关键词：近视；角膜塑形镜；离焦框架镜；0.01%低浓度阿托品

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The objective of the project for the reporting period was to generate a number prostate cancer cell lines that that are either myosin IC isoform A deficient or that constitutively express GFP-myosin IC isoform A. We used shRNA to generate isoform Anegative PC-3 cells and we generated a stable LNCaP cell line that expresses constitutively myosin IC isoform A-GFP. We are now in the process of analyzing the effect of these expression changes on secretion in these cell lines to determine the consequences of isoform A expression changes for the metastatic ability of prostate cancer cells. Using serial cloning of the 5 prime UTR of the human myosin IC gene we have identified a region that is involved in regulatory expression of myosin IC isoform A. We are now in the process of using ChIP assays to identifying the transcriptional elements that bind to this region and induce expression of myosin IC isoform A in prostate cancer cells.

关键词：基因芯片；前列腺癌；异常凝蛋白异构体

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Laboratory studies support the potential for jet fuel to promote noise induced hearing loss. Noise alone induces hearing loss due to loss of hair cells in the cochlea, associated with oxidative stress. Jet fuel toxicity in association with noise may be at least partially explained by increased free radical production and oxidative stress at the cellular level, resulting in hair cell dysfunction and loss. This project combines a physiologically-based pharmacokinetic (PBPK) model to describe jet fuel component concentrations in the cochlea with pharmacodynamic (PD) models of free radical formation in the cochlea by both noise and jet fuel components, and mathematical models to predict the combined impact on hair cell functionality and loss. Further development of this preliminary combined PBPK-PD model of JP-8 induced hearing loss with noise will provide the basis for estimating the potential risk to humans exposed to the same chemical and sound scenarios in occupational settings.

关键词：血流量；体重；耳蜗；自由基；毛细胞

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Former Johnson Space Center engineer David Bergeron used his experience on the Advanced Refrigeration Technology Team to found SunDanzer Refrigeration Inc., a company specializing in solar-powered refrigerators. The company has created a battery-free unit that provides safe storage for vaccines in rural and remote areas around the world.

关键词：电池；电能；公共健康

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Carbon-coated magnetite nanoparticles (NPs) were synthetized by the mechanochemical method with hematite as precursor and amorphous carbon as inorganic reductor. After 18 hours of milling in an inert atmosphere, a nanocomposite material of magnetite and carbon was obtained. Structural and magnetic properties of the NPs were investigated by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDS) and vibrating sample magnetometry. XRD patterns, refined with the Rietveld method, show that magnetite is present in samples milled from 6 hours onward and that after milling for 18 hours and annealing in Ar, the sample contains a single crystalline phase. Magnetization curves for samples with different milling times show saturation magnetization values that range from 34.1 emu/g after 1 h to 78.0 emu/g after 18 h. Coercive fields are about 500 Oe for all samples. TEM studies reveal that the samples are made of amorphous carbon clusters with magnetite NPs of 20 nm. The obtained NPs, associated to electrochemical transducers, show an improved enhancement of the charge transfer for redox processes involving different bioanalytes. Thus, these NPs offer unique properties as a catalyst in biosensing strategies for the electrochemical detection of high-impact markers and the development of theranostics smart-devices for biomedical applications.

关键词：电池；电能；纳米颗粒

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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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Therapies designed to damage DNA (e.g. chemotherapy and irradiation) cure many primary prostate carcinomas (PCa) and produce significant responses in a subset of advanced metastatic cancers. However, a subset of localized cancers resist genotoxic treatments, and most advanced cancers treated with such therapies eventually progress to a lethal phenotype. Thus, therapy resistance is a major contributor to PCa morbidity and mortality. We want to explore the hypothesis that DNA damaging therapeutics generates responses in benign cell types comprising TME that promote tumor cell survival and enhance resistance. We have assessed the outcome of targeting individual mediators of this microenvironment-derived DDSP---specifically a member of the Wnt superfamily, WNT16B and demonstrated the highly effective neutralization of prostate cancer cell malignancy in vitro by purified anti-WNT16B. We anticipate that suppressing WNT16B will diminish treatment-initiated resistance, and improve in vivo tumor responses. We have established primary mouse prostate fibroblast cell lines and examined their responses including DDSP development upon DNA damage, and demonstrated the potential complication of regulatory mechanisms of DDSP program.

关键词：前列腺癌；脱氧核糖核酸；分泌

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The project is based on the generation of metastatic brain tumors using a brain selective cell line, 231-BR, derived from human breast cancer. Therefore, the experimental model to be used must be immune compromised. The other requirement we have for this project is that the experimental animals express human HLA-A2 complexes (major histocompatibility complex class I). The antibody we want to evaluate as a potential therapeutic agent is a T-cell receptor mimic restricted to human HLA-A2. Therefore, we must use HLA-A2 transgenic mice. In experiments conducted to date the mouse strain, which fulfills both requirements, JAX 9617, and the corresponding non-transgenic control strain, 5557, were receptive for tumor growth not only in brain, but in a number of peripheral organs (e.g. lung, liver, spleen). To avoid the confounding influence of peripheral metastases, we currently explore alternative methods to generate brain tumors intracarotid injections, stereotaxic brain implantation. Regarding the analytical side, we have established an immunoradiometric assay for the RL6A antibody with high sensitivity. In saturation and in competition experiments, radioiodinated RL6A and unlabeled antibody showed a Kd value of 1.16 nM and a Ki of 1.26 nM, respectively.

关键词：抗体；乳腺癌细胞；转移；肿瘤

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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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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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