Many heavy metals, including nickel, cadmium, and chromium are toxic industrial chemicals with an exposure. While these substances are known to produce adverse health effects leading to health problems, the detailed mechanisms remain unclear. To elucidate the processes involved in the toxicity of these metals at the molecular level and to perform a comparative analysis, H4-II-E-C3 rat liver-derived cell lines were treated with each metal and gene expression patterns were determined. We identified both common and unique biological responses to exposure to the metals. All three metals induced oxidative stress. Although all three metals are known to be genotoxic, evidence for DNA damage in our study only exists in response to chromium. Nickel induced a hypoxic response as well as inducing genes involved in chromatin structure. Cadmium distinctly perturbed genes related to endoplasmic reticulum stress and invoked the unfolded protein response leading to apoptosis. With these studies, we have completed the first gene expression comparative analysis of nickel, cadmium, and chromium in H4-II-E-C3 cells.

关键词：镉细胞（生物学）；铬；卫生；重金属

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Although most prostate cancers are initially responsive to androgen ablation therapy, they become treatment resistant as tumor cells develop mechanisms to evade the treatment. Early knowledge of the androgen receptor dysfunctions will help in patient stratification for emerging therapeutic strategies. We proposed an approach for monitoring potential dysfunctions of the androgen receptor by measuring expression of a panel of genes directly regulated by androgen receptor. We examined human prostate cancer tissues (surgery or diagnostic biopsy specimens) at early stages of the disease and matched with longitudinal follow up data. Within the first reporting period we have completed the quality control of detecting PSA/KLK3, PMEPA1, NKX3.1, ODC1, AMD1 and TMPRSS2-ERG genes in VCap cell culture model monitoring kinetic and dose response to androgen. In the second reporting period we have completed the qRT-PCR evaluation of in 77 patients by monitoring ERG, PSA, PMEPA1 and GAPDH levels. Also, we have completed the evaluation of 40 whole mounted sections of RP specimens by immunohistochemistry assessing AR, ERG, NKX3.1 and PSA proteins and compared the results to corresponding GeneCHip mRNA expression levels from the same tumor foci. The result indicated remarkable accuracy of the androgen regulated gene expression at mRNA levels performed better in prediction favorable outcomes in tumors with well differentiated morphology. By the completion of the proposed research we will provide a quantitative index of AR dysfunction for enhancing prognostic accuracy and to stratify patients for specific therapeutic approaches at early stages of prostate cancer treatment.

关键词：雄激素；肿瘤；前列腺癌；受体位点（生理学）

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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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The hypothesis of the original proposal was to discover novel imaging probes for the diagnosis of prostate cancer by targeting simultaneously PSMA and hepsin, which are highly expressed in advanced and metastatic prostate cancer. In Year 3, we successfully established the synthetic strategy for PSMA- hepsin heterobivalent ligands and synthesized two dual-targeting conjugates 12- 13 labeled with optical dye Cy 5.5 and Cy 7, respectively. We also synthesized two peptide-based IPLLVVPL analogs (15,17) linked with DOTA and evaluated their inhibitory activities against hepsin protease. With respect to biological experiments, we developed the PC3/ML cell lines which express PSMA, hepsin, and PSMA/hepsin for in vitro cell uptake and in vivo imaging studies. Compound 13 showed a low but detectable increased cell uptake into the developed cell lines as compared to the control. From these results, we will carry out structural optimization of compound 13 and evaluate their biological activities in vitro and in vivo in Final Year.

关键词：抗原；诊断（医学）；膜（生物学）

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From petri dish to complex micro-devices, technological advances in microfluidic devices allowed us to study various disease cases in greater depth. Multiple Sclerosis (MS) is an autoimmune disease which occurs in the brain. The inflammation during MS is also known to occur at the wall of the tissue where Neural Progenitor Cells reside (NPC). These NPCs are recognized for their regenerative property; they can replace old or damaged neurons with newly formed neurons. Thus, in MS patients, it is difficult to maintain neurogenesis for restorative therapy as it is constantly inhibited due to the inflammation. Pathological studies reveal that the two microenvironments surrounding the inflammation site are different. This calls for a novel microfluidic device that mimics distinct microenvironments of the disease condition. Hence, we have developed a three-compartment system microfluidic system that can be used to study such disease. Using this device, the cellular and molecular signaling mechanism under MS in the NPCs may be elucidated for the first time.

关键词：中枢神经系统；神经系统疾病；神经内科

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CD82 is a non enzymatic transmembrane molecular scaffold that was initially identified as a metastasis suppressor in the rat AT6.1 prostate tumor model (1). CD82 has been shown to regulate several key factors important for metastasis, including growth factor receptor signaling, (Epidermal Growth Factor Receptor and Hepatocyte Growth Factor Receptor) and Ecadherin (2 6). E cadherin is responsible for the formation of adherens junctions in the cell, a multi molecular complex that regulates epithelial cell polarity and cell cell adhesion. Loss of cell cell adhesion and apical basal cellular polarity are hallmarks of metastatic cancer, loss of which are required for escape from the primary tumor and extravasation into the blood stream. Tetraspanin family members including CD82 form membrane microdomains on the cell surface, known as Tetraspanin Enriched Microdomains (TEMs) that serve to regulate interacting partners by their inclusion or exclusion from these domains (7). These domains are light in density, and float in the light density fractions upon cellular density gradient fractionation, allowing biochemical analysis of proteins localizing in TEMS. Although CD82 regulates multiple signaling molecules, the mechanisms by which it does so remain poorly defined. The purpose of this study was to determine whether there are any structural determinants within CD82 that define its ability to regulate E cadherin in TEMs. While CD82 has a known Y X X internalization motif (8), no other interaction domains within the protein have been identified.

关键词：黏附细胞（生物学）；生长（生理学）；前列腺癌

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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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Targeted therapy for cancer is based upon the notion that tumors have characteristics that are quantitatively or qualitatively different from normal tissues, or that tumor cells are uniquely dependent, or addicted , to certain of these characteristic differences. Genetic changes including somatic mutation, gene amplification, and chromosomal translocation often serve as irreversible drivers of tumor growth and survival making them attractive targets for therapy. The amplification of ERBB2/Her-2 on chromosome 17q12 in 15% of breast cancers led to the identification of Her-2 as a driver oncogene and successful target for therapy. Other chromosomal regions are recurrently amplified in breast cancer almost as frequently as 17q12: these include 8p11-12 and 11q13. Amplification of 8p11-12 has been shown to confer a high risk of metastasis after primary breast cancer surgery and adjuvant therapy, and it is therefore critical to identify the oncogene(s) driving this aggressive behavior.

关键词：乳腺癌；扩增细胞（生物学）；染色体

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We report the synthesis of the amphiphilic PEG-b (PAA)-b-P(HDFMA-co- MMA) copolymers that proved to encapsulate 1%-2% v/v PFP forming nanodroplets. Combining these nanodroplets with histotripsy proved to generate a cavitation bubble cloud with similar behavior but lower pressure compared to histotripsy itself. Moreover, these nanodroplets maintained their average size and concentration upon incubation with BSA for 24 hours at 37 degrees celcius, which prove their promise for cancer cell ablation and warrant their future testing in vivo.

关键词：前列腺癌；烧蚀；气泡；空化

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In this project, we focus on oxidation and glycosylation PTMs on proteins known to be secreted by the breast as candidate biomarkers for the early detection of breast cancer. ELISA microarray technology has employed to evaluate assays that have potential be used as breast cancer biomarkers. During the third year of this project we have continued the validation for our PTM- ELISA microarray. And we validated the chosen PTM antibody for pre-clinical or translational molecular imaging studies. The microPET imaging suggested that those PTM antibodies have high specific accumulation for breast cancer in tumor xenograft mice. Overall, our data suggest that the PTM ELISA microarray platform is a promising tool for discovery and evaluation of biomarkers that have potential for the early detection of breast cancer.

关键词：乳腺癌；正电子发射断层扫描；抗体

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