interacts_with DB01037?
DB01037 transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson 's disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine-restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg/24 hours , tyramine dietary restrictions are not needed . Short-term treatment with fixed ( 6 mg/24 hours ) or flexible ( 6 , 9 or 12 mg/24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6- or 8-week , randomised , double-blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long-term treatment with a fixed dose of selegiline transdermal system 6 mg/24 hours was superior to placebo as maintenance therapy in a 52-week , randomised , double-blind , multicentre , relapse-prevention trial in patients with MDD . DB01037 transdermal system therapy was generally well tolerated in placebo-controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo . A review of treatment with mepolizumab , an anti- P05113 mAb , in hypereosinophilic syndromes and asthma . The hypereosinophilic syndromes ( HESs ) are a heterogeneous group of diseases characterized by peripheral blood eosinophilia with end-organ damage and varying in severity from nonspecific symptoms to life-threatening . Treatment objectives are a safe reduction of blood and tissue eosinophil levels and prevention of eosinophil-mediated tissue damage . Current treatment of patients with HESs , who lack the Q7L523 -like 1-platelet-derived growth factor receptor alpha ( Q6UN15 - P16234 ) fusion gene , is mainly systemic corticosteroid therapy . Eosinophil development from hematopoietic progenitor cells is regulated by P05113 , which influences maturation , differentiation , mobilization , activation , and survival . Consequently , inhibiting P05113 is a logical therapeutic objective for patients with HESs or selected patients with asthma . DB06612 is a fully humanized anti- P05113 monoclonal IgG(1) antibody that binds to free P05113 with high affinity and specificity to prevent P05113 from associating with the P05113 receptor complex alpha-chain on the surface of eosinophils . In clinical trials with patients with HESs , mepolizumab reduced blood eosinophil counts and the maintenance corticosteroid dose and had no major safety concerns . DB06612 reduced airway and blood eosinophils and prevented asthma exacerbations . Thus , mepolizumab may be effective for long-term treatment of patients with selected eosinophilic disorders . Interaction of early environment , gender and genes of monoamine neurotransmission in the aetiology of depression in a large population-based Finnish birth cohort . Objectives Depression is a worldwide leading cause of morbidity and disability . Genetic studies have recently begun to elucidate its molecular aetiology . The authors investigated candidate genes of monoamine neurotransmission and early environmental risk factors for depressiveness in the genetically isolated population-based Northern Finland Birth Cohort 1966 ( 12 058 live births ) . Design The authors ascertained and subdivided the study sample ( n=5225 ) based on measures of early development and of social environment , and examined candidate genes of monoamine neurotransmission , many of which have shown prior evidence of a gene-environment interaction for affective disorders , namely P31645 , Q8IWU9 , P21964 , P21397 and the dopamine receptor genes P21728 - P21918 . Results and conclusion The authors observed no major genetic effects of the analysed variants on depressiveness . However , when measures of early development and of social environment were considered , some evidence of interaction was observed . Allelic variants of P21964 interacted with high early developmental risk ( p=0.005 for rs2239393 and p=0.02 for rs4680 ) so that the association with depression was detected only in individuals at high developmental risk group ( p=0.0046 and β=0.056 for rs5993883-rs2239393-rs4680 risk haplotype CGG including Val158 ) , particularly in males ( p=0.0053 and β=0.083 for the haplotype CGG ) . Rs4274224 from P14416 interacted with gender ( p=0.017 ) showing a significant association with depressiveness in males ( p=0.0006 and β=0.0023 ; p=0.00005 and β=0.069 for rs4648318-rs4274224 haplotype GG ) . The results support the role of genes of monoamine neurotransmission in the aetiology of depression conditional on environmental risk and sex , but not direct major effects of monoaminergic genes in this unselected population . DB06096 , a selective P29475 inhibitor and a P28222 /1D receptor agonist , inhibits P80511 release in preclinical migraine models . BACKGROUND : DB06096 is a combined neuronal nitric oxide synthase ( P29475 ) inhibitor and 5-hydroxytryptamine 1B/1D ( P28222 /1D ) receptor agonist . Using preclinical models , we evaluated whether these two unique therapeutic principles have a synergistic effect in attenuating stimulated calcitonin gene-related peptide ( P80511 ) release , a marker of trigeminal activation . METHODS : We examined the effect of DB06096 on : ( 1 ) DB00761 - , capsaicin- and resiniferatoxin ( RTX ) -induced immunoreactive P80511 ( iCGRP ) release from isolated preparation of rat dura mater , trigeminal ganglion ( TG ) and trigeminal nucleus caudalis ( P24821 ) ; and ( 2 ) capsaicin- and electrical stimulation ( ES ) -induced middle meningeal artery ( MMA ) dilation in a rat closed-cranial window . RESULTS : DB06096 inhibited : ( 1 ) DB00761 -stimulated iCGRP release from dura mater ( % decrease mean ± SEM , lowest effective concentration ) ( 35 ± 6 % , 30 µM ) , TG ( 24 ± 11 % , 10 µM ) and P24821 ( 40 ± 8 % , 10 µM ) ; ( 2 ) capsaicin- and RTX-induced iCGRP release from dura mater ; and ( 3 ) capsaicin- and ES-induced increase in dural artery diameter ( 32 ± 5 % , 3 mg kg(-1) intravenous ( i.v. ) and 36 ± 1 % , 10 mg kg(-1) i.v. ) . CONCLUSIONS : DB06096 inhibits P80511 release from migraine-relevant cephalic tissues . Its effect is most likely mediated via a combination of P29475 -inhibition and P28222 /1D receptor agonism in dura mater while the mechanisms of action for inhibition of P80511 release from TG and P24821 have to be investigated further . Molecular-pathological prognostic factors of gastric cancer : a review . Invasion and metastasis are critical determinants of cancer morbidity . Genes and molecules participating in these steps must be regarded as potential prognostic factors . Growth factors and their receptors , cell-cycle regulators , cell-adhesion molecules and matrix-degrading enzymes are those to be used as prognostic factors , including epidermal growth factor ( P01133 ) , P01133 receptor , P21802 , HER-2 , interleukin ( IL ) -8 , vascular endothelial growth factor ( P15692 ) , cyclin E , p27 , P12830 , CD44v6 , matrix metalloproteinase-1 ( P03956 ) , and tissue inhibitor of matrix metalloproteinase-1 ( P01033 ) . Alterations in epigenetics , such as aberrant DNA methylation and histone modification that are , in part , associated with the tumor progression of gastric cancer , can be candidate prognostic factors . The number of methylated genes may serve as a marker of tumor progression . Genetic polymorphism not only affects cancer susceptibility but also influences malignant phenotype ; examples include single-nucleotide polymorphism in the HER-2 and P14780 genes . Comprehensive gene expression analyses are useful to search for novel genes related to invasion and metastasis and potential prognostic factors . Serial analysis of gene expression ( Q9NXZ1 ) has identified several these genes , such as Q12864 , P02649 , P35637 , P02452 , P08123 , Q6UX06 , and Q16674 . Overexpression of Q16674 is found to be associated with poor prognosis . Microarray analysis has great potential for identifying the characteristics of individual cancers , from the view point of gene expression profiles . A combination of these examinations can not only foretell a patient 's prognosis but can also give information directly connected with personalized cancer medicine and prevention . Characterization of gonadotropin-releasing hormone analogs based on a sensitive cellular luciferase reporter gene assay . A novel cellular assay for the functional characterization of agonistic and antagonistic analogs of gonadotropin-releasing hormone ( DB00644 ) was developed . This assay is based on a fusion of the c-fos immediate-early gene promoter to Photinus pyralis luciferase ( Luc ) as a reporter gene , stably transfected in a recombinant cell line expressing the human P30968 . Transcription of endogenous c-fos and fos-Luc fusion gene are transiently induced quite similar by fetal calf serum or the superagonistic analog [ D-Trp6 ] DB00644 in a selected cell line . The reporter gene was therefore used to monitor agonist-induced signaling via the human P30968 . Whereas Luc activity was induced in a dose-dependent manner by DB00644 or [ D-Trp6 ] DB00644 , different antagonistic peptides completely inhibited this stimulation . The antagonistic potency ( IC50 ) of various peptides with DB00050 and Antarelix as lead compounds in general correlated well with the binding affinity ( KD ) as determined from ligand binding experiments . The specificity of an inhibitory effect was confirmed by P30968 -independent stimulation with the phorbol ester 12-O-tetradecanoylphorbol 13-acetate or basic fibroblast growth factor . Since this new reporter gene assay is sensitive and simple and can be performed in a microtiter plate , it will significantly facilitate screening and functional characterization of DB00644 analogs . Inhibition of P04275 -mediated platelet activation and thrombosis by the anti- P04275 A1-domain aptamer DB05202 . BACKGROUND : P04275 ( P04275 ) has a role in both hemostasis and thrombosis . Platelets adhere to damaged arteries by interactions between the P04275 A1-domain and glycoprotein Ib receptors under conditions of high shear . This initial platelet binding event stimulates platelet activation , recruitment , and activation of the clotting cascade , promoting thrombus formation . OBJECTIVE : To characterize the inhibitory activity of a P04275 inhibitory aptamer . METHODS : Using in vitro selection , aptamer stabilization , and conjugation to a 20-kDa poly ( ethylene glycol ) , we generated a nuclease-resistant aptamer , DB05202 , that binds to the P04275 A1-domain with high affinity ( K(D) approximately 2 nM ) . The aptamer was assessed for inhibition of P04275 -induced platelet aggregation . In vitro inhibition of platelet adhesion was assessed on collagen-coated slides and injured pig aortic segments . In vivo activity was assessed in a cynomolgus monkey carotid electrical injury thrombosis model . RESULTS AND CONCLUSION : DB05202 inhibited botrocetin-induced platelet aggregation ( IC90 approximately 300 nM ) and shear force-induced platelet aggregation ( IC95 approximately 400 nM ) . It reduced adhesion of platelets to collagen-coated matrices and formation of platelet thrombi on denuded porcine arteries . DB05202 also inhibited the formation of occlusive thrombi in cynomolgus monkeys . We have discovered a novel anti- P04275 aptamer that could have therapeutic use as an anti- P04275 agent in the setting of P04275 -mediated thrombosis . A dose ranging phase I/II trial of the P04275 inhibiting aptamer DB05202 in patients with congenital thrombotic thrombocytopenic purpura . Congenital thrombotic thrombocytopenic purpura ( TTP ) is a very rare but potentially life-threatening disorder . This phase I/II trial compared the pharmacokinetics and pharmacodynamics and safety of three different administration modes of the anti- P04275 ( P04275 ) aptamer DB05202 . This was a prospective clinical trial with a partial cross-over design : three periods comprised subcutaneous injections of 50 mg of DB05202 on seven subsequent days , a low-dose infusion of DB05202 ( 0.002 mg/kg/min ) for 24-72 hours and a high-dose infusion ( 0.004-0.006 mg/kg/min ) up to 72 hours . DB05202 concentrations were determined with high performance liquid chromatography , P04275 inhibition was measured with enzyme immunoassay and platelet function was determined with the platelet function analyser ( PFA-100 ) and impedance aggregometry . DB05202 was well tolerated without any bleeding at concentrations spanning over three orders of magnitude . The daily s.c. injection yielded plasma levels ( 0.5 μg/ml ) of the drug that were too low to sufficiently suppress P04275 . The low-dose i.v. infusion increased platelet counts in one patient , whereas the high i.v. dose increased plasma concentrations up to 69 μg/ml , completely blocked free A1 domains , P04275 -dependent platelet plug formation and enhanced platelet counts in 2/3 patients . In conclusion , infusion of DB05202 dose-dependently inhibits P04275 -dependent platelet function and during infusion DB05202 increases or stabilises platelet counts in congenital TTP . However , the tested doses , particularly the daily s.c. injections , did not correct all clinical or laboratory features of TTP . Gateways to clinical trials . 11D10 , 9vPnC-MnCc ; DB00051 , DB00718 , DB00092 , ALN-RSV01 , AME-133 , Q99217 -317 , DB00992 , Amlodipine besylate/atorvastatin calcium , Anisodamine , Anti- P05113 receptor antibody , Apremilast , Aripiprazole , Atacicept , DB01072 sulfate , Atrasentan ; DB04975 , DB00112 , BIBW-2992 , DB04853 , BMS-387032 ; cAC10 , Caldaret hydrate , CD-NP , DB04918 medocaril , Celivarone fumarate , DB08904 , Cholesteryl hydrophobized polysaccharide-Her2 protein complex , Choline fenofibrate , Cilengitide , Cinaciguat , Curcumin , Custirsen sodium , Cypher , CYT-6091 ; Dalcetrapib , Deforolimus , Desvenlafaxine succinate , DB05297 , DP6-001 ; E-7010 , E75 , Ecogramostim , P01133 -P64K , EnvPro , Enzastaurin hydrochloride , DB01175 oxalate , DB00973 , DB00973 /simvastatin ; DB05076 ; Gefitinib , Golimumab , Green tea catechins , GTI-2040 , GW-406381 ; HPV16 E6 E7 , HPV-16/18 AS04 , HPV-6/11/16/18 ; ICC-1132 , Immune globulin intravenous ( human ) , DB05039 , Intranasal insulin ; Kahalalide F ; Lactobacillus rhamnosus , Laromustine , Laropiprant , GTI-2040 ; MAb 3H1 , DB06612 , Mifamurtide , Milataxel , DB05313 ; Nebicapone , DB01280 , Neuradiab ; Oncolytic HSV ; PCV7 , PHX-1149 , Pimecrolimus , DB06813 , Pramiconazole ; DB01270 , Reolysin , DB06372 , Rolofylline , DB06176 ; S-32865 , Shigella dysenteriae 1 vaccine ; Taranabant , Taxus , DB05657 ; Ustekinumab ; Vitespen ; Zileuton , Zycure . Increased contribution of Q12879 subunit to synaptic DB01221 receptors in developing rat cortical neurons . 1. Pharmacologically isolated miniature DB01221 receptor-mediated excitatory postsynaptic currents ( mN-EPSCs ) were recorded in large visual cortical neurons in layer V of rat cortical slices . DB00502 ( 100 microM ) and CP101,606 ( 10 microM ) , two specific blockers of DB01221 receptors comprising Q9UHB4 / Q13224 subunits , were tested on mN-EPSCs in rats at postnatal days 7 and 8 ( Q0GE19 -P8 ) and P13-P15 . At both ages tested , no significant effects of these drugs were seen in the whole population of neurons , although in few neurons at both ages changes in amplitude were observed with haloperidol . Other dopamine receptor antagonists , spiperone and clozapine , failed to decrease mN-EPSCs in cortical neurons at P13-P15 . 2 . CP101,606 ( 10 microM ) significantly decreased the amplitude of evoked N-EPSCs ( eN-EPSCs ) in visual cortical slices from rats at P09131 - Q15084 , a developmental stage at which mRNA studies have indicated the virtual absence of Q12879 mRNA . CP101,606 failed to significantly change evoked AMPA-mediated EPSCs at Q15084 and eN-EPSCs at Q0GE19 -P8 and P13-P15 . 3 . DB01221 receptor-mediated currents were also studied in somatic outside-out patches at P13-P15 with fast application of L-glutamate ( 1 mM ) . DB00502 ( 50 microM ) and CP101,606 ( 10 muM ) blocked these currents in all patches tested . The effect of CP101,606 was concentration dependent . 4 . We suggest that rather early in development synaptic receptors comprising Q9UHB4 / Q13224 subunits could be associated with other subunits so that blockade by haloperidol and CP101,606 is prevented . Moreover , the consistent blockade seen in outside out patches might be ascribed to the confinement of Q9UHB4 / Q13224 receptors to an extrasynaptic population . Large-scale association study for structural soundness and leg locomotion traits in the pig . BACKGROUND : Identification and culling of replacement gilts with poor skeletal conformation and feet and leg ( FL ) unsoundness is an approach used to reduce sow culling and mortality rates in breeding stock . Few candidate genes related to soundness traits have been identified in the pig . METHODS : In this study , 2066 commercial females were scored for 17 traits describing body conformation and FL structure , and were used for association analyses . Genotyping of 121 SNPs derived from 95 genes was implemented using Sequenom 's MassARRAY system . RESULTS : Based on the association results from single trait and principal components using mixed linear model analyses and false discovery rate testing , it was observed that P02649 , P34820 , P30988 , P08123 , P20849 , DKFZ , P35555 and VDBP were very highly significantly ( P < 0.001 ) associated with body conformation traits . The genes P09917 , P34820 , P30988 , O00300 , P30559 and Q9UBV4 were very highly significantly ( P < 0.001 ) associated with FL structures , and P02649 , P30988 , P08123 , P30968 , Q14623 , P42898 and Q9UBV4 were highly significantly ( P < 0.01 ) associated with overall leg action . Strong linkage disequilibrium between P30988 and P08123 on SSC9 was detected , and haplotype -ACGACC- was highly significantly ( P < 0.01 ) associated with overall leg action and several important FL soundness traits . CONCLUSION : The present findings provide a comprehensive list of candidate genes for further use in fine mapping and biological functional analyses . Preclinical rationale for combining an P00533 antibody with cisplatin/gemcitabine for the treatment of NSCLC . BACKGROUND : Although the addition of epidermal growth factor receptor ( P00533 ) antibodies to various platinum-based chemotherapy regimens for non-small cell lung cancer ( NSCLC ) is being actively pursued in the clinic , rationale for the prioritization of specific regimens is lacking . MATERIALS AND METHODS : We evaluated the antitumor effects of necitumumab , a recombinant human IgG1 antibody targeting P00533 , in combination with cisplatin plus gemcitabine , pemetrexed , or paclitaxel in a panel of 9 subcutaneous tumor models of NSCLC established in nu/nu athymic mice . RESULTS : DB09559 in combination with cisplatin/gemcitabine was particularly effective , although interestingly , the mechanisms underlying these benefits were model dependent . For example , increased tumor cell apoptosis contributed towards combination efficacy in the A549 model , in association with increased expression of hsa-miR-29b and reduced expression of antiapoptotic genes including DNA methyltransferase Q9UBC3 , commonly up-regulated in patients with NSCLC . Such inverse effects of combination therapy on Q9UBC3 and hsa-miR-29b expression were found in multiple models . Importantly , in the A549 model , hsa-miR-29b down-regulation of DMNT3b reduced promoter methylation of tumor suppressor genes such as Q9BY67 ( Q9BY67 ) , Ras associated ( Q12967 /AF-6 ) domain family member 1 ( Q9NS23 ) , and Fragile histidine triad gene ( P49789 ) , increasing their expression . CONCLUSION : These results offer a preclinical rationale for combining an P00533 antibody with cisplatin/gemcitabine for patients with NSCLC , and provide potential molecular biomarkers for tailoring therapy . Expression of serotonergic system components during early Xenopus embryogenesis . Despite abundant research studies on the physiological and biochemical nature of embryonic neurotransmitter function , little is known about the molecular genetic mechanisms involved . The expression of the main components of the serotonergic system during early Xenopus embryogenesis was investigated using RT-PCR , real time PCR and in situ hybridization . Transcripts encoding the serotonin receptors P28335 and P34969 , as well as the vesicular monoamine transporter Q05940 , the serotonin transporter ( P31645 ) and the serotonin synthesis enzymes tryptophan hydroxylase ( Q8IWU9 ) and aromatic amino acid decarboxylase ( AAAD ) were found to be expressed during the cleavage division stages , whereas the degradation enzyme monoamine oxidase A ( P21397 ) was absent . The main components of the serotonergic system were found to be expressed during the earliest stages of embryonic development . The embryonic transmitter mechanism , its complexity , and its variability among various species are discussed . DB06594 : a novel mechanism of antidepressant action involving the melatonergic and the serotonergic system . The clinical finding that depressive disorders are often associated with desynchronization of internal rhythms has encouraged the idea that resetting normal circadian rhythms may have antidepressant potential . DB06594 , a naphthalene analog of melatonin , is both an agonist of human cloned melatonergic MT1 and P02795 receptors and a serotonin P28335 receptor antagonist . DB06594 combines zeitgeber ( synchroniser of the circadian system ) activity with neurotransmitter augmentation properties ( enhances the levels of dopamine and noradrenaline in frontal cortex ) . The efficacy of agomelatine in treating depression has been shown in three short-term , pivotal , randomized , placebo-controlled studies . These studies have demonstrated agomelatine to be efficacious in Major Depressive Disorder at the standard dose of 25mg/day , with the possibility of increasing doses to 50mg/day in those patients with insufficient improvement . The number of adverse events during the treatment period was comparable to placebo . Four studies have shown the positive effect of agomelatine on sleep continuity and quality and shortening of sleep latency . Despite these promising data , further studies are needed to examine agomelatine 's efficacy over a longer treatment period . Luteinizing Hormone-Releasing Hormone ( P01148 ) -I antagonist cetrorelix inhibits myeloma cell growth in vitro and in vivo . The objective of this study was to determine the effects of an luteinizing hormone-releasing hormone ( P01148 ) -I antagonist , DB00050 , on human multiple myeloma ( MM ) cells and to elucidate the mechanisms of action . We showed that P01148 -I and P22888 -I genes were expressed in MM cell lines and primary MM cells . Treatment with DB00050 inhibited growth and colony-forming ability of myeloma cells , including cell lines resistant to arsenic trioxide , bortezomib , or lenalidomide . DB00050 induced apoptosis in myeloma cells including primary myeloma cells . In addition , DB00050 inhibited the growth of human myeloma cells xenografted into mice without any apparent side effects . DB00050 downregulated the nuclear factor-kappa B ( NF-κB ) pathway activity and the expression of cytokines , including interleukin 6 , insulin-like growth factor 1 , P15692 , and stromal-derived factor 1 , important for myeloma cell growth and survival in myeloma cells and/or marrow stromal cells from myeloma patients . DB00050 decreased the phosphorylation of extracellular signal regulated kinase 1/2 and P40763 in myeloma cells , two crucial pathways for myeloma cells growth and survival . Moreover , the expression of P38936 and p53 was increased , whereas that of antiapoptotic proteins Bcl-2 and Bcl-x(L) was reduced by DB00050 . Our findings indicate that DB00050 induces cytotoxicity in myeloma cells through various mechanisms and provide a rationale for investigating DB00050 for the treatment of MM . CCK1-receptor stimulation protects against gut mediator-induced lung damage during endotoxemia . BACKGROUND/AIMS : Cholecystokinin 1-receptor ( P32238 ) activation by long chain fatty acid ( LCFA ) absorption stimulates vago-vagal reflex pathways in the brain stem . The present study determines whether this reflex also activates the cholinergic anti-inflammatory pathway , a pathway known to modulate cytokine release during endotoxemia . METHODS : Mesenteric lymph was obtained from wild type ( WT ) and P32238 knockout ( P32238 (-/-) ) mice intraperitoneally challenged with Lipopolysaccharid ( LPS ) ( endotoxemic lymph , EL ) and intestinally infused with vehicle or LCFA-enriched solution . The lymph was analyzed for TNFα , P05231 and P22301 concentration and administered to healthy recipient mice via jugular infusion . Alveolar wall thickness , myeloperoxidase ( P05164 ) and TUNEL positive cells were determined in lung tissue of recipient mice . RESULTS : LCFA infusion in WT mice reduced TNFα concentration in EL by 49 % compared to vehicle infusion , but had no effect in P32238 (-/-) mice . EL significantly increased the alveolar wall thickness , the number of P05164 -positive and TUNEL-positive cells compared to control lymph administration . LCFA infusion in WT , but not in CCK1R(-/-) mice , significantly reduced these pathological effects of EL . CONCLUSION : During endotoxemia enteral LCFA absorption reduces TNFα release into mesenteric lymph and attenuates histomorphologic parameters of lung dysfunction . Failure to elicit this effect in CCK1R(-/-) mice demonstrates that anti-inflammatory properties of LCFAs are mediated through CCK1-Rs . Multiplex protein signature for the detection of bladder cancer in voided urine samples . PURPOSE : Accurate urine assays for bladder cancer detection would benefit patients and health care systems . Through extensive genomic and proteomic profiling of urine components we previously identified a panel of 8 biomarkers that can facilitate the detection of bladder cancer in voided urine samples . In this study we confirmed this diagnostic molecular signature in a diverse multicenter cohort . MATERIALS AND METHODS : We performed a case-control , phase II study in which we analyzed voided urine from 102 subjects with bladder cancer and 206 with varying urological disorders . The urinary concentration of 8 biomarkers ( P10145 , P14780 and 10 , P05121 , P15692 , P03950 , Q16790 and P02649 ) was assessed by enzyme-linked immunosorbent assay . Diagnostic performance of the panel of tested biomarkers was evaluated using ROCs and descriptive statistical values , eg sensitivity and specificity . RESULTS : Seven of the 8 urine biomarkers were increased in subjects with bladder cancer relative to those without bladder cancer . The 7 biomarkers were assessed in a new model , which had an AUROC of 0.88 ( 95 % CI 0.84-0.93 ) , and 74 % sensitivity and 90 % specificity . In contrast , the sensitivity of voided urine cytology and the UroVysion® cytogenetic test in this cohort was 39 % and 54 % , respectively . Study limitations include analysis performed on banked urine samples and the lack of voided urine cytology and cytogenetic test data on controls . CONCLUSIONS : The study provides further evidence that the reported panel of diagnostic biomarkers can reliably achieve the noninvasive detection of bladder cancer with higher sensitivity than currently available urine based assays . Candidate gene studies of ADHD : a meta-analytic review . Quantitative genetic studies ( i.e. , twin and adoption studies ) suggest that genetic influences contribute substantially to the development of attention deficit hyperactivity disorder ( ADHD ) . Over the past 15 years , considerable efforts have been made to identify genes involved in the etiology of this disorder resulting in a large and often conflicting literature of candidate gene associations for ADHD . The first aim of the present study was to conduct a comprehensive meta-analytic review of this literature to determine which candidate genes show consistent evidence of association with childhood ADHD across studies . The second aim was to test for heterogeneity across studies in the effect sizes for each candidate gene as its presence might suggest moderating variables that could explain inconsistent results . Significant associations were identified for several candidate genes including Q01959 , P21917 , P21918 , P31645 , P28222 , and P60880 . Further , significant heterogeneity was observed for the associations between ADHD and Q01959 , P21917 , P21918 , P09172 , P08913 , P31645 , Q8IWU9 , P21397 , and P60880 , suggesting that future studies should explore potential moderators of these associations ( e.g. , ADHD subtype diagnoses , gender , exposure to environmental risk factors ) . We conclude with a discussion of these findings in relation to emerging themes relevant to future studies of the genetics of ADHD . Pharmacological modulation of dopamine receptor D2-mediated transmission alters the metabolic phenotype of diet induced obese and diet resistant C57Bl6 mice . High fat feeding induces a variety of obese and lean phenotypes in inbred rodents . Compared to Diet Resistant ( DR ) rodents , Diet Induced Obese ( DIO ) rodents are insulin resistant and have a reduced dopamine receptor D2 ( P14416 ) mediated tone . We hypothesized that this differing dopaminergic tone contributes to the distinct metabolic profiles of these animals . C57Bl6 mice were classified as DIO or DR based on their weight gain during 10 weeks of high fat feeding . Subsequently DIO mice were treated with the P14416 agonist bromocriptine and DR mice with the P14416 antagonist haloperidol for 2 weeks . Compared to DR mice , the bodyweight of DIO mice was higher and their insulin sensitivity decreased . DB00502 treatment reduced the voluntary activity and energy expenditure of DR mice and induced insulin resistance in these mice . Conversely , bromocriptine treatment tended to reduce bodyweight and voluntary activity , and reinforce insulin action in DIO mice . These results show that P14416 activation partly redirects high fat diet induced metabolic anomalies in obesity-prone mice . Conversely , blocking P14416 induces an adverse metabolic profile in mice that are inherently resistant to the deleterious effects of high fat food . This suggests that dopaminergic neurotransmission is involved in the control of metabolic phenotype . Convergent and divergent cellular responses by ErbB4 isoforms in mammary epithelial cells . Associations of ErbB4 ( Q15303 / Q15303 ) , the fourth member of the P00533 family , with cancer are variable , possibly as a result of structural diversity of this receptor . There are multiple structural isoforms of Q15303 arising by alternative mRNA splicing , and a subset undergo proteolysis that releases membrane-anchored and soluble isoforms that associate with transcription factors and coregulators to modulate transcription . To compare the differential and common signaling activities of full-length ( FL ) and soluble intracellular isoforms of Q15303 , four JM-a isoforms ( FL and soluble intracellular domain ( ICD ) CYT-1 and CYT-2 ) were expressed in isogenic MCF10A cells and their biologic activities were analyzed . Both FL and ICD CYT-2 promoted cell proliferation and invasion , and CYT-1 suppressed cell growth . Transcriptional profiling revealed several new and underexplored Q15303 -regulated transcripts , including : proteases/protease inhibitors ( P08254 and P07093 ) , the YAP/Hippo pathway ( P29279 , O00622 , and P09486 ) , the mevalonate/cholesterol pathway ( P04035 , Q01581 , P01130 , and Q9UBM7 ) , and cytokines ( P10145 , P78556 , and P09341 ) . Many of these transcripts were subsequently validated in a luminal breast cancer cell line that normally expresses Q15303 . Furthermore , ChIP-seq experiments identified O75689 , P02649 , P09486 , P16949 , and Q05195 as novel molecular targets of Q15303 . These findings clarify the diverse biologic activities of Q15303 isoforms , and reveal new and divergent functions . IMPLICATIONS : ErbB4 as a regulator of Hippo and mevalonate pathways provides new insight into milk production and anabolic processes in normal mammary epithelia and cancer . A pyrazole curcumin derivative restores membrane homeostasis disrupted after brain trauma . We have assessed potential mechanisms associated with the deleterious effects of TBI on the integrity of plasma membranes in the hippocampus , together with consequences for behavioral function . In addition , we have investigated the efficacy of a dietary intervention based on a pyrazole curcumin derivative with demonstrated bioactivity and brain absorption , to re-establish membrane integrity . We report that moderate fluid percussion injury ( FPI ) increases levels of 4-Hydroxynonenal ( HNE ) , an intermediary for the harmful effects of lipid peroxidation on neurons . A more direct action of FPI on membrane homeostasis was evidenced by a reduction in calcium-independent phospholipase A2 ( iPLA₂ ) important for metabolism of membrane phospholipids such as DB01708 , and an increase in the fatty acid transport protein ( FATP ) involved in translocation of long-chain fatty acids across the membrane . A potential association between membrane disruption and neuronal function was suggested by reduced levels of the Q13224 subunit of the transmembrane DB01221 receptor , in association with changes in iPLA2 and syntaxin-3 ( Q92186 -3 , involved in the action of membrane DB01708 on synaptic membrane expansion ) . In addition , changes in iPLA2 , 4-HNE , and Q92186 -3 were proportional to reduced performance in a spatial learning task . In turn , the dietary supplementation with the curcumin derivative counteracted all the effects of FPI , effectively restoring parameters of membrane homeostasis . Results show the potential of the curcumin derivative to promote membrane homeostasis following TBI , which may foster a new line of non-invasive therapeutic treatments for TBI patients by endogenous up-regulation of molecules important for neural repair and plasticity . Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual 's response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome . Drugs targeting nitric oxide synthase for migraine treatment . INTRODUCTION : Ample evidence that nitric oxide ( NO ) is a causative molecule in migraine has encouraged research to develop drugs that target the NO-cGMP cascade for migraine treatment . NO synthase ( NOS ) inhibition is an innovative therapeutic principle . AREAS COVERED : This paper reviews the rationale underlying NOS inhibition in migraine treatment . It also provides a review on the efficacy and safety data for NOS inhibitors ( nonselective NOS inhibitor L-N(G)-methyl-arginine hydrochloride [ L-NMMA ] , selective inducible NOS [ P35228 ] inhibitors GW273629 and GW274150 , combined neuronal NOS [ P29475 ] inhibitor and P28222 /1D receptor agonist DB06096 ) in acute or preventive migraine treatment . EXPERT OPINION : The data highlighted herein , from four placebo-controlled trials and 1 open-labeled clinical trial using 4 different NOS inhibitors on a total of 705 patients , provide convincing efficacy data only for the nonselective NOS inhibitor L-NMMA . Unfortunately , this NOS inhibitor raises cardiovascular safety concerns and has an unfavorable pharmacokinetic profile . As experimental studies predicted , P35228 inhibitors are ineffective in migraine . Still , upcoming selective P29475 inhibitors are a hope for migraine treatment , with the P29475 isoform being most clearly involved in trigeminovascular transmission and central sensitization . Future studies should help to clarify whether NOS inhibition is equally fruitful in acute and preventive treatment . It should also clarify if P29475 inhibition holds promise as a therapeutic tool for the treatment of chronic migraine and other forms of headache . Association analysis between 12 genetic variants of ten genes and personality traits in a young chinese Han population . Some genes involved in neurotransmission synthesis and transmission have been hypothesized to affect personality traits . To investigate the possible roles of these genes in personality traits of 16 Personality Factor Questionnaire , we performed a population-based study in a young Chinese Han cohort . In the study , we selected some functional variations in ten candidate genes ( P21964 , P09172 , DRD(2) , DRD(3) , Q01959 , P21397 , GRM(1) , Q13224 , 5-TH(2A) , and 5-TH(6) ) encoding components in dopamine , glutamate , and 5-hydroxytryptamine pathways . The results showed the T102C in 5-TH(2A) was associated with X3 ( emotional and quiet alertness ) and B ( reasoning ) ( F = 4.71 and 6.23 ; p = 0.009 and 0.002 ) , Val158Met in P21964 with E ( dominance ) ( F = 7.01 ; p = 0.0009 ) , while the variations in P09172 , DRD(2) , DRD(3) , P21397 , GRM(1) , Q13224 , and 5-TH(6) were not associated with any of the personality traits . This finding suggests that T102C in 5-TH(2A) and Val158Met in P21964 play roles in some human personality traits . Chronic treatment with agomelatine or venlafaxine reduces depolarization-evoked glutamate release from hippocampal synaptosomes . BACKGROUND : Growing compelling evidence from clinical and preclinical studies has demonstrated the primary role of alterations of glutamatergic transmission in cortical and limbic areas in the pathophysiology of mood disorders . Chronic antidepressants have been shown to dampen endogenous glutamate release from rat hippocampal synaptic terminals and to prevent the marked increase of glutamate overflow induced by acute behavioral stress in frontal/prefrontal cortex . DB06594 , a new antidepressant endowed with MT1/ P02795 agonist and P28335 serotonergic antagonist properties , has shown efficacy at both preclinical and clinical levels . RESULTS : Chronic treatment with agomelatine , or with the reference drug venlafaxine , induced a marked decrease of depolarization-evoked endogenous glutamate release from purified hippocampal synaptic terminals in superfusion . No changes were observed in GABA release . This effect was accompanied by reduced accumulation of SNARE protein complexes , the key molecular effector of vesicle docking , priming and fusion at presynaptic membranes . CONCLUSIONS : Our data suggest that the novel antidepressant agomelatine share with other classes of antidepressants the ability to modulate glutamatergic transmission in hippocampus . Its action seems to be mediated by molecular mechanisms located on the presynaptic membrane and related with the size of the vesicle pool ready for release . Targeting mitochondrial 18 kDa translocator protein ( TSPO ) regulates macrophage cholesterol efflux and lipid phenotype . The aim of the present study was to establish mitochondrial cholesterol trafficking 18 kDa translocator protein ( TSPO ) as a potential therapeutic target , capable of increasing macrophage cholesterol efflux to (apo)lipoprotein acceptors . Expression and activity of TSPO in human ( THP-1 ) macrophages were manipulated genetically and by the use of selective TSPO ligands . Cellular responses were analysed by quantitative PCR ( Q-PCR ) , immunoblotting and radiolabelling , including [3H]cholesterol efflux to (apo)lipoprotein A-I ( apoA-I ) , high-density lipoprotein ( HDL ) and human serum . Induction of macrophage cholesterol deposition by acetylated low-density lipoprotein ( AcLDL ) increased expression of TSPO mRNA and protein , reflecting findings in human carotid atherosclerosis . Transient overexpression of TSPO enhanced efflux ( E % ) of [3H]cholesterol to apoA-I , HDL and human serum compared with empty vector ( EV ) controls , whereas gene knockdown of TSPO achieved the converse . Ligation of TSPO ( using PK11195 , FGIN-1-27 and flunitrazepam ) triggered increases in [3H]cholesterol efflux , an effect that was amplified in TSPO-overexpressing macrophages . Overexpression of TSPO induced the expression of genes [ Q07869 ( peroxisome-proliferator-activated receptor α ) , Q13133 ( nuclear receptor 1H3/liver X receptor α ) , O95477 ( DB00171 -binding cassette A1 ) , Q9H172 ( DB00171 -binding cassette G4 ) and P02649 ( apolipoprotein E ) ] and proteins ( O95477 and PPARα ) involved in cholesterol efflux , reduced macrophage neutral lipid mass and lipogenesis and limited cholesterol esterification following exposure to AcLDL . Thus , targeting TSPO reduces macrophage lipid content and prevents macrophage foam cell formation , via enhanced cholesterol efflux to (apo)lipoprotein acceptors . Functional blockade of platelet-derived growth factor receptor-beta but not of receptor-alpha prevents vascular smooth muscle cell accumulation in fibrous cap lesions in apolipoprotein E-deficient mice . BACKGROUND : The vascular smooth muscle cell ( VSMC ) is the central cell component involved in the fibroproliferative response in atherogenesis . As the lesion advances , VSMCs migrate from the media into the subendothelial space , thereby forming fibrous plaque lesions . Platelet-derived growth factor ( PDGF ) has been known to be a potent chemoattractant and mitogen for SMCs , but the pathophysiological role of the 2 PDGF receptors , receptor-alpha ( P16234 ) and receptor-beta ( P09619 ) in atherogenesis is poorly understood . To clarify this problem , we prepared antagonistic rat monoclonal antibodies , APA5 and APB5 , against murine P16234 and P09619 , respectively . METHODS AND RESULTS : P02649 -deficient mice were fed a high-fat diet containing 0.3 % cholesterol from 6 weeks of age and subjected to injection with 1 mg/d IP of either antibody from 12 to 18 weeks every other day . In the mice injected with APB5 , the aortic atherosclerotic lesion size and the number of intimal VSMCs were reduced by 67 % and 80 % , respectively , compared with the control mice injected with irrelevant rat IgG . In contrast , the mice that received APA5 showed only minimal reduction of lesion size , and a large number of VSMCs were observed in the intima . In the intima of advanced lesions , APB5 immunolabeled VSMCs , whereas APA5 could detect VSMCs mainly in the media . CONCLUSIONS : These results indicate that P09619 plays a significant role in formation of fibrous atherosclerotic lesions and that regulation of the signal transduction through P09619 could affect atherogenesis in mice . Effects of docosahexaenoic acid on some megakaryocytic cell gene expression of some enzymes controlling prostanoid synthesis . Beneficial effects of docosahexaenoic acid ( DB01708 ) intake in the prevention of cardiovascular diseases are known , and platelets play a crucial role in cardiovascular complications . However , high doses of DB01708 may increase lipid peroxidation and induce deleterious effects , notably in platelets . This led us to investigate the effect of DB01708 on gene expression of some enzymes controlling redox status and prostanoid formation in human megakaryoblastic cells ( P29074 -01 cell line ) . P29074 -01 cells were incubated in presence of DB01708 ( 10 and 100 micromol/L ) for 6h . DB01708 enrichment up-regulated glutathione peroxidase-1 and thromboxane synthase mRNA . DB01708 increased gene catalase expression and up-regulated Q07869 beta/delta and Q07869 gamma mRNA in presence of high concentration of DB01708 . In conclusion , our results support an antioxidant mechanism of DB01708 . The effects of DB01708 on cellular redox status could , with others , provide an explanation for the beneficial influence of low consumption of DB01708 on cardiovascular events . Possible role of cholecystokinin-A receptors in regulation of thyrotropin ( DB00024 ) secretion in male rats . We studied the importance of cholecystokinin ( CCK ) system in the regulation of thyrotropin ( DB00024 ) and prolactin ( PRL ) secretion in male rats . To this end , we tested the effects of both unselective CCK agonists CCK-8 and caerulein , and CCK-B selective agonists Q13308 and pentagastrin as well as the selective CCK antagonists ( devazepide and L-365,260 ) at wide dose-ranges on the cold-stimulated and TRH-induced DB00024 and PRL secretion . DB00403 , given s.c . 15 min before sacrifice , decreased DB00024 levels at 5 micrograms/kg . In time course-studies , the maximum inhibition was seen at 15 min but the effect lasted at least 30 , but less than 60 min . Also CCK-8 decreased DB00024 levels at the doses of 20 and 50 micrograms/kg at 15 min . Devazepide and L-365,260 did not affect DB00024 or PRL levels at any dose . The effect of caerulein ( 5 micrograms/kg ) was antagonized by devazepide , a CCK-A antagonist , at 100 micrograms/kg , but not by a CCK-B antagonist L-365,260 tested at a wide dose range . PRL levels were not affected by any treatment . DB00403 ( 5 micrograms/kg ) , given at the same time as TRH ( 500 ng/kg ) , inhibited the TRH-induced DB00024 levels at 15 min , but not at 30 or 60 min . CCK-8 ( 50 micrograms/kg ) , Q13308 ( 100 micrograms/kg ) and pentagastrin ( 500 micrograms/kg ) did not affect the TRH-induced DB00024 secretion . The results probably indicate that P32238 stimulation inhibits DB00024 secretion at the level of the anterior pituitary gland . PRL levels in male rats are not affected by CCK system . Genetic ablation of Adamts13 gene dramatically accelerates the formation of early atherosclerosis in a murine model . OBJECTIVE : Q76LX8 ( a disintegrin and metalloprotease with thrombospondin type 1 repeats-13 ) cleaves P04275 , thereby modulating thrombosis and inflammation . Low plasma Q76LX8 activity is associated with cardiovascular events , including myocardial and cerebral infarction . Here , we investigated the role of Q76LX8 in the development of early atherosclerosis in a murine model . METHODS AND RESULTS : P02649 -null ( ApoE(-/-) ) and Adamts13-null ( Adamts13(-/-) ) ApoE(-/-) mice were fed with a high-fat Western diet for 12 weeks . Atherosclerotic lesions in the aorta and aortic roots were quantified after staining . Leukocyte rolling and adhesion onto cremaster venules after oxidative injury were determined by intravital microscopy . Although plasma cholesterol levels were largely similar in both groups , the extent of atherosclerotic lesions in the aorta en face and in the aortic roots in the Adamts13(-/-)ApoE(-/-) mice increased ≈ 5.5-fold ( P=0.0017 ) and ≈ 6.1-fold ( P=0.0037 ) , respectively . In addition , the ratio of plasma high- to low-molecular-weight P04275 multimers increased ≈ 3-fold . The leukocyte rolling velocities were significantly reduced ( P < 0.001 ) , with an increased number of leukocyte rolling ( P=0.0026 ) and macrophage infiltration into the atherosclerotic lesions in the Adamts13(-/-)ApoE(-/-) mice . CONCLUSIONS : Our results suggest that Q76LX8 plays a critical role in modulating the development of early atherosclerosis , likely through the proteolytic cleavage of ultra-large P04275 multimers , thereby inhibiting platelet deposition and inflammation . Cholecystokinin-related peptides , after systemic or central administration , prevent carbon monoxide-induced amnesia in mice . The neuroprotective actions of cholecystokinin ( CCK ) peptides were investigated in a mouse hypoxia model , in which the animals were successively exposed to CO gas . Working memory impairment 5 days after CO exposure was examined by using a Y-maze test ; delayed amnesia was examined 7 days after CO exposure , by using a step-down type passive avoidance test . DB00403 ( 1-100 micrograms/kg , given s.c. 30 min before CO exposure ) significantly prevented the CO-induced impairment of performance in both tests , the improvement being correlated with the severity of hypoxia . This severity was increased by maintaining the body temperature at 38 degrees C . DB00403 was less effective when injected immediately after a single CO exposure . The order of potency of the CCK-peptides administered systemically was : ceruletide > CCK-8S > CCK-8NS >> Q13308 . DB00403 ( 0.03-0.3 micrograms/mouse ) and CCK-8S ( 0.03-1 microgram/mouse ) prevented CO-induced amnesia after i.c.v. administration . Under all experimental conditions , dizocilpine [ MK-801 , (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate , 500 micrograms/kg s.c. or 10 micrograms/mouse i.c.v. ] prevented completely the CO-induced amnesia . The protective effects of systemic ceruletide were blocked , partially but significantly , by the preadministration of L-364,718 ( 3S-(-)-N- [ 2,3-dihydro-1-methyl-2-oxo-S-phenyl-1H-1,4- benzodiazepine-3-yl ] -1H-indole-2-carboxamide , 1-10 mg/kg i.p. ) , a selective P32238 antagonist . L-365,260 ( [ 3R-(+)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl ] -N ' - [3-methyl-phenyl]urea ) , a CCK-B antagonist , also decreased ceruletide-induced protection. ( ABSTRACT TRUNCATED AT 250 WORDS ) DB09559 in the treatment of advanced non-small cell lung cancer : translation from preclinical to clinical development . INTRODUCTION : Treatment outcomes in unselected patients with advanced NSCLC remain disappointing with platinum-based chemotherapy . The addition of monoclonal antibodies targeting P00533 to standard first-line therapy is a validated strategy and has been associated with statistically significant survival advantage in advanced NSCLC . Necitumunab is a fully human IgG1 monoclonal antibody targeting P00533 , having the potential benefit of lower hypersensitivity reaction risk as compared with cetuximab and also equivalent antibody-dependent cell-mediated cytotoxicity . AREAS COVERED : This paper reviews literature on preclinical and early clinical development of necitumumab that is available in PubMed and published abstracts from conferences , as well as ongoing trials as specified by clinicaltrials.gov . Recently , the Phase III clinical trial evaluating the addition of necitumumab to pemetrexed and cisplatin in non-squamous NSCLC was prematurely closed due to concerns about the increased risk of thromboembolic events in the experimental arm . Accrual in the Phase III trial of necitumumab in combination with gemcitabine and cisplatin in squamous NSCLC is ongoing . EXPERT OPINION : Results of the ongoing large randomized trials will be instrumental in determining the drug 's clinical significance and , with the analysis of potential molecular predictive factors , are expected to bring valuable additions to future therapeutic strategies in NSCLC .