interacts_with DB00921?
DB00104 and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy-induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 -stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing 's disease . We have compared the effects of pasireotide and octreotide on adrenalectomy-induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2-6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 -immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 -positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response . The unexpected effect of cyclosporin A on CD56+CD16- and CD56+CD16+ natural killer cell subpopulations . DB00091 ( Q13216 ) is commonly used to prevent graft-versus-host disease . The influence of Q13216 on T-cell function has been extensively investigated ; however , the effect of Q13216 on natural killer ( NK ) cells is less understood . NK cells were cultured with P60568 and P40933 with and without Q13216 for 1 week . Compared with controls , Q13216 -treated cultures showed fewer CD56(+)CD16(+) P55040 (+) NK cells and a reciprocal increase in CD56(+)CD16(-) P55040 (-) cells . These changes were due mainly to a reduced proliferation of the CD56(dim) NK-cell subpopulation and a relative resistance of CD56(bright) NK cells to Q13216 . Following coculture with K562 targets , Q13216 -exposed NK cells differed from controls and lacked Ca(2+) oscillations , nuclear factor of activated T cells ( NFAT ) dephosphorylation , and NFAT nuclear translocation . NK cells cultured in Q13216 retained cytotoxicity against K562 , Raji , and P55040 ligand-expressing lymphoblastoid cells . NK cells cultured in Q13216 showed increases in O14931 and reductions in O95944 and P26718 . Following IL-12 and Q14116 stimulation , Q13216 -treated NK cells showed more P01579 -producing cells . Using in vitro NK-cell differentiation , progenitor cells gave rise to more CD56(+) P55040 (-) NK cells in the presence of Q13216 than controls . Collectively , these studies show that Q13216 influences NK-cell function and phenotype , which may have important implications for graft-versus-leukemia effects . mu-Opioid receptor agonists differentially regulate the expression of miR-190 and Q13562 . The agonists of mu-opioid receptor ( P35372 ) induce extracellular signal-regulated kinase ( P29323 ) phosphorylation through different pathways : morphine uses the protein kinase C ( PKC ) -pathway , whereas fentanyl functions in a beta-arrestin2-dependent manner . In addition , the two pathways result in the different cellular location of phosphorylated P29323 and the activation of different sets of transcriptional factors . In the current study , the influence of the two pathways on the expression of microRNAs ( miRNAs ) was investigated . After treating the primary culture of rat hippocampal neurons and the mouse hippocampi with morphine or fentanyl for 3 days , seven miRNAs regulated by one or two of the agonists were identified . One of the identified miRNAs , miR-190 , was down-regulated by fentanyl but not by morphine . This down-regulation was attenuated by 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene ( U0126 ) , which blocks the phosphorylation of P29323 . When fentanyl-induced but not morphine-induced P29323 phosphorylation was blocked in the primary cultures from beta-arrestin2(-/-) mouse , fentanyl did not decrease the expression of miR-190 . However , a PKC inhibitor that blocked morphine-induced P29323 phosphorylation specifically had no effect on the miR-190 down-regulation . Therefore the decrease in miR-190 expression resulted from the agonist-selective P29323 phosphorylation . In addition , the expressional changes in one of the miR-190 targets , neurogenic differentiation 1 ( Q13562 ) , correlated with those in miR-190 expression , suggesting the P35372 could regulate the Q13562 pathways via the control of miR-190 expression . The P35372 promotes opioid and growth factor-induced proliferation , migration and Epithelial Mesenchymal Transition ( EMT ) in human lung cancer . Recent epidemiologic studies implying differences in cancer recurrence based on anesthetic regimens raise the possibility that the mu opioid receptor ( MOR ) can influence cancer progression . Based on our previous observations that overexpression of MOR in human non-small cell lung cancer ( NSCLC ) cells increased tumor growth and metastasis , this study examined whether MOR regulates growth factor receptor signaling and epithelial mesenchymal transition ( EMT ) in human NSCLC cells . We utilized specific siRNA , shRNA , chemical inhibitors and overexpression vectors in human H358 NSCLC cells that were either untreated or treated with various concentrations of DAMGO , morphine , fentanyl , P01133 or IGF . Cell function assays , immunoblot and immunoprecipitation assays were then performed . Our results indicate MOR regulates opioid and growth factor-induced P01133 receptor signaling ( Src , Gab-1 , PI3K , Akt and P40763 activation ) which is crucial for consequent human NSCLC cell proliferation and migration . In addition , human NSCLC cells treated with opioids , growth factors or MOR overexpression exhibited an increase in snail , slug and vimentin and decrease ZO-1 and claudin-1 protein levels , results consistent with an EMT phenotype . Further , these effects were reversed with silencing ( shRNA ) or chemical inhibition of MOR , Src , Gab-1 , PI3K , Akt and P40763 ( p < 0.05 ) . Our data suggest a possible direct effect of MOR on opioid and growth factor-signaling and consequent proliferation , migration and EMT transition during lung cancer progression . Such an effect provides a plausible explanation for the epidemiologic findings . Comparison of three GPCR structural templates for modeling of the Q9H244 nucleotide receptor . The P2Y(12) receptor ( P2Y(12)R ) is an ADP-activated G protein-coupled receptor ( GPCR ) that is an important target for antithrombotic drugs . Three homology models of P2Y(12)R were compared , based on different GPCR structural templates : bovine rhodopsin ( bRHO ) , human A(2A) adenosine receptor ( A(2A)AR ) , and human P61073 ( P61073 ) . By criteria of sequence analysis ( 25.6 % identity in transmembrane region ) , deviation from helicity in the second transmembrane helix ( TM2 ) , docked poses of ligands highlighting the role of key residues , accessibility of a conserved disulfide bridge that is reactive toward irreversibly-binding antagonists , and the presence of a shared disulfide bridge between the third extracellular loop ( EL3 ) and the N-terminus , the P61073 -based model appeared to be the most consistent with known characteristics of P2Y(12)R . The docked poses of agonist 2MeSADP and charged anthraquinone antagonist PSB-0739 in the binding pocket of P2Y(12)R-CXC agree with previously published site-directed mutagenesis studies of Arg256 and Lys280 . A sulfonate at position 2 of the anthraquinone core created a strong interaction with the Lys174(EL2) side chain . The docking poses of the irreversibly-binding , active metabolite ( existing as two diastereoisomers in vivo ) of the clinically utilized antagonist DB00758 were compared . The free thiol group of the 4S diastereoisomer , but not the 4R isomer , was found in close proximity ( ~4.7 Å ) to the sulfur atom of a disulfide bridge involving Cys175 , suggesting greater activity in covalent binding . Therefore , ligand docking to the P61073 -based model of the P2Y(12)R predicted poses of both reversibly and irreversibly-binding small molecules , consistent with observed pharmacology and mutagenesis studies . Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time-averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . DB04844 almost abolished phasic dopamine release but increased extracellular dopamine to ∼500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20-30 nM ) and largely arises from phasic dopamine transients . Non-human primate models of alcohol-related phenotypes : the influence of genetic and environmental factors . Because of their complex social structures , behaviors , and genetic similarities to humans , nonhuman primates are useful for studying how genetic factors influence alcohol consumption . The neurobiological systems that influence addiction vulnerability may do so by acting on alcohol response , reward pathways , behavioral dyscontrol , and vulnerability to stress and anxiety . Rhesus macaques show individual differences in alcohol response and temperament , and such differences are influenced by genetic variants that are similar functionally to those present in humans . Genes at which variation moderates these phenotypes include those encoding monoamine oxidase A ( P21397 -LPR ) , the serotonin transporter ( HTTLPR ) , corticotropin releasing hormone ( P06850 -248C/T and -2232 C/G ) , Neuropeptide Y ( P01303 -1002 T/G ) , and the μ-opioid receptor ( P35372 C77G ) . These provide opportunities for modeling how genetic and environmental factors ( i.e. , stress , individual 's sex , or alcohol exposure ) interact to influence alcohol consumption . Studies in primates may also reveal selective factors have driven maintenance or fixation of alleles that increase risk for alcohol use disorders in modern humans . Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer : a pilot study . PURPOSE : Severe chemotherapy-induced gastrointestinal toxicity ( CIGT ) is common and results in treatment delays , dose reductions , and potential premature treatment discontinuation . Currently , there is no diagnostic marker to predict CIGT . Proinflammatory cytokines , produced via toll-like receptor signaling , are key mediators of this toxicity . Hence , this pilot study investigated the association between immune genetic variability and severe CIGT risk . METHODS : Genomic DNA from 34 patients ( 10 with severe CIGT ) who had received 5-fluoruracil-based chemotherapy regimens was analyzed for variants of IL-1B , P60568 , P05231 , IL-6R , P22301 , P01375 , TGF-b , O60603 , O00206 , Q9Y6Y9 , Q99836 , P23560 , CRP , ICE , and P35372 . Multivariate logistic regression created a prediction model of severe CIGT risk . RESULTS : There were no significant differences between patients with and without severe CIGT with regards to age , sex , type of cancer , or chemotherapy treatment regimens . The prediction model of severe CIGT risk included O60603 and P01375 genetic variability and cancer type ( colorectal and gastric ) . This prediction model was both specific and sensitive , with a receiver operator characteristic area under the curve of 87.3 % . CONCLUSIONS : This is the first report of immune genetic variability , together with cancer type , being predictive of severe CIGT risk . These outcomes are being validated in a larger patient population . A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue-specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two-hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 's DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull-down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co-immunoprecipitation of Q9Y6X2 . Co-transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP-6 promoter-luciferase reporter demonstrated up to 94 % inhibition of O75030 -mediated transcriptional activation . Using a gel-shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development . P35372 phosphorylation , desensitization , and ligand efficacy . Mu opioid receptors are subject to phosphorylation and desensitization through actions of at least two distinct biochemical pathways : agonist-dependent mu receptor phosphorylation and desensitization induced by a biochemically distinct second pathway dependent on protein kinase C activation ( 1 ) . To better understand the nature of the agonist-induced mu receptor phosphorylation events , we have investigated the effects of a variety of opiate ligands of varying potencies and intrinsic activities on mu receptor phosphorylation and desensitization . Exposure to the potent full agonists sufentanil , dihydroetorphine , etorphine , etonitazine , and [ D-Ala2 , MePhe4 , Glyol5 ] enkephalin ( DAMGO ) led to strong receptor phosphorylation , while methadone , l-alpha-acetylmethadone ( DB01227 ) , morphine , meperidine , DADL , beta-endorphin(1-31) , enkephalins , and dynorphin A(1-17) produced intermediate effects . The partial agonist buprenorphine minimally enhanced receptor phosphorylation while antagonists failed to alter phosphorylation . DB00921 and full antagonists each antagonized the enhanced mu receptor phosphorylation induced by morphine or DAMGO . The rank order of opiate ligand efficacies in producing mu receptor-mediated functional desensitization generally paralleled their rank order of efficacies in producing receptor phosphorylation . Interestingly , the desensitization and phosphorylation mediated by methadone and DB01227 were disproportionate to their efficacies in two distinct test systems . This generally good fit between the efficacies of opiates in mu receptor activation , phosphorylation , and desensitization supports the idea that activated receptor/agonist/G-protein complexes and/or receptor conformational changes induced by agonists are required for agonist-induced mu receptor phosphorylation . Data for methadone and DB01227 suggest possible contribution from their enhanced desensitizing abilities to their therapeutic efficacies . Influence of a 3-day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug-drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . DB00207 was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg/day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C(max) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5/day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98,116 ) and 119 ( 104,136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg/dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together . Differential expression of the alternatively spliced P35372 isoform μ-opioid receptor-1K in HIV-infected individuals . OBJECTIVE : We previously examined the expression of specific C-terminal μ-opioid receptor ( MOR ) splice variants in human central nervous system cell types and HIV-infected brain tissue from individuals with neurocognitive impairment ± HIV encephalitis ( HIVE ) . In the present study , we examined the N-terminal splice variant MOR-1K , which mediates excitatory cellular signaling . METHODS AND RESULTS : We found segregation of expression ranging from undetectable to seemingly exclusive across nervous system cell types compared to the pool of C-terminal MOR splice variants using the real-time polymerase chain reaction ( RT-PCR ) . Expression of MOR-1K mRNA was also increased in HIV-infected individuals with combined neurocognitive impairment and HIVE compared with the other groups . MOR-1K expression correlated with the level of patient neurocognitive impairment , whereas the pool of C-terminal MOR splice variants did not . HIVE was also associated with increased expression of the inflammatory mediators P13500 , P80075 , and RANTES , but not the host HIV coreceptors P61073 and P51681 or the P01730 receptor using qRT-PCR . Network analysis of microarray data from these same patients revealed filamin A ( P21333 ) as a possible interaction partner with MOR-1K , and P21333 gene expression was also found to be upregulated in HIVE using qRT-PCR . Overexpression of P21333 in HEK293 cells redistributed MOR-1K from intracellular compartments to the cell surface . CONCLUSION : These results suggest that HIVE , and neurocognitive impairment depending on its severity , are associated with enhanced MOR-1K signaling through both increased expression and trafficking to the cell surface , which may alter the contribution of MOR receptor isoforms and exacerbate the effects of MOR activation in neuroAIDS . [ 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 . Generation and properties of a new human ventral mesencephalic neural stem cell line . Neural stem cells ( NSCs ) are powerful research tools for the design and discovery of new approaches to cell therapy in neurodegenerative diseases like Parkinson 's disease . Several epigenetic and genetic strategies have been tested for long-term maintenance and expansion of these cells in vitro . Here we report the generation of a new stable cell line of human neural stem cells derived from ventral mesencephalon ( hVM1 ) based on v-myc immortalization . The cells expressed neural stem cell and radial glia markers like nestin , vimentin and 3CB2 under proliferation conditions . After withdrawal of growth factors , proliferation and expression of v-myc were dramatically reduced and the cells differentiated into astrocytes , oligodendrocytes and neurons . hVM1 cells yield a large number of dopaminergic neurons ( about 12 % of total cells are TH+ ) after differentiation , which also produce dopamine . In addition to proneural genes ( Q9H2A3 , MASH1 ) , differentiated cells show expression of several genuine mesencephalic dopaminergic markers such as : Q8TE12 , O60663 , P48051 , P00325 , P43354 , O75364 , Q05940 and Q01959 , indicating that they retain their regional identity . Our data indicate that this cell line and its clonal derivatives may constitute good candidates for the study of development and physiology of human dopaminergic neurons in vitro , and to develop tools for Parkinson 's disease cell replacement preclinical research and drug testing . DB00338 , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . DB00338 is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P-type H+/K+ ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . DB00338 topically applied to the skin of UV-irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . DB00338 had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P-type ATPase in the trans-Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans-Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . DB00338 treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase . P15056 inhibitors suppress apoptosis through off-target inhibition of JNK signaling . DB08881 and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug-induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib/PLX4720 in suppressing apoptosis through the inhibition of multiple off-target kinases upstream of c-Jun N-terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib-treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK-dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http://dx.doi.org/10.7554/eLife.00969.001 . Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol-A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER-labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER-labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER-labelled neurons in the VMH . EE and Q03001 increased ER-labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats . Association of polymorphisms in nicotinic acetylcholine receptor alpha 4 subunit gene ( P43681 ) , mu-opioid receptor gene ( P35372 ) , and ethanol-metabolizing enzyme genes with alcoholism in Korean patients . Findings obtained from several studies indicate that ethanol enhances the activity of alpha4beta2 neuronal nicotinic acetylcholine receptor and support the possibility that a polymorphism of the nicotinic acetylcholine receptor alpha4 subunit gene ( P43681 ) modulates enhancement of nicotinic receptor function by ethanol . To identify the association between the CfoI polymorphism of the P43681 and alcoholism , we examined distribution of genotypes and allele frequencies in Korean patients diagnosed with alcoholism ( n = 127 ) and Korean control subjects without alcoholism ( n = 185 ) with polymerase chain reaction-restriction fragment length polymorphism methods . We were able to detect the association between the CfoI polymorphism of the P43681 and alcoholism in Korean patients ( genotype P = .023 ; allele frequency P = .047 ) . The genotypes and allele frequencies of known polymorphisms in other alcoholism candidate genes , such as alcohol metabolism-related genes [ alcohol dehydrogenase 2 ( P00325 ) , aldehyde dehydrogenase 2 ( P05091 ) , alcohol dehydrogenase 3 ( P00326 ) , and cytochrome P450 2E1 ( P05181 ) ] and mu-opioid receptor gene ( P35372 ) , were studied . The polymorphisms of P00325 , P05091 , and P05181 were significantly different in Korean patients with alcoholism and Korean control subjects without alcoholism , but P00326 and P35372 did not differ between the two groups . DB06643 -- an emerging treatment for postmenopausal osteoporosis . IMPORTANCE OF THE FIELD : Osteoporosis is a common skeletal disease that is associated with an imbalance in bone remodeling . DB06643 is an investigational fully human monoclonal antibody to receptor activator of NF-kappaB ligand ( O14788 ) , a cytokine member of the P01375 family that is the principal mediator of osteoclastic bone resorption . AREAS COVERED IN THIS REVIEW : The efficacy and safety of denosumab in the management of postmenopausal osteoporosis is evaluated by reviewing the published literature and presentations at scientific meetings through 2009 . WHAT THE READER WILL GAIN : This review focuses on the data on fracture risk reduction and safety endpoints of denosumab in the treatment of postmenopausal osteoporosis . TAKE HOME MESSAGE : In postmenopausal women with osteoporosis , denosumab ( 60 mg by subcutaneous injection every 6 months ) increased bone mineral density , reduced bone turnover markers , and reduced the risk of vertebral , hip and non-vertebral fractures . DB06643 was well tolerated with a safety profile generally similar to placebo . It is a promising emerging drug for the prevention and treatment of postmenopausal osteoporosis . DB00227 , a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3-Hydroxy-3-methylglutaryl coenzyme A ( HMG- DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization/flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3-dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer . Clinical and genetic factors associated with nausea and vomiting in cancer patients receiving opioids . BACKGROUND : This study investigates whether demographical , disease-related and genetic factors contribute to inter-individual differences in nausea and vomiting among patients receiving opioids for cancer pain . METHODS : Cancer patients receiving opioids were included from 17 centres in 11 European countries . Intensities of nausea and vomiting were reported by 1579 patients on four-point categorical scales . In stratified regression models including demographical and disease-related factors as covariates , 96 single nucleotide polymorphisms ( SNPs ) in 16 candidate genes related to opioid- or nausea/vomiting signalling pathways ( P08183 , P35372 , P41145 , P32121 , P42226 , P21964 , P20309 , P08912 , P35367 , P14416 , P35462 , P25103 , P46098 , O95264 , Q8WXA8 , P21554 ) were analysed for association with nausea and vomiting . FINDINGS : Age , body mass index , Karnofsky Performance Status , gender , use of antiemetics , type of opioid , type of cancer and eight SNPs were associated with the inter-individual differences in nausea and vomiting among cancer patients treated with opioids ( p < 0.01 ) . The SNPs were rs1176744 , rs3782025 and rs1672717 in O95264 ; rs165722 , rs4680 and rs4633 in P21964 ; rs10802789 and rs685550 in P20309 . Only the SNP rs1672717 in O95264 passed the Benjamini-Hochberg criterion for a 10 % false discovery rate . INTERPRETATION : Clinical characteristics and SNPs within the O95264 , P21964 and P20309 genes may be associated with the variability in nausea and vomiting among cancer patients receiving opioids . This knowledge may help to identify patients at particular risk for nausea and vomiting during treatment with opioids for cancer pain .