The human prostate gland is an important target organ of androgenic hormones. Testosterone and dihydrotestosterone interact with the androgen receptor to regulate vital aspects of prostate growth and function including cellular proliferation, differentiation, apoptosis, metabolism, and secretory activity. Our objective in this study was to characterize the temporal program of transcription that reflects the cellular response to androgens and to identify specific androgen-regulated genes (ARGs) or gene networks that participate in these responses. We used cDNA microarrays representing about 20,000 distinct human genes to profile androgen-responsive transcripts in the LNCaP adenocarcinoma cell line and identified 146 genes with transcript alterations more than 3-fold. Of these, 103 encode proteins with described functional roles, and 43 represent transcripts that have yet to be characterized. Temporal gene expression profiles grouped the ARGs into four distinct cohorts. Five uncharacterized ARGs demonstrated exclusive or high expression levels in the prostate relative to other tissues studied. A search of available DNA sequence upstream of 28 ARGs identified 25 with homology to the androgen responseelement consensus-binding motif. These results identify previously uncharacterized and unsuspected genes whose expression levels are directly or indirectly regulated by androgens; further, they provide a comprehensive temporal view of the transcriptional program of human androgen-responsive cells.T he androgenic hormones testosterone and dihydrotestosterone exert their cellular effects by means of interactions with the androgen receptor (AR), a member of the family of intracellular steroid hormone receptors that function as liganddependent transcription factors (1). Ligand-activated AR, complexed with coactivator proteins and general transcription factors, binds to cis-acting androgen response elements (AREs) located in the promoter regions of specific target genes and serves to activate or to repress transcription (1, 2). During human development, circulating androgens and a functional AR mediate a wide range of reversible and irreversible effects that include the morphogenesis and differentiation of major target tissues such as the prostate, seminal vesicles, and epididimus. The prostate gland has been used extensively as a model system to study androgen effects. In part, this is because of the fact that androgens promote the development and progression of prostate diseases that account for significant morbidity in the population including benign prostatic hypertrophy and prostate adenocarcinoma (2). The recognition that normal and neoplastic prostate epithelial cells depend on circulating androgens for their continued survival and growth led to the development of effective endocrine-based therapy for prostate carcinoma (3). To date, manipulating the androgen pathway by means of surgical or chemical castration remains the primary therapeutic modality for advanced prostate cancer.In the human prostate, the AR mediates ...

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The first searches for axions and axionlike particles with the Large Underground Xenon experiment are presented. Under the assumption of an axioelectric interaction in xenon, the coupling constant between axions and electrons g Ae is tested using data collected in 2013 with an exposure totaling 95 live days ×118 kg. A double-sided, profile likelihood ratio statistic test excludes g Ae larger than 3.5 × 10 −12 (90% C.L.) for solar axions. Assuming the Dine-Fischler-Srednicki-Zhitnitsky theoretical description, the upper limit in coupling corresponds to an upper limit on axion mass of 0.12 eV=c 2 , while for the KimShifman-Vainshtein-Zhakharov description masses above 36.6 eV=c 2 are excluded. For galactic axionlike particles, values of g Ae larger than 4.2 × 10 −13 are excluded for particle masses in the range 1-16 keV=c 2 . These are the most stringent constraints to date for these interactions.

We present measurements of the electron-recoil (ER) response of the LUX dark matter detector based upon 170,000 highly pure and spatially-uniform tritium decays. We reconstruct the tritium energy spectrum using the combined energy model and find good agreement with expectations. We report the average charge and light yields of ER events in liquid xenon at 180 V/cm and 105 V/cm and compare the results to the NEST model. We also measure the mean charge recombination fraction and its fluctuations, and we investigate the location and width of the LUX ER band. These results provide input to a re-analysis of the LUX Run3 WIMP search .

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The proteins identified can be used as reference dataset in future work comparing prostasome proteins between normal and pathological states such as prostate cancer, benign prostatic hyperplasia, prostatitis, and infertility.

We present a robust and general shotgun glycoproteomics approach to comprehensively profile glycoproteins in complex biological mixtures. In this approach, glycopeptides derived from glycoproteins are enriched by selective capture onto a solid support using hydrazide chemistry followed by enzymatic release of the peptides and subsequent analysis by tandem mass spectrometry. The approach was validated using standard protein mixtures that resulted in a close to 100% capture efficiency. Our capture approach was then applied to microsomal fractions of the cisplatinresistant ovarian cancer cell line IGROV-1/CP. With a Protein Prophet probability value greater than 0.9, we identified a total of 302 proteins with an average protein identification rate of 136 ؎ 19 (n ‫؍‬ 4) in a single linear quadrupole ion trap (LTQ) mass spectrometer nano-LC-MS experiment and a selectivity of 91 ؎ 1.6% (n ‫؍‬ 4) for the N-linked glycoconsensus sequence. Our method has several advantages. 1) Digestion of proteins initially into peptides improves the solubility of large membrane proteins and exposes all of the glycosylation sites to ensure equal accessibility to capture reagents. 2) Capturing glycosylated peptides can effectively reduce sample complexity and at the same time increase the confidence of MS-based protein identifications (more potential peptide identifications per protein). 3) The utility of sodium sulfite as a quencher in our capture approach to replace the solid phase extraction step in an earlier glycoprotein chemical capture approach for removing excess sodium periodate allows the overall capture procedure to be completed in a single vessel. This improvement minimizes sample loss, increases sensitivity, and makes our protocol amenable for high throughput implementation, a feature that is essential for biomarker identification and validation of a large number of clinical samples. 4) The approach is demonstrated here on the analysis of N-linked glycopeptides; however, it can be applied equally well to

Nearly all women diagnosed with ovarian cancer receive combination chemotherapy including cis-or carboplatin. Despite high initial response rates, resistance to cisplatin develops in roughly one-third of women during primary treatment and in all women treated for recurrent disease. ICAT coupled with tandem MS is a quantitative proteomic technique for high throughput protein expression profiling of complex protein mixtures. Using ICAT/MS/MS we profiled the nuclear, cytosolic, and microsomal fractions obtained from IGOV-1 (cisplatin-sensitive) and IGOV-1/CP (cisplatin-resistant) ovarian cancer cell lines. The proteomes of cisplatin-sensitive and -resistant ovarian cancer cells were compared, and protein expression was correlated with mRNA expression profiles. A total of 1117 proteins were identified and quantified. The relative expression of 121 of these varied between the two cell lines. Sixty-three proteins were overexpressed in cisplatin-sensitive, and 58 were over expressed in cisplatin-resistant cells. Examples of proteins at least 5-fold overexpressed in resistant cells and with biological relevance to cancer include cell recognition molecule CASPR3 (13.3-fold), S100 protein family members (8.7-fold), junction adhesion molecule Claudin 4 (7.2-fold), and CDC42-binding protein kinase ␤ (5.4-fold). Examples of cancer-related proteins at least 5-fold overexpressed in sensitive cells include hepatocyte growth factor inhibitor 1B (13.3-fold) and programmed cell death 6-interacting protein (12.7-fold). The direction of changes in expression levels between proteins and mRNAs were not always in the same direction, possibly reflecting posttranscriptional control of protein expression. We identified proteins whose expression profiles correlate with cisplatin resistance in ovarian cancer cells.