词：癌症；核糖核酸；细胞凋亡；细胞

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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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Rho-family GTPases are the major regulators of the actin and microtubule cytoskeleton. Regulators of the GTPases include GEFs and GAPs, which control activation and deactivation, respectively, of this family of molecular switches. This study explores the role of the GEF Tiam2 in breast cancer cell proliferation and invasion, which was initially discovered using a siRNA screen in MDA-MB-231 breast cancer cells. Protein expression studies are performed using a panel of cell lines, revealing that Tiam2 expression is upregulated in Ras mutant cells. Additionally, Tiam2 depletion causes MDA-MB- 231 cells to form fewer colonies in soft agar colony formation assays. A specific role for Tiam2 in tumor formation and proliferation in mouse models remains to be elucidated. This work adds insight into the molecular mechanisms by which cancer cells invade into surrounding tissue and eventually result in death.

关键词：乳腺癌细胞（生物学）；肌肉蛋白质；突变

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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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Traumatic brain injury (TBI) contributes to 50% of all trauma deaths. The mortality rate for adults following severe TBI (Glasgow Coma Scale < 9) is estimated to be 33%. There is currently no therapy to reverse the primary injury associated with TBI. Over the past 10 years there has been a growing body of literature supporting the use of various progenitor cell types to treat acute neurological injuries such as TBI. Our primary hypothesis is that bone marrow mononuclear cell (BMMNC) autologous transplantation after TBI is safe (harvest and infusion related toxicity) after TBI. Our secondary hypothesis is that functional outcomes measures will improve after BMMNC infusion, (3) BMMMC infusion will reduce BBB permeability, and (4) BMMMC is neuroprotective and preserves grey matter and white matter volumes after TBI. Patients, ages 18 to 55 years old, admitted to Memorial Hermann Hospital Trauma Center with Glascow Coma Scores (GCS) of 5 to 8 are screened. This is a dose-escalation study consisting of 4 cohorts including a control group (5 subjects/cohort). The first five subjects will not undergo the bone marrow harvest procedure; though they will be followed and treated the same as the other study participants and complete all follow-up procedures. Subjects are followed for safety, have plasma and CSF (if available) collected for neuroinflammatory markers, and at 30-days and 6 months post-injury, neuropsych and functional outcomes testing and DTMRI are performed. To date, 12 subjects have been enrolled (all controls) and have had plasma collected for neuroinflammatory markers and have returned for their 30-day follow-up visits. 6 subjects have completed their 6 month follow-up assessments.

关键词：骨髓；死亡；外伤性脑损伤；创伤和损伤

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Production of IL-17 from joint TH-17 cells can strongly contribute to RA angiogenesis (4) through a mechanism that is in part due to induction of VEGF from RA ST fibroblasts (5, 6). We document that CCL21 is expressed from endothelial cells activated by IL-17 (23) and neutralization of CCL21 markedly reduces IL-17 mediated VEGF transcription from the RA ST. Like IL-17, CCL21 is also capable of enhancing production of VEGF from RA ST fibroblasts and can further synergize with VEGF in facilitating endothelial chemotaxis. Hence CCL21 may be the unidentified connecting factor between the IL-17 and VEGF cascades. Therapeutic targeting of VEGF and VEGFR has led to disappointing results regarding drug toxicity and lack of efficacy in patients with advanced tumor growth (24, 25) therefore RA patients were not treated with anti-VEGF or anti- VEGFR therapies. However, since we demonstrate that CCL21 induced by IL-17 can modulate VEGF expression in RA ST, targeting CCL21 may disconnect the link between IL-17 and VEGF cascade and therefore more efficiently suppress RA neovascularization.

关键词：血管生成；关节炎；将细胞（生物）

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The purpose of this project is to determine if rescinnamine is effective against prostate cancer and treatment resistance. We found that rescinnamine is less effective against prostate cancer that against cancers from other organs. In organisms, the concentration that would effectively cause tumor growth inhibition is limited by its hypotensive activity. We are currently exploring rescinnamine derivatives that have decreased hypotensive activity, and increased tumor growth inhibition.

关键词：成长（生理）；前列腺癌；低血压

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Myelodysplastic syndromes (MDS) are clonal bone marrow failure (BMF) disorders defined by blood cytopenias due to ineffective hematopoiesis, genomic instability, and a predisposition to acute myeloid leukemia (AML). The most commonly recurring genomic alteration in MDS is deletion of chromosome 5q (del(5q)). MDS patients with an isolated del(5q) presenting with anemia, neutropenia, and elevated platelets associated with dysplastic megakaryocytes are considered to have 5q- syndrome. The majority of MDS patients with del(5q) do not exhibit these particular symptoms and, instead, are referred to as del(5q) MDS . We have recently identified miR- 146a, which target the TRAF6 arm of the innate immune pathway, a gene within the deleted region in del(5q) MDS. We posit that multiple genes on chr 5q coordinate TRAF6 activation in del(5q) MDS. A search of annotated genes within or near the CDRs revealed a known inhibitor of TRAF6, TIFAB, on band q31.1. We hypothesize that deletion of TIFAB promotes activation of the TRAF6 complex in human CD34+ cells resulting in hematopoietic defects resembling MDS with del(5q). The overall objectives of this proposal are to (1) determine whether loss of TIFAB in human CD34+ cells contributes to MDS in mice; (2) to investigate whether deletions of TIFAB activate TRAF6 in MDS; and (3) to determine the consequences of TIFAB deletion on signal transduction in human CD34+ cells, and whether these could explain features of MDS. In preliminary data from the first 2 year of the proposal, we have evidence that TIFAB is a regulator of human hematopoietic cells. Our key observations show that knockdown of TIFAB in human CD34+ hematopoietic stem/progenitor cells results in increased survival and proliferation, TIFAB inhibits TRAF6 protein expression and activation, resulting in lower NF-kB activation, and TIFAB expression impacts leukemic cell survival, growth and progenitor function. Given that TIFAB is deleted in many MDS patients, these findings could have major implications in MDS subtypes with deletions of chr 5q. The observation that del(5q) results in inappropriate activation of TTRAF6 provides a strong rationale to study the contribution of TIFAB to deregulation of the TRAF6 pathway in MDS.

关键词：骨髓；血小板；染色体；故障

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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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We have developed silicon nanotweezers and microfluidics system for the study of X-ray iiradiation effect to DNA molecules at the aspect of bio-mechanical characteristics. Trapped DNA bundle between nanotweezers are irradiated by X-ray and resonance frequency change was monitored in real time. Real time measurement in water is achieved by combination of Labview controlled nanotweezers and microfluidics. We have obtained stiffness reduction of DNA bundle during irradiation, but it has not enough reproducibility. Remaining instability aspects, such as stability of resonance frequency, numbers of trapped molecules have to be solved reliable data acquisition and analysis.

关键词：DNA；X射线；微机电

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