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Varambally S Dhanasekaran SM Zhou M Barrette TR Kumar-Sinha C Sanda MG Ghosh D Pienta KJ Sewalt RG Otte AP Rubin MA Chinnaiyan AM 《Nature》2002,419(6907):624-629
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Delineation of prognostic biomarkers in prostate cancer 总被引:112,自引:0,他引:112
Dhanasekaran SM Barrette TR Ghosh D Shah R Varambally S Kurachi K Pienta KJ Rubin MA Chinnaiyan AM 《Nature》2001,412(6849):822-826
Prostate cancer is the most frequently diagnosed cancer in American men. Screening for prostate-specific antigen (PSA) has led to earlier detection of prostate cancer, but elevated serum PSA levels may be present in non-malignant conditions such as benign prostatic hyperlasia (BPH). Characterization of gene-expression profiles that molecularly distinguish prostatic neoplasms may identify genes involved in prostate carcinogenesis, elucidate clinical biomarkers, and lead to an improved classification of prostate cancer. Using microarrays of complementary DNA, we examined gene-expression profiles of more than 50 normal and neoplastic prostate specimens and three common prostate-cancer cell lines. Signature expression profiles of normal adjacent prostate (NAP), BPH, localized prostate cancer, and metastatic, hormone-refractory prostate cancer were determined. Here we establish many associations between genes and prostate cancer. We assessed two of these genes-hepsin, a transmembrane serine protease, and pim-1, a serine/threonine kinase-at the protein level using tissue microarrays consisting of over 700 clinically stratified prostate-cancer specimens. Expression of hepsin and pim-1 proteins was significantly correlated with measures of clinical outcome. Thus, the integration of cDNA microarray, high-density tissue microarray, and linked clinical and pathology data is a powerful approach to molecular profiling of human cancer. 相似文献
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Parameshwaran K Buabeid MA Karuppagounder SS Uthayathas S Thiruchelvam K Shonesy B Dityatev A Escobar MC Dhanasekaran M Suppiramaniam V 《Cellular and molecular life sciences : CMLS》2012,69(5):829-841
In the developing brain, nicotinic acetylcholine receptors (nAChRs) are involved in cell survival, targeting, formation of
neural and sensory circuits, and development and maturation of other neurotransmitter systems. This regulatory role is disrupted
when the developing brain is exposed to nicotine, which occurs with tobacco use during pregnancy. Prenatal nicotine exposure
has been shown to be a strong risk factor for memory deficits and other behavioral aberrations in the offspring. The molecular
mechanisms underlying these neurobehavioral outcomes are not clearly elucidated. We used a rodent model to assess behavioral,
neurophysiological, and neurochemical consequences of prenatal nicotine exposure in rat offspring with specific emphasis on
the hippocampal glutamatergic system. Pregnant dams were infused with nicotine (6 mg/kg/day) subcutaneously from the third
day of pregnancy until birth. Results indicate that prenatal nicotine exposure leads to increased anxiety and depressive-like
effects and impaired spatial memory. Synaptic plasticity in the form of long-term potentiation (LTP), basal synaptic transmission,
and AMPA receptor-mediated synaptic currents were reduced. The deficit in synaptic plasticity was paralleled by declines in
protein levels of vesicular glutamate transporter 1 (VGLUT1), synaptophysin, AMPA receptor subunit GluR1, phospho(Ser845)
GluR1, and postsynaptic density 95 (PSD-95). These results suggest that prenatal nicotine exposure by maternal smoking could
result in alterations in the glutamatergic system in the hippocampus contributing to the abnormal neurobehavioral outcomes. 相似文献
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Vijaykrishna D Smith GJ Pybus OG Zhu H Bhatt S Poon LL Riley S Bahl J Ma SK Cheung CL Perera RA Chen H Shortridge KF Webby RJ Webster RG Guan Y Peiris JS 《Nature》2011,473(7348):519-522
Swine influenza A viruses (SwIV) cause significant economic losses in animal husbandry as well as instances of human disease and occasionally give rise to human pandemics, including that caused by the H1N1/2009 virus. The lack of systematic and longitudinal influenza surveillance in pigs has hampered attempts to reconstruct the origins of this pandemic. Most existing swine data were derived from opportunistic samples collected from diseased pigs in disparate geographical regions, not from prospective studies in defined locations, hence the evolutionary and transmission dynamics of SwIV are poorly understood. Here we quantify the epidemiological, genetic and antigenic dynamics of SwIV in Hong Kong using a data set of more than 650 SwIV isolates and more than 800 swine sera from 12?years of systematic surveillance in this region, supplemented with data stretching back 34?years. Intercontinental virus movement has led to reassortment and lineage replacement, creating an antigenically and genetically diverse virus population whose dynamics are quantitatively different from those previously observed for human influenza viruses. Our findings indicate that increased antigenic drift is associated with reassortment events and offer insights into the emergence of influenza viruses with epidemic potential in swine and humans. 相似文献
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Tomlins SA Laxman B Dhanasekaran SM Helgeson BE Cao X Morris DS Menon A Jing X Cao Q Han B Yu J Wang L Montie JE Rubin MA Pienta KJ Roulston D Shah RB Varambally S Mehra R Chinnaiyan AM 《Nature》2007,448(7153):595-599
Recently, we identified recurrent gene fusions involving the 5' untranslated region of the androgen-regulated gene TMPRSS2 and the ETS (E26 transformation-specific) family genes ERG, ETV1 or ETV4 in most prostate cancers. Whereas TMPRSS2-ERG fusions are predominant, fewer TMPRSS2-ETV1 cases have been identified than expected on the basis of the frequency of high (outlier) expression of ETV1 (refs 3-13). Here we explore the mechanism of ETV1 outlier expression in human prostate tumours and prostate cancer cell lines. We identified previously unknown 5' fusion partners in prostate tumours with ETV1 outlier expression, including untranslated regions from a prostate-specific androgen-induced gene (SLC45A3) and an endogenous retroviral element (HERV-K_22q11.23), a prostate-specific androgen-repressed gene (C15orf21), and a strongly expressed housekeeping gene (HNRPA2B1). To study aberrant activation of ETV1, we identified two prostate cancer cell lines, LNCaP and MDA-PCa 2B, that had ETV1 outlier expression. Through distinct mechanisms, the entire ETV1 locus (7p21) is rearranged to a 1.5-megabase prostate-specific region at 14q13.3-14q21.1 in both LNCaP cells (cryptic insertion) and MDA-PCa 2B cells (balanced translocation). Because the common factor of these rearrangements is aberrant ETV1 overexpression, we recapitulated this event in vitro and in vivo, demonstrating that ETV1 overexpression in benign prostate cells and in the mouse prostate confers neoplastic phenotypes. Identification of distinct classes of ETS gene rearrangements demonstrates that dormant oncogenes can be activated in prostate cancer by juxtaposition to tissue-specific or ubiquitously active genomic loci. Subversion of active genomic regulatory elements may serve as a more generalized mechanism for carcinoma development. Furthermore, the identification of androgen-repressed and insensitive 5' fusion partners may have implications for the anti-androgen treatment of advanced prostate cancer. 相似文献
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