interacts_with DB00184?
P03952 suppresses tumor growth and is decreased in squamous cell carcinoma of the skin . Non-melanoma skin cancer represents the most common cancer in the United States . Squamous cell carcinoma ( SCC ) of the skin is a subtype of NMSC that shows a greater potential for invasion and metastasis . The current study identifies the protein kinase C-associated kinase ( P03952 ) , which is also known as the receptor-interacting protein kinase 4 , as a suppressor of tumor growth in SCC of the skin . We show that expression of P03952 is decreased in human SCC of the skin compared with normal skin . Further , suppression of P03952 in human keratinocytes leads to increased cell proliferation . The use of RNA interference to reduce P03952 expression in keratinocytes leads to an increase in S phase and in proteins that promote cell cycle progression . Consistent with the results obtained from cell culture , there is a marked increased tumorigenesis after P03952 knockdown in a xenotransplant model and in soft agar assays . The loss of tumor suppression involves the NF-κB and p63 pathways . NF-κB is inhibited through inhibition of inhibitor of NF-κB kinase function and there is increased nuclear Q9H3D4 activity after P03952 knockdown . This study opens new avenues both in the discovery of disease pathogenesis and for potential treatments . Determination of the dose of agomelatine , a melatoninergic agonist and selective 5-HT(2C) antagonist , in the treatment of major depressive disorder : a placebo-controlled dose range study . DB06594 ( S 20098 ) has a unique and new pharmacological profile . It is a melatoninergic agonist and selective antagonist of P28335 receptors , and has been shown to be active in several animal models of depression . The aim of this study was to determine the active dose of agomelatine in the treatment of major depressive disorder ( DSM-IV criteria ) . The methodology used was a conventional double-blind design comparing three different doses of agomelatine ( 1 , 5 and 25 mg once a day ) with placebo over an 8-week treatment period . Paroxetine was used as the study validator . Seven hundred and eleven patients with a baseline mean score of 27.4 on the 17-item Hamilton Rating Scale for Depression ( HAM-D ) were included . On the pivotal analysis , the mean final HAM-D total score ( Q8N1N2 Analysis Set LOCF ) demonstrated agomelatine 25 mg to be statistically more effective than placebo . This was confirmed by other analyses and criteria ( responders , remission , subpopulation of severely depressed patients , Montgomery-Asberg Depression Rating Scale , Clinical Global Impression-Severity of Illness ) . DB06594 25 mg alleviated the anxiety associated with depression , as measured on Hamilton Anxiety Scale . Paroxetine was found to be effective on pivotal analysis and most of the secondary criteria used to validate the study methodology and population . DB06594 , whatever the dose , showed good acceptability with a side-effects profile close to that of placebo . In conclusion , this study demonstrates that agomelatine is efficient in the treatment of major depressive disorder and that 25 mg is the target dose . P30532 gene D398N polymorphism in Japanese lung adenocarcinoma . BACKGROUND : Recently , to identify genetic factors that modify lung cancer risk , P30532 non-synonymous variant amino acid position 398 ( D398N ) was identified . The site was a highly conserved in the second cellular loop of the nicotinic acetylcholine receptor subunit protein . MATERIALS AND METHODS : We have investigated P30532 gene polymorphism status in 302 surgically treated lung adenocarcinoma cases from Nagoya City University Hospital . The presence or absence of P30532 polymorphism was analyzed by direct sequences . P00533 mutations status was already investigated and reported . RESULTS : We detected nine cases ( 2.98 % ) of P30532 polymorphism ( D398N ) in our cohort . Total P00533 mutations were present in 129 patients ( 42.7 % ) . The polymorphism statuses were not correlated with gender ( women ; 2.1 % versus men ; 3.7 % , P = 0.5119 ) , smoking status ( never smoker ; 2.0 % versus smoker ; 4.0 % , P = 0.3339 ) , pathological stages ( stage I ; 2.6 % versus stage II-IV ; 3.8 % , P = 0.7246 ) , and P00533 mutation status of the lung adenocarcinomas ( mutation ; 2.3 % versus wild type ; 3.7 % , P = 0.7373 ) . In this analysis , P30532 polymorphism ( D398N ) patients had significantly worse prognosis ( 5/9 were dead ; mean survival = 27.1 mo ) than the patients with P30532 wild type ( 74/293 were dead ; mean survival = 113.9 mo ) ( log-rank test ; P = 0.0146 ) . CONCLUSION : Although P30532 polymorphism is rare from Japanese lung cancer , polymorphism status might be correlated with shorter survival . The effects of mitiglinide ( KAD-1229 ) , a new anti-diabetic drug , on DB00171 -sensitive K+ channels and insulin secretion : comparison with the sulfonylureas and nateglinide . DB01252 ( KAD-1229 ) , a new anti-diabetic drug , is thought to stimulate insulin secretion by closing the DB00171 -sensitive K+ ( K( DB00171 ) ) channels in pancreatic beta-cells . However , its selectivity for the various K( DB00171 ) channels is not known . In this study , we examined the effects of mitiglinide on various cloned K( DB00171 ) channels ( Kir6.2/ Q09428 , Kir6.2/SUR2A , and Kir6.2/SUR2B ) reconstituted in COS-1 cells , and compared them to another meglitinide-related compound , nateglinide . Patch-clamp analysis using inside-out recording configuration showed that mitiglinide inhibits the Kir6.2/ Q09428 channel currents in a dose-dependent manner ( IC50 value , 100 nM ) but does not significantly inhibit either Kir6.2/SUR2A or Kir6.2/SUR2B channel currents even at high doses ( more than 10 microM ) . DB00731 inhibits Kir6.2/ Q09428 and Kir6.2/SUR2B channels at 100 nM , and inhibits Kir6.2/SUR2A channels at high concentrations ( 1 microM ) . Binding experiments on mitiglinide , nateglinide , and repaglinide to Q09428 expressed in COS-1 cells revealed that they inhibit the binding of [3H]glibenclamide to Q09428 ( IC50 values : mitiglinide , 280 nM ; nateglinide , 8 microM ; repaglinide , 1.6 microM ) , suggesting that they all share a glibenclamide binding site . The insulin responses to glucose , mitiglinide , tolbutamide , and glibenclamide in MIN6 cells after chronic mitiglinide , nateglinide , or repaglinide treatment were comparable to those after chronic tolbutamide and glibenclamide treatment . These results indicate that , similar to the sulfonylureas , mitiglinide is highly specific to the Kir6.2/ Q09428 complex , i.e. , the pancreatic beta-cell K( DB00171 ) channel , and suggest that mitiglinide may be a clinically useful anti-diabetic drug . A Q8NBP7 -binding antibody that structurally mimics the P01133 (A) domain of LDL-receptor reduces LDL cholesterol in vivo . Proprotein convertase subtilisin-like/kexin type 9 ( Q8NBP7 ) regulates LDL cholesterol levels by inhibiting P01130 ( LDLr ) -mediated cellular LDL uptake . We have identified a fragment antigen-binding ( Fab ) 1D05 which binds Q8NBP7 with nanomolar affinity . The fully human antibody 1D05-IgG2 completely blocks the inhibitory effects of wild-type Q8NBP7 and two gain-of-function human Q8NBP7 mutants , S127R and D374Y . The crystal structure of 1D05-Fab bound to Q8NBP7 reveals that 1D05-Fab binds to an epitope on the Q8NBP7 catalytic domain which includes the entire LDLr P01133 (A) binding site . Notably , the 1D05-Fab CDR-H3 and CDR-H2 loops structurally mimic the P01133 (A) domain of LDLr . In a transgenic mouse model ( P11597 /LDLr-hemi ) , in which plasma lipid and Q8NBP7 profiles are comparable to those of humans , 1D05-IgG2 reduces plasma LDL cholesterol to 40 % and raises hepatic LDLr protein levels approximately fivefold . Similarly , in healthy rhesus monkeys , 1D05-IgG2 effectively reduced LDL cholesterol 20 % -50 % for over 2 weeks , despite its relatively short terminal half-life ( t(1/2) = 3.2 days ) . Importantly , the decrease in circulating LDL cholesterol corresponds closely to the reduction in free Q8NBP7 levels . Together these results clearly demonstrate that the LDL-lowering effect of the neutralizing anti- Q8NBP7 1D05-IgG2 antibody is mediated by reducing the amount of Q8NBP7 that can bind to the LDLr . Reopening of DB00171 -sensitive potassium channels reduces neuropathic pain and regulates astroglial gap junctions in the rat spinal cord . DB00171 -sensitive potassium ( K( DB00171 ) ) channels are suggested to be involved in pathogenesis of neuropathic pain , but remain underinvestigated in primary afferents and in the spinal cord . We examined alterations of K( DB00171 ) channels in rat spinal cord and tested whether and how they could contribute to neuropathic pain . The results showed that protein expression for K( DB00171 ) channel subunits Q09428 , SUR2 , and Kir6.1 , but not Kir6.2 , were significantly downregulated and associated with thermal hyperalgesia and mechanical allodynia after sciatic nerve injury . Spinal administration of a K( DB00171 ) channel opener cromakalim ( CRO , 5 , 10 , and 20 μg , respectively ) prevented or suppressed , in a dose-dependent manner , the hyperalgesia and allodynia . Nerve injury also significantly increased expression and phosphorylation of connexin 43 , an astroglial gap junction protein . Such an increase of phosphorylation of connexin 43 was inhibited by CRO treatment . Furthermore , preadministration of an astroglial gap junction decoupler carbenoxolone ( 10 μg ) completely reversed the inhibitory effects of CRO treatment on the hyperalgesia and allodynia and phosphorylation of Q9UHB4 and Q13224 receptors and the subsequent activation of Ca(2+)-dependent signals Ca(2+)/calmodulin-dependent kinase II and cyclic adenosine monophosphate ( DB02527 ) response element binding protein . These findings suggest that nerve injury-induced downregulation of the K( DB00171 ) channels in the spinal cord may interrupt the astroglial gap junctional function and contribute to neuropathic pain , thus the K( DB00171 ) channels opener can reduce neuropathic pain probably partly via regulating the astroglial gap junctions . This study may provide a new strategy for treating neuropathic pain using K( DB00171 ) channel openers in the clinic . Incorporating age at onset of smoking into genetic models for nicotine dependence : evidence for interaction with multiple genes . DB00184 dependence is moderately heritable , but identified genetic associations explain only modest portions of this heritability . We analyzed 3369 SNPs from 349 candidate genes and investigated whether incorporation of SNP-by-environment interaction into association analyses might bolster gene discovery efforts and prediction of nicotine dependence . Specifically , we incorporated the interaction between allele count and age at onset of regular smoking ( AOS ) into association analyses of nicotine dependence . Subjects were from the Collaborative Genetic Study of DB00184 Dependence and included 797 cases ascertained for Fagerström nicotine dependence and 811 non-nicotine-dependent smokers as controls , all of European descent . Compared with main effect models , SNP x AOS interaction models resulted in higher numbers of nominally significant tests , increased predictive utility at individual SNPs and higher predictive utility in a multi-locus model . Some SNPs previously documented in main effect analyses exhibited improved fits in the joint analysis , including rs16969968 from P30532 and rs2314379 from Q9Y6R4 . P30532 exhibited larger effects in later-onset smokers , in contrast with a previous report that suggested the opposite interaction ( Weiss et al. 2008 ) . However , a number of SNPs that did not emerge in main effect analyses were among the strongest findings in the interaction analyses . These include SNPs located in Q13224 ( P = 1.5 x 10(-5) ) , which encodes a subunit of the N-methyl-D-aspartate receptor channel , a key molecule in mediating age-dependent synaptic plasticity . Incorporation of logically chosen interaction parameters , such as AOS , into genetic models of substance use disorders may increase the degree of explained phenotypic variation and constitutes a promising avenue for gene discovery . Rare human nicotinic acetylcholine receptor α4 subunit ( P43681 ) variants affect expression and function of high-affinity nicotinic acetylcholine receptors . DB00184 , the primary psychoactive component in tobacco smoke , produces its behavioral effects through interactions with neuronal nicotinic acetylcholine receptors ( nAChRs ) . α4β2 nAChRs are the most abundant in mammalian brain , and converging evidence shows that this subtype mediates the rewarding and reinforcing effects of nicotine . A number of rare variants in the P43681 gene that encode the α4 nAChR subunit have been identified in human subjects and appear to be underrepresented in a cohort of smokers . We compared three of these variants ( α4R336C , α4P451L , and α4R487Q ) to the common variant to determine their effects on α4β2 nAChR pharmacology . We examined [(3)H]epibatidine binding , interacting proteins , and phosphorylation of the α4 nAChR subunit with liquid chromatography and tandem mass spectrometry ( LC-MS/MS ) in P29320 293 cells and voltage-clamp electrophysiology in Xenopus laevis oocytes . We observed significant effects of the α4 variants on nAChR expression , subcellular distribution , and sensitivity to nicotine-induced receptor upregulation . Proteomic analysis of immunopurified α4β2 nAChRs incorporating the rare variants identified considerable differences in the intracellular interactomes due to these single amino acid substitutions . Electrophysiological characterization in X. laevis oocytes revealed alterations in the functional parameters of activation by nAChR agonists conferred by these α4 rare variants , as well as shifts in receptor function after incubation with nicotine . Taken together , these experiments suggest that genetic variation at P43681 alters the assembly and expression of human α4β2 nAChRs , resulting in receptors that are more sensitive to nicotine exposure than those assembled with the common α4 variant . The changes in nAChR pharmacology could contribute to differences in responses to smoked nicotine in individuals harboring these rare variants . Met326Ile aminoacid polymorphism in the human p85 alpha gene has no major impact on early insulin signaling in type 2 diabetes . Class I alpha phosphatidylinositol ( PI ) 3-kinase is an important enzyme in the early insulin signaling cascade , and plays a key role in insulin-mediated glucose transport . Despite extensive investigation , the genes responsible for the development of the common forms of type 2 diabetes remain unknown . This study was performed to identify variants in the coding region of p85 alpha , the regulatory subunit of PI 3-kinase . Fibroblasts from skin biopsies from type 2 diabetics and controls were established to address this issue . P85 alpha cDNA was sequenced , and a single point mutation at codon 326 was found . This mutation resulted in a homozygous missense amino acid change DB00134 --> DB00167 in one subject with type 2 diabetes and heterozygous variant in two other diabetic patients and one with severe insulin resistance . Interestingly , those patients revealed an impaired insulin-mediated insulin receptor substrate ( P41252 ) -1 binding to p85 alpha without any alteration in Q9Y4H2 /p85 alpha association . Furthermore , P35568 , Q9Y4H2 , p85 alpha and MAPK protein contents were not significantly changed , and neither were MAPK or Akt phosphorylation . We conclude from our data that this variant may have only minor impact on signaling events ; however , in combination with variants in other genes encoding signaling proteins , this may have a functional impact on early insulin signaling . Inhibition of cholinergic signaling causes apoptosis in human bronchioalveolar carcinoma . Recent case-controlled clinical studies show that bronchioalveolar carcinomas ( BAC ) are correlated with smoking . DB00184 , the addictive component of cigarettes , accelerates cell proliferation through nicotinic acetylcholine receptors ( nAChR ) . In this study , we show that human BACs produce acetylcholine ( ACh ) and contain several cholinergic factors including acetylcholinesterase ( P22303 ) , choline acetyltransferase ( P28329 ) , choline transporter 1 ( Q9GZV3 , Q9GZV3 ) , vesicular acetylcholine transporter ( Q16572 , Q16572 ) , and nACh receptors ( AChRs , CHRNAs ) . DB00184 increased the production of ACh in human BACs , and ACh acts as a growth factor for these cells . DB00184 -induced ACh production was mediated by α7- , α3β2- , and β3-nAChRs , P28329 and Q16572 pathways . We observed that nicotine upregulated P28329 and Q16572 . Therefore , we conjectured that Q16572 antagonists , such as vesamicol , may suppress the growth of human BACs . Vesamicol induced potent apoptosis of human BACs in cell culture and nude mice models . Vesamicol did not have any effect on P01133 or insulin-like growth factor-II-induced growth of human BACs. siRNA-mediated attenuation of Q16572 reversed the apoptotic activity of vesamicol . We also observed that vesamicol inhibited Akt phosphorylation during cell death and that overexpression of constitutively active Akt reversed the apoptotic activity of vesamicol . Taken together , our results suggested that disruption of nicotine-induced cholinergic signaling by agents such as vesamicol may have applications in BAC therapy . Tetrathiafulvalene-1,3,5-triazines as (multi)donor-acceptor systems with tunable charge transfer : structural , photophysical , and theoretical investigations . Palladium-catalyzed cross-coupling reactions between chlorinated 1,3,5-triazines ( TZ ) and tetrathiafulvalene ( Q15669 ) trimethyltin derivatives afford mono- and P01024 symmetric tris( Q15669 )-triazines as donor-acceptor compounds in which the intramolecular charge transfer ( ICT ) is modulated by the substitution scheme on Q15669 and TZ and by chemical or electrochemical oxidation . The Q15669 -TZ-Cl2 and (SMe)2TTF-TZ-Cl2 derivatives show fully planar structures in the solid state as a consequence of the conjugation between the two units . Electrochemical and photophysical investigations , supported by theoretical calculations , clearly demonstrate that the lowest excited state can be ascribed to the intramolecular charge transfer ( ICT ) π( Q15669 )→π*(TZ) transition . The tris( Q15669 ) compound [(SMe)2TTF]3-TZ shows fluorescence when excited in the ICT band , and the emission is quenched upon oxidation . The radical cations Q15669 (+•) are easily observed in all of the cases through chemical and electrochemical oxidation by steady-state absorption experiments . In the case of [(SMe)2TTF]3-TZ , a low energy band at 5000 cm(-1) , corresponding to a coupling between Q15669 (+•) and Q15669 units , is observed . A crystalline radical cation salt with the Q15669 -TZ-Cl2 donor and PF6(-) anion , prepared by electrocrystallization , is described . Dissection of the phenotypic and genotypic associations with nicotinic dependence . INTRODUCTION : Strong evidence demonstrates that nicotine dependence is associated with 4 genetic variants rs16969968 , rs6474412 , rs3733829 , and rs1329650 in large-scale Genome-Wide Association Studies . We examined how these identified genetic variants relate to nicotine dependence defined by different categorical and dimensional measures . METHODS : Four genetic variants were analyzed in 2,047 subjects of European descent ( 1,062 cases and 985 controls ) . DB00184 dependence was assessed with multiple smoking measures , including the Fagerström Test for DB00184 Dependence , the Diagnostic and Statistical Manual for Mental Disorders-IV ( DSM-IV ) nicotine dependence , the DB00184 Dependence Syndrome Scale , and the Wisconsin Inventory of Smoking Dependence Motives . Single-item measures of cigarettes per day ( O75976 ) and time to first cigarette ( Q15669 ) in the morning were also examined . RESULTS : Among the variants , association effect sizes were largest for rs16969968 , with measures of craving and heavy smoking , especially cigarettes smoked per day , showing the largest effects . Significant but weaker associations were found for rs6474412 and rs3733729 but not for rs1329650 . None of the more comprehensive measures of smoking behaviors yielded stronger genetic associations with these variants than did O75976 . CONCLUSIONS : O75976 is an important simple measure that captures in part the genetic associations of P30532 and nicotine dependence , even when other more comprehensive measures of smoking behaviors are examined . The P30532 gene is associated with heavy compulsive smoking and craving ; this should inform the mission to improve the diagnostic validity of DSM-V . Support for association between ADHD and two candidate genes : NET1 and P21728 . Attention deficit hyperactivity disorder ( ADHD ) is a common , multifactorial disorder with significant genetic contribution . Multiple candidate genes have been studied in ADHD , including the norepinephrine transporter ( NET1 ) and dopamine D1 receptor ( P21728 ) . NET1 is implicated in ADHD because of the efficacy of atomoxetine , a selective noradrenergic reuptake inhibitor , in the treatment of ADHD . P21728 is primarily implicated through mouse models of ADHD . DNA from 163 ADHD probands , 192 parents , and 129 healthy controls was used to investigate possible associations between ADHD and polymorphisms in 12 previously studied candidate genes ( P28222 , 5- Q13049 , P28335 , P08913 , P43681 , P21964 , Q01959 , P21728 , P21917 , P21918 , NET1 , and P60880 ) . Analyses included case-control and family-based methods , and dimensional measures of behavior , cognition , and anatomic brain magnetic resonance imaging ( Q9BWK5 ) . Of the 12 genes examined , two showed a significant association with ADHD . Transmission disequilibrium test ( P04053 ) analysis revealed significant association of two NET1 single nucleotide polymorphisms ( SNPs ) with ADHD ( P < or = 0.009 ) ; case-control analysis revealed significant association of two P21728 SNPs with ADHD ( P < or = 0.008 ) . No behavioral , cognitive , or brain Q9BWK5 volume measurement significantly differed across NET1 or P21728 genotypes at an alpha of 0.01 . This study provides support for an association between ADHD and polymorphisms in both NET1 and P21728 ; polymorphisms in ten other candidate genes were not associated with ADHD . Because family-based and case-control methods gave divergent results , both should be used in genetic studies of ADHD . Financial and psychological risk attitudes associated with two single nucleotide polymorphisms in the nicotine receptor ( P43681 ) gene . With recent advances in understanding of the neuroscience of risk taking , attention is now turning to genetic factors that may contribute to individual heterogeneity in risk attitudes . In this paper we test for genetic associations with risk attitude measures derived from both the psychology and economics literature . To develop a long-term prospective study , we first evaluate both types of risk attitudes and find that the economic and psychological measures are poorly correlated , suggesting that different genetic factors may underlie human response to risk faced in different behavioral domains . We then examine polymorphisms in a spectrum of candidate genes that affect neurotransmitter systems influencing dopamine regulation or are thought to be associated with risk attitudes or impulsive disorders . Analysis of the genotyping data identified two single nucleotide polymorphisms ( SNPs ) in the gene encoding the alpha 4 nicotine receptor ( P43681 , rs4603829 and rs4522666 ) that are significantly associated with harm avoidance , a risk attitude measurement drawn from the psychology literature . Novelty seeking , another risk attitude measure from the psychology literature , is associated with several P21964 ( catechol-O-methyl transferase ) SNPs while economic risk attitude measures are associated with several Q05940 ( vesicular monoamine transporter ) SNPs , but the significance of these associations did not withstand statistical adjustment for multiple testing and requires larger cohorts . These exploratory results provide a starting point for understanding the genetic basis of risk attitudes by considering the range of methods available for measuring risk attitudes and by searching beyond the traditional direct focus on dopamine and serotonin receptor and transporter genes . A common haplotype of the nicotine acetylcholine receptor alpha 4 subunit gene is associated with vulnerability to nicotine addiction in men . DB00184 is the major addictive substance in cigarettes , and genes involved in sensing nicotine are logical candidates for vulnerability to nicotine addiction . We studied six single-nucleotide polymorphisms ( SNPs ) in the P43681 gene and four SNPs in the P17787 gene with respect to nicotine dependence in a collection of 901 subjects ( 815 siblings and 86 parents ) from 222 nuclear families with multiple nicotine-addicted siblings . The subjects were assessed for addiction by both the Fagerstrom Test for DB00184 Dependence ( FTND ) and the Revised Tolerance Questionnaire ( RTQ ) . Because only 5.8 % of female offspring were smokers , only male subjects were included in the final analyses ( 621 men from 206 families ) . Univariate ( single-marker ) family-based association tests ( FBATs ) demonstrated that variant alleles at two SNPs , rs1044396 and rs1044397 , in exon 5 of the P43681 gene were significantly associated with a protective effect against nicotine addiction as either a dichotomized trait or a quantitative phenotype ( i.e. , age-adjusted FTND and RTQ scores ) , which was consistent with the results of the global haplotype FBAT . Furthermore , the haplotype-specific FBAT showed a common ( 22.5 % ) P43681 haplotype , GCTATA , which was significantly associated with both a protective effect against nicotine addiction as a dichotomized trait ( Z=-3.04 , P < .005 ) and significant decreases of age-adjusted FTND ( Z=-3.31 , P < .005 ) or RTQ scores ( Z=-2.73 , P=.006 ) . Our findings provide strong evidence suggesting a common P43681 haplotype might be protective against vulnerability to nicotine addiction in men . DB00184 consumption is regulated by a human polymorphism in dopamine neurons . Smoking is the most important preventable cause of morbidity and mortality worldwide . Recent genome-wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer . Several polymorphisms in the P32297 - P30532 - P30926 cluster coding for the nicotinic acetylcholine receptor ( nAChR ) α3 , α5 and β4 subunits were implicated . In mouse models , we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic ( DAergic ) neurons of the ventral tegmental area ( VTA ) . We first investigated the reinforcing effects of nicotine in drug-naive α5(-/-) mice using an acute intravenous nicotine self-administration task and ex vivo and in vivo electrophysiological recordings of nicotine-elicited DA cell activation . We designed lentiviral re-expression vectors to achieve targeted re-expression of wild-type or mutant α5 in the VTA , in general , or in DA neurons exclusively . Our results establish a crucial role for α5*-nAChRs in DAergic neurons . These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement . Finally , we demonstrate that a single-nucleotide polymorphism , the non-synonymous α5 variant rs16969968 , frequent in many human populations , exhibits a partial loss of function of the protein in vivo . This leads to increased nicotine consumption in the self-administration paradigm . We thus define a critical link between a human predisposition marker , its expression in DA neurons and nicotine intake . DB00184 activates P46937 through nAChRs mediated signaling in esophageal squamous cell cancer ( ESCC ) . Cigarette smoking is an established risk factor for esophageal cancers . P46937 ( P46937 ) , the key transcription factor of the mammalian Hippo pathway , has been reported to be an oncogenic factor for many cancers . In this study , we find nicotine administration can induce nuclear translocation and activation of P46937 in ESCC . Consistently , we observed nuclear translocation and activation of P46937 by knockdown of P32297 , which is a negative regulator of nicotine signaling in bronchial and esophageal cancer cells . DB00184 administration or P32297 depletion substantially increased proliferation and migration in esophageal cancer cells . Interestingly , we find that P46937 physically interacts with nAChRs , and nAChRs-signaling dissociates P46937 from its negative regulatory complex composed with α-catenin , β-catenin and 14-3-3 in the cytoplasm , leading to upregulation and nuclear translocation of P46937 . This process likely requires PKC activation , as PKC specific inhibitor Enzastaurin can block nicotine induced P46937 activation . In addition , we find nicotine signaling also inhibits the interaction of P46937 with Q9H3D4 , which contributes to the inhibitory effect of nicotine on apoptosis . Using immunohistochemistry analysis we observed upregulation of P46937 in a significant portion of esophageal cancer samples . Consistently , we have found a significant association between P46937 upregulation and cigarette smoking in the clinical esophageal cancer samples . Together , these findings suggest that the nicotine activated nAChRs signaling pathway which further activates P46937 plays an important role in the development of esophageal cancer , and this mechanism may be of a general significance for the carcinogenesis of smoking related cancers . Q9Y4H2 Deficiency impairs DB01221 receptor-dependent long-term potentiation . The beneficial effects of insulin and insulin-like growth factor I on cognition have been documented in humans and animal models . Conversely , obesity , hyperinsulinemia , and diabetes increase the risk for neurodegenerative disorders including Alzheimer 's disease ( AD ) . However , the mechanisms by which insulin regulates synaptic plasticity are not well understood . Here , we report that complete disruption of insulin receptor substrate 2 ( Irs2 ) in mice impairs long-term potentiation ( LTP ) of synaptic transmission in the hippocampus . Basal synaptic transmission and paired-pulse facilitation were similar between the 2 groups of mice . Induction of LTP by high-frequency conditioning tetanus did not activate postsynaptic N-methyl-D-aspartate ( DB01221 ) receptors in hippocampus slices from Irs2(-/-) mice , although the expression of Q12879 , Q13224 , and P78352 was equivalent to wild-type controls . Activation of Fyn , AKT , and MAPK in response to tetanus stimulation was defective in Irs2(-/-) mice . Interestingly , Q9Y4H2 was phosphorylated during induction of LTP in control mice , revealing a potential new component of the signaling machinery which modulates synaptic plasticity . Given that Q9Y4H2 expression is diminished in Type 2 diabetics as well as in AD patients , these data may reveal an explanation for the prevalence of cognitive decline in humans with metabolic disorders by providing a mechanistic link between insulin resistance and impaired synaptic transmission . Antibody mediated rejection associated with complement factor h-related protein 3/1 deficiency successfully treated with eculizumab . Antibody mediated rejection ( AMR ) activates the classical complement pathway and can be detrimental to graft survival . AMR can be accompanied by thrombotic microangiopathy ( TMA ) . DB01257 , a monoclonal P01031 antibody prevents induction of the terminal complement cascade ( TCC ) and has recently emerged as a therapeutic option for AMR . We present a highly sensitized 13-year-old female with end-stage kidney disease secondary to spina bifida-associated reflux nephropathy , who developed severe steroid- , ATG- and plasmapheresis-resistant AMR with TMA 1 week post second kidney transplant despite previous desensitization therapy with immunoglobulin infusions . DB01257 rescue therapy resulted in a dramatic improvement in biochemical ( P01024 ; creatinine ) and hematological ( platelets ) parameters within 6 days . The patient was proven to be deficient in complement Factor H-related protein 3/1 ( Q02985 /1 ) , a plasma protein that regulates the complement cascade at the level of P01031 conversion and has been involved in the pathogenesis of atypical hemolytic uremic syndrome caused by P08603 autoantibodies ( DEAP-HUS ) . Q03591 deficiency may have worsened the severe clinical progression of AMR and possibly contributed to the development of donor-specific antibodies . Thus , screening for Q02985 /1 deficiency should be considered in patients with severe AMR associated with TMA . DB05311 ( DX-88 ) , a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery . BACKGROUND : P03952 plays a major role in the contact ( kallikrein-kinin ) cascade producing bradykinin . Bradykinin is a vasodilator , which increases vascular permeability , activates inflammation and produces pain . P03952 is also crosslinked to the coagulation system and the complement cascade . OBJECTIVE : DB05311 ( DX-88 ) is a potent and specific inhibitor of plasma kallikrein . DB05311 is a recombinantly produced and engineered small protein based on the first Kunitz domain of human tissue factor pathway inhibitor . It was identified through phage display technology . METHODS : The search terms ' ecallantide ' , ' DX-88 ' and ' hereditary angioedema ' were entered into Pubmed/Medline , ClinicalTrials and Google . RESULTS/CONCLUSION : At present , the drug is being studied for two major indications . First , the results for the treatment of hereditary angioedema are promising . Second , a prospective randomised multi-centre trial for the reduction of blood loss during on-pump cardiothoracic surgery will be terminated in October 2008 . Hybrid molecules inhibiting myeloperoxidase activity and serotonin reuptake : a possible new approach of major depressive disorders with inflammatory syndrome . OBJECTIVES : Major depressive disorder ( MDD ) is accompanied with an imbalance in the immune system and cardiovascular impairments , such as atherosclerosis . Several mechanisms have been pointed out to underlie this rather unexpected association , and among them the activity of myeloperoxidase ( P05164 ) . The aim of our study was to find compounds that inhibit both P05164 and serotonin transporter ( P31645 ) for treating MDD associated with cardiovascular diseases . METHODS : P31645 inhibition was assessed with measuring of [ ( 3 ) H ] -serotonin uptake using P29320 -293 Q9UBK8 cells . P05164 inhibition was determined by taurine chloramine test on 3-(aminoalkyl)-5-fluoroindole derivatives and on clinically relevant antidepressants . All kinetic measurements were performed using a temperature-controlled stopped-flow apparatus ( model SX-18 MV ) . Promising lead compounds were docked onto P31645 3D structure modelled using the LeuT structure complexed to tryptophan ( PDB code 3F3A ) . Their toxicological profile was also assessed . KEY FINDINGS : 3-(aminoalkyl)-5-fluoroindole derivative with 5 carbons on the side chain and paroxetine showed the best activity on both P05164 and P31645 at the nanomolar range . Paroxetine was found to be the first irreversible P05164 inhibitor at nanomolar concentrations . CONCLUSIONS : Our results put forward the first hybrid molecule ( compound 25 ) and drug ( paroxetine ) that can be especially used in MDD associated with inflammatory syndrome . Current situation of DB01269 , DB05101 , Nimotuzumab and Zalutumumab . P00533 overexpression usually correlates with a more advanced disease stage , a poorer prognosis and a worse chemotherapy response . P00533 expression increase has been observed in many tumours . For all the aforementioned reasons , P00533 inhibition can be considered an attractive approach in cancer treatment . One strategy has been receptor inhibition of extracellular domain using monoclonal antibodies . Cetuximab is the most developed one and there is plenty information on the literature about its current status . In this review we focus on other P00533 monoclonal antibodies under clinical development . The more developed one is DB01269 . Its clinical development is taking place very quickly and it has mainly been studied in colorectal cancer showing promising results . There are also other interesting drugs such as DB05101 , Nimotuzumab and Zalutumumab . Serotonin neurotoxins -- past and present . Autoxidation pathways and redox reactions of dihydroxytryptamines ( 5,6- and 5,7- DB02901 ) and of 6-hydroxydopamine ( 6-OH-DA ) are illustrated , and their potential role in aminergic neurotoxicity is discussed . It is proposed that certain aspects of the cytotoxicity of 6-OH-DA and of the DHTs , namely redox cycling of their quinone- and quinoneimine-intermediates as a source of free radicals , may also apply to quinoidal reactive intermediates and to glutathionyl- or cysteinyl conjugates ( " thioether adducts " ) of o-dihydroxylated ( catechol-like ) metabolites of certain substituted amphetamines ( of methylenedioxymethamphetamine ( DB01454 ) and of methylenedioxyamphetamine ( MDA ) ) . Despite similarities in their primary interaction with the plasmalemmal ( serotonergic transporter/dopamine transporter , P31645 / Q01959 ) and vesicular monoamine transporters ( Q05940 ) , DB01454 and fenfluramine ( N-ethyl-meta-trifluoromethamphetamine , Fen ) differ substantially in many aspects of their metabolism , pharmacokinetics , pharmacology , and neurotoxicology profile ; the consequences of these differences for neuronal response patterns and long-term survival prospects are not yet fully understood . However , sustained hyperthermia appears to be a critical factor in these differences . Methodological requirements for adequate detection and description of pre- and postsynaptic forms of drug-induced neurotoxicity are exemplified using recently published accounts . The inclusion of microglial markers into research strategies has widened contemporary pathogenetic concepts on methamphetamine ( MA ) -induced neurotoxicity as an example of inflammatory neurodegeneration , thus complementing the traditional ROS and RNS-dependent stress models . Amphetamine-type neurotoxicity studies may assist in elaborating of preventive strategies for human neurodegenerative disorders . Effects of DB01045 , a potent inducer of drug-metabolizing enzymes and an inhibitor of Q9Y6L6 /3 transport , on the single dose pharmacokinetics of anacetrapib . Anacetrapib is a novel cholesteryl ester transfer protein ( P11597 ) inhibitor in development for treatment of dyslipidemia . This open-label , fixed-sequence , 3-period study was intended to evaluate the potential of anacetrapib to be a victim of Q9Y6L6 /3 inhibition and strong CYP3A induction using acute and chronic dosing of rifampin , respectively , as a probe . In this study , 16 healthy subjects received 100 mg anacetrapib administered without rifampin ( Day 1 , Period 1 ) , with single-dose ( SD ) 600 mg rifampin ( Day 1 , Period 2 ) , and with multiple-dose ( MD ) 600 mg rifampin for 20 days ( Day 14 , Period 3 ) . Log-transformed anacetrapib AUC0-∞ and Cmax were analyzed by a linear mixed effects model . The GMRs and 90 % CIs for anacetrapib AUC0-∞ and Cmax were 1.25 ( 1.04 , 1.51 ) and 1.43 ( 1.13 , 1.82 ) for SD rifampin ( Period 2/Period 1 ) and 0.35 ( 0.29 , 0.42 ) and 0.26 ( 0.21 , 0.32 ) for MD rifampin ( Period 3/Period 1 ) , respectively . Anacetrapib was generally well tolerated in both the absence/presence of SD and MD rifampin . In conclusion , treatment with SD rifampin , which inhibits the Q9Y6L6 /3 transporter system , did not substantially influence the SD pharmacokinetics of anacetrapib , while chronic ( 20 days ) administration of rifampin , which strongly induces CYP3A isozymes , reduced mean systemic exposure to SD anacetrapib by 65 % . DB00158 -related nutrients , genetic polymorphisms , and colorectal cancer risk : the fukuoka colorectal cancer study . One-carbon metabolism plays an important role in colorectal carcinogenesis . Meta-analyses have suggested protective associations of folate and vitamin B6 intakes with colorectal cancer primarily based on studies in Caucasians , and genetic polymorphisms pertaining to the folate metabolism have been a matter of interest . Less investigated are the roles of methionine synthase ( Q99707 ) and thymidylate synthetase ( TS ) polymorphisms in colorectal carcinogenesis . In a study of 816 cases and 815 community controls in Japan , we investigated associations of dietary intakes of folate , methionine , vitamin B2 , vitamin B6 , and vitamin B12 with colorectal cancer risk . The associations with Q99707 2756A > G , Q9UBK8 66A > G , and TSER repeat polymorphism were examined in 685 cases and 778 controls . DB00134 and vitamin B12 intakes were inversely associated with colorectal cancer risk , but the associations were totally confounded by dietary calcium and n-3 fatty acids . The other nutrients showed no association with the risk even without adjustment for calcium and n-3 fatty acids . The TSER 2R allele was dose-dependently associated with an increased risk . The Q99707 and Q9UBK8 polymorphisms were unrelated to colorectal cancer risk . There was no measurable gene-gene or gene-nutrient interaction , but increased risk associated with the TSER 2R allele seemed to be confined to individuals with high folate status . This study does not support protective associations for folate and vitamin B6 . The TSER 2R allele may confer an increased risk of colorectal cancer . The role of the TSER polymorphism in colorectal carcinogenesis may differ by ethnicity .