interacts_with DB02901?
P10275 -dependent activation of endothelial nitric oxide synthase in vascular endothelial cells : role of phosphatidylinositol 3-kinase/akt pathway . The mechanisms of testosterone-induced vasodilatation are not fully understood . This study investigated the effect of testosterone on nitric oxide ( NO ) synthesis and its molecular mechanism using human aortic endothelial cells ( HAEC ) . DB00624 at physiological concentrations ( 1-100 nm ) induced a rapid ( 15-30 min ) increase in NO production , which was associated with phosphorylation and activation of endothelial NO synthase ( P29474 ) . Then , the involvement of the androgen receptor ( AR ) , which is abundantly expressed in HAEC , was examined . The effect of testosterone on P29474 activation and NO production were abolished by pretreatment with an AR antagonist nilutamide and by transfection with AR small interference RNA . In contrast , testosterone-induced P29474 phosphorylation was unchanged by pretreatment with an aromatase inhibitor or by transfection with ERalpha small interference RNA . DB02901 , a nonaromatizable androgen , also stimulated P29474 phosphorylation . Next , the signaling cascade that leads to P29474 phosphorylation was explored . DB00624 stimulated rapid phosphorylation of Akt in a time- and dose-dependent manner , with maximal response at 15-60 min . The rapid phosphorylation of P29474 or NO production induced by testosterone was inhibited by Akt inhibitor SH-5 or by phosphatidylinositol ( PI ) 3-kinase inhibitor wortmannin . Co-immunoprecipitation assays revealed a testosterone-dependent interaction between AR and the p85alpha subunit of P19957 -kinase . In conclusion , testosterone rapidly induces NO production via AR-dependent activation of P29474 in HAEC . Activation of P19957 -kinase/Akt signaling and the direct interaction of AR with p85alpha are involved , at least in part , in P29474 phosphorylation . Phorbol ester-mediated desensitization of histamine H1 receptors on a cultured smooth muscle cell line . The present study was undertaken in order to examine the effect of protein kinase C ( PKC ) on histamine H1 receptors ( P35367 ) present on the smooth muscle cell line , DDT1MF-2 . [ 3H ] - DB06691 binding revealed that specific [ 3H ] - DB06691 binding sites were reduced by pretreatment with 12-O-tetradecanoylphorbol-13-acetate ( TPA ) , an activator of PKC , but not the Kd . The TPA analogue , 4 alpha phorbol 12,13-didecanoate , which does not activate PKC , failed to induce down-regulation of P35367 . TPA-induced down-regulation of P35367 was inhibited by pretreatment with 1-(5-Isoquinilinesulfonyl)-2-methylpiperazine dihydrochloride ( H-7 ) , a PKC inhibitor , in a dose dependent manner . The H-7 analogue , H-8 , which is a less potent inhibitor of PKC , but a potent inhibitor of cyclic nucleotide dependent protein kinase , had no effect on P35367 . Moreover , treatment with TPA inhibited histamine-induced increases in [Ca2+]i in cells loaded with the fluorescent indicator , indo-1 . These data suggest that P35367 in DDT1MF-2 cells are functionally regulated by PKC . DB00533 decreases renal injury in obese Zucker rats . The present study tested the hypothesis that altered vascular regulation of arachidonic acid enzymes in obese Zucker rats contributes to renal damage . Protein expression of CYP450 ( cytochrome P450 ) and P36551 ( cyclo-oxygenase ) enzymes in renal microvessels was studied in obese and lean Zucker rats at 20-21 weeks of age . Body weight and blood glucose averaged 649+/-13 g and 142+/-10 mg/dl in obese Zucker rats compared with 437+/-10 g and 111+/-5 mg/dl in age-matched lean Zucker rats . Renal microvascular CYP4A and P35354 protein levels were increased and CYP2C protein levels decreased in obese Zucker rats . TX ( thromboxane ) B2 excretion was 2-fold higher and PG ( prostaglandin ) E2 excretion significantly lower in obese Zucker rats . Additional studies investigated the ability of the P35354 inhibitor , rofecoxib , to slow the progression of renal injury in obese Zucker rats . DB00533 treatment decreased urinary PGF2alpha and 8-isoprostane levels in obese Zucker rats . Renal microvessel mRNA expression of pro-inflammatory chemokines was decreased in P35354 -inhibitor-treated obese Zucker rats . Urinary albumin excretion , an index of kidney damage , averaged 95+/-11 mg/day in vehicle-treated and 9+/-1 mg/day in rofecoxib-treated obese Zucker rats . Glomerulosclerosis , characterized by mesangial expansion , tubulo-interstitial fibrosis and extracellular matrix accumulation , was prominent in obese Zucker rats compared with a lack of damage in age-matched lean Zucker rats and rofecoxib-treated obese Zucker rats . These results suggest that altered vascular arachidonic acid enzymes contribute to the renal damage , and that P35354 inhibition decreases glomerular injury in obese Zucker rats . A 77-base pair LINE-like sequence elicits androgen-dependent mvdp/akr1-b7 expression in mouse vas deferens , but is dispensable for adrenal expression in rats . Mvdp/akr1-b7 ( mouse vas deferens protein/aldo-keto reductase 1- P33681 ) encodes an enzyme responsible for detoxification of a steroidogenesis byproduct . MVDP/AKR1- P33681 is expressed in both rat and mouse adrenal cortex under DB01285 control , whereas strong androgen-dependent accumulation in the vas deferens is mouse specific . Comparison of the regulatory regions of the two orthologs reveals a strong identity , disrupted by acquisition of a 77-bp LINE-derived sequence in the mouse promoter . Although DB01285 responsiveness is observed in both species , the absence of this 77-bp sequence in the rat is associated with changes in transcription initiation sites . Transfection studies demonstrate that the CCAAT/enhancer-binding protein and selective promoter factor 1-binding sites previously shown to be essential for DB02527 / DB01285 induction in the mouse are consequently dispensable in the rat . Our data support the idea that the most striking change generated by this acquisition is the strong , androgen-dependent , vas deferens expression observed in mouse . 1 ) In rat vas deferens , rakr1-b7 expression is barely detectable and is not androgen sensitive . 2 ) P10275 binds efficiently to an androgen response element within the 77-bp mouse-specific element . 3 ) Its insertion confers androgen sensitiveness to rakr1-b7 regulatory regions in an androgen response element-dependent manner in transient transfections . We propose that this acquired androgen-responsive region may be responsible for vas deferens androgen-regulated gene expression in vivo . ELK3 suppresses angiogenesis by inhibiting the transcriptional activity of ETS-1 on P50281 . Ets transcription factors play important roles in vasculogenesis and angiogenesis . Knockout of the Ets gene family members in mice resulted in disrupted angiogenesis and malformed vascular systems . In this study , the role and mechanism of ELK3 , an Ets factor , in angiogenesis was investigated using ELK3-specific siRNA in human vascular endothelial cells ( HUVECs ) and in vivo implantation assay . The suppression of ELK3 expression resulted in the reinforcement of P15692 -induced tube formation in HUVECs . The in vivo Matrigel plug assay also showed that ELK3 knockdown resulted in increased angiogenesis . Luciferase activity of the P50281 promoter induced by ETS-1 factor was attenuated ELK3 co-transfection . Q9UNE7 assay showed the binding of ELK3 on the P50281 promoter . P50281 knockdown in the ELK3 knockdowned cells resulted in the decrease of tube formation suggesting that P50281 transcriptional repression is required for ELK3-mediated anti-angiogenesis effect . Our data also showed that the suppressive effect of ELK3 on the angiogenesis was partly due to the inhibitory effect of ELK3 to the ETS-1 transcriptional activity on the P50281 promoter rather than direct suppression of ELK3 on the target gene , since the expression level of co-repressor Sin3A is low in endothelial cells . Our results suggest that ELK3 plays a negative role of P15692 -induced angiogenesis through indirectly inhibiting ETS-1 function . Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity . BACKGROUND : Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen-depletion independent status . However , the mechanism of bicalutamide resistance remains unclear because few cell models have been generated . METHODS : We generated a bicalutamide-resistant subline , LNCaP- O43633 , from LNCaP after prolonged treatment with bicalutamide . Androgen and/or bicalutamide responsiveness for proliferation and prostate-specific antigen ( PSA ) secretion were examined in vitro and in vivo . DB00624 and dihydrotestosterone ( DB02901 ) levels in xenografted tumors were analyzed by liquid chromatography-tandem mass spectrometry . P10275 ( AR ) gene mutation and amplification and AR and pAR(210) expression were determined . RESULTS : LNCaP- O43633 did not grow in an androgen-depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCaP . LNCaP- O43633 grew in castrated male mice , and the DB02901 level in grafted LNCaP- O43633 tumors was 7.7-fold lower than in LNCaP tumors . DB01128 stimulated LNCaP- O43633 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP- O43633 was weaker than that of LNCaP in vivo . Additional AR mutation and AR gene amplification were not detected in LNCaP- O43633 , but AR and pAR(210) expression and PSA secretion in LNCaP- O43633 were higher than in LNCaP . CONCLUSIONS : DB01128 -resistant LNCaP- O43633 exhibited AR overexpression and hypersensitivity to low levels of androgen . Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion . In addition , pAR(210) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP- O43633 . Granulocyte macrophage-colony stimulating factor increases the expression of histamine and histamine receptors in monocytes/macrophages in relation to arteriosclerosis . OBJECTIVE : To study the effect of granulocyte macrophage-colony-stimulating factor ( GM- P04141 ) on histamine metabolism in arteriosclerosis , the expression of histidine decarboxylase ( HDC ; histamine-producing enzyme ) , histamine receptors 1 and 2 ( P35367 and P25021 ) , and GM- P04141 was investigated in human and mouse arteriosclerotic carotid arteries . Furthermore , the molecular mechanisms of GM- P04141 -induced HDC and P35367 expression in monocytic U937 cells were investigated . METHODS AND RESULTS : Immunohistochemistry showed that atherosclerotic human coronary and mouse ligated carotid arteries contained HDC-expressing macrophages . Gene expression of HDC , P35367 , P25021 , and GM- P04141 was also detected in the lesions . In U937 cells , GM- P04141 enhanced histamine secretion and gene expression of HDC and P35367 . A promoter assay showed that GM- P04141 enhanced gene transcription of HDC and P35367 but not P25021 . CONCLUSIONS : The present results indicate that HDC and HHR are expressed in arteriosclerotic lesion , and that GM- P04141 induces HDC and P35367 expression in monocytes . Locally produced histamine might participate in atherogenesis by affecting the expression of atherosclerosis-related genes in monocytes and smooth muscle cells . The presence of histamine-producing macrophages and gene expression of histamine receptors and GM- P04141 was demonstrated in arteriosclerotic lesions . In monocytic U937 cells , GM- P04141 upregulated the expression of histamine and P35367 . Coordinated expression of histamine and its receptors by GM- P04141 would participate in atherogenesis by affecting monocytic and SMC gene expression . DB00996 prevents oxaliplatin-induced central sensitization in the dorsal horn neurons in rats . OBJECTIVES : The present study aims to study the alteration of glutamatergic transmission in the dorsal horn neurons and the effect of gabapentin on oxaliplatin-induced neuropathic pain in rats . MATERIALS AND METHODS : DB00526 ( 5 mg/kg ) or saline was administered to adult male Sprague-Dawley rats . DB00996 ( 60 mg/kg , IP ) or vehicle was injected daily . Mechanical allodynia was assessed using a series of von Frey filaments . The expression of glutamate receptor subunits ( Q13224 and GluR1 ) and brain-derived neurotrophic factor ( P23560 ) was measured in the dorsal horn . The glutamatergic strength was recorded in the spinal cord slices . RESULTS : Administration of oxaliplatin induced significant hyperreactivity to mechanical stimuli in rats , which was attenuated by gabapentin . Significant increase in the expression of P23560 was found in the dorsal horn in rats receiving oxaliplatin , which was prevented by gabapentin . Further studies also observed a significant increase in the expression of GluR1 and Q13224 , as well as enhanced glutamatergic transmission in the dorsal horn neurons in rats treated with oxaliplatin . The upregulation of glutamatergic transmission was significantly reversed by gabapentin . CONCLUSION : These results illustrated an increased expression of P23560 and enhanced glutamatergic transmission in rats with oxaliplatin-induced neuropathic pain , which was markedly attenuated by gabapentin . Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 -induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen-activated protein kinase ( MAPK ) or nuclear factor-kappaB ( NF-kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] -thymidine incorporation into DNA . Activation of PKC , MAPK and NF-kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal-regulated protein kinase 1/2 and NF-kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N-acetyl-l-cysteine resulted in a significant decrease in P51606 -induced activation of PKC- , MAPK- and NF-kappaB-signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF-kappaB in P51606 -induced BREC proliferation and P15692 expression . DB01120 inhibits BREC proliferation by interfering with these intracellular signal transduction pathways . Immunohistochemical analysis of carcinomatous and sarcomatous components in the uterine carcinosarcoma : a case report . Uterine carcinosarcoma ( malignant mixed Mullerian tumor ) is an uncommon female genital tract neoplasm characterized by an admixture of epithelial and stromal malignant cells . We report a case of 50-year-old peri-menopausal woman diagnosed to have early-stage ( IB due to FIGO ) uterine carcinosarcoma of the homologous type with superficial ( 3mm ) myo-invasion . The patient showed no clinical symptoms of the disease and had no family history of female genital tract malignancies . Positive immunostaining for steroid receptors ( estrogen-alpha and progesterone receptors ) , cytokeratin , and P00533 was detected only in the carcinomatous area , whereas beta-catenin , BCL-2 , P35354 , p16(INK4a) , P60484 , Q8IUH3 , and vimentin were immunoreactive in both components . P10275 , CD10 , desmin , HER-2/neu , and P04637 were found to be negative either in the carcinomatous or in the sarcomatous area . Tumor proliferative activity was higher in the carcinomatous ( 25 % ) than in the sarcomatous ( 2 % ) component . Based on these findings , immunohistochemical evaluation of multiple receptor status in the carcinomatous and sarcomatous areas of carcinosarcoma may provide a clue to the pathogenesis and hormonal receptor status of this uncommon uterine malignancy . De novo mutations in moderate or severe intellectual disability . Genetics is believed to have an important role in intellectual disability ( ID ) . Recent studies have emphasized the involvement of de novo mutations ( DNMs ) in ID but the extent to which they contribute to its pathogenesis and the identity of the corresponding genes remain largely unknown . Here , we report a screen for DNMs in subjects with moderate or severe ID . We sequenced the exomes of 41 probands and their parents , and confirmed 81 DNMs affecting the coding sequence or consensus splice sites ( 1.98 DNMs/proband ) . We observed a significant excess of de novo single nucleotide substitutions and loss-of-function mutations in these cases compared to control subjects , suggesting that at least a subset of these variations are pathogenic . A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID ( Q8NFD5 , CHD2 , P55316 , P28472 , Q8WXI9 , Q13224 , Q9P267 , Q71F56 , Q9Y6X0 , Q16650 , TCF4 , Q9Y484 ) , resulting in a diagnostic yield of ∼29 % . We also identified 12 possibly pathogenic DNMs in genes ( Q00839 , Q9BTA9 , Q92736 , Q01105 , P18146 , P35580 , Q9UL18 , Q9Y5P4 , O43633 , P62140 , Q9UN37 , Q00005 ) that have not previously been causally linked to ID . Interestingly , no case was explained by inherited mutations . Protein network analysis indicated that the products of many of these known and candidate genes interact with each other or with products of other ID-associated genes further supporting their involvement in ID . We conclude that DNMs represent a major cause of moderate or severe ID . P10275 is expressed in murine choroid plexus and downregulated by 5alpha-dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen-responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha-dihydrotestosterone ( DB02901 ) in castrated male and female mice subjected to DB02901 replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by DB02901 in mice CPs . Novel di-tertiary-butyl phenylhydrazones as dual cyclooxygenase-2/ P09917 inhibitors : synthesis , P36551 / P28300 inhibition , molecular modeling , and insights into their cytotoxicities . Although dual inhibition of P35354 ( P35354 ) and 5-Lipoxygenase ( 5- P28300 ) enzymes is highly effective than targeting P36551 or P28300 alone , there are only a few reports of examining such compounds in case of colorectal cancers ( CRC ) . In the present work we report that the novel di-tert-butyl phenol-based dual inhibitors DTPSAL , DTPBHZ , DTPINH , and DTPNHZ exhibit significant cytotoxicity against human CRC cell lines . Molecular docking studies revealed a good fit of these compounds in the P35354 and 5- P28300 protein cavities . The inhibitors show significant inhibition of P35354 and 5- P28300 activities and are effective against a panel of human colon cancer cell lines including HCA-7 , HT-29 , SW480 and intestinal Apc10.1 cells as well as the hyaluronan synthase-2 ( Has2 ) enzyme over-expressing colon cancer cells , through inhibition of the DB08818 /CD44v6 cell survival pathway . Western blot analysis and qRT-PCR analyses indicated that the di-tert-butyl phenol-based dual inhibitors reduce the expression of P35354 , 5- P28300 , and CD44v6 in human colon cancer HCA-7 cells , while the combination of CD44v6shRNA and DTPSAL has an additional inhibitory effect on CD44v6 mRNA expression . The synergistic inhibitory effect of Celecoxib and DB04725 on CD44v6 mRNA expression suggests that the present dual inhibitors down-regulate cyclooxygenase and lipoxygenase enzymes through CD44v6 . The compounds also exhibited enhanced antiproliferative potency compared to standard dual P36551 / P28300 inhibitor , viz . DB04725 . Importantly , the HA/CD44v6 antagonist CD44v6shRNA in combination with synthetic compounds had a sensitizing effect on the cancer cells which enhanced their antiproliferative potency , a finding which is crucial for the anti-proliferative potency of the novel synthetic di-tert-butyl phenol based dual P36551 - P28300 inhibitors in colon cancer cells . The antiproliferative effect of lidocaine on human tongue cancer cells with inhibition of the activity of epidermal growth factor receptor . Local anesthetics suppress proliferation in several cancer cells . The mechanism of the suppression , however , is unknown . Our previous study shows that lidocaine , at the level of tissue concentration under topical or local administration , has a direct inhibitory effect on the activity of epidermal growth factor receptor ( P00533 ) , which is a potential target for antiproliferation in cancer cells . Therefore , we hypothesized that lidocaine would suppress the proliferation of cancer cells through the inhibition of P00533 activity . We investigated the effects of lidocaine ( 40-4000 microM ) on proliferation of a human tongue cancer cell line , CAL27 , which has a high level of P00533 expression , and also examined the effect of lidocaine on epidermal growth factor ( P01133 ) -stimulated autophosphorylation of P00533 in CAL27 cells . A clinical concentration of lidocaine ( 400 microM ) suppressed both serum-induced and P01133 -induced proliferation of CAL27 cells and inhibited P01133 -stimulated tyrosine kinase activity of P00533 without cytotoxicity . A larger concentration of lidocaine ( 4000 microM ) showed cytotoxicity with an antiproliferative effect . We suggest that the inhibition of P01133 -stimulated P00533 activity is one of the mechanisms of the antiproliferative effect of lidocaine on CAL27 cells . DB00281 administered topically within the oral cavity for cancer pain relief may suppress the proliferation of human tongue cancer cells . DB00126 is dispensable for oxygen sensing in vivo . Prolyl-4-hydroxylation is necessary for proper structural assembly of collagens and oxygen-dependent protein stability of hypoxia-inducible transcription factors ( HIFs ) . In vitro function of HIF prolyl-4-hydroxylase domain ( P20941 ) enzymes requires oxygen and 2-oxoglutarate as cosubstrates with iron(II) and vitamin C serving as cofactors . Although vitamin C deficiency is known to cause the collagen-disassembly disease scurvy , it is unclear whether cellular oxygen sensing is similarly affected . Here , we report that vitamin C-deprived Gulo(-/-) knockout mice show normal HIF-dependent gene expression . The systemic response of Gulo(-/-) animals to inspiratory hypoxia , as measured by plasma erythropoietin levels , was similar to that of animals supplemented with vitamin C . Hypoxic HIF induction was also essentially normal under serum- and vitamin C-free cell-culture conditions , suggesting that vitamin C is not required for oxygen sensing in vivo . Glutathione was found to fully substitute for vitamin C requirement of all 3 P20941 isoforms in vitro . Consistently , glutathione also reduced HIF-1α protein levels , transactivation activity , and endogenous target gene expression in cells exposed to CoCl(2) . A Cys201Ser mutation in Q9GZT9 increased basal hydroxylation rates and conferred resistance to oxidative damage in vitro , suggesting that this surface-accessible Q9GZT9 cysteine residue is a target of antioxidative protection by vitamin C and glutathione . DB04901 ( IDEC ) . IDEC is developing a PRIMATIZED-anti- P33681 antibody ( DB04901 ) for the treatment of autoimmune and inflammatory diseases , such as psoriasis and rheumatoid arthritis . It is currently undergoing phase II trials in patients with psoriasis [ 395813 ] . A randomized , blind , placebo-controlled , multiple-dose phase II study was initiated in January 2001 to evaluate the potential clinical activity and safety of DB04901 in patients with moderate-to-severe psoriasis [ 395813 ] . The antibody targets the P33681 antigen on the surface of antigen-presenting cells that normally interact with T-cells to initiate an immune response . Antibodies directed at P33681 may be useful in preventing unwanted immune responses in autoimmune diseases such as systemic lupus erythematosus , idiopathic thrombocytopenic purpura as well as transplant rejection [ 178382 ] , [ 178929 ] . PRIMATIZED antibodies , genetically engineered from cynomolgus macaque monkey and human components , are structurally indistinguishable from human antibodies . They may , therefore , be less likely to cause adverse reactions in humans , making them potentially suited for long-term , chronic treatment [ 244805 ] . IDEC has signed an antibody humanization patent licensing agreement with Protein Design Labs [ 240591 ] . IDEC is also collaborating with Mitsubishi-Tokyo ( formerly Mitsubishi Kasei ) on the development of this antibody [ 178382 ] . Changing paradigms in management of metastatic Castration Resistant Prostate Cancer ( mCRPC ) . Recently , the standard of care for metastatic Castration Resistant Prostate Cancer ( mCRPC ) has changed considerably . Persistent androgen receptor ( AR ) signaling has been identified as a target for novel therapies and reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer . P10275 gene amplification and over expression have been found to result in a higher concentration of androgen receptors on tumor cells , making them extremely sensitive to low levels of circulating androgens . Additionally , prostate cancer cells are able to maintain dihydrotestosterone ( DB02901 ) concentration in excess of serum concentrations to support tumor growth . For many years ketoconazole was the only P05093 inhibitor that was used to treat mCRPC . However , significant toxicities limit its use . Newly approved chemotherapeutic agents such as DB05812 ( an oral selective inhibitor of CYP17A ) , which blocks androgen biosynthesis both within and outside the prostate cancer cells ) , and enzalutamide ( blocks AR signaling ) have improved overall survival . There are also ongoing phase III trials for Orteronel ( P50750 - 700 ) , ARN- 509 and Galeterone ( TOK-001 ) , which targets androgen signaling . In this review , we will present the rationale for the newly approved hormonal treatments , their indications and complications , and we will discuss ongoing trials that are being done to improve the efficacy of the approved agents . Finally , we will talk about the potential upcoming hormonal treatments for mCRPC . P10275 mediates the expression of UDP-glucuronosyltransferase 2 B15 and Q9NYP3 genes . BACKGROUND : Enhanced androgen receptor ( AR ) activity by increased testosterone availability may play important roles in prostate cancer progressing to castration resistant state . Comparison of expression profiles in androgen dependent and independent prostate tumors demonstrated a marked increase of the expression of P54855 ( P54855 ) , an androgen catabolic enzyme . We investigated mechanisms controlling the differential expression of P54855 and Q9NYP3 in response to androgen treatments . METHODS : Gene expression was determined by RT-PCR . The association of AR with P54855 / Q9NYP3 genes was determined by Chromatin immuno-precipitation ( Q9UNE7 ) . RNA interference was used to knock-down gene expression . RESULTS : P54855 and Q9NYP3 genes were not expressed in AR negative prostate cancer cell lines , PC3 and DU145 , while they were expressed in AR positive cell lines , LNCaP , LNCaP-abl ( an androgen independent LNCaP sub-line ) , and VCaP . The expression levels of P54855 / Q9NYP3 were up-regulated in LNCaP-abl comparing to those in LNCaP . These results suggest the requirement of AR for the expression of P54855 / Q9NYP3 . Treatment with DB02901 down-regulated the expression of P54855 / Q9NYP3 in LNCaP in a time and dose dependent manner and this down-regulation was competitively antagonized by flutamide and bicalutimide , suggesting a pathway mediated by AR . Further Q9UNE7 experiments demonstrated the direct interaction of AR with the promoter regions of P54855 / Q9NYP3 genes . Knocking down AR expression in LNCaP significantly reduced the expression of P54855 / Q9NYP3 and completely inhibited the DB02901 -induced down-regulation of P54855 / Q9NYP3 genes . CONCLUSIONS : We demonstrated that P54855 and Q9NYP3 are primary androgen-regulated genes and AR is required for both their basal expression and their androgen-regulated expression . Endothelial nitric oxide synthase uncoupling : a novel pathway in OSA induced vascular endothelial dysfunction . The mechanism of vascular endothelial dysfunction ( VED ) and cardiovascular disease in obstructive sleep apnea ( OSA ) is unknown . We performed a comprehensive evaluation of endothelial nitric oxide synthase ( P29474 ) function directly in the microcirculatory endothelial tissue of OSA patients who have very low cardiovascular risk status . Nineteen OSA patients underwent gluteal biopsies before , and after effective treatment of OSA . We measured superoxide ( O2(•-) ) and nitric oxide ( NO ) in the microcirculatory endothelium using confocal microscopy . We evaluated the effect of the NOS inhibitor l- DB04223 -Methyl-Ester ( l-NAME ) and the NOS cofactor tetrahydrobiopterin ( BH4 ) on endothelial O2(•-) and NO in patient endothelial tissue before and after treatment . We found that P29474 is dysfunctional in OSA patients pre-treatment , and is a source of endothelial O2(•-) overproduction . P29474 dysfunction was reversible with the addition of BH4 . These findings provide a new mechanism of endothelial dysfunction in OSA patients and a potentially targetable pathway for treatment of cardiovascular risk in OSA . Shared and unique signals of high-altitude adaptation in geographically distinct Tibetan populations . Recent studies have used a variety of analytical methods to identify genes targeted by selection in high-altitude populations located throughout the Tibetan Plateau . Despite differences in analytic strategies and sample location , hypoxia-related genes , including Q99814 and Q9GZT9 , were identified in multiple studies . By applying the same analytic methods to genome-wide SNP information used in our previous study of a Tibetan population ( n = 31 ) from the township of Maduo , located in the northeastern corner of the Qinghai-Tibetan Plateau ( 4200 m ) , we have identified common targets of natural selection in a second geographically and linguistically distinct Tibetan population ( n = 46 ) in the Tuo Tuo River township ( 4500 m ) . Our analyses provide evidence for natural selection based on iHS and XP-EHH signals in both populations at the p < 0.02 significance level for Q99814 , Q9GZT9 , P30519 , and P05093 and for P30613 , Q30201 , and P68871 and P69892 , which have also been reported in other studies . We highlight differences ( i.e. , stratification and admixture ) in the two distinct Tibetan groups examined here and report selection candidate genes common to both groups . These findings should be considered in the prioritization of selection candidate genes in future genetic studies in Tibet . P10275 controls P00533 and P04626 gene expression at different levels in prostate cancer cell lines . P00533 or P04626 contributes to prostate cancer ( PCa ) progression by activating the androgen receptor ( AR ) in hormone-poor conditions . Here , we investigated the mechanisms by which androgens regulate P00533 and P04626 expression in PCa cells . In steroid-depleted medium ( SDM ) , P00533 protein was less abundant in androgen-sensitive LNCaP than in androgen ablation-resistant 22Rv1 cells , whereas transcript levels were similar . DB02901 ( DB02901 ) treatment increased both P00533 mRNA and protein levels and stimulated RNA polymerase II recruitment to the P00533 gene promoter , whereas it decreased P04626 transcript and protein levels in LNCaP cells . DB02901 altered neither P00533 or P04626 levels nor the abundance of prostate-specific antigen ( PSA ) , TMEPA1 , or O15393 mRNAs in 22Rv1 cells , which express the full-length and a shorter AR isoform deleted from the COOH-terminal domain ( ARDeltaCTD ) . The contribution of both AR isoforms to the expression of these genes was assessed by small interfering RNAs targeting only the full-length or both AR isoforms . Silencing of both isoforms strongly reduced PSA , TMEPA1 , and O15393 transcript levels . Inhibition of both AR isoforms did not affect P00533 and P04626 transcript levels but decreased P00533 and increased P04626 protein levels . Proliferation of 22Rv1 cells in SDM was inhibited in the absence of AR and ARDeltaCTD . A further decrease was obtained with PKI166 , an P00533 / P04626 kinase inhibitor . Overall , we showed that ARDeltaCTD is responsible for constitutive P00533 expression and P04626 repression in 22Rv1 cells and that ARDeltaCTD and tyrosine kinase receptors are necessary for sustained 22Rv1 cell growth .