interacts_with DB06698?
Polymorphisms of human histamine receptor H4 gene are associated with breast cancer in Chinese Han population . Previous investigations indicated that histamine receptor H4 ( Q9H3N8 ) played important roles in many aspects of breast cancer pathogenesis , and that the polymorphisms of Q9H3N8 gene may result in expression and functional changes of Q9H3N8 proteins . However , the relationship between polymorphisms of Q9H3N8 and breast cancer risk and malignant degree is unclear . In the present study , we conducted a case-control investigation among 185 Chinese Han breast cancer patients and 199 ethnicity-matched health controls . Four tag-SNPs ( i.e. rs623590 , rs16940762 , rs11662595 and rs1421125 ) of Q9H3N8 were genotyped and association analysis was performed . Odds ratios ( ORs ) with 95 % confidence intervals ( CI ) were used to assess the association . We found that the T allele of rs623590 had a decreased risk of breast cancer ( adjusted OR , 0.667 ; 95 % CI , 0.486-0.913 ; P=0.012 ) while the A allele of rs1421125 had an increased risk ( adjusted OR , 1.653 ; 95 % CI , 1.139-2.397 ; P=0.008 ) . Further haplotype analysis showed that the CAA haplotype of rs623590-rs11662595-rs1421125 was more frequent among patients with breast cancer ( adjusted OR , 1.856 ; 95 % CI , 1.236-2.787 ; P=0.003 ) . Additionally , polymorphisms of rs623590 and rs11662595 were also correlated with clinical stages , lymph node involvement , and P04626 status . These findings indicated that the variants of rs623590 , rs11662595 and rs1421125 genotypes of Q9H3N8 gene were significantly associated with the risk and malignant degree of breast cancer in Chinese Han populations , which may provide us novel insight into the pathogenesis of breast cancer although further studies with larger participants worldwide are still needed for conclusion validation . Synthetic delivery system for tuberculosis vaccines : immunological evaluation of the M. tuberculosis 38 kDa protein entrapped in biodegradable P00747 microparticles . Tuberculosis remains a major public health burden which could be ameliorated by effective and well-defined subunit vaccines , particularly because the protective efficacy of current M. bovis BCG vaccines is both unpredictable and variable . The immunodominant 38 kDa antigen from Mycobacterium tuberculosis was entrapped in biodegradable poly ( DL-lactide co-glycolide ) ( P00747 ) microparticles which served as a delivery system . Both cellular and humoral immune responses were assessed and compared with those obtained after immunization with the 38 kDa protein emulsified in incomplete Freund 's adjuvant ( IFA ) . Vaccination of mice with a single dose of antigen-loaded microparticles resulted in specific IgG titres peaking after five weeks comparable to those achieved after vaccination with protein emulsified in incomplete Freund 's adjuvant ( IFA ) . T-cell responses were found to be superior to those induced with antigen/IFA . The T- and B-cell epitope specificities ad judged with synthetic peptides were identical following immunization with antigen in microparticles or IFA . Differences in adjuvanticity were revealed by measuring antigen-specific IgG1 , IgG2a and antigen-induced P01579 secretion in vitro : substantially higher titres of IgG2a were observed following immunization with antigen/microparticles than with 38 kDa protein/IFA . This was paralleled by a tenfold higher secretion of P01579 in mice injected with antigen/microparticles . Reduction in colony-forming units was not consistent in mice immunized with 38 kDa protein entrapped in microparticles which were subsequently infected with live tubercle bacilli . Taken together these results indicate that biodegradable P00747 microparticles constitute a favorable candidate vaccine delivery system worthy of further assessment in the quest to develop better and defined agents protecting against tuberculosis . Chronic daily tadalafil prevents the corporal fibrosis and veno-occlusive dysfunction that occurs after cavernosal nerve resection . OBJECTIVES : To determine whether a long-term single daily oral dose of a longer half-life phosphodiesterase-5 ( O76074 ) inhibitor , tadalafil , has a similar effect to that of the shorter half-life O76074 inhibitors sildenafil and vardenafil , and can prevent the fibrosis and resultant corporal veno-occlusive dysfunction ( CVOD ) occurring after cavernosal nerve ( CN ) injury . MATERIALS AND METHODS : Male rats ( 10 per group ) had either a sham operation , unilateral CN resection ( P21554 ) or bilateral P21554 , and were left untreated or given retrolingually 5 mg/kg per day of tadalafil . After 45 days , CVOD was assessed via cavernosometry , and the underlying corporal tissue changes were examined by immunohistochemistry and histochemistry ( followed by quantitative image analysis ) , Western blots , and ad hoc methods . RESULTS : DB00820 treatment normalized the low response to papaverine and high drop rate in the intracavernosal pressure measured by cavernosometry after P21554 compared with sham-operated rats . DB00820 also normalized the increase in penile shaft collagen content , and the reduction in corporal smooth muscle cell ( SMC ) content , SMC/collagen , and replication index , and improved the lower collagen III/I ratio and the increase in apoptotic index , caused by P21554 , compared with sham operation . There were no effects of tadalafil on increased transforming growth factor beta1 , inducible nitric oxide synthase and xanthine oxidoreductase levels . CONCLUSIONS : A long-term single daily dose of tadalafil prevented CVOD and the underlying corporal fibrosis in the rat caused by CN damage , as effectively as the previously reported continuous treatment with vardenafil or sildenafil , through a cGMP-related mechanism that appears to be independent of inducible nitric oxide synthase induction . [ Effects of plasminogen and streptokinase on the vital functions of nervous tissue cells in culture ] . In the protein-deficient media plasminogen stimulated the vital functions of cells and in concentrations 10(-7)-10(-10) M it protected cells of sympathetic ganglia , neocortex and continues cell lines under damaging actions of H2O2 ( 0.0001 M ) , NH4CI ( 0.01 M ) and cooling . DB00086 essentially influenced the mode of damaging effect of DB00171 ( 0.001 M ) . Even a short-term exposition ( 20 min ) of PC12 cells with both proteins ( each in the concentration 10(-9) M ) led to sharp alterations in intracellular DB00171 - or Ca(2+)-activated proteolysis . In some cases plasminogen and streptokinase provided acceleration of cultured tissue maturation , improvement of cell adhesion , high survival rate , the increase in quantity and length of processes and their arborisation . Electronic microscopy established the character of structural rearrangements of nervous tissue cells ( neurons , astrocytes , oligodendrocytes ) , reflecting the protective action of plasminogen and streptokinase . In the presence of plasminogen and especially streptokinase , the total number of cultured glioma P13671 and neuroblastoma IMR-32 cells , the intracellular contents of protein , RNA and DNA increased several-fold . Addition of plasminogen promoted formation of processes by neuroblastoma cells , this suggests initiation of differentiation of cellular elements . In cultures of sensitive and sympathetic ganglia streptokinase increased proliferation of Schwann cells . These proteins did not cause transformation of PC12 enterochromaffine cells to neurons , though plasminogen facilitated it . P00747 addition to cell cultures did not increase fibrinolytic activity of the culture medium in the culture medium , and streptokinase did not lose its plasminogen-activating capacity . Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor/ P04626 -positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F. Hoffmann-La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 -positive metastatic breast cancer , trastuzumab/chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . DB00072 adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single-agent activity in breast cancer , including capecitabine ( DB01101 ; F. Hoffmann-La Roche ) , gemcitabine , and vinorelbine . DB00072 is also being investigated as part of triplet drug regimens . DB00072 has good single-agent activity in first-line therapy . This is of relevance to women with P04626 -positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab-containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible . Dynamic genetic linkage of intermediate blood pressure phenotypes during postural adaptations in a founder population . Blood pressure ( BP ) is a dynamic phenotype that varies rapidly to adjust to changing environmental conditions . Standing upright is a recent evolutionary trait , and genetic factors that influence postural adaptations may contribute to BP variability . We studied the effect of posture on the genetics of BP and intermediate BP phenotypes . We included 384 sib-pairs in 64 sib-ships from families ascertained by early-onset hypertension and dyslipidemia . Blood pressure , three hemodynamic and seven neuroendocrine intermediate BP phenotypes were measured with subjects lying supine and standing upright . The effect of posture on estimates of heritability and genetic covariance was investigated in full pedigrees . Linkage was conducted on 196 candidate genes by sib-pair analyses , and empirical estimates of significance were obtained . A permutation algorithm was implemented to study the postural effect on linkage . ADRA1A , APO , CAST , Q9Y5Q5 , P34998 , P24530 , P09038 , GC , P17302 , Q92953 , P08254 , P01303 , P08235 , P26678 , P37173 , P25445 , and P34981 showed evidence of linkage with any phenotype in the supine position and not upon standing , whereas P15121 , P16671 , P25101 , P12259 , P14780 , PKD2 , P27169 , P37231 , Q9UBK2 , P17252 , and P07949 were specifically linked to standing phenotypes . Genetic profiling was undertaken to show genetic interactions among intermediate BP phenotypes and genes specific to each posture . When investigators perform genetic studies exclusively on a single posture , important genetic components of BP are missed . Supine and standing BPs have distinct genetic signatures . Standardized maneuvers influence the results of genetic investigations into BP , thus reflecting its dynamic regulation . DB00472 induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . DB00472 ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5-HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase-2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX-gavage ( 30mgkg(-1) ) and , a single dose of 1,2 dimethylhydrazine ( Q03001 ; i.p. , 125mgkg(-1) ) . After 6 weeks of FLX-treatment , our results revealed that FLX and nor-fluoxetine ( N-FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5-HT ) levels ( P < 0.05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0.05 ) resulting in lower 5-hydroxyindoleacetic acid ( 5-HIAA ) levels ( P < 0.01 ) and , P28335 receptor mRNA expressions . FLX-treatment decreased dysplastic Q9NQ94 development ( P < 0.01 ) and proliferative process ( P < 0.001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0.05 ) , P15692 ( P < 0.001 ) , and P35354 expression ( P < 0.01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5-HT metabolism and/or its ability to reduce colonic malignant events . P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104-115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2+ or Ca2+ to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104-115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2+ or Ca2+ . TnC and P62158 in the presence of either Ca2+ or Mg2+ bound to the TnI peptide 104-115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N-terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2+ but , in the presence of Mg2+ , did not bind to TnC and only bound weakly to P62158 . DB00623 bound to TnC and P62158 only in the presence of Ca2+ . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0.1 M DB00974 compared with the 0.01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins. ( ABSTRACT TRUNCATED AT 250 WORDS ) Retinoblastoma and the related pocket protein P28749 act as coactivators of Q13562 to enhance gene transcription . Gene inactivation studies have suggested that the product of the retinoblastoma gene , P06400 , is particularly limiting in pituitary pro-opiomelanocortin ( P01189 ) -expressing cell lineages . Indeed , in P06400 knock-out mice , these cells develop tumors with high frequency . To understand the implication of limiting P06400 expression in these cells , we investigated the action of P06400 and its related pocket proteins , P28749 and Q08999 , on P01189 gene transcription . This led to the identification of the neurogenic basic helix-loop-helix transcription factor , Q13562 , as a target of P06400 action . P06400 and to a lesser extent P28749 , but not Q08999 , enhance Q13562 -dependent transcription , and this activity appears to depend on direct protein interactions between the P06400 pocket and the helix-loop-helix domain of Q13562 . In vivo , Q13562 is found in a complex that includes P06400 and also the orphan nuclear receptor NGFI-B , which mediates corticotropin-releasing hormone activation of P01189 transcription . The formation of a similar complex in vitro requires the presence of P06400 as a bridge between Q13562 and NGFI-B . In P01189 -expressing AtT-20 cells , P06400 and P28749 are present on the P01189 promoter and inhibition of their expression through small interfering RNA decreases P01189 mRNA levels . The action of P06400 and its related proteins on P01189 transcription may contribute to the establishment and/or maintenance of the differentiation phenotype . Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender-dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 -length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E(2) ) binding was similar , E(2) stimulated proliferation only in cells from females , and this response was inhibited by anti-estrogens 4-hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E(2) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element-driven reporter gene was stimulated by E(2) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E(2) in two out of five adenocarcinoma cell lines from females , but none from males . E(2) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF-7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males . Central neuropeptide Y enhances bile secretion through vagal and muscarinic but not nitric oxide pathways in rats . Neuropeptide Y ( P01303 ) acts in the central nervous system to regulate gastrointestinal functions in rats and dogs . The effects of intracisternal injection of P01303 on bile secretion and biliary components were investigated in urethane-anesthetized rats with bile duct cannula . Intracisternal P01303 ( 0.02-0.12 nmol ) dose-dependently increased bile secretion by 9. P98173 .5 % . The secretory response occurred within the first 20-40 min and lasted for the 120-min observation period . Intravenous injection of P01303 ( 0.12 nmol ) did not modify bile secretion under identical conditions . Biliary bile acid , phospholipid , and cholesterol secretion were not modified by intracisternal injection of P01303 ( 0.12 nmol ) , whereas bicarbonate was increased by 19.0 +/- 1.7 % from 40 to 120 min after P01303 injection . Cervical cord transection at the P13671 level , acute bilateral adrenalectomy ( -120 min ) , or injection of NG-nitro-L-arginine methyl ester ( 10 mg/kg , IV , -15 min ) , an inhibitor of nitric oxide biosynthesis , did not alter intracisternal P01303 ( 0.12 nmol ) -induced stimulation of bile secretion . Atropine ( 2.0 mg/kg , IP , -30 min ) and bilateral cervical vagotomy ( -120 min ) completely abolished the stimulatory effect of intracisternal P01303 ( 0.12 nmol ) on bile secretion . These findings indicate that P01303 acts in the brain to stimulate bicarbonate-dependent bile secretion through vagal and muscarinic pathways and suggest that peptides in the central nervous system may be involved in the vagal regulation of bile secretion . DB06698 treatment in managing vertigo and improving vestibular compensation : clarification . DB06698 dihydrochloride ( betahistine ) is currently used in the management of vertigo and vestibular pathologies with different aetiologies . The main goal of this review is to clarify the mechanisms of action of this drug , responsible for the symptomatic relief of vertigo and the improvement of vestibular compensation . The review starts with a brief summary recalling the role of histamine as a neuromodulator/neurotransmitter in the control of the vestibular functions , and the role of the histaminergic system in vestibular compensation . Then are presented data recorded in animal models demonstrating that betahistine efficacy can be explained by mechanisms targeting the histamine receptors ( HRs ) at three different levels : the vascular tree , with an increase of cochlear and vestibular blood flow involving the P35367 ; the central nervous system , with an increase of histamine turnover implicating the Q9Y5N1 , and the peripheral labyrinth , with a decrease of vestibular input implying the Q9Y5N1 / Q9H3N8 . Clinical data from vestibular loss patients show the impact of betahistine treatment for the long-term control of vertigo , improvement of balance and quality of life that can be explained by these mechanisms of action . However , two conditions , at least , are required for reaching the betahistine therapeutic effect : the dose and the duration of treatment . Experimental and clinical data supporting these requirements are exposed in the last part of this review . Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35-year-old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0.9 mg/kg of Recombinant Tissue P00747 Activator ( rtPA , DB00009 ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a " neurological dose " of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra-arterial catheter-directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis . DB05039 inhibits tumor cell invasiveness and P14780 expression by suppressing IKK/NF-κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein-coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra-long-acting inhaled β2-agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β-arrestin-2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor-α ( P01375 -α ) -induced NF-κB activity by reducing levels of both phosphorylated-IKK and -IκBα , thereby decreasing NF-κB nuclear translocation and the expression of P14780 , an NF-κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 -α/NF-κB-induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF-κB activity in a β-arrestin2-dependent manner , preventing further lung damage and improving lung function in P48444 patients . Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen-only contraceptives . Many women using progestogen ( P ) -only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to DB00294 users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) -exposed pseudo-pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12- , 18- , 24- and 48-h post-treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre-decidualized state by 48 h post-treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 -positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor-positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using DB00294 who were treated with a single dose of mifepristone . Reduced levels of P12830 correlate with progression of corticotroph pituitary tumours . OBJECTIVES : Loss of P12830 is an important marker of epithelial tumour progression . The aims of this study were to explore whether P12830 expression and localization correlate to corticotroph tumour progression , relate the expression of the P12830 gene ( CDH1 ) to immunohistochemical P12830 staining pattern , and study whether the P12830 levels were correlated to methylation status of the CDH1 promoter region . DESIGN : Immunohistochemical analyses of P12830 protein were performed , as was RT-qPCR of the CDH1 and the P01189 genes . Methylation pattern of the promoter region of CDH1 was measured using pyrosequencing of bisulfite-treated DNA . PATIENTS : Forty-five patients operated at a tertiary referral centre in Oslo , Norway . Adenoma tissue sections and RNA samples from patients with verified Cushing 's disease or Nelson 's syndrome were collected . MEASUREMENTS : Expression of P12830 mRNA and protein in pituitary corticotroph adenomas and average percentage of methylated cytosines in a cytosine-phosphate-guanosine island of the CDH1 promoter . RESULTS : Correlations were observed between tumour progression and both nuclear expression of P12830 and reduced CDH1 mRNA . The P12830 expression was not determined by the methylation pattern of the CDH1 promoter . CONCLUSIONS : Corticotroph tumour progression was associated with reduced expression of the epithelial marker P12830 . Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon-rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 -R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid-like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . DB04839 did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet-related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event . Neuropeptide Y induces cardiomyocyte hypertrophy via calcineurin signaling in rats . Neuropeptide Y ( P01303 ) has been shown to participate in cardiac hypertrophy . However , the mechanisms by which P01303 induces cardiomyocyte hypertrophy are poorly understood . This study tested the hypothesis that P01303 induces cardiomyocyte hypertrophy through Ca2+/ P62158 -dependent calcineurin ( CaN ) pathway in cultured neonatal rat cardiomyocytes . After 24-h treatment , P01303 ( 100 nM ) significantly increased 3H-leucine incorporation and c-Jun mRNA expression , concomitant with augment of CaN activity and protein level in cardiomyocytes compared to those cells without P01303 treatment . The enhancement of 3H-leucine incorporation and c-Jun mRNA expression in cardiomyocytes treated with P01303 were markedly inhibited by cyclosporine A ( DB00091 ) , a selective inhibitor of CaN . We also investigated the effect of P01303 on intracellular Ca2+ level in cardiomyocytes . There were no obvious changes in intracellular Ca2+ level of cytoplasm and nucleus in cardiomyocytes treated with P01303 ( 100 nM ) for 10 min . However , P01303 significantly increased intracellular Ca2+ level of cytoplasm and nucleus in cardiomyocytes after 24-h treatment . The result suggested that P01303 could induce hypertrophy of cardiomyocytes via Ca2+/ P62158 -dependent CaN signal pathway . The enhancement of [Ca2+]i caused by P01303 may activate CaN signal pathways to mediate cardiac hypertrophy . Regulation of Con A-dependent cytokine production from P01730 + and CD8+ T lymphocytes by autosecretion of histamine . OBJECTIVES : Previously we have shown that both P01730 + T cells and CD8+ T cells produce histamine when activated with Con A . The aim of this study was to examine whether cytokine production by these cells is regulated by autosecretion of histamine . MATERIALS : P01730 + and CD8+ T cells were separated from spleen cells of C57BL/6 mice and mice lacking the H1 receptor ( P35367 ) or P25021 , using anti- P01730 +- and anti-CD8+-coupled magnetic beads , respectively . RESULTS : Depletion of the P35367 resulted in decreases in the release of P60568 and P22301 from both P01730 + and CD8+ cells and increases in the release of P05112 from P01730 + T cells and P01579 from CD8+ cells . Mice lacking the P25021 showed up-regulation of P01579 secretion from CD8+ cells and of P05112 from P01730 + and CD8+ T cells . Release of P60568 and P22301 from P01730 + as well as CD8+ cells was down-regulated in these mice . Both P01730 + and CD8+ T cell fractions synthesized histamine , which was enhanced in the P35367 -deficient CD8+ T cells . Treatment of the cells with alpha-fluoromethyl-histidine , a specific inhibitor of HDC , or histaminase increased P01579 from CD8+ cells , whereas it had no appreciable effect on P05112 secretion from P01730 + cells . CONCLUSION : These results suggest that cytokine production by P01730 + and CD8+ T lymphocytes is regulated by autosecretion of histamine . Fluvoxamine exerts anorexic effect in P28335 receptor mutant mice with heterozygous mutation of beta-endorphin gene . Serotonin ( 5-hydroxytryptamine ; 5-HT ) 2C receptors and the downstream melanocortin pathway are suggested to mediate the anorexic effects of m-chlorophenylpiperazine ( mCPP ) and fenfluramine . We previously reported that fluvoxamine , a selective serotonin reuptake inhibitor , together with pharmacological inactivation of P28335 receptors exert feeding suppression through activation of P28222 receptors in mice . Here , we report that fluvoxamine exerted anorexic effects in P28335 receptor mutant mice with heterozygous mutation of beta-endorphin gene ( 2CREnd mice ) , whereas fluvoxamine had no effect on food intake in age-matched wild-type mice and P28335 receptor mutant mice , which are associated with decreases in hypothalamic proopiomelanocortin ( P01189 ) expression . mCPP suppressed food intake in P28335 receptor mutant mice , 2CREnd mice and age-matched wild-type mice . These results suggest that fluvoxamine-induced feeding suppression requires a perturbation of P28335 receptor and beta-endorphin signalling plus functional hypothalamic P01189 activity , whereas mCPP-induced feeding suppression does not always require functional P28335 receptor , beta-endorphin , and P01189 activity in mice . DB06698 ameliorates olanzapine-induced weight gain through modulation of histaminergic , P01303 and AMPK pathways . Olanzapine is widely used to treat schizophrenia and other disorders , but causes adverse obesity and other metabolic side-effects . Both animal and clinical studies have shown that co-treatment with betahistine ( a histaminergic H1 receptor agonist and H3 receptor antagonist ) is effective for ameliorating olanzapine-induced weight gain/obesity . To reveal the mechanisms underlying these effects , this study investigated the effects of co-treatment of olanzapine and betahistine ( O+B ) on expressions of histaminergic H1 receptor ( P35367 ) , AMP-activated protein kinase ( AMPK ) , neuropeptide Y ( P01303 ) , and proopiomelanocortin ( P01189 ) in the hypothalamus associated with reducing olanzapine-induced weight gain . Olanzapine significantly upregulated the mRNA and protein expressions of P35367 , while O+B co-treatment significantly downregulated the P35367 levels , compared to the olanzapine-only treatment group . The P01303 mRNA expression was significantly enhanced by olanzapine , but it was significantly reversed by O+B co-treatment . The hypothalamic P35367 expression was positively correlated with total food intake , and P01303 expression . Olanzapine also increased AMPKα activation measured by the AMPKα phosphorylation ( pAMPKα ) /AMPKα ratio compared with controls , whereas O+B co-treatment decreased the pAMPKα/AMPKα ratio , compared with olanzapine only treatment . The pAMPKα/AMPKα ratio was positively correlated with total food intake and P35367 expression . Although olanzapine administration decreased the P01189 mRNA level , this level was not affected by O+B co-treatment . Therefore , these results suggested that co-treatment with betahistine may reverse olanzapine-induced body weight gain via the P35367 - P01303 and P35367 -pAMPKα pathways . The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor/nuclear receptor interaction . As disconnecting mitogenic signaling from AR-mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR-mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild-type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus . Pharmacological treatment of alcohol dependence : target symptoms and target mechanisms . Alcoholism is a major public health problem and resembles , in many ways , other chronic relapsing medical conditions . At least 2 separate dimensions of its symptomatology offer targetable pathophysiological mechanisms . Systems that mediate positive reinforcement by alcohol are likely important targets in early stages of the disease , particularly in genetically susceptible individuals . In contrast , long term neuroadaptive changes caused by chronic alcohol use primarily appear to affect systems mediating negative affective states , and gain importance following a prolonged history of dependence . Feasibility of pharmacological treatment in alcoholism has been demonstrated by a first wave of drugs which consists of 3 currently approved medications , the aldehyde dehydrogenase blocker disulfiram , the opioid antagonist naltrexone ( NTX ) and the functional glutamate antagonist acamprosate ( ACM ) . The treatment toolkit is likely to be expanded in the near future . This will improve overall efficacy and allow individualized treatment , ultimately taking in account the patient 's genetic makeup . In a second wave , early human efficacy data are available for the 5HT3 antagonist ondansetron , the GABA-B agonist baclofen and the anticonvulsant topiramate . The third wave is comprised of compounds predicted to be effective based on a battery of animal models . Using such models , a short list of additional targets has accumulated sufficient preclinical validation to merit clinical development . These include the cannabinoid P21554 receptor , receptors modulating glutamatergic transmission ( Q14416 , 3 and 5 ) , and receptors for stress-related neuropeptides corticotropin releasing factor ( CRF ) , neuropeptide Y ( P01303 ) and nociceptin . Once novel treatments are developed , the field faces a major challenge to assure their delivery to patients .