interacts_with DB00279?
P10828 mutants : Dominant negative regulators of peroxisome proliferator-activated receptor gamma action . Thyroid hormone ( DB00279 ) and peroxisome proliferators have overlapping metabolic effects in the maintenance of lipid homeostasis . Their actions are mediated by their respective receptors : thyroid hormone receptors ( TR ) and peroxisome proliferator-activated receptors ( Q07869 ) . We recently found that a dominantly negative TRbeta mutant ( PV ) that causes a genetic disease , resistance to thyroid hormone , acts to repress the ligand (troglitazone)-mediated transcriptional activity of PPARgamma in cultured thyroid cells . This finding suggests that TRbeta mutants could crosstalk with PPARgamma-signaling pathways . The present study explored the molecular mechanisms by which PV represses the PPARgamma transcriptional activity . Gel-shift assays show that the PV , similar to wild-type TRbeta , bound to the peroxisome proliferator response element ( PPRE ) as homodimers and heterodimers with PPARgamma or the retinoid X receptor ( RXR ) , thereby competing with PPARgamma for binding to PPRE and for sequestering RXR . Association of PPRE-bound PV with corepressors [ e.g. , nuclear receptor corepressor ( NCoR ) ] that led to transcriptional repression was independent of DB00279 and troglitazone . Chromatin immunoprecipitation assay further demonstrated that , despite the presence of ligands , NCoR was recruited to PPRE-bound PV on a PPARgamma-target gene , the lipoprotein lipase , in vivo , suggesting the dominant action of PV on PPARgamma-mediated transcriptional activity . Thus , the dominant negative action of PV is not limited on the wild-type TRs . The findings that TRbeta mutants affect PPARgamma functions through dominant negative action provide insights into the molecular mechanisms by which TR regulates the PPARgamma-target genes involved in metabolic pathways , lipid homeostasis , and carcinogenesis . Using mass spectrometry to detect , differentiate , and semiquantitate closely related peptide hormones in complex milieu : measurement of P01344 and vesiculin . The search for an islet β-cell growth factor has been a key objective in recent diabetes research , because the ability to regenerate and/or protect the functioning β-cell population in patients could result in a great advancement for diabetes treatment . P05019 and P01344 are known to play crucial roles in fetal growth and prenatal development , and there is growing evidence that P01344 increases β-cell proliferation and survival in vitro and in vivo . A search for the source of P01344 -like immunoreactivity in isolated β-cell secretory granules from the murine cell line βTC6- P08709 revealed a novel 2-chain P01344 -derived peptide , which we named vesiculin and which has been shown to be a full insulin agonist . Here , we present a liquid chromatography-tandem mass spectrometry method that enables selective detection and semiquantitation of the highly related P01344 and vesiculin molecules . We have used this method to measure these 2 peptides in conditioned media from 2 β-cell lines , produced under increasing glucose concentrations . This technique detected both P01344 and vesiculin in media conditioned by MIN6 and βTC6- P08709 cells at levels in the range of 0 to 6 μM ( total insulin , 80-450 μM ) and revealed a glucose-stimulated increase in insulin , P01344 , and vesiculin . P01344 was detected in adult human and neonatal mouse serum in high levels , but vesiculin was not present . The methodology we present herein has utility for detecting and differentiating active peptides that are highly related and of low abundance . DB02546 and bortezomib synergistically cause ubiquitinated protein accumulation in prostate cancer cells . PURPOSE : Protein ubiquitination is a novel strategy used to treat malignancies . We investigated whether the histone deacetylase inhibitor vorinostat ( Cayman Chemical , Ann Arbor , Michigan ) and the proteasome inhibitor bortezomib ( LC Laboratories , Woburn , Massachusetts ) would synergistically cause the accumulation of ubiquitinated proteins in prostate cancer cells . MATERIALS AND METHODS : LNCaP , PC-3 and DU 145 cells ( ATCC™ ) were treated with vorinostat and/or bortezomib . Cell viability and induction of apoptosis were assessed . In vivo efficacy was evaluated in a murine subcutaneous tumor model using PC-3 cells . The influence of androgen receptor expression on bortezomib efficacy was examined using RNA interference . Changes in the expression of ubiquitinated proteins , cell cycle associated proteins and acetylated histone were evaluated . RESULTS : P10275 expression seemed to decrease bortezomib activity . PC-3 and DU 145 cells were more susceptible to bortezomib than LNCaP cells and the silencing of androgen receptor expression in LNCaP cells enhanced bortezomib activity . DB02546 and bortezomib synergistically induced apoptosis , inhibited prostate cancer cell growth and suppressed tumor growth in a murine xenograft model . The combination decreased cyclin D1 and cyclin-dependent kinase 4 expression , and increased P38936 expression . The combination synergistically caused the accumulation of ubiquitinated proteins and histone acetylation . This histone acetylation was a consequence of the accumulation of ubiquitinated proteins . CONCLUSIONS : DB02546 and bortezomib inhibit the growth of prostate cancer cells synergistically by causing ubiquitinated proteins to accumulate in cells . The current study provides a framework for testing the combination in patients with advanced prostate cancer . Lack of clinical manifestations in asymptomatic dengue infection is attributed to broad down-regulation and selective up-regulation of host defence response genes . OBJECTIVES : Dengue represents one of the most serious life-threatening vector-borne infectious diseases that afflicts approximately 50 million people across the globe annually . Whilst symptomatic infections are frequently reported , asymptomatic dengue remains largely unnoticed . Therefore , we sought to investigate the immune correlates conferring protection to individuals that remain clinically asymptomatic . METHODS : We determined the levels of neutralizing antibodies ( nAbs ) and gene expression profiles of host immune factors in individuals with asymptomatic infections , and whose cognate household members showed symptoms consistent to clinical dengue infection . RESULTS : We observed broad down-regulation of host defense response ( innate , adaptive and matrix metalloprotease ) genes in asymptomatic individuals as against symptomatic patients , with selective up-regulation of distinct genes that have been associated with protection . Selected down-regulated genes include : P01375 α ( P01375 ) , P10145 , P09871 , factor B ( P00751 ) , P60568 , P08700 , P05112 , P05113 , P10145 , P15248 , P22301 and P35225 , P33681 , P10747 , and Q14116 , P22894 , P09238 , P39900 , P51511 , P51512 , and Q9Y5R2 . Selected up-regulated genes include : RANTES ( P13501 ) , MIP-1α ( P16619 / P16619 ) , MIP-1β ( Q8NHW4 ) , TGFβ ( P01137 ) , and P01033 . CONCLUSION : Our findings highlight the potential association of certain host genes conferring protection against clinical dengue . These data are valuable to better explore the mysteries behind the hitherto poorly understood immunopathogenesis of subclinical dengue infection . Mammalian Q99572 receptor pharmacology : comparison of recombinant mouse , rat and human Q99572 receptors . BACKGROUND AND PURPOSE : Acute activation of Q99572 receptors rapidly opens a non-selective cation channel . Sustained Q99572 receptor activation leads to the formation of cytolytic pores , mediated by downstream recruitment of hemichannels to the cell surface . Species- and single-nucleotide polymorphism-mediated differences in Q99572 receptor activation have been reported that complicate understanding of the physiological role of Q99572 receptors . Studies were conducted to determine pharmacological differences between human , rat and mouse Q99572 receptors . EXPERIMENTAL APPROACH : Receptor-mediated changes in calcium influx and Yo-Pro uptake were compared between recombinant mouse , rat and human Q99572 receptors . For mouse Q99572 receptors , wild-type ( BALB/c ) and a reported loss of function ( C57BL/6 ) Q99572 receptor were also compared . KEY RESULTS : BzATP [ 2,3-O-(4-benzoylbenzoyl)- DB00171 ] was more potent than DB00171 in stimulating calcium influx and Yo-Pro uptake at rat , human , BALB/c and C57BL/6 mouse Q99572 receptors . Two selective Q99572 receptor antagonists , A-740003 and A-438079 , potently blocked Q99572 receptor activation across mammalian species . Several reported P51575 receptor antagonists [ e.g. P59665 2159 ( 4- [ ( 4-formyl-5-hydroxy-6-methyl-3- [ (phosphonooxy)methyl } -2-pyridinyl ) azo ] -benzoic acid ) , PPNDS and NF279 ] blocked Q99572 receptors . NF279 fully blocked human Q99572 receptors , but only partially blocked BALB/c Q99572 receptors and was inactive at C57BL/6 Q99572 receptors . CONCLUSIONS AND IMPLICATIONS : These data provide new insights into Q99572 receptor antagonist pharmacology across mammalian species . Q99572 receptor pharmacology in a widely used knockout background mouse strain ( C57BL/6 ) was similar to wild-type mouse Q99572 receptors . Several structurally novel , selective and competitive Q99572 receptor antagonists show less species differences compared with earlier non-selective antagonists . Prenatal exposure to bisphenol A promotes angiogenesis and alters steroid-mediated responses in the mammary glands of cycling rats . Prenatal exposure to Q03001 disturbs mammary gland histoarchitecture and increases the carcinogenic susceptibility to chemical challenges administered long after Q03001 exposure . Our aim was to assess the effect of prenatal Q03001 exposure on mammary gland angiogenesis and steroid hormone pathways in virgin cycling rats . Pregnant Wistar rats were exposed to either 25 or 250 g/kg/day ( 25 and 250 Q03001 , respectively ) or to vehicle . Female offspring were autopsied on postnatal day ( P01160 ) 50 or 110 . Ovarian steroid serum levels , the expression of steroid receptors and their co-regulators Q9Y6Q9 and Q9Y618 in the mammary gland , and angiogenesis were evaluated . At P01160 50 , all Q03001 -treated animals had lower serum levels of progesterone , while estradiol levels remained unchanged . The higher dose of Q03001 increased mammary ERα and decreased Q9Y6Q9 expression at P01160 50 and P01160 110 . Q9Y618 protein levels were similar among groups at P01160 50 , whereas at P01160 110 , animals exposed to 250 Q03001 showed a lower Q9Y618 expression . Interestingly , in the control and 25 Q03001 groups , Q9Y618 increased from P01160 50 to P01160 110 . At P01160 50 , an increased vascular area associated with higher P15692 expression was observed in the 250 Q03001 -treated rats . At P01160 110 , the vascular area was still increased , but P15692 expression was similar to that of control rats . The present results demonstrate that prenatal exposure to Q03001 alters the endocrine environment of the mammary gland and its angiogenic process . Increased angiogenesis and altered steroid hormone signals could explain the higher frequency of pre-neoplastic lesions found later in life . This article is part of a Special Issue entitled ' Endocrine disruptors ' . [ Molecular mechanism of age-related osteoporosis ] . Bone loss by ageing has been investigated from standpoints of systemic abnormality and some deficiency in osteoblastic bone formation . This seminar summarizes the involvements of a key molecule of adipocytic differentiation P37231 , essential P05019 signaling molecules P35568 and Q9Y4H2 , and an anti-aging gene klotho in the pathophysiology of age-related osteoporosis . DB00316 -inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774.2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin-induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late-appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL-1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol . Airway epithelium mediates the anti-inflammatory effects of exercise on asthma . Airway epithelium plays an important role in the asthma physiopathology . Aerobic exercise decreases Th2 response in murine models of allergic asthma , but its effects on the structure and activation of airway epithelium in asthma are unknown . BALB/c mice were divided into control , aerobic exercise , ovalbumin-sensitized and ovalbumin-sensitized plus aerobic exercise groups . Ovalbumin sensitization occurred on days 0 , 14 , 28 , 42 , and aerosol challenge from day 21 to day 50 . Aerobic exercise started on day 22 and ended on day 50 . Total cells and eosinophils were reduced in ovalbumin-sensitized group submitted to aerobic exercise . Aerobic exercise also reduced the oxidative and nitrosative stress and the epithelial expression of Th2 cytokines , chemokines , adhesion molecules , growth factors and NF-kB and Q99572 receptor . Additionally , aerobic exercise increased the epithelial expression of P22301 in non-sensitized and sensitized animals . These findings contribute to the understanding of the beneficial effects of aerobic exercise for chronic allergic airway inflammation , suggesting an immune-regulatory role of exercise on airway epithelium . Downregulation of P19957 -K/Akt/ P60484 pathway and activation of mitochondrial intrinsic apoptosis by Diclofenac and Curcumin in colon cancer . Phosphatidylinositol 3-kinase ( P19957 -K ) / P60484 /Akt signaling is over activated in various tumors including colon cancer . Activation of this pathway regulates multiple biological processes such as apoptosis , metabolism , cell proliferation , and cell growth that underlie the biology of a cancer cell . In the present study , the chemopreventive effects have been observed of Diclofenac , a preferential P35354 inhibitory non-steroidal anti-inflammatory drugs , and Curcumin , a natural anti-inflammatory agent , in the early stage of colorectal carcinogenesis induced by 1,2-dimethylhydrazine dihydrochloride in rats . The tumor-promoting role of P19957 -K/Akt/ P60484 signal transduction pathway and its association with anti-apoptotic family of proteins are also observed . Both Diclofenac and Curcumin downregulated the P19957 -K and Akt expression while promoting the apoptotic mechanism . Diclofenac and Curcumin administration significantly increased the expression of pro-apoptotic Bcl-2 family members ( Bad and Bax ) while decreasing the anti-apoptotic Bcl-2 protein . An up-regulation of cysteine protease family apoptosis executioner , such as caspase-3 and -9 , is seen . Diclofenac and Curcumin inhibited the Bcl-2 protein by directly interacting at the active site by multiple hydrogen bonding , as also evident by negative glide score of Bcl-2 . These drugs stimulated apoptosis by increasing reactive oxygen species ( ROS ) generation and simultaneously decreasing the mitochondrial membrane potential ( ΔΨ M ) . Diclofenac and Curcumin showed anti-neoplastic effects by downregulating P19957 -K/Akt/ P60484 pathway , inducing apoptosis , increasing ROS generation , and decreasing ΔΨ M . The anti-neoplastic and apoptotic effects were found enhanced when both Diclofenac and Curcumin were administered together , rather than individually . The somatotropic axis in neonatal calves can be modulated by nutrition , growth hormone , and Long-R3- P05019 . Effects on the somatotropic axis [ plasma levels of insulin-like growth factors ( IGFs ) I and II , IGF-binding proteins ( IGFBPs ) , and growth hormone ( GH ) ] of feeding different amounts of colostrum or milk replacer , of Long-R3- P05019 ( administered subcutaneously or orally ; 50 micrograms.kg body wt-1.day-1 for 7 days ) , and of subcutaneously injected recombinant bovine GH ( rbGH ; 1 mg.kg body wt-1.day-1 for 7 days ) were evaluated in calves during the 1st wk of life . Plasma Long-R3- P05019 increased after subcutaneous application but not with the oral dose . Endogenous P05019 was higher in calves fed colostrum six times compared with those fed only milk replacer . Native P05019 was highest in rbGH-injected calves but was lowered by the subcutaneous injection of Long-R3- P05019 . P01344 concentrations were not modified by any of the treatments . P18065 increased in calves fed only milk replacer and those receiving subcutaneous Long-R3- P05019 . GH was not modulated by differences in nutrition but increased after rbGH administration and similarly in all groups after intravenous injection of GH-releasing factor analog P01286 -(1-29) . Parenteral administration of Long-R3- P05019 decreased GH concentration but did not affect the secretory pattern . The data demonstrate that the somatotrophic axis is basically functioning in neonatal calves and is influenced by nutrition , GH , and Long-R3- P05019 . Androgens induce prostate cancer cell proliferation through mammalian target of rapamycin activation and post-transcriptional increases in cyclin D proteins . P10275 ( AR ) plays a central role in prostate cancer , with most tumors responding to androgen deprivation therapies , but the molecular basis for this androgen dependence has not been determined . Androgen [ 5alpha-dihydrotestosterone ( DB02901 ) ] stimulation of LNCaP prostate cancer cells , which have constitutive phosphatidylinositol 3-kinase ( PI3K ) /Akt pathway activation due to P60484 loss , caused increased expression of cyclin D1 , D2 , and D3 proteins , retinoblastoma protein hyperphosphorylation , and cell cycle progression . However , cyclin D1 and D2 message levels were unchanged , indicating that the increases in cyclin D proteins were mediated by a post-transcriptional mechanism . This mechanism was identified as mammalian target of rapamycin ( P42345 ) activation . DB02901 treatment increased P42345 activity as assessed by phosphorylation of the downstream targets P08133 S6 kinase and Q13541 , and P42345 inhibition with rapamycin blocked the DB02901 -stimulated increase in cyclin D proteins . Significantly , DB02901 stimulation of P42345 was not mediated through activation of the PI3K/Akt or mitogen-activated protein kinase/p90 ribosomal S6 kinase pathways and subsequent tuberous sclerosis complex 2/tuberin inactivation or by suppression of AMP-activated protein kinase . In contrast , P42345 activation by DB02901 was dependent on AR-stimulated mRNA synthesis . Oligonucleotide microarrays showed that DB02901 -stimulated rapid increases in multiple genes that regulate nutrient availability , including transporters for amino acids and other organic ions . These results indicate that a critical function of AR in P60484 -deficient prostate cancer cells is to support the pathologic activation of P42345 , possibly by increasing the expression of proteins that enhance nutrient availability and thereby prevent feedback inhibition of P42345 . Leukemogenesis as a new approach to investigate the correlation between up regulated gene 4/upregulator of cell proliferation ( Q8TCY9 / Q8TCY9 ) and signal transduction genes in leukemia . The aim of the study is to the determine the profiles of cell cycle genes and a new candidate oncogene of Q8TCY9 / Q8TCY9 which play role in leukemia , establishing the association between the early prognosis of cancer and the quantitation of genetic changes , and bringing a molecular approach to definite diagnosis . In this study , 36 newly diagnosed patients ' with ALL-AML in the range of 0-18 years and six control group patients ' bone marrow samples were included . Total RNA was isolated from samples and then complementary DNA synthesis was performed . The obtained cDNAs have been installed 96 well plates after prepared appropriate mixtures and assessed with LightCycler(®) 480 Real-Time PCR quantitatively . O14757 , Q8TCY9 / Q8TCY9 , P51959 , P24863 , Q13042 , P01116 , P55273 genes in the T-ALL group ; P30279 , Q13315 , P49336 , O14757 , P04637 , O96017 , Q16589 , P11802 , CDKN2A , Q16254 , P24863 , P01116 genes in the precursor B-ALL group and P30279 , Q00534 genes in the AML group have shown significant increase in mRNA expression level . In the featured role of acute leukemia the regulating signaling pathways of leukemogenesis partially defined , although identification of new genetic markers in acute leukemia subgroups , will allow the development of early diagnostic and new treatment protocols . Polymorphism identification in the P11310 , P01008 , P22301 , P15173 and P01222 genes of cattle . Changes of thyroid hormone levels and related gene expression in zebrafish on early life stage exposure to triadimefon . In this study , zebrafish was exposed to triadimefon . Thyroid hormones levels and the expression of related genes in the hypothalamic-pituitary-thyroid ( Q9HD23 ) axis , including thyroid-stimulating hormone ( P01222 ) , deiodinases ( dio1 and dio2 ) and the thyroid hormone receptor ( thraa and thrb ) were evaluated . After triadimefon exposure , increased DB00451 can be explained by increased thyroid-stimulating hormone ( P01222 ) . The conversion of DB00451 to DB00279 ( deiodinase type I-dio1 ) was decreased , which reduced the DB00279 level . P10828 ( thrb ) mRNA levels were significantly down-regulated , possibly as a response to the decreased DB00279 levels . The overall results indicated that triadimefon exposure could alter gene expression in the Q9HD23 axis and that mechanisms of disruption of thyroid status by triadimefon could occur at several steps in the synthesis , regulation , and action of thyroid hormones . Induction of platelet-derived growth factor B/ DB00102 by the v-erbA oncogene in glial cells . The v-erbA oncogene codes for a mutated form of the thyroid hormone receptor TR/ P10827 . Thyroid hormone ( triiodothyronine , DB00279 ) regulates glial functions such as myelination and both astrocytes and oligodendrocytes have been shown to express thyroid hormone receptors ( TRs ) . To study putative effects of v-erbA on glial precursors , we have expressed it in a glial clonal cell line established from early embryonal mouse brain . We have found that v-erbA increases cell survival in serum-free conditions . Moreover , v-erbA-expressing cells show a substantial growth in the presence of insulin or P05019 , whereas normal and TR/c-erbA-over-expressing cells progressively degenerate . By Northern blotting , immunofluorescence , immunoprecipitation , and neutralization experiments , we show that v-erbA actions are mediated by an increase in the levels of PDGF B/ DB00102 mRNA and protein . We used anti-PDGF receptor and anti-phosphotyrosine antibodies to show the constitutive activation of PDGF receptors in B3.1 + v-erbA cells , and neutralizing anti-PDGF antibodies to demonstrate that v-erbA enhances the secretion of active PDGF into the culture medium . Our data indicate that v-erbA induces PDGF B/ DB00102 , a factor involved in the generation of gliomas , the most common central nervous system tumor in humans . MicroRNAs in thyroid cancer . CONTEXT : Traditionally , factors predisposing to diseases are either genetic ( " nature " ) or environmental , also known as lifestyle-related ( " nurture " ) . Papillary thyroid cancer is an example of a disease where the respective roles of these factors are surprisingly unclear . EVIDENCE ACQUISITION : Original articles and reviews summarizing our current understanding of the role of microRNA in thyroid tumorigenesis are reviewed and evaluated . CONCLUSION : The genetic predisposition to papillary thyroid cancer appears to consist of a variety of gene mutations that are mostly either of low penetrance and common or of high penetrance but rare . Moreover , they likely interact with each other and with environmental factors . The culpable genes may not be of the traditional , protein-coding type . A limited number of noncoding candidate genes have indeed been described , and we propose here that the failure to find mutations in traditional protein-coding genes is not coincidental . Instead , a more likely hypothesis is that changes in the expression of multiple regulatory RNA genes , e.g. microRNAs , may be a major mechanism . Our review of the literature strongly supports this notion in that a polymorphism in one microRNAs ( miR-146a ) predisposes to thyroid carcinoma , whereas numerous other microRNAs are involved in signaling ( mainly P60484 /PI3K/AKT and DB00279 / P10828 ) that is central to thyroid carcinogenesis . The proto-oncoprotein O95365 interacts with O95983 to recruit the Mi-2/NuRD-HDAC complex and Q6W2J9 and to silence p21WAF/ P38936 by DNA methylation . The tumour-suppressor gene P38936 ( encoding p21Waf/Cip1 ) is thought to be epigenetically repressed in cancer cells . O95365 ( O95365 ) is a proto-oncogenic transcription factor repressing the alternative reading frame and p21WAF/ P38936 genes of the p53 pathway . O95365 interacts directly with O95983 ( methyl-CpG-binding domain protein 3 ) in the nucleus . We demonstrated that O95365 binds both non-methylated and methylated DNA and that O95983 is recruited to the P38936 promoter through its interaction with O95365 , where it enhances transcriptional repression by O95365 . O95365 also interacts with the co-repressors nuclear receptor corepressor ( NCoR ) , silencing mediator for retinoid and thyroid receptors ( Q9Y618 ) and Q6W2J9 ( Q6W2J9 ) to repress transcription . O95983 regulates a molecular interaction between the co-repressor and O95365 . O95983 decreases the interaction between O95365 and NCoR/ Q9Y618 but increases the interaction between O95365 and Q6W2J9 . Because O95983 is a subunit of the Mi-2 autoantigen ( Mi-2 ) /nucleosome remodelling and histone deacetylase ( NuRD ) -HDAC complex , O95365 recruits the Mi-2/NuRD-HDAC complex via O95983 . Q6W2J9 interacts with the Mi-2/NuRD-HDAC complex , DNMTs and P59665 . O95983 and Q6W2J9 play a significant role in the recruitment of the Mi-2/NuRD-HDAC complex- and the NuRD complex-associated proteins , DNMTs and HP . By recruiting DNMTs and P59665 , Mi-2/NuRD-HDAC complex appears to play key roles in epigenetic repression of P38936 by DNA methylation . Effects of chrisotherapeutic gold compounds on prostaglandin E2 production . The mechanism of action of anti-rheumatic gold compounds on 12-O-tetradecanoylphorbol 13-acetate ( TPA ) -induced prostaglandin E(2) ( PGE(2) ) production in rat peritoneal macrophages were examined . DB00995 ( AF ) at 3-10 muM inhibited TPA-induced PGE(2) production in a concentration-dependent manner . In the pharmacological experiments , prostaglandin G/H synthase ( PGHS ) -2-dependent PGE(2) production was inhibited by 10 muM of AF . The enzyme activities of both P23219 and P35354 were not affected by the 10 muM AF . Other gold compounds , aurothioglucose ( ATG ) and aurothiomalate ( Q13315 ) did not inhibit DB00917 production at 10 muM . AF decreased the P35354 protein content , but had no effect on the P23219 protein content . AF at 3-10 muM decreased the P35354 messenger RNA ( mRNA ) level by RT-PCR determination . Then , the effect of AF on nuclear factor kappa B ( NF-kappaB ) , one of the transcription factors known to regulate transcription of a group of proinflammatory proteins , was determined . AF at 1-10 muM inhibited nuclear translocation of NF-kappaB in a concentration-dependent manner . ATG and Q13315 at 10 muM did not inhibit NF-kappaB nuclear translocation , but with 20 h preincubation , ATG and Q13315 inhibited PGE(2) production and NF-kappaB nuclear translocation . AF , ATG , and Q13315 did not affect the binding of NF-kappaB to its specific DNA . These observations may suggest that the effects of gold compounds on the inhibition of NF-kappaB nuclear translocation plays one of the major role in its anti-inflammatory effects in rat peritoneal macrophages . Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1/2 pluripotent cells through an androgen receptor-mediated pathway . DB00624 supplementation increases skeletal muscle mass and decreases fat mass ; however , the underlying mechanisms are unknown . We hypothesized that testosterone regulates body composition by promoting the commitment of mesenchymal pluripotent cells into myogenic lineage and inhibiting their differentiation into adipogenic lineage . Mouse C3H 10T1/2 pluripotent cells were treated with testosterone ( 0-300 nM ) or dihydrotestosterone ( DB02901 , 0-30 nM ) for 0-14 d , and myogenic conversion was evaluated by immunocytochemical staining for early ( MyoD ) and late ( myosin heavy chain II ; MHC ) myogenic markers and by measurements of MyoD and MHC mRNA and protein . Adipogenic differentiation was assessed by adipocyte counting and by measurements of peroxisomal proliferator-activated receptor gamma 2 ( Q07869 gamma 2 ) mRNA and Q07869 gamma 2 protein and CCAAT/enhancer binding protein alpha . The number of MyoD+ myogenic cells and MHC+ myotubes and MyoD and MHC mRNA and protein levels increased dose dependently in response to testosterone and DB02901 treatment . Both testosterone and DB02901 decreased the number of adipocytes and down-regulated the expression of Q07869 gamma 2 mRNA and Q07869 gamma 2 protein and CCAAT/enhancer binding protein alpha . P10275 mRNA and protein levels were low at baseline but increased after testosterone or DB02901 treatment . The effects of testosterone and DB02901 on myogenesis and adipogenesis were blocked by bicalutamide . Therefore , testosterone and DB02901 regulate lineage determination in mesenchymal pluripotent cells by promoting their commitment to the myogenic lineage and inhibiting their differentiation into the adipogenic lineage through an androgen receptor-mediated pathway . The observation that differentiation of pluripotent cells is androgen dependent provides a unifying explanation for the reciprocal effects of androgens on muscle and fat mass in men . P10275 -induced tumor suppressor , B2CW77 , inhibits breast cancer growth and transcriptionally activates p53/p73-mediated apoptosis in breast carcinomas . P10275 ( AR ) expression by immunohistochemistry correlates with better prognosis and survival among breast cancer patients . We and others have shown that AR inhibits proliferation and induces apoptosis in breast cancer cells . However , the mechanism of AR 's anti-tumor effect in breast cancer is still not fully understood . Our recent study indicates that AR upregulates expression of tumor suppressor gene P60484 by promoter activation in breast cancer . B2CW77 , encoding B2CW77 protein , is a newly identified gene , which shares a bidirectional promoter with P60484 and is transcribed in the opposite direction . So far , the function of B2CW77 has never been studied in tumorigenesis . Here , we define B2CW77 as a tumor suppressor in breast carcinomas , which inhibits tumor growth and invasiveness . After analyzing 188 normal breast and 1247 malignant breast cancer tissues , we observed the loss of B2CW77 in multiple breast cancer subtypes and this decreased B2CW77 expression associates with tumor progression and increasing histological grade in invasive carcinomas . We characterize B2CW77 , for the first time , as a transcription factor , directly promoting the expression of P04637 and O15350 , with consequent elevated apoptosis and cell cycle arrest in breast cancer cells . We demonstrate , in vitro and in murine xenograph models , that both B2CW77 and P60484 are AR-target genes , mediating androgen-induced growth inhibition and apoptosis in breast cancer cells . Our observations suggest that B2CW77 might be used as a potential prognostic marker and novel therapy target for breast carcinomas . DB11588 donors or heme oxygenase-1 ( P09601 ) overexpression blocks interleukin-18-mediated NF-kappaB- P60484 -dependent human cardiac endothelial cell death . The objective of this study was to determine whether heme oxygenase-1 ( P09601 ) or heme metabolites exert cytoprotective effects on interleukin-18-mediated endothelial cell ( EC ) death . Treatment with interleukin ( IL ) -18 increased NF-kappaB activation and P60484 induction , suppressed Akt activation , and stimulated EC death . While ectopic expression of p65 enhanced P60484 transcription , adenoviral transduction of dnIkappaB-alpha , dnp65 , or dnIKKbeta was inhibitory . Furthermore , Q14116 suppressed P09601 mRNA expression via enhanced mRNA degradation . Overexpression of P09601 , treatment with P09601 inducer hemin , or the CO donor cobalt ( III ) protoporphyrin IX all reversed Q14116 -mediated NF-kappaB activation , P60484 induction , Akt suppression , and EC death . Furthermore , hemin induced P09601 expression , and P09601 knockdown , P09601 inhibition , or CO scavengers all reversed the prosurvival effects of hemin . In addition , the CO donors CORM-1 and CORM-3 and the heme metabolites biliverdin and bilirubin attenuated Q14116 -induced EC death via a similar signaling pathway . Q14116 induced p38alpha MAPK activation , and suppressed p38beta isoform expression . While p38alpha knockdown attenuated , p38beta knockdown potentiated Q14116 -mediated EC death . DB03404 and P09601 reversed Q14116 -mediated p38alpha induction and restored p38beta levels . These results demonstrate that Q14116 suppresses P09601 expression and induces EC death . P09601 overexpression , P09601 induction , or treatment with heme metabolites all reverse Q14116 -mediated p38alpha MAPK and NF-kappaB activation , P60484 induction , Akt suppression , and EC death . Thus , P09601 inducers and CO donors may have the therapeutic potential to effectively block Q14116 signaling and reduce Q14116 -dependent vascular injury and inflammation . DB00501 enhances antigen-specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti-ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti-ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB/c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA-specific IgG(1) , IgG(2a) and/or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA-sensitized BALB/c mice promoted Th2 cytokine secretion by OVA-stimulated spleen cells in vitro and increased serum levels of OVA-specific IgE , IgG(1) and IgG(2a) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies . First report of warfarin dose requirements in patients possessing the P11712 *12 allele . BACKGROUND : DB00682 is the most frequently prescribed anticoagulant in North America and Europe . It is administered as a racemate , but S-warfarin is principally responsible for its anticoagulant activity . Cytochrome P450 ( CYP ) 2C9 is the enzyme primarily responsible for the metabolism of S-warfarin . Numerous variant alleles of P11712 have been identified . The P11712 *12 ( rs9332239 ) allele harbors a P489S substitution in P11712 which has been shown to result in a 40 % decline in catalytic activity in vitro . CASES : Four Caucasian patients with a low mean weekly warfarin dose ( MWWD ) were genotyped for P11712 , Q9BQB6 and P02649 variant alleles . None of the four patients carried the common P11712 variant alleles ( *2 , *3 , *5 , *6 , *7 , *8 , *9 , *11 , *13 ) despite a relatively low MWWD ( 23.4±7.94 mg ) compared to 208 patients carrying the CYP29C9*1 genotype ( 32.2±12.65 mg ) . Given that P11712 *12 confers decreased in vitro activity to the enzyme , we investigated whether these patients carried this allele . All four patients were P11712 *12 CT heterozygotes . Individual comparisons with patients possessing the same Q9BQB6 and P02649 genotypes also demonstrated lower dose requirements in the patients that possessed P11712 *12 allele . CONCLUSIONS : There are no reports of the clinical impact of rs9332239 on P11712 substrates . This is the first report of patients with the rare P11712 *12 genotype and lower warfarin dose requirements . A novel thrombopoietin-stem-cell factor fusion protein possesses enhanced potential in stimulating megakaryocyte proliferation and differentiation . P07202 ( thrombopoietin ) and P21583 ( stem-cell factor ) are functionally related cytokines with overlapping but distinct haematopoietic effects . In the present study , a novel P07202 - P21583 fusion protein that combined the complementary biological effects of P07202 and P21583 into a single molecule was expressed in , and purified from , Sf9 [ Spodoptera frugiperda ( fall armyworm ) ] insect cells . The specific activity of rhTPO ( recombinant human P07202 ) - P21583 in megakaryoblastic Mo7e cell proliferation assays was 2.90+/-0.35 x 10(7) units/micromol , approx . 1.7 times as high as that of rhTPO . The specific activity of rhTPO- P21583 in TF-1 cells proliferation assays was 7.10+/-0.95 x 10(6) units/micromol , approx . 1.2 times as high as that of rhSCF ( recombinant human P21583 ) . In a megakaryocyte-colony-forming assay using human peripheral-blood P28906 (+) cells , the P21583 moiety of rhTPO- P21583 worked in a synergistic way to augment the colony number and exhibited a higher potential to stimulate megakaryocyte colony growth . According to the results of EMSA ( electrophoretic mobility-shift assay ) and semi-quantitative RT ( reverse transcriptase ) -PCR , the synergistic effects of the P21583 moiety were also reflected in increased P42229 ( signal transducer and activator of transcription 5 ) DNA binding and enhanced up-regulation of P38936 expression in Mo7e cells treated by rhTPO- P21583 , suggesting that rhTPO- P21583 could be more potent in promoting megakaryocyte proliferation and differentiation . Efficacy and safety of repeated dosing of netupitant , a neurokinin-1 receptor antagonist , in treating overactive bladder . AIM : NK-1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double-blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( -13.85 for placebo to -16.17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . DB09048 was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks . Functional development of the inferior colliculus ( IC ) and its relationship with the auditory brainstem response ( Q12979 ) in the tammar wallaby ( Macropus eugenii ) . To discover the developmental relationship between the auditory brainstem response ( Q12979 ) and the focal inferior colliculus ( IC ) response , 32 young tammar wallabies were used , by the application of simultaneous Q12979 and focal brainstem recordings , in response to acoustic clicks and tone bursts of seven frequencies . The IC of the tammar wallaby undergoes a rapid functional development from postnatal day ( P01160 ) 114 to 160 . The earliest ( P01160 114 ) auditory evoked response was recorded from the rostral IC . With development , more caudal parts of the IC became functional until age about P01160 127 , when all parts of the IC were responsive to sound . Along a dorsoventral direction , the duration of the IC response decreased , the peak latency shortened , while the amplitude increased , reaching a maximum value at the central IC , then decreased . After P01160 160 , the best frequency ( BF ) of the ventral IC was the highest , with values between 12.5 and 16 kHz , the BF of the dorsal IC was the lowest , varying between 3.2 and 6.4 kHz , while the BF of the central IC was between 6.4 and 12.5 kHz . Between P01160 114 and 125 , the IC response did not have temporal correlation with the Q12979 . Between P01160 140 and 160 , only the early components of the responses from the ventral and central IC correlated with the P4 waves of the Q12979 . After P01160 160 , responses recorded from different depths of the IC had a temporal correlation with the Q12979 . P10828 is essential for development of auditory function . Congenital thyroid disorders are often associated with profound deafness , indicating a requirement for thyroid hormone ( DB00279 ) and its receptors in the development of hearing . Two DB00279 receptor genes , Tr alpha and Tr beta are differentially expressed , although in overlapping patterns , during development . Thus , the extent to which they mediate unique or redundant functions is unclear . We demonstrate that Tr beta-deficient ( Thrb-/- ) mice exhibit a permanent deficit in auditory function across a wide range of frequencies , although they show no other overt neurological defects . The auditory-evoked brainstem response ( Q12979 ) in Thrb-/- mice , although greatly diminished , displayed normal waveforms , which suggested that the primary defect resides in the cochlea . Although hypothyroidism causes cochlear malformation , there was no evidence of this in Thrb-/- mice . These findings suggest that Tr beta controls the maturation of auditory function but not morphogenesis of the cochlea . Thrb-/- mice provide a model for the human endocrine disorder of resistance to thyroid hormone ( RTH ) , which is typically associated with dominant mutations in Tr beta . However , deafness is generally absent in RTH , indicating that dominant and recessive mutations in Tr beta have different consequences on the auditory system . Our results identify Tr beta as an essential transcription factor for auditory development and indicate that distinct Tr genes serve certain unique functions . Evaluation of hearing loss with auditory brainstem responses in the early and late period of bacterial meningitis in children . The hearing function of 50 children with bacterial meningitis was evaluated at the second and 10th days , and eight weeks after admission with auditory brain system responses ( Q12979 ) to investigate whether meningitis causes hearing loss . Normal values were obtained in all tests from both ears of 24 patients ( 48 per cent ) . Twelve patients ( 24 per cent ) had temporary , and seven ( 14 per cent ) patients had persistent mild degree hearing loss . Severe hearing loss was detected bilaterally in five ( 10 per cent ) patients and unilaterally in two ( four per cent ) patients . Patients , with other complications such as subdural effusion , convulsion , brain oedema and paralysis were found to have a higher incidence of hearing loss . We observed that patients treated with dexamethasone had 7.7 per cent persistent hearing loss , 11.6 per cent mild hearing loss , 34.6 per cent transient hearing loss , but in the group who did not receive dexamethasone there was 19.2 per cent persistent hearing loss , 15.3 per cent mild hearing loss and 11.6 per cent transient hearing loss . There were other significant differences between the two groups in restoration of normal body temperature , the P04141 /plasma glucose concentration ratio was elevated , P04141 ( cerebro-spinal fluid ) protein concentration was decreased and the cell count in the P04141 was decreased in the dexamethasone group , significantly more than the group who were not receiving dexamethasone . The hearing loss tended to be more frequent among younger children . Genetic and epigenetic markers in the evaluation of pancreatic masses . BACKGROUND : Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma . The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with P01116 mutation detection in the evaluation of pancreatic masses . EXPERIMENTAL DESIGN : Sixty-one fine needle aspirates of pancreatic masses ( 43 pancreatic adenocarcinomas and 18 chronic pancreatitis ) were studied . Methylation status of P25021 , Q05925 , P09486 , P55290 and P25054 were analysed using melting curve analysis after DNA bisulfite treatment . P01116 mutations were also analysed . RESULTS : The methylation panel had a sensitivity of 73 % ( 27 of 37 , CI 95 % 56 to 86 % ) and a specificity of 100 % whenever two or more promoters were found hypermethylated . P01116 mutations showed a sensitivity of 77 % ( 33 of 43 , CI 95 % 62 to 88 % ) and a specificity of 100 % . Both molecular analyses added useful information to cytology by increasing the number of informative cases . When genetic and epigenetic analyses were combined sensitivity was 84 % ( 36 of 43 CI 95 % 69 to 93 % ) maintaining a 100 % specificity . CONCLUSIONS : Analysis of hypermethylation status of a panel of genes and P01116 mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses . The combined molecular analysis increases the number of informative cases without diminishing specificity . Wistar rats : a forgotten model of age-related hearing loss . Age-related hearing loss ( ARHL ) is one of the most frequent sensory impairments in senescence and is a source of important socio-economic consequences . Understanding the pathological responses that occur in the central auditory pathway of patients who suffer from this disability is vital to improve its diagnosis and treatment . Therefore , the goal of this study was to characterize age-related modifications in auditory brainstem responses ( Q12979 ) and to determine whether these functional responses might be accompanied by an imbalance between excitation and inhibition in the cochlear nucleus of Wistar rats . To do so , Q12979 recordings at different frequencies and immunohistochemistry for the vesicular glutamate transporter 1 ( Q9P2U7 ) and the vesicular GABA transporter ( Q9H598 ) in the ventral cochlear nucleus ( VCN ) were performed in young , middle-aged and old male Wistar rats . The results demonstrate that there was a significant increase in the auditory thresholds , a significant decrease in the amplitudes and an increase in the latencies of the Q12979 waves as the age of the rat increased . Additionally , there were decreases in Q9P2U7 and Q9H598 immunostaining in the VCN of older rats compared to younger rats . Therefore , the observed age-related decline in the magnitude of auditory evoked responses might be due in part to a reduction in markers of excitatory function ; meanwhile , the concomitant reduction in both excitatory and inhibitory markers might reflect a common central alteration in animal models of ARLH . Together , these findings highlight the suitability of the Wistar rat as an excellent model to study ARHL . The thyroid hormone receptor β induces DNA damage and premature senescence . There is increasing evidence that the thyroid hormone ( TH ) receptors ( THRs ) can play a role in aging , cancer and degenerative diseases . In this paper , we demonstrate that binding of TH DB00279 ( triiodothyronine ) to P10828 induces senescence and deoxyribonucleic acid ( DNA ) damage in cultured cells and in tissues of young hyperthyroid mice . DB00279 induces a rapid activation of Q13315 ( ataxia telangiectasia mutated ) /PRKAA ( adenosine monophosphate-activated protein kinase ) signal transduction and recruitment of the NRF1 ( nuclear respiratory factor 1 ) and P10828 to the promoters of genes with a key role on mitochondrial respiration . Increased respiration leads to production of mitochondrial reactive oxygen species , which in turn causes oxidative stress and DNA double-strand breaks and triggers a DNA damage response that ultimately leads to premature senescence of susceptible cells . Our findings provide a mechanism for integrating metabolic effects of THs with the tumor suppressor activity of P10828 , the effect of thyroidal status on longevity , and the occurrence of tissue damage in hyperthyroidism . Prognostic significance of loss of heterozygosity at loci on chromosome 17p13.3-ter in sporadic breast cancer is evidence for a putative tumour suppressor gene . Several studies indicate that the short arm of chromosome 17 is one of the most frequently altered regions in sporadic breast carcinomas ( 45-60 % ) . In the present report the 17p13.3-ter locus in tumour DNA of breast cancer patients , along with their matching normal lymphocyte DNA , have been mapped with four markers ( D17S5 , D17S379 , Q12979 and D17S34 ) , spanning nearly 3 cM of the telomer . Sixty-five of 143 heterozygous tumours had lost at least one of the markers at the minimum region of loss ( 45 % ) . High levels of loss of these distal markers on 17p13.3 are independent of P04637 mutations and are associated with tumour cell proliferation . A follow-up period of over 7 years demonstrates that loss of these markers correlates both with disease-free ( P = 0.004 ) and overall survival ( P = 0.007 ) . In addition we show that for disease-free survival the prognostic power of this genetic alteration is second only to axillary lymph node involvement ( 3.1 vs 6.3 relative risk ) , and is a better predictor than the mutational status of P04637 ( 1.6 relative risk ) . Our results are further evidence of the presence , within the region , of at least a second tumour suppressor gene distal to P04637 , that might be targeted by deletions . 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 . Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : DB08907 is a sodium glucose co-transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : (14)C-alpha-methylglucoside uptake in Chinese hamster ovary-K cells expressing human , rat , or mouse SGLT2 or P13866 ; (3)H-2-deoxy-d-glucose uptake in Q9BTT4 myoblasts ; and 2-electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT(G) ) in vehicle or canagliflozin-treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg/kg lowered RT(G) from 415±12 mg/dl to 94±10 mg/dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT(G) . DB08907 dose-dependently decreased BG concentrations in db/db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : DB08907 lowered RT(G) and increased UGE , improved glycemic control and beta-cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity . DB00502 induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist/coagonist sites , other modulator sites , including butyrophenone site may regulate the N-methyl-D-aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co-immunoprecipitated by anti-Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol-binding proteins , P29475 and Ras- P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras- P01286 from membranes and activation of c-Jun-kinase . Inclusion of insulin prevented relocalization of Ras- P01286 and subsequent neuronal death . DB00502 -induced dissociation of Ras- P01286 leads to inhibition of membrane-bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway . Q9BQB6 pharmacogenetics and pharmacoproteomics in patients on warfarin anticoagulant therapy : transthyretin precursor as a potential biomarker . BACKGROUND : Recognizing specific protein changes in response to drug administration in humans has the potential for the development of personalized medicine . Such changes can be identified by pharmacoproteomics approach based on proteomic technologies . It can also be helpful in matching a particular target-based therapy to a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism . DB00682 is a commonly prescribed oral anticoagulant in patients with prosthetic valve disease , venous thromboembolism and stroke . METHODS AND FINDING : We used a combined pharmacogenetics and iTRAQ-coupled LC-MS/MS pharmacoproteomics approach to analyze plasma protein profiles of 53 patients , and identified significantly upregulated level of transthyretin precursor in patients receiving low dose of warfarin but not in those on high dose of warfarin . In addition , real-time RT-PCR , western blotting , human P05231 ELISA assay were done for the results validation . CONCLUSION : This combined pharmacogenomics and pharmacoproteomics approach may be applied for other target-based therapies , in matching a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism . To cell cycle , swing the P25054 /C . For successful mitosis , P12004 B1 and O95997 must be degraded efficiently before anaphase . Destruction of these mitotic regulators by the 26S proteasome is the result of their poly-ubiquitination by a multi-subunit E3 ligase : the Anaphase-Promoting Complex or Cyclosome ( P25054 /C ) . Clearly , the P25054 /C is not just important for mitosis . Destruction of P25054 /C substrates such as Cdc20 , Plk1 , Aurora A and Skp2 directs events in P55008 . Strikingly , the P25054 /C needs to stay active even in quiescent cells to keep them out of the cell cycle and forms an intriguing link with P06400 . An inactive P25054 /C stabilizes O75496 , P12004 A and P12004 B1 , thereby securing completion of DNA synthesis and progression through G2-phase . In prometaphase the P25054 /C becomes active again , but is controlled by the spindle assembly checkpoint . Here we discuss how the P25054 /C is either held in check or released . We argue that shedding more light on the P25054 /C is also important to understand cancer and could help the design of treatment . Statins exhibit anticancer effects through modifications of the pAkt signaling pathway . Statins are cholesterol lowering drugs that exhibit antitumor effects in several in vitro and in vivo models , and epidemiological studies indicate that statins prevent cancer . However , the molecular mechanism underlying the effects of statins still needs to be elucidated . We previously demonstrated that single doses of different statins rapidly affect Akt signaling via the purinergic receptor Q99572 . In particular , statins down-regulated nuclear pAkt . Here , we report that long-term treatment of A549 cells with high concentrations of statins ( 15-75 µM ) selects cell sub-populations exhibiting altered P2X receptor expression , signs of increased P60484 activity , enhanced Q6ZVD8 , decreased PI3K p110β and inhibited downstream pAkt signaling . Furthermore , the nuclear accumulation of pAkt in response to insulin was inhibited in selected cells . Statin-selected cells displayed reduced proliferation rate and were more vulnerable to etoposide- and 5-fluorouracil-elicited cytotoxic effects . The stability of a selected phenotype ( 50 µM ) was tested for three weeks in the absence of statins . This resulted in a reversal of some , but not all alterations . Importantly , the truncated nuclear insulin response was retained . We conclude that long-term treatment with high doses of statins selects cells exhibiting stable alterations in insulin-Akt signaling and which are vulnerable to DNA damage . Our studies strengthen the hypothesis that an altered Akt signaling has a role in chemopreventive effects of statins . Differential regulation of DB01221 receptor function by Q99497 and Q9BXM7 . Dysfunction of P60484 -induced kinase 1 ( Q9BXM7 ) or Q99497 promotes neuronal death and is implicated in the pathogenesis of Parkinson 's disease , but the underlying mechanisms remain unclear . Given the roles of N-methyl-d-aspartate receptor ( NMDAr ) -mediated neurotoxicity in various brain disorders including cerebral ischemia and neurodegenerative diseases , we investigated the effects of Q9BXM7 and Q99497 on NMDAr function . Using protein overexpression and knockdown approaches , we showed that Q9BXM7 increased NMDAr-mediated whole-cell currents by enhancing the function of Q12879 -containing NMDAr subtype ( NR2ACNR ) . However , Q99497 decreased NMDAr-mediated currents , which was mediated through the inhibition of both NR2ACNR and Q13224 -containing NMDAr subtype ( NR2BCNR ) . We revealed that the knockdown of Q99497 enhanced P60484 expression , which not only potentiated NR2BCNR function but also increased Q9BXM7 expression that led to NR2ACNR potentiation . These results indicate that NMDAr function is differentially regulated by Q99497 -dependent signal pathways Q99497 / P60484 /NR2BCNR and Q99497 / P60484 / Q9BXM7 /NR2ACNR . Our results further showed that the suppression of Q99497 , while promoted DB01221 -induced neuronal death through the overactivation of P60484 /NR2BCNR-dependent cell death pathway , induced a neuroprotective effect to counteract Q99497 dysfunction-mediated neuronal death signaling through activating P60484 / Q9BXM7 /NR2ACNR cell survival-promoting pathway . Thus , Q9BXM7 acts with Q99497 in a common pathway to regulate NMDAr-mediated neuronal death . This study suggests that the Q99497 / P60484 /NR2BCNR and Q99497 / P60484 / Q9BXM7 /NR2ACNR pathways may represent potential therapeutic targets for the development of neuroprotection strategy in the treatment of brain injuries and neurodegenerative diseases such as Parkinson 's disease . Greglist : a database listing potential G-quadruplex regulated genes . The double helix is a conformation that genomic DNA usually assumes ; under certain conditions , however , guanine-rich DNA sequences can form a four-stranded structure , G-quadruplex , which is found to play a role in regulating gene expression . Indeed , it has been demonstrated that the G-quadruplex formed in the c-MYC promoter suppresses its transcriptional activity . Recent studies suggest that G-quadruplex motifs ( GQMs ) are enriched in human gene promoters . To facilitate the research of G-quadruplex , we have constructed Greglist , a database listing potentially G-quadruplex regulated genes . Greglist harbors genes that contain promoter GQMs from genomes of various species , including humans , mice , rats and chickens . Many important genes are found to contain previously unreported promoter GQMs , such as Q13315 , Q92934 , P31749 , LEPR , P25874 , P02649 , O94907 , P19544 , P30291 , P04628 and O15516 . Furthermore , we find that not only protein coding genes , 126 human microRNAs also contain promoter GQMs . Greglist therefore provides candidates for further studying G-quadruplex functions and is freely available at http://tubic.tju.edu.cn/greglist . DB01032 reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P. aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase-1 and release of IL-1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P. aeruginosa pneumonia . Treatment of mice prior to infection with P. aeruginosa resulted in an enhanced clearance of P. aeruginosa and reduced levels of inflammatory mediators , such as IL-1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell-derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P. aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation . Neonatal estrogen exposure disrupts uterine development in the postnatal sheep . Postnatal development of the ovine uterus between birth and postnatal day ( P01160 ) 56 involves budding differentiation of the endometrial glandular epithelium from the luminal epithelium ( LE ) followed by extensive coiling and branching morphogenesis of the tubular glands . To determine the short- and long-term effects of estrogen on neonatal ovine uterine development after P01160 14 , neonatal sheep were randomly assigned at birth ( P01160 0 ) to be treated daily with estradiol-17beta benzoate ( EB ; 0 , 0.01 , 0.1 , 1 , or 10 microg/kg body weight.d ) during one of two developmental periods ( P01160 14-27 or 42-55 ) . All ewes were hemiovariohysterectomized at the end of EB treatment on either P01160 28 or 56 , and the remaining uterine horn and ovary removed on P01160 112 . Immediate responses to EB treatment included dose- and age-dependent increases in uterine wet weight , thickness of the endometrium , myometrium , and LE , but decreases in endometrial glands on P01160 28 and 56 . Transient exposure to EB decreased gland number and thickness of the endometrium and LE on P01160 112 but did not affect extrauterine reproductive tract structures . The mechanism of estrogen inhibition of uterine development did not involve effects on cell proliferation . Real-time PCR analyses found that EB exposure disrupted normal patterns of growth factor ( P05019 , P01344 , fibroblast growth factor-7 , fibroblast growth factor-10 , and hepatocyte growth factor ) and receptor mRNA expression in the uterus . Transient exposure of the neonatal ewe to estrogens during critical periods specifically alters growth factor networks that perturb normal development of the uterus , leading to permanent alterations in uterine structure and function . DB00501 induces interleukin-18 production through H2-agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 ) antagonist cimetidine . This agent , but not the P25021 antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) -18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine-induced Q14116 production . DB00501 induced the activation of caspase-1 , which is reported to modify immature Q14116 to mature/active Q14116 , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 production were reproduced in peripheral blood mononuclear cells from wild-type mice , but not in those from P25021 knockout mice . In conclusion , cimetidine , a partial agonist for P25021 , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers . [ Role of neurokinin-1 receptor in lung injury in rats with acute necrotizing pancreatitis ] . OBJECTIVE : To investigate the expression of neurokinin-1 receptor ( P25103 ) in the lung tissue , and the relationship between expression of P25103 and lung injury in rats with acute necrotizing pancreatitis ( P01160 ) . METHODS : One hundred and twenty adult Sprague-Dawley rats were randomly divided into P01160 and control groups . Animals in group P01160 were induced by the retrograde intraductal infusion of 5 % sodium taurocholate ( 0.1 ml/kg ) , and animals in normal control group received laparotomy only . The accumulation of polymorphonuclear leukocytes in lung tissues was measured with myeloperoxidase ( P05164 ) assay . Lung endothelial barrier destruction was measured by lung capillary permeability ( LCP ) . Reverse transcription polymerase chain reaction ( RT-PCR ) was used to determine the mRNA expression of P25103 , western blot analysis was used to determine P25103 protein expression levels , and immunohistochemistry was used to localize expression site of P25103 . RESULTS : P25103 mRNA level was enhanced in the lung of P01160 compared with normal control group . Western blot analysis showed overexpression of P25103 protein level exited in P01160 group . Statistical analysis revealed correlation between P25103 mRNA and P05164 ( r=0.83 , P < 0.01 ) and LCP ( r=0.79 , P < 0.01 ) respectively . With immunohistochemistry staining , moderate to strong P25103 immunoreactivity was localized to alveolar membrane , I epithelium , II epithelium and polymorphonuclear leukocytes in the lung of P01160 . CONCLUSION : In P01160 , overexpression of P25103 contributes to disturbance of neuropeptides loop , resulting in aggregation of neutrophilic granulocyte and promoting deterioration of lung injury . The v-ErbA oncoprotein quenches the activity of an erythroid-specific enhancer . v-ErbA is a mutated variant of thyroid hormone receptor ( TRalpha/ P10827 ) borne by the Avian Erythroblastosis virus causing erythroleukemia . TRalpha is known to activate transcription of specific genes in the presence of its cognate ligand , DB00279 hormone , while in its absence it represses it . v-ErbA is unable to bind ligand , and hence is thought to contribute to leukemogenesis by actively repressing erythroid-specific genes such as the carbonic anhydrase II gene ( CA II ) . In the prevailing model , v-ErbA occludes liganded TR from binding to its cognate elements and constitutively interacts with the corepressors NCoR/ Q9Y618 . We previously identified a v-ErbA responsive element ( VRE ) within a P24855 hypersensitive region ( Q5VYS8 ) located in the second intron of the CA II gene . We now show that Q5VYS8 fulfils all the requirements for a genuine enhancer that functions independent of its orientation and position with a profound erythroid-specific activity in normal erythroid progenitors ( T2ECs ) and in leukemic erythroid cell lines . We find that the Q5VYS8 enhancer activity is governed by two adjacent GATA-factor binding sites . v-ErbA as well as unliganded TR prevent Q5VYS8 activity by nullifying the positive function of factors bound to GATA-sites . However , v-ErbA , in contrast to TR , does not convey active repression to silence the transcriptional activity intrinsic to a heterologous tk promoter . We propose that depending on the sequence and context of the binding site , v-ErbA contributes to leukemogenesis by occluding liganded TR as well as unliganded TR thereby preventing activation or repression , respectively . Association of haplotypes of inflammation-related genes with gastric preneoplastic lesions in African Americans and Caucasians . Identification of biomarkers is needed for development of screening programs to prevent gastric cancer . Because racial differences exist in cancer rates , we aimed to evaluate the association between polymorphisms in inflammation-related genes and gastric preneoplastic lesions in African Americans and Caucasians from Louisiana , USA . Gastric biopsies from 569 adults ( 361 African Americans and 208 Caucasians ) undergoing diagnostic endoscopy were used for histological diagnosis and genomic DNA extraction . Polymorphisms within eight genes ( P01584 , P10145 , P05231 , P01375 , P35354 , P05089 , P22301 and P01137 ) were investigated by TaqMan . The cagA status of Helicobacter pylori infection was assessed by PCR . Haplotype logistic regression models were used to identify variables associated with intestinal metaplasia or dysplasia . African Americans carrying the haplotype P01584 -511T/-31C/+3954T , which includes the three risk-associated alleles at the P01584 locus , were more likely to being diagnosed with intestinal metaplasia or dysplasia than those carrying the most common haplotype T-C-C ( adjusted OR : 2.51 , 95 % CI : 1.1-5.5 ) . None of the polymorphisms were associated with intestinal metaplasia and dysplasia in Caucasians . Age and cagA-positive status were independent factors associated with these lesions . Haplotypes at the P01584 locus may participate in mediating the susceptibility to gastric carcinogenesis and might be useful as markers of advanced premalignant lesions in African Americans . Interestingly , carriage of P01584 +3954T allele seems to be the key factor , even though the role played by other polymorphisms can not be excluded . Salacia oblonga extract increases glucose transporter 4-mediated glucose uptake in Q9BTT4 rat myotubes : role of mangiferin . BACKGROUND AND AIMS : To evaluate if the antidiabetic properties of Salacia oblonga extract are mediated not only by inhibiting intestinal alpha-glycosidases but also by enhancing glucose transport in muscle and adipose cells . METHODS : S. oblonga extract effects on 2-deoxy-D-glucose uptake were assayed in muscle Q9BTT4 -myotubes and 3T3-adipocytes . In Q9BTT4 -myotubes , the amount and translocation of glucose transporters were assayed . A fractionation of the extract was carried out to identify the active compounds . Furthermore , we analyzed the phosphorylation status of key components of signaling pathways that are involved in the molecular mechanisms regulating glucose uptake . RESULTS : S. oblonga extract increased 2-deoxy-D-glucose uptake by 50 % in Q9BTT4 -myotubes and 3T3-adipocytes . In Q9BTT4 -myotubes , the extract increased up to a 100 % the P14672 content , activating P14672 promoter transcription and its translocation to the plasma membrane . Mangiferin was identified as the bioactive compound . Furthermore , mangiferin effects were concomitant with the phosphorylation of DB00131 -activated protein kinase without the activation of P31749 /Akt . The effect of mangiferin on 2-deoxy-D-glucose uptake was blocked by GW9662 , an irreversible P37231 antagonist . CONCLUSIONS : S. oblonga extract and mangiferin may exert their antidiabetic effect by increasing P14672 expression and translocation in muscle cells . These effects are probably mediated through two independent pathways that are related to DB00131 -activated protein kinase and P37231 . P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration-resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen-androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR-targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with DB08899 , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state . Expression of O95997 and P60484 in endometrial carcinoma : correlation with tumorigenesis and progression . Human pituitary tumor-transforming gene 1 ( O95997 ) is a newly identified proto-oncogene , and its overexpression occurs in a wide variety of human cancers . The tumor suppressor gene phosphatase and tensin homolog deleted from chromosome 10 ( P60484 ) is frequently mutated or deleted in numerous tumors , especially in endometrial carcinoma . The aim of this study was to investigate whether the aberrant expression of O95997 and P60484 is associated with tumorigenesis and progression of endometrial carcinoma . Tissue microarray and immunohistochemical staining were undertaken in 124 endometrial carcinoma , 28 atypical hyperplasia and 35 normal endometrium samples . Then , the correlation of O95997 and P60484 expression with the clinicopathological features and with the levels of estrogen and progesterone receptor was analyzed . The presence of O95997 and P60484 protein was significantly increased and decreased , respectively , as lesions progressed from normal endometrium to atypical hyperplasia to carcinoma . O95997 protein showed a significantly positive correlation with TNM stage , but not with other characteristics . In addition , P60484 protein did not correlate with any parameters except for histological grade , to which it was found to be inversely related . Statistical analysis confirmed a significant relationship between an increase in O95997 and a decrease in P60484 . These results indicate that high expression of O95997 and low expression of P60484 may be involved in pathogenesis and development of endometrial carcinoma . The findings also provide evidence that combined evaluation of the two markers may be useful in predicting tumor behavior and thus prognosis . Thyroid hormone status interferes with estrogen target gene expression in breast cancer samples in menopausal women . We investigated thyroid hormone levels in menopausal BrC patients and verified the action of triiodothyronine on genes regulated by estrogen and by triiodothyronine itself in BrC tissues . We selected 15 postmenopausal BrC patients and a control group of 18 postmenopausal women without BrC . We measured serum P07202 -AB , DB00024 , FT4 , and estradiol , before and after surgery , and used immunohistochemistry to examine estrogen and progesterone receptors . BrC primary tissue cultures received the following treatments : ethanol , triiodothyronine , triiodothyronine plus 4-hydroxytamoxifen , 4-hydroxytamoxifen , estrogen , or estrogen plus 4-hydroxytamoxifen . Genes regulated by estrogen ( P01135 , P01137 , and P06401 ) and by triiodothyronine ( Q07011 , P22004 , and P10827 ) in vitro were evaluated . DB00024 levels in BrC patients did not differ from those of the control group ( 1.34 ± 0.60 versus 2.41 ± 1.10 μ U/mL ) , but FT4 levels of BrC patients were statistically higher than controls ( 1.78 ± 0.20 versus 0.95 ± 0.16 ng/dL ) . P01135 was upregulated and downregulated after estrogen and triiodothyronine treatment , respectively . DB00279 increased P06401 expression ; however 4-hydroxytamoxifen did not block triiodothyronine action on P06401 expression . DB04468 , alone or associated with triiodothyronine , modulated gene expression of Q07011 , P22004 , and P10827 , similar to triiodothyronine treatment . Thus , our work highlights the importance of thyroid hormone status evaluation and its ability to interfere with estrogen target gene expression in BrC samples in menopausal women . Calpain and STriatal-Enriched protein tyrosine phosphatase ( P54829 ) activation contribute to extrasynaptic DB01221 receptor localization in a Huntington 's disease mouse model . In Huntington 's disease ( HD ) , the mutant huntingtin ( mhtt ) protein is associated with striatal dysfunction and degeneration . Excitotoxicity and early synaptic defects are attributed , in part , to altered DB01221 receptor ( NMDAR ) trafficking and function . Deleterious extrasynaptic NMDAR localization and signalling are increased early in yeast artificial chromosome mice expressing full-length mhtt with 128 polyglutamine repeats ( YAC128 mice ) . NMDAR trafficking at the plasma membrane is regulated by dephosphorylation of the NMDAR subunit Q13224 tyrosine 1472 ( Y1472 ) residue by STriatal-Enriched protein tyrosine Phosphatase ( P54829 ) . NMDAR function is also regulated by calpain cleavage of the Q13224 C-terminus . Activation of both P54829 and calpain is calcium-dependent , and disruption of calcium homeostasis occurs early in the HD striatum . Here , we show increased calpain cleavage of Q13224 at both synaptic and extrasynaptic sites , and elevated extrasynaptic total Q13224 expression in the YAC128 striatum . Calpain inhibition significantly reduced extrasynaptic Q13224 expression in the YAC128 but not wild-type striatum . Furthermore , calpain inhibition reduced whole-cell NMDAR current and the surface/internal Q13224 ratio in co-cultured striatal neurons , without affecting synaptic Q13224 localization . Synaptic P54829 activity was also significantly higher in the YAC128 striatum , correlating with decreased Q13224 Y1472 phosphorylation . A substrate-trapping P54829 protein ( TAT- P54829 C-S ) significantly increased Q9P2U7 - Q13224 colocalization , as well as increasing synaptic Q13224 expression and Y1472 phosphorylation . Moreover , combined calpain inhibition and P54829 inactivation reduced extrasynaptic , while increasing synaptic Q13224 expression in the YAC128 striatum . These results indicate that increased P54829 and calpain activation contribute to altered NMDAR localization in an HD mouse model , suggesting new therapeutic targets for HD . Novel non-genomic signaling of thyroid hormone receptors in thyroid carcinogenesis . The thyroid hormone receptors ( TRs ) are transcription factors that mediate the pleiotropic activities of the thyroid hormone , DB00279 . Four DB00279 -binding isoforms , TRalpha1 , TRbeta1 , TRbeta2 , and TRbeta3 , are encoded by two genes , P10827 and P10828 . Mutations and altered expression of TRs have been reported in human cancers . A targeted germ-line mutation of the Thrbeta gene in the mouse leads to spontaneous development of follicular thyroid carcinoma ( TRbeta(PV/PV) mouse ) . The TRbetaPV mutant has lost DB00279 -binding activity and displays potent dominant negative activity . The striking phenotype of thyroid cancer exhibited by TRbeta(PV/PV) mice has recently led to the discovery of novel non-genomic actions of TRbetaPV that contribute to thyroid carcinogenesis . These actions involve direct physical interaction of TRbetaPV with cellular proteins , namely the regulatory subunit of the phosphatidylinositol 3-kinase ( p85alpha ) , the pituitary tumor transforming gene ( O95997 ) and beta-catenin , that are critically involved in cell proliferation , motility , migration , and metastasis . Thus , a TRbeta mutant ( TRbetaPV ) , via a novel mode of non-genomic action , acts as an oncogene in thyroid carcinogenesis . Inhibition of peroxisome proliferator-activated receptor gamma increases estrogen receptor-dependent tumor specification . P37231 ( PPARgamma ) is a nuclear receptor that regulates gene transcription associated with intermediary metabolism , adipocyte differentiation , and tumor suppression and proliferation . To understand the role of PPARgamma in tumorigenesis , transgenic mice were generated with mammary gland-directed expression of the dominant-negative transgene Pax8PPARgamma . Transgenic mice were phenotypically indistinguishable from wild-type ( WT ) mice , but mammary epithelial cells expressed a greater percentage of CD29(hi)/ P25063 (neg) , CK5(+) , and double-positive CK14/CK18 cells . These changes correlated with reduced P60484 and increased Ras and extracellular signal-regulated kinase ( P29323 ) and AKT activation . Although spontaneous tumorigenesis did not occur , transgenic animals were highly susceptible to progestin/7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis , which in contrast to WT mice resulted in a high tumor multiplicity and , most importantly , in the appearance of predominantly estrogen receptor alpha-positive ( ER(+) ) ductal adenocarcinomas . Tumors expressed a similar P60484 (lo)/pERK(hi)/pAKT(hi) phenotype as mammary epithelium and exhibited high activation of estrogen response element-dependent reporter gene activity . Tumorigenesis in MMTV-Pax8PPARgamma mice was insensitive to the chemopreventive effect of a PPARgamma agonist but was profoundly inhibited by the ER antagonist fulvestrant . These results reveal important new insights into the previously unrecognized role of PPARgamma in the specification of mammary lineage and the development of ER(+) tumors . A set of consensus mammalian mediator subunits identified by multidimensional protein identification technology . The Mediator is a multiprotein transcriptional coactivator that is expressed ubiquitously in eukaryotes from yeast to mammals and is required for induction of RNA polymerase II ( pol II ) transcription by DNA binding transcription factors . In the work described here , we exploit multidimensional protein identification technology ( MudPIT ) to carry out a proteomic analysis of the subunit composition of the mammalian Mediator complex . By comparing MudPIT data sets obtained from six independent Mediator preparations immunoaffinity purified through their Nut2 ( Q9BTT4 ) , Med25 ( Q9NWA0 ) , Intersex ( Q9NX70 ) , A0JLT2 ( A0JLT2 ) , AK007855 ( Q9H204 ) , or CRSP70 ( O95402 ) subunits , we identify a set of consensus mammalian Mediator subunits . In addition , we identify as Mediator-associated proteins the P49336 -like cyclin-dependent kinase CDK11 and the Q9UHV7 -like Q71F56 protein ( Q71F56 ) , which is mutated in patients with the congenital heart defect transposition of the great arteries ( TGA ) . Radiation-induced senescence in securin-deficient cancer cells promotes cell invasion involving the P05231 / P40763 and DB00102 / P09619 pathways . O95997 overexpression correlates with poor prognosis in various tumours . We have previously shown that securin depletion promotes radiation-induced senescence and enhances radiosensitivity in human cancer cells . However , the underlying molecular mechanisms and the paracrine effects remain unknown . In this study , we showed that radiation induced senescence in securin-deficient human breast cancer cells involving the Q13315 /Chk2 and p38 pathways . Conditioned medium ( CM ) from senescent cells promoted the invasion and migration of non-irradiated cancer and endothelial cells . Cytokine assay analysis showed the up-regulation of various senescence-associated secretory phenotypes ( SASPs ) . The P05231 / P40763 signalling loop and platelet-derived growth factor-BB ( DB00102 ) /PDGF receptor ( P09619 ) pathway were important for CM-induced cell migration and invasion . Furthermore , CM promoted angiogenesis in the chicken chorioallantoic membrane though the induction of P05231 / P40763 - and DB00102 / P09619 -dependent endothelial cell invasion . Taken together , our results provide the molecular mechanisms for radiation-induced senescence in securin-deficient human breast cancer cells and for the SASP responses . Consequences of the Y139F Vkorc1 mutation on resistance to AVKs : in-vivo investigation in a 7th generation of congenic Y139F strain of rats . OBJECTIVES : In humans , warfarin is used as an anticoagulant to reduce the risk of thromboembolic clinical events . DB00682 derivatives are also used as rodenticides in pest control . The gene encoding the protein targeted by anticoagulants is the Vitamin K-2,3-epoxide reductase subunit 1 ( Q9BQB6 ) . Since its discovery in 2004 , various amino acid and transcription-regulatory altering Q9BQB6 mutations have been identified in patients who required extreme antivitamin K dosages , or wild populations of rodents that were difficult to control with anticoagulant rodenticides . One unresolved question concerns the dependency of the Q9BQB6 on the genetic background in humans and rodents that respond weakly or not at all to anticoagulants . Moreover , an important question requiring further analyses concerns the role of the Vkorc1 gene in mediating resistance to more recently developed warfarin derivatives ( superwarfarins ) . METHODS : In this study , we bred a quasicongenic rat strain by using a wild-caught anticoagulant resistant rat as a donor to introduce the Y > F amino acid change at position 139 in the Vkorc1 into the genetic background of an anticoagulant susceptible Spraque-Dawley recipient strain . RESULTS AND CONCLUSION : In this manuscript we report the prothrombin times measured in the P08709 generation after exposure to chlorophacinone , bromadiolone , difenacoum and difethialone . We observed that the mutation Y139F mediates resistance in an otherwise susceptible genetic background when exposed to chlorophacinone and bromadiolone . However , the physiological response to the super-warfarins , difenacoum and difethialone , may be strongly dependent on other genes located outside the congenic interval ( 28.3 cM ) bracketing the Vkorc1 in our P08709 generation congenic strain .