interacts_with DB00073?
Platelets trigger a P25942 -dependent inflammatory response in the microvasculature of inflammatory bowel disease patients . BACKGROUND & AIMS : Platelets circulate in an activated state in patients with inflammatory bowel disease ( Q9UKU7 ) , but their role in the pathogenesis of Q9UKU7 is unclear . The recent demonstration that activated platelets express P29965 ( L ) provides a mechanism of interaction with P25942 -positive endothelial cells , inducing them to produce proinflammatory mediators . We investigated whether platelets from patients with Q9UKU7 express enhanced levels of P29965 and induce human intestinal microvascular endothelial cells ( HIMEC ) to up-regulate cell adhesion molecule ( P62158 ) expression and secrete chemokines . METHODS : P29965 expression was assessed in resting and thrombin-activated platelets by flow cytometry and in mucosal microthrombi by confocal microscopy . Platelet-HIMEC cocultures were used to study P62158 up-regulation , and interleukin ( IL ) -8 and RANTES production by HIMEC . RESULTS : Q9UKU7 platelets expressed significantly higher P29965 levels than those of healthy subjects , and P29965 -positive platelets were detected in Q9UKU7 -involved mucosa . Activated platelets up-regulated expression of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 as well as production of interleukin 8 by HIMEC in a P25942 -dependent fashion . High levels of RANTES were present in platelet-HIMEC cocultures and platelets were identified as the source of this chemokine , which mediated T-cell adhesion to HIMEC . CONCLUSIONS : These results show that platelets can actively contribute to mucosal inflammation and represent a previously unrecognized component of Q9UKU7 pathogenesis . Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with DB01259 and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 -positive breast cancer . We report a patient with breast cancer overexpressing HER-2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine . Polymorphisms in inflammatory cytokines and Fcgamma receptors in childhood chronic immune thrombocytopenic purpura : a pilot study . Inflammatory cytokines and low-affinity Fcgamma receptor ( FcgammaR ) polymorphisms were investigated in 37 children with chronic immune thrombocytopenic purpura ( cITP ) and 218 controls . Genotype analysis included common variants in the regulatory regions of cytokines , P01375 , P01374 , P18510 , P01583 , P01584 , P05112 , P05231 and P22301 , and structural variants of the low affinity FcgammaRs , P12318 , P08637 and O75015 . Associations were observed for P01375 ( P = 0.0032 ) , P01374 ( P = 0.019 ) , P08637 ( P = 0.038 ) and O75015 ( P = 0.0034 ) . Two combinations of genotypes ( P01375 and P08637 ; P = 0.0003 , and P01374 and O75015 ; P = 0.011 ) were significantly associated with cITP . These results provide preliminary evidence that variant genotypes of FcgammaRs and cytokines contribute to cITP pathogenesis . Synthesis and evaluation of ( S ) -2-(2-[18F]fluoroethoxy)-4- ( [ 3-methyl-1-(2-piperidin-1-yl-phenyl)-butyl-carbamoyl ] -methyl ) -benzoic acid ( [18F]repaglinide ) : a promising radioligand for quantification of pancreatic beta-cell mass with positron emission tomography ( PET ) . 18F-labeled non-sulfonylurea hypoglycemic agent ( S ) -2-(2-[(18)F]fluoroethoxy)-4- ( ( 3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl ) -methyl ) -benzoic acid ( [(18)F]repaglinide ) , a derivative of the sulfonylurea-receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non-invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta-cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [(18)F] DB00912 could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2-[(18)F]fluoroethyltosylate . Specific activity was in the range of 50-60 GBq/micromol . Labeling was conducted by exchanging the ethoxy-moiety into a 2-[(18)F]fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non-radioactive (19)F-compound for binding to the human Q09428 isoform was assessed . [(19)F] DB00912 induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1.03 ) yielding a dissociation constant ( K(D) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [(18)F]repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i.v. injection . Pancreatic tissue displayed a stable accumulation of approximately 0.12 % of the injected dose from 10 min to 30 min p.i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [(18)F]repaglinide might be suitable for in vivo investigation with PET . Altered gene expression by low-dose arsenic exposure in humans and cultured cardiomyocytes : assessment by real-time PCR arrays . Chronic arsenic exposure results in higher risk of skin , lung , and bladder cancer , as well as cardiovascular disease and diabetes . The purpose of this study was to investigate the effects on expression of selected genes in the blood lymphocytes from 159 people exposed chronically to arsenic in their drinking water using a novel RT-PCR TaqMan low-density array ( TLDA ) . We found that expression of tumor necrosis factor-α ( P01375 -α ) , which activates both inflammation and NF-κB-dependent survival pathways , was strongly associated with water and urinary arsenic levels . Expression of P22460 , which encodes a potassium ion channel protein , was positively associated with water and toe nail arsenic levels . Expression of 2 and 11 genes were positively associated with nail and urinary arsenic , respectively . Because arsenic exposure has been reported to be associated with long QT intervals and vascular disease in humans , we also used this TLDA for analysis of gene expression in human cardiomyocytes exposed to arsenic in vitro . Expression of the ion-channel genes CACNA1 , Q12809 , P51787 and P15382 were down-regulated by 1-μM arsenic . Alteration of some common pathways , including those involved in oxidative stress , inflammatory signaling , and ion-channel function , may underlay the seemingly disparate array of arsenic-associated diseases , such as cancer , cardiovascular disease , and diabetes . Differences in transcript levels of ABC transporters between pancreatic adenocarcinoma and nonneoplastic tissues . OBJECTIVES : The aim of this study was to evaluate transcript levels of all 49 human DB00171 -binding cassette transporters ( ABCs ) in one of the most drug-resistant cancers , namely , the pancreatic ductal adenocarcinoma ( PDAC ) . Association of ABCs levels with clinical-pathologic characteristics and P01116 mutation status was followed as well . METHODS : Tumors and adjacent nonneoplastic tissues were obtained from 32 histologically verified PDAC patients . The transcript profile of ABCs was assessed using quantitative real-time polymerase chain reaction with a relative standard curve . P01116 mutations in exon 2 were assessed by high-resolution melting analysis and sequencing . RESULTS : Most ABCs were deregulated in PDAC and 10 ABCs were associated with clinical-pathologic characteristics . P01116 mutations did not change the global expression profile of ABCs . CONCLUSIONS : The expression of ABC transporters was significantly deregulated in PDAC tumors when compared to nonmalignant tissues . The observed up-regulation of P21439 , O95342 , P33527 , O15438 , O15440 , Q5T3U5 , and Q9UNQ0 in tumors may contribute to the generally poor treatment response of PDAC . The up-regulation of O95477 , Q8IZY2 , and P45844 implicates a serious impairment of cellular cholesterol homeostasis in PDAC . On the other hand , the observed down-regulation of Q99758 , O95255 , P13569 , and Q09428 suggests a possible role of stem cells in the development and progression of PDAC . DB00073 -dependent cytotoxicity by natural killer cells : influence of P08637 polymorphism on the concentration-effect relationship . The P08637 gene dimorphism generates two allotypes : FcgammaRIIIa-158V and FcgammaRIIIa-158F . The genotype homozygous for FcgammaRIIIa-158V ( VV ) is associated with higher clinical response to rituximab , a chimeric anti- P11836 IgG1 used in the treatment of B lymphoproliferative malignancies . Our objective was to determine whether this genetic association relates to rituximab-dependent cytotoxicity mediated by FcgammaRIIIa/CD16a+ cells . The number of CD16+ circulating monocytes , T cells , and natural killer ( NK ) cells in 54 donors was first shown to be unrelated to P08637 polymorphism . We then demonstrated that FcgammaRIIIa-158V displays higher affinity for rituximab than FcgammaRIIIa-158F by comparing rituximab concentrations inhibiting the binding of 3G8 mAb ( anti-CD16 ) with VV NK cells and NK cells homozygous for FcgammaRIIIa-158F ( FF ) . VV and FF NK cells killed Daudi cells similarly after FcgammaRIIIa engagement by saturating concentrations of rituximab or 3G8 . However , the rituximab concentration resulting in 50 % lysis ( EC(50) ) observed with NK cells from VV donors was 4.2 times lower than that observed with NK cells from FF donors ( on average 0.00096 and 0.00402 microg/ml , respectively , P = 0.0043 ) . Finally , the functional difference between VV and FF NK cells was restricted to rituximab concentrations weakly sensitizing P11836 . This study supports the conclusion that P08637 genotype is associated with response to rituximab because it affects the relationship between rituximab concentration and NK cell-mediated lysis of P11836 + cells . DB00073 administration could therefore be adjusted according to P08637 genotype . P23458 / P40763 activation directly inhibits IL-12 production in dendritic cells by preventing P50750 /P-TEFb recruitment to the p35 promoter . Inhibition of Janus-activated kinase-1 ( P23458 ) is a promising clinical concept for post-transplant immunosuppression and autoimmunity . However , it also raises concerns regarding possible immunosuppressive side effects . Our study investigates P23458 signalling in the context of P29965 and bacterially activated human MoDC using siRNA and biological inhibitors . We demonstrate that strong stimuli ( e.g. intact Escherichia coli or LPS in addition to IL-1β ) induce IL-12p70 via a ROS/ Q04206 / P50750 pathway that is inhibited by simultaneous P23458 / P40763 signalling . Transcription is effective if Q04206 recruits the positive transcription elongation factor b ( P-TEFb ) component P50750 to a combined Q04206 / P40763 binding site -50 to -20bp upstream of the start site of the IL-12p35 promoter . P40763 simultaneously attaches to this site and inhibits P50750 binding . In the presence of IFNγ , P23458 /2 inhibitors block P42224 / P10914 / Q02556 -dependent activation and simultaneously enhance P50750 -dependent activation signals . This inverse regulation of IFNγ- vs. E. coli-induced cytokine production by JAK inhibitors including DB08877 was similarly observed for P05231 and P01375 -α production , but not for P22301 production . Thus , P23458 inhibition enhances IL-12p70 production in this context by increased DNA binding of P50750 . In contrast , weak Q04206 -activation signals ( P29965 , LPS ) depended on IFN-γ induced P42224 / P10914 / Q02556 co-signalling , which was completely blocked by JAK inhibitors as reported before . Our results suggest a novel molecular mechanism of how cytokine responses to invading pathogens are separable from IFNγ-dependent autoimmunity by targeting P23458 / P40763 activation . DB01296 sulfate inhibits P01375 and P01579 -induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : DB01296 sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine-induced expression of the gene for intercellular adhesion molecule ( ICAM ) -1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE-19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT-PCR ) . The activation and nuclear translocation of the nuclear factors NF-kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time- and dose-dependent manner in ARPE-19 cells . GS effectively downregulated the P01375 - or P01579 -induced expression of P05362 in the protein and mRNA level in a dose-dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 -stimulated ARPE-19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE-19 cell stimulated with P01375 or P01579 through blockade of NF-kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye . TTSS2-deficient hha mutant of Salmonella Typhimurium exhibits significant systemic attenuation in immunocompromised hosts . Non-typhoidal Salmonella ( P30990 ) infections are emerging as leading problem worldwide and the variations in host immune status append to the concern of P30990 . Salmonella enterica serovar Typhimurium is one of the causative agents of P30990 infections and has been extensively studied . The inactivation of Salmonella pathogenicity island 2 ( SPI2 ) encoded type-III secretion system 2 ( TTSS2 ) has been reported rendering the strain incapable for systemic dissemination to host sites and has also been proposed as live-attenuated vaccine . However , infections from TTSS2-deficient Salmonella have also been reported . In this study , mutant strain MT15 was developed by inactivation of the hemolysin expression modulating protein ( hha ) in TTSS2-deficient S. Typhimurium background . The MT15 strain showed significant level of attenuation in immune-deprived murine colitis model when tested in iNos(-/-) , P22301 (-/-) , and P29965 (-/-) mice groups in C57BL/6 background . Further , the mutation in hha does not implicate any defect in bacterial colonization to the host gut . The long-term infection of developed mutant strain conferred protective immune responses to suitably immunized streptomycin pre-treated C57BL/6 mice . The immunization enhanced the P01730 (+) and CD8(+) cell types involved in bacterial clearance . The serum IgG and luminal secretory IgA ( sIgA ) was also found to be elevated after the due course of infection . Additionally , the immunized C57BL/6 mice were protected from the subsequent lethal infection of Salmonella Typhimurium . Collectively , these findings implicate the involvement of hemolysin expression modulating protein ( Hha ) in establishment of bacterial infection . In light of the observed attenuation of the developed mutant strain , this study proposes the possible significance of SPI2-deficient hha mutant as an alternative live-attenuated vaccine strain for use against lethal Salmonella infections . Stage-dependent inhibition of Plasmodium falciparum by potent Ca2+ and calmodulin modulators . The effects of Ca2+ channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W-7 and W-5 , on Plasmodium falciparum in culture were examined . Among Ca2+ blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4.3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W-7 with IC50 of 3.4 and 4.5 microM , respectively , than to Q9HCM9 and W-5 . All Ca2+ blockers and P62158 inhibitors suppressed parasite development at later stages . DB00622 , diltiazem , calmidazolium and W-5 also retarded parasite development at earlier stages and/or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2+ and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2+ channels or P62158 . Systems pharmacology assessment of the 5-fluorouracil pathway . AIM : To assess the impact of the 5-fluorouracil ( DB00544 ) drug-pathway genes on cytotoxicity , and determine whether loss-of-function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose-response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC(50) for shRNA-exposed cells were three standard deviations outside the mean IC(50) for control-treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples . P12318 polymorphism is correlated with clinical outcome after immunotherapy of neuroblastoma with anti-GD2 antibody and granulocyte macrophage colony-stimulating factor . PURPOSE : Anti-GD2 murine IgG3 antibody 3F8 kills neuroblastoma cells by antibody-dependent cell-mediated cytotoxicity ( ADCC ) . Granulocyte macrophage colony-stimulating factor ( GM- P04141 ) enhances phagocyte-mediated ADCC . The differential affinity of the human FCGR polymorphic alleles for 3F8 may influence the effectiveness of antibody immunotherapy . PATIENTS AND METHODS : The entire cohort of high risk neuroblastoma patients ( N = 136 ) treated on protocol using 3F8 and GM- P04141 were the subjects of this analysis . Tumor response was measured by standard clinical tools plus sensitive molecular monitoring using quantitative reverse transcription-polymerase chain reaction ( qRT-PCR ) . Polymorphic alleles of P12318 and P08637 were determined by PCR plus direct sequencing using genomic DNA samples obtained from marrow or blood of patients . RESULTS : P12318 ( R/R ) genotype correlated with progression-free survival for the entire cohort ( P = .049 ) and for the subset of patients with no history of prior relapse ( P = .023 ) . P12318 ( R/R ) also correlated with marrow remission 2.5 months after treatment initiation : by histology ( P = .021 and P = .036 , for the entire cohort and the subset , respectively ) and by qRT-PCR ( P = .052 and P = .033 , respectively ) . CONCLUSION : The favorable outcome associated with P12318 ( R/R ) genotype is consistent with the proposed role of P12318 and phagocyte-mediated ADCC in 3F8 plus GM- P04141 immunotherapy . Molecular predictors of combination targeted therapies ( cetuximab , bevacizumab ) in irinotecan-refractory colorectal cancer ( BOND-2 study ) . BACKGROUND : To test whether intratumoral gene expression levels and germline polymorphisms predict clinical outcome in metastatic colorectal cancer ( mCRC ) patients treated with cetuximab and bevacizumab plus irinotecan ( CBI ) vs. cetuximab and bevacizumab ( CB ) (BOND2) . PATIENTS AND METHODS : Genomic DNA was extracted for genotyping from 65 patients ( 31 : CBI arm and 34 : CB arm ) . Thirty five patients had tissue samples available for the gene expression assay ( 18 : CBI arm and 17 : CB arm ) . RESULTS : High intratumoral gene expression levels of P00533 , P35968 and NRP1 were associated with longer overall survival ( OS ) in patients receiving combined monoclonal antibodies with or without irinotecan . P08637 V158F , CyclinD1 A870G and P00533 R497K polymorphisms are associated with clinical outcome in patients received combined cetuximab and bevacizumab . CONCLUSIONS : Intratumoral gene expression levels of P00533 , P35968 and NRP as well as polymorphisms in P08637 , CyclinD1 and P00533 could predict clinical outcome in mCRC patients enrolled in BOND2 , independent of P01116 mutation status . Association of the P08637 -158F/V gene polymorphism with the response to rituximab treatment in Spanish systemic autoimmune disease patients . DB00073 is being used as treatment for systemic autoimmune diseases . The objective of this study was to determine whether the genetic variant in the Fc gamma-receptor III a ( P08637 ) gene , 158F/V , contributes to the observed variation in response to rituximab in patients with systemic autoimmune diseases . DNA samples from 132 Spanish patients with different systemic autoimmune diseases receiving rituximab were genotyped for P08637 -158F/V ( rs396991 ) gene polymorphism using the TaqMan(®) allelic discrimination technology . Six months after infusion with rituximab we evaluated the response to the drug : 61 % of the patients showed a complete response , partial 27 % and 12 % did not respond to the treatment . A statistically significant difference was observed in V allele frequency between responder ( 38 % ) and nonresponder ( 16 % ) patients ( p=0.01 ; odds ratio [OR]=3.24 , 95 % confidence interval [ CI ] 1.17-11.1 ) . DB00073 was also more effective in V allele carriers ( 94 % ) than in homozygous FF patients ( 81 % ) : p=0.02 ; OR=3.96 , 95 % CI 1.10-17.68 . These results suggest that P08637 -158F/V ( rs396991 ) gene polymorphism play a role in the response to rituximab in autoimmune diseases . Validation of these findings in independent cohorts is warranted . T lymphocytes expressing a CD16 signaling receptor exert antibody-dependent cancer cell killing . To expand applications for T-cell-based immunotherapy in cancer , we designed a receptor that binds the Fc portion of human immunoglobulins and delivers activation signals . The construct included the high-affinity CD16 ( P08637 ) V158 variant , CD8α hinge , and transmembrane domains , along with signaling domains from CD3ζ and 4-1BB ( Q07011 ) , forming a chimeric receptor termed CD16V-BB-ζ . After retrovirus-mediated expression in human T cells , CD16V-BB-ζ bound humanized antibodies with higher affinity than a control receptor containing the more common F158 variant . Engagement of CD16V-BB-ζ provoked T-cell activation , exocytosis of lytic granules , and sustained proliferation , with a mean cell recovery after 4-week coculture with Daudi lymphoma cells and rituximab of nearly 70-fold relative to input cells . In contrast , unbound antibody alone produced no effect . CD16V-BB-ζ T cells specifically killed lymphoma cells and primary chronic lymphocytic leukemia cells in combination with rituximab at a low effector:target ratio , even when assayed on mesenchymal cells . DB00072 triggered CD16V-BB-ζ-mediated killing of P04626 ( P04626 ) (+) breast and gastric cancer cells ; similar results were obtained with an anti-GD2 antibody in neuroblastoma and osteosarcoma cells . Furthermore , coadministration of CD16V-BB-ζ T cells with immunotherapeutic antibodies exerted considerable antitumor activity in vivo . Signaling mediated by 4-1BB-CD3ζ induced higher T-cell activation , proliferation , and cytotoxicity than CD3ζ or FcεRIγ , and the receptor was expressed effectively after mRNA electroporation without viral vectors , facilitating clinical translation . Our results offer preclinical proof of concept for CD16V-BB-ζ as a universal , next-generation chimeric receptor with the potential to augment the efficacy of antibody therapies for cancer . P08637 -158 polymorphism influences the biological response to infliximab in Crohn 's disease through affecting the ADCC activity . An association between P08637 -158 V/F polymorphism and biological responses to infliximab has been reported in Crohn 's disease ( CD ) in Western countries . However , little is known about the mechanism by which gene polymorphism affects the responses to infliximab . The aims of this study were to confirm the association in Japanese CD patients and to reveal the effect of gene polymorphism on biological responses to infliximab . Japanese CD patients were examined retrospectively at weeks 8 and 30 . Clinical and biological responses were assessed by the Crohn 's disease activity index and P02741 levels , respectively . The infliximab-binding affinity of natural killer ( NK ) cells from P08637 -158 V/V , V/F and F/F donors was examined . DB00065 -mediated antibody-dependent cell-mediated cytotoxicity ( ADCC ) activities were also determined using transmembrane P01375 -α-expressing Jurkat T cells as target cells and peripheral blood mononuclear cells ( PBMCs ) from V/V , V/F and F/F donors as effector cells . Biological responses at week 8 were statistically higher in V/V patients , whereas no significant differences were observed in either clinical responses at weeks 8 and 30 or biological responses at week 30 among the three genotypes . NK cells and PBMCs from V/V patients also showed higher infliximab-binding affinity and infliximab-mediated ADCC activity , respectively . Our results suggest that P08637 -158 polymorphism is a predicting factor of biological responses to infliximab in the early phases . P08637 -158 polymorphism was also found to affect the infliximab-binding affinity of NK cells and infliximab-mediated ADCC activity in vitro , suggesting that an effect on ADCC activity influences biological responses to infliximab in CD patients . Effect of acetazolamide on aquaporin-1 and fluid flow in cultured choroid plexus . DB00819 ( AZA ) , used in treatment of early or infantile hydrocephalus , is effective in some cases , while its effect on the choroid plexus ( CP ) remains ill-defined . The drug reversibly inhibits aquaporin-4 ( P55087 ) , the most ubiquitous " water pore " in the brain , and perhaps modulation of P29972 ( located apically on CP cells ) by AZA may reduce cerebrospinal fluid ( P04141 ) production . We sought to elucidate the effect of AZA on P29972 and fluid flow in CP cell cultures.CP tissue culture from 10-day Sprague-Dawley rats and a TRCSF-B cell line were grown on Transwell permeable supports and treated with 100 μM AZA . Fluid assays to assess direction and extent of fluid flow , and P29972 expression patterns by immunoblot , Immuncytochemistry ( ICC ) , and quantitative reverse transcriptase polymerase chain reaction ( qRT-PCR ) were performed.Immunoblots and ICC analyses showed a decrease in P29972 protein shortly after AZA treatment ( lowest at 12 h ) , with transient P29972 reduction mediated by mRNA expression ( lowest at 6 h ) . Transwell fluid assays indicated a fluid shift at 2 h , before significant changes in P29972 mRNA or protein levels.Timing of AZA effect on P29972 suggests the drug alters protein transcription , while affecting fluid flow by a concomitant method . It is plausible that other mechanisms account for these phenomena , as the processes may occur independently . Central opioid inhibition of neuroendocrine stress responses in pregnancy in the rat is induced by the neurosteroid allopregnanolone . The hypothalamus-pituitary-adrenal ( Q9Y251 ) axis is the major neuroendocrine stress response system . P06850 ( P06850 ) neurons in the parvocellular paraventricular nucleus ( pPVN ) play a key role in coordinating responses of this system to stressors . The cytokine interleukin-1beta ( IL-1beta ) , mimicking infection , robustly activates these P06850 neurons via a noradrenergic input arising from the nucleus tractus solitarii ( P30990 ) . In late pregnancy , Q9Y251 axis responses to stressors , including IL-1beta , are attenuated by a central opioid mechanism that auto-inhibits noradrenaline release in the PVN . Here we show that the neuroactive progesterone metabolite allopregnanolone induces these changes in Q9Y251 responsiveness to IL-1beta in pregnancy . In late pregnancy , inhibition of 5alpha-reductase ( an allopregnanolone-synthesizing enzyme ) with finasteride restored Q9Y251 axis responses ( rapidly increased pPVN P06850 mRNA expression , DB01285 , and corticosterone secretion ) to IL-1beta . Conversely , allopregnanolone reduced Q9Y251 responses in virgin rats . In late pregnancy , activity of the allopregnanolone-synthesizing enzymes ( 5alpha-reductase and 3alpha-hydroxysteroid dehydrogenase ) was increased in the hypothalamus as was mRNA expression in the P30990 and PVN . Naloxone , an opioid antagonist , restores Q9Y251 axis responses to IL-1beta in pregnancy but had no additional effect after finasteride , indicating a causal connection between allopregnanolone and the endogenous opioid mechanism . Indeed , allopregnanolone induced opioid inhibition over Q9Y251 responses to IL-1beta in virgin rats . Furthermore , in virgin rats , allopregnanolone treatment increased , whereas in pregnant rats finasteride decreased proenkephalin-A mRNA expression in the P30990 . Thus , in pregnancy , allopregnanolone induces opioid inhibition over Q9Y251 axis responses to immune challenge . This novel opioid-mediated mechanism of allopregnanolone action may alter regulation of other brain systems in pregnancy . Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( DB06144 ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4(3)-based assays were found to be the most economical but had high false-hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color-quenching problems but was expensive and still gave false hits . The nonradioactive Rb+ efflux assay was the most sensitive of all the assays evaluated and had the lowest false-hit rate . Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9-hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 -arg144 , P11712 -cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH-generating system . DB01267 was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9-hydroxyrisperidone , with activities of 7.5 , 0.4 and 0.2 pmol pmol(-1) CYP min(-1) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9-hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9-hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9-hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9-hydroxyrisperidone in rat . The formation of 9-hydroxyrisperidone is highly correlated with testosterone 6beta-hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat . Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene-environment studies on cancer : data from population-based Japanese random samples . Knowledge of genetic polymorphisms in gene-environment studies may contribute to more accurate identification of avoidable risks and to developing tailor-made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene-environment studies on cancer in Japan . SNP typing was performed on middle-aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples . [ Innate resistance to thymidylate synthase inhibition after 5-fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of DB00322 MP binding sites of thymidylate thynthase ( TS-BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7-days administration of DB09327 ( U-7 group ) , total TS-BS was significantly increased compared with non-treatment group and the group received only DB09327 ( U-1 group ) . For free TS-BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U-7 group compared with U-1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg/kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect . Platelet-associated antibodies , cellular immunity and FCGR3a genotype influence the response to rituximab in immune thrombocytopenia . DB00073 is widely used in autoimmune diseases including immune thrombocytopenia ( ITP ) , although the mechanism of effect remains unclear . This study describes the effects of rituximab on platelet-associated antibodies ( PA-APAs ) , B and T cell counts and clonality ( IGHV and TRG @ gene rearrangements ) , P08637 ( FcγRIIIa ) and P12318 ( FcγRIIa ) polymorphisms and correlation to anti- P29965 ( P29965 ) response . PA-APA levels fell more frequently in responders ( 6/8 ) than in non-responders ( 2/10 : P = 0·08-0·15 ) . Two responders had no PA-APAs . Two non-responders with a fall in PA-APAs had very high CD8 levels . One non-responder had a B cell clone , one responder and one non-responder had a T cell clone . 15/16 patients had the same responses to rituximab and antiCD40L . Patients with P08637 V/V polymorphisms were more likely to respond to rituximab ( P = 0·03 ) . In summary , the fall in PA-APAs in responders confirms the humoural effect of rituximab . Failure to respond in patients with very high CD8 levels , despite PA-APA fall indicates a role for T cell-mediated platelet/megakaryocyte destruction . Concordance of response to anti- P29965 suggests autoantibody-producing cells are under T cell control . Finally , the effect of FCGR polymorphisms on response confirms the importance of FCGR-mediated depletion of B cells in autoimmunity . This has implications on the pathology of ITP as well as the immunological effect of B cell depletion . Hyper-IgM , neutropenia , mild infections and low response to polyclonal stimulation : hyper-IgM syndrome or common variable immunodeficiency ? A young woman presenting respiratory infections , polyarthritis , severe neutropenia , and increased serum IgM was treated with intravenous immunoglobulin ( IVIG ) with good clinical and laboratory outcome followed by a loss of efficacy . The increased serum IgM associated to recurrent infections and autoimmune manifestations suggested the diagnosis of a hyper-IgM syndrome ( HIGMs ) . The frequency of peripheral T cells , the expression of P25942 on the patients ' B cells and P29965 on T cells and the activation-induced cytidine deaminase ( Q9GZX7 ) and uracil-DNA glycosylase ( P13051 ) at mRNA level was comparable to controls . In contrast , the frequency of B cells was one half of the healthy control and all cells showed an atypical phenotype . Although Q9GZX7 and P13051 were normal , class-switch recombination was not very efficient because circulating switched memory were reduced and , once stimulated with CpG , generated less antibody-secreting cells than controls . An increase in serum B Lymphocytes stimulator ( Q9Y275 ) was also found . The patient presented a peculiar clinical and immunological phenotype fitting for many aspects of both HIGM4 and Common Variable Immunodeficiency ( CVID ) . These findings underline the need to better explore the complex link between these two diseases .