interacts_with DB08895?
Dysfunction of the P19957 kinase/Rap1/integrin α(IIb)β(3) pathway underlies ex vivo platelet hypoactivity in essential thrombocythemia . Patients with myeloproliferative disorders ( MPDs ) , such as essential thrombocythemia ( ET ) have increased risk of thrombosis and bleeding , which are major sources of morbidity and mortality . Most P53602 patients have a gain of function mutation in O60674 ( JAK2V617F ) , but little is known how JAK2V617F affects platelet function . Here , we demonstrate that platelets from ET patients have impaired SFLLRN-mediated fibrinogen binding and have lost the potentiating effect of thrombopoietin ( which couples to O60674 ) on this pathway . In contrast , SFLLRN-mediated P16109 expression , DB00171 secretion , phosphorylation of the PKC substrate pleckstrin , and Ca(2+) mobilization were unaffected in JAK2V617F positive platelets . In addition , thrombopoietin-mediated O60674 phosphorylation was unchanged , suggesting that signaling pathways activated downstream of O60674 are impaired . Indeed , we found that platelets from JAK2V617F positive ET patients have significantly reduced phosphorylation of the P19957 kinase substrate Akt , and have reduced activation of Rap1 in response to thrombopoietin , DB01277 ,ADP , SFLLRN , and thrombin . This effect was independent of Giα Q9H244 purinergic receptor function as ADP-mediated inhibition of P50552 phosphorylation was unchanged . These results demonstrate that the P19957 kinase/Rap1 pathway is intrinsically impaired in platelets from JAK2V617F-positive ET patients , resulting in diminished thrombin and thrombopoietin-mediated integrin α(IIb)β(3) activation . Tumour suppressor Fus1 provides a molecular link between inflammatory response and mitochondrial homeostasis . Fus1 , encoded by a 3p21.3 tumour suppressor gene , is down-regulated , mutated or lost in the majority of inflammatory thoracic malignancies . The mitochondrial localization of Fus1 stimulated us to investigate how Fus1 modulates inflammatory response and mitochondrial function in a mouse model of asbestos-induced peritoneal inflammation . Asbestos treatment resulted in a decreased Fus1 expression in wild-type ( WT ) peritoneal immune cells , suggesting that asbestos exposure may compromise the Fus1-mediated inflammatory response . Untreated Fus1(-/-) mice had an ~eight-fold higher proportion of peritoneal granulocytes than Fus1(+/+) mice , pointing at ongoing chronic inflammation . Fus1(-/-) mice exhibited a perturbed inflammatory response to asbestos , reflected in decreased immune organ weight and peritoneal fluid protein concentration , along with an increased proportion of peritoneal macrophages . Fus1(-/-) immune cells showed augmented asbestos-induced activation of key inflammatory , anti-oxidant and genotoxic stress response proteins P27361 /2 , NFκB , P04179 , γ P16104 , etc . Moreover , Fus1(-/-) mice demonstrated altered dynamics of pro- and anti-inflammatory cytokine expression , such as IFNγ , TNFα , IL-1A , IL-1B and P22301 . ' Late ' response cytokine Ccl5 was persistently under-expressed in Fus1(-/-) immune cells at both basal and asbestos-activated states . We observed an asbestos-related difference in the size of CD3(+) P01730 (-) CD8(-) DN T cell subset that was expanded four-fold in Fus1(-/-) mice . Finally , we demonstrated Fus1-dependent basal and asbestos-induced changes in major mitochondrial parameters ( ROS production , mitochondrial potential and P55851 expression ) in Fus1(-/-) immune cells and in Fus1-depleted cancer cells , thus supporting our hypothesis that Fus1 establishes its immune- and tumour-suppressive activities via regulation of mitochondrial homeostasis . Efficacy and safety of tofacitinib for treatment of rheumatoid arthritis . DB08895 is the first in a new class of nonbiologic disease-modifying antirheumatic drugs ( DMARDs ) , a targeted , synthetic DMARD , approved for the treatment of rheumatoid arthritis ( RA ) as monotherapy or in combination with methotrexate or other non-biologic DMARD . DB08895 , an orally administered Janus kinase ( JAK ) inhibitor , decreases T-cell activation , pro-inflammatory cytokine production , and cytokine signaling by inhibiting binding of type I cytokine receptors family and γ-chain cytokines to paired P23458 / P52333 receptors . The net effect of tofacitinb 's mechanism of action is decreased synovial inflammation and structural joint damage in RA patients . To date , six phase 3 trials have been conducted to evaluate the safety and efficacy of tofacitinib under the oral rheumatoid arthritis triaLs ( ORAL ) series . This review describes the pharmacology of the novel agent , tofacitinib , and details the safety and efficacy data of the ORAL trials . Thrombocytopenia induced by the histone deacetylase inhibitor abexinostat involves p53-dependent and -independent mechanisms . Abexinostat is a pan histone deacetylase inhibitor ( HDACi ) that demonstrates efficacy in malignancy treatment . Like other HDACi , this drug induces a profound thrombocytopenia whose mechanism is only partially understood . We have analyzed its effect at doses reached in patient plasma on in vitro megakaryopoiesis derived from human P28906 (+) cells . When added at day 0 in culture , abexinostat inhibited CFU-MK growth , megakaryocyte ( MK ) proliferation and differentiation . These effects required only a short incubation period . Decreased proliferation was due to induction of apoptosis and was not related to a defect in P07202 / P40238 / O60674 / P35610 signaling . When added later ( day 8 ) , the compound induced a dose-dependent decrease ( up to 10-fold ) in proplatelet ( PPT ) formation . Gene profiling from MK revealed a silencing in the expression of DNA repair genes with a marked Q06609 decrease at protein level . DNA double-strand breaks were increased as attested by elevated γ P16104 phosphorylation level . Moreover , Q13315 was phosphorylated leading to p53 stabilization and increased Q07812 and P38936 expression . The use of a p53 shRNA rescued apoptosis , and only partially the defect in PPT formation . These results suggest that HDACi induces a thrombocytopenia by a p53-dependent mechanism along MK differentiation and a p53-dependent and -independent mechanism for PPT formation . Hepatic stellate cells undermine the allostimulatory function of liver myeloid dendritic cells via P40763 -dependent induction of P14902 . Hepatic stellate cells ( HSCs ) are critical for hepatic wound repair and tissue remodeling . They also produce cytokines and chemokines that may contribute to the maintenance of hepatic immune homeostasis and the inherent tolerogenicity of the liver . The functional relationship between HSCs and the professional migratory APCs in the liver , that is , dendritic cells ( DCs ) , has not been evaluated . In this article , we report that murine liver DCs colocalize with HSCs in vivo under normal , steady-state conditions , and cluster with HSCs in vitro . In vitro , HSCs secrete high levels of DC chemoattractants , such as MΙP-1α and P13500 , as well as cytokines that modulate DC activation , including P01375 -α , P05231 , and IL-1β . Culture of HSCs with conventional liver myeloid ( m ) DCs resulted in increased P05231 and P22301 secretion compared with that of either cell population alone . Coculture also resulted in enhanced expression of costimulatory ( P33681 , P42081 ) and coinhibitory ( Q9NZQ7 ) molecules on mDCs . P19526 -induced mDC maturation required cell-cell contact and could be blocked , in part , by neutralizing MΙP-1α or P13500 . P19526 -induced mDC maturation was dependent on activation of P40763 in mDCs and , in part , on P19526 -secreted P05231 . Despite upregulation of costimulatory molecules , mDCs conditioned by HSCs demonstrated impaired ability to induce allogeneic T cell proliferation , which was independent of Q9NZQ7 , but dependent upon P19526 -induced P40763 activation and subsequent upregulation of P14902 . In conclusion , by promoting P14902 expression , HSCs may act as potent regulators of liver mDCs and function to maintain hepatic homeostasis and tolerogenicity . Novel marine phenazines as potential cancer chemopreventive and anti-inflammatory agents . Two new ( 1 and 2 ) and one known phenazine derivative ( lavanducyanin , 3 ) were isolated and identified from the fermentation broth of a marine-derived Streptomyces sp . ( strain CNS284 ) . In mammalian cell culture studies , compounds 1 , 2 and 3 inhibited P01375 -α-induced NFκB activity ( IC₅₀ values of 4.1 , 24.2 , and 16.3 μM , respectively ) and LPS-induced nitric oxide production ( IC₅₀ values of > 48.6 , 15.1 , and 8.0 μM , respectively ) . PGE₂ production was blocked with greater efficacy ( IC₅₀ values of 7.5 , 0.89 , and 0.63 μM , respectively ) , possibly due to inhibition of cyclooxygenases in addition to the expression of P35354 . Treatment of cultured HL-60 cells led to dose-dependent accumulation in the subG1 compartment of the cell cycle , as a result of apoptosis . These data provide greater insight on the biological potential of phenazine derivatives , and some guidance on how various substituents may alter potential anti-inflammatory and anti-cancer effects . EGCG enhances the therapeutic potential of gemcitabine and CP690550 by inhibiting P40763 signaling pathway in human pancreatic cancer . BACKGROUND : Signal Transducer and Activator of Transcription 3 ( P40763 ) is an oncogene , which promotes cell survival , proliferation , motility and progression in cancer cells . Targeting P40763 signaling may lead to the development of novel therapeutic approaches for human cancers . Here , we examined the effects of epigallocathechin gallate ( EGCG ) on P40763 signaling in pancreatic cancer cells , and assessed the therapeutic potential of EGCG with gemcitabine or P52333 inhibitor CP690550 ( DB08895 ) for the treatment and/or prevention of pancreatic cancer . METHODOLOGY/PRINCIPAL FINDINGS : Cell viability and apoptosis were measured by XTT assay and TUNEL staining , respectively . Gene and protein expressions were measured by qRT-PCR and Western blot analysis , respectively . The results revealed that EGCG inhibited the expression of phospho and total P52333 and P40763 , P40763 transcription and activation , and the expression of P40763 -regulated genes , resulting in the inhibition of cell motility , migration and invasion , and the induction of caspase-3 and PARP cleavage . The inhibition of P40763 enhanced the inhibitory effects of EGCG on cell motility and viability . Additionally , gemcitabine and CP690550 alone inhibited P40763 target genes and synergized with EGCG to inhibit cell viability and induce apoptosis in pancreatic cancer cells . CONCLUSIONS/SIGNIFICANCE : Overall , these results suggest that EGCG suppresses the growth , invasion and migration of pancreatic cancer cells , and induces apoptosis by interfering with the P40763 signaling pathway . Moreover , EGCG further enhanced the therapeutic potential of gemcitabine and CP690550 against pancreatic cancer . Novel treatments with small molecules in psoriatic arthritis . Current treatment options for patients with active psoriatic arthritis ( PsA ) include synthetic disease-modifying antirheumatic drugs and biologic agents . Propelled by increased understanding of immunopathogenesis of PsA , new therapeutic agents targeting different biologic pathways have been evaluated . This article discusses novel small-molecule , orally available treatments that are currently in clinical development for the treatment of psoriasis and PsA . This includes the phosphodiesterase 4 inhibitor apremilast and Janus kinase ( JAK ) inhibitors . Apremilast has demonstrated significant improvements in patients with moderate to severe psoriasis and PsA in phase II and III clinical trials and has recently been approved for the treatment of PsA . DB08895 , an oral inhibitor of P52333 , P23458 , and , to a lesser degree , O60674 , approved for the treatment of rheumatoid arthritis in several countries , has demonstrated positive results in psoriasis in phase II studies . Studies in PsA are ongoing . With these new developments , treatment options will continue to improve in the future . Effect of targeting janus kinase 3 on the development of intestinal tumors in the adenomatous polyposis coli(min) mouse model of familial adenomatous polyposis . Familial adenomatous polyposis ( FAP ) is associated with germ-line mutations in the tumor suppressor gene , adenomatous polyposis coli ( P25054 ) located on chromosome 5q21 . Multiple intestinal neoplasia ( Min ) in mice resembles FAP in humans , resulting from a single point mutation in the murine homolog of the P25054 gene . The effects of the rationally-designed P52333 ( P52333 ) inhibitor JANEX-1 ( 4-(4'-hydroxyphenyl) amino-6,7-dimethoxy-quinazoline , WHI-P131 , CAS 202475-60-3 ) on the development of intestinal tumors in the P25054 ( min/+ ) mouse model of FAP were examined . The Min mice were fed with rodent chow or chow supplemented with JANEX-1 once a week starting at 1.5 months of age . The cumulative proportions of mice remaining alive at 7 months were 13 +/- 6 % for control mice versus 72 +/-12 % for JANEX-1 treated mice ( P < 0.0002 ) . In contrast , Compound DDE24 , a synthetically activated genistein , an inhibitor of Epidermal Growth Factor receptor ( P01133 -R ) , cellular homologue of oncogene product from Raus Avian sarcoma virus ( P12931 ) and Syk tyrosine kinases , which Thus , selective targeting of P52333 was highly effective in preventing development of intestinal tumors in Min mice resulting in markedly improved survival outcomes . P52333 inhibitors may therefore be useful in the prevention of colorectal cancer in individuals with FAP . Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti-inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( DB00605 ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U.S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers . JAK inhibitors : treatment efficacy and safety profile in patients with psoriasis . Janus kinase ( JAK ) pathways are key mediators in the immunopathogenesis of psoriasis . Psoriasis treatment has evolved with the advent of targeted therapies , which inhibit specific components of the psoriasis proinflammatory cascade . JAK inhibitors have been studied in early phase trials for psoriasis patients , and the data are promising for these agents as potential treatment options . DB08895 , an oral or topically administered P23458 and P52333 inhibitor , and ruxolitinib , a topical P23458 and O60674 inhibitor , have been most extensively studied in psoriasis , and both improved clinical symptoms of psoriasis . Additional P23458 or P52333 inhibitors are being studied in clinical trials . In phase III trials for rheumatoid arthritis , tofacitinib was efficacious in patients with inadequate responses to tumor necrosis factor inhibitors , methotrexate monotherapy , or disease-modifying antirheumatic drugs . The results of phase III trials are pending for these therapies in psoriasis , and these agents may represent important alternatives for patients with inadequate responses to currently available agents . Further investigations with long-term clinical trials are necessary to verify their utility in psoriasis treatment and assess their safety in this patient population . Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas . A phase I trial of ABT-888 ( veliparib ) , a PARP inhibitor , in combination with topotecan , a topoisomerase I-targeted agent , was carried out to determine maximum tolerated dose ( MTD ) , safety , pharmacokinetics , and pharmacodynamics of the combination in patients with refractory solid tumors and lymphomas . Varying schedules and doses of intravenous topotecan in combination with ABT-888 ( 10 mg ) administered orally twice a day ( P55957 ) were evaluated . Plasma and urine pharmacokinetics were assessed and levels of poly(ADP-ribose) ( PAR ) and the DNA damage marker γ P16104 were measured in tumor and peripheral blood mononuclear cells ( PBMC ) . Twenty-four patients were enrolled . Significant myelosuppression limited the ability to coadminister ABT-888 with standard doses of topotecan , necessitating dose reductions . Preclinical studies using athymic mice carrying human tumor xenografts also informed schedule changes . The MTD was established as topotecan 0.6 mg/m²/d and ABT-888 10 mg P55957 on days one to five of 21-day cycles . DB01030 did not alter the pharmacokinetics of ABT-888 . A more than 75 % reduction in PAR levels was observed in 3 paired tumor biopsy samples ; a greater than 50 % reduction was observed in PBMCs from 19 of 23 patients with measurable levels . Increases in γ P16104 response in circulating tumor cells ( CTC ) and PBMCs were observed in patients receiving ABT-888 with topotecan . We show a mechanistic interaction of a PARP inhibitor , ABT-888 , with a topoisomerase I inhibitor , topotecan , in PBMCs , tumor , and CTCs . Results of this trial reveal that PARP inhibition can modulate the capacity to repair topoisomerase I-mediated DNA damage in the clinic . Thalidomide suppresses Up-regulation of human immunodeficiency virus coreceptors P61073 and P51681 on P01730 + T cells in humans . Concurrent infection in patients with human immunodeficiency virus ( HIV ) infection increases the expression of HIV coreceptors P61073 and P51681 . Thalidomide has beneficial effects in a number of HIV-associated diseases . The effect of thalidomide on P61073 and P51681 expression on P01730 + T cells was determined . Thalidomide produced a dose-dependent inhibition of lipopolysaccharide ( LPS ) -induced up-regulation of P61073 and P51681 in vitro . Antibody to tumor necrosis factor-alpha ( P01375 ) also attenuated the LPS-induced HIV coreceptor up-regulation , which was not further reduced by thalidomide . Thalidomide ( 400 mg ) was orally administered to 6 men , and their blood was stimulated ex vivo with LPS , staphylococcal or mycobacterial antigens , or antibody to CD3 or P10747 cells . All stimuli induced up-regulation of HIV coreceptors , which was reduced after ingestion of thalidomide . Thalidomide may be beneficial in the treatment of intercurrent infections during HIV infection by reducing the up-regulation of P61073 and P51681 expression on P01730 + T cells induced by bacterial and mycobacterial antigens , by a mechanism that involves inhibition of P01375 . DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs-coupled receptor . DB00171 and ADP activate functionally distinct G protein-coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide-specific P2Y receptors on cord blood-derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP-specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 /UTP-specific P41231 receptor ; and the DB00171 -selective Q96G91 receptor . ADP ( 0.05-50 muM ) induced calcium flux that was completely blocked by a P47900 receptor-selective antagonist and was not cross-desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 -selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP-1beta in response to leukotriene D(4) . These effects were mimicked by two DB00171 analogues , adenosine 5'-O-(3-thiotriphosphate) and 2',3'-O-(4-benzoyl-benzoyl) adenosine 5'-triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5'-O-(3-thiotriphosphate) , and 2',3'-O-(4-benzoyl-benzoyl) adenosine 5'-triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up-regulated the expression of inducible DB02527 early repressor , a CREB-dependent inhibitor of cytokine transcription . Human MCs thus express several ADP-selective P2Y receptors and at least one G(s)-coupled ADP/ DB00171 receptor . Nucleotides could therefore contribute to MC-dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs . DNA replication stalling attenuates tyrosine kinase signaling to suppress S phase progression . Here we report that T cell protein tyrosine phosphatase ( P17706 ) -dependent and -independent pathways attenuate the JAK and Src protein tyrosine kinases ( PTKs ) and P40763 phosphorylation to suppress cyclin D1 expression and S phase progression in response to DNA replication stress . Cells that lack P17706 fail to suppress P23458 , Src , and P40763 , allowing for sustained cyclin D1 levels and progression through S phase despite continued replication stress . Cells that bypass the checkpoint undergo aberrant mitoses with lagging chromosomes that stain for the DNA damage marker gamma P16104 . Therefore , inactivating JAK , Src , and P40763 signaling pathways in response to DNA replication stress may be essential for the suppression of S phase progression and the maintenance of genomic stability . DB08895 . DB08895 ( CP-690,550 ; CP-690550 ; CP690550 ) , an orally active immunosuppressant , is being developed by Pfizer for the treatment of rheumatoid arthritis , inflammatory bowel disease , dry eyes , ankylosing spondylitis , psoriasis , psoriatic arthritis , and for the prevention of transplant rejection . DB08895 specifically inhibits Janus activated kinase 3 ( P52333 ) , which has a pivotal role in cytokine signal transduction that governs lymphocyte survival , proliferation , differentiation , and apoptosis . This review discusses the key development milestones and therapeutic trials of this drug . How I treat patients who mobilize hematopoietic stem cells poorly . Transplantation with 2-5 × 10(6) mobilized P28906 (+)cells/kg body weight lowers transplantation costs and mortality . Mobilization is most commonly performed with recombinant human G- P04141 with or without chemotherapy , but a proportion of patients/donors fail to mobilize sufficient cells . BM disease , prior treatment , and age are factors influencing mobilization , but genetics also contributes . Mobilization may fail because of the changes affecting the P19526 /progenitor cell/BM niche integrity and chemotaxis . Poor mobilization affects patient outcome and increases resource use . Until recently increasing G- P04141 dose and adding P21583 have been used in poor mobilizers with limited success . However , plerixafor through its rapid direct blockage of the P61073 / P48061 chemotaxis pathway and synergy with G- P04141 and chemotherapy has become a new and important agent for mobilization . Its efficacy in upfront and failed mobilizers is well established . To maximize P19526 harvest in poor mobilizers the clinician needs to optimize current mobilization protocols and to integrate novel agents such as plerixafor . These include when to mobilize in relation to chemotherapy , how to schedule and perform apheresis , how to identify poor mobilizers , and what are the criteria for preemptive and immediate salvage use of plerixafor . Preclinical to clinical translation of tofacitinib , a Janus kinase inhibitor , in rheumatoid arthritis . A critical piece in the translation of preclinical studies to clinical trials is the determination of dosing regimens that allow maximum therapeutic benefit with minimum toxicity . The preclinical pharmacokinetic ( PK ) /pharmacodynamic ( PD ) profile of tofacitinib , an oral Janus kinase ( JAK ) inhibitor , in a mouse collagen-induced arthritis ( mCIA ) model was compared with clinical PK/PD data from patients with rheumatoid arthritis ( RA ) . Preclinical evaluations included target modulation and PK/PD modeling based on continuous subcutaneous infusion or oral once- or twice-daily ( P55957 ) dosing paradigms in mice . The human PK/PD profile was obtained from pooled data from four phase 2 studies in patients with RA , and maximal effect models were used to evaluate efficacy after 12 weeks of tofacitinib treatment ( 1-15 mg P55957 ) . In mCIA , the main driver of efficacy was inhibition of cytokine receptor signaling mediated by P23458 heterodimers , but not O60674 homodimers , and continuous daily inhibition was not required to maintain efficacy . Projected efficacy could be predicted from total daily exposure irrespective of the oral dosing paradigm , with a total steady-state plasma concentration achieving 50 % of the maximal response ( Cave50 ) of ~100 nM . DB08895 potency ( ED50 ) in clinical studies was ~3.5 mg P55957 ( 90 % confidence interval : 2.3 , 5.5 ) or total Cave50 of ~40 nM , derived using Disease Activity Scores from patients with RA . The collective clinical and preclinical data indicated the importance of Cave as a driver of efficacy , rather than maximum or minimum plasma concentration ( Cmax or Cmin ) , where Cave50 values were within ~2-fold of each other . Association of cigarette smoking and CRP levels with DNA methylation in α-1 antitrypsin deficiency . Alpha-1 antitrypsin ( P01009 ) deficiency and tobacco smoking are confirmed risk factors for Chronic Obstructive Pulmonary Disease . We hypothesized that variable DNA methylation would be associated with smoking and inflammation , as reflected by the level of C-Reactive Protein ( CRP ) in P01009 -deficient subjects . Methylation levels of 1,411 autosomal CpG sites from the Illumina GoldenGate Methylation Cancer Panel I were analyzed in 316 subjects . Associations of five smoking behaviors and CRP levels with individual CpG sites and average methylation levels were assessed using non-parametric testing , linear regression and linear mixed effect models , with and without adjustment for age and gender . Univariate linear regression analysis revealed that methylation levels of 16 CpG sites significantly associated with ever-smoking status . A CpG site in the Q15582 gene was the only site associated with ever-smoking after adjustment for age and gender . No highly significant associations existed between age at smoking initiation , pack-years smoked , duration of smoking , and time since quitting smoking as predictors of individual CpG site methylation levels . However , ever-smoking and younger age at smoking initiation associated with lower methylation level averaged across all sites . DNA methylation at CpG sites in the Q13761 , P52333 and P04264 genes associated with CRP levels . The most significantly associated CpG sites with gender and age mapped to the P55212 and O00144 genes , respectively . In summary , this study identified multiple potential candidate CpG sites associated with ever-smoking and CRP level in P01009 -deficient subjects . Phenotypic variability in Mendelian diseases may be due to epigenetic factors . Q9Y6J6 forms potassium channels with P22001 and P51787 in the choroid plexus epithelium . Cerebrospinal fluid ( P04141 ) is crucial for normal function and mechanical protection of the CNS . The choroid plexus epithelium ( CPe ) is primarily responsible for secreting P04141 and regulating its composition by mechanisms currently not fully understood . Previously , the heteromeric P51787 - Q9Y6J6 K(+) channel was functionally linked to epithelial processes including gastric acid secretion and thyroid hormone biosynthesis . Here , using Kcne2(-/-) tissue as a negative control , we found cerebral expression of Q9Y6J6 to be markedly enriched in the CPe apical membrane , where we also discovered expression of P51787 . Targeted Kcne2 gene deletion in C57B6 mice increased CPe outward K(+) current 2-fold . The Kcne2 deletion-enhanced portion of the current was inhibited by XE991 ( 10 μM ) and margatoxin ( 10 μM ) but not by dendrotoxin ( 100 nM ) , indicating that it arose from augmentation of KCNQ subfamily and P22001 but not Q09470 K(+) channel activity . Kcne2 deletion in C57B6 mice also altered the polarity of CPe P51787 and P22001 trafficking , hyperpolarized the CPe membrane by 9 ± 2 mV , and increased P04141 [ Cl(-) ] by 14 % compared with wild-type mice . These findings constitute the first report of CPe dysfunction caused by cation channel gene disruption and suggest that Q9Y6J6 influences blood- P04141 anion flux by regulating P51787 and P22001 in the CPe . Inherited disorders of cytokines . PURPOSE OF REVIEW : Cytokines are soluble mediators involved in the development or function of the immune system . This paper reviews the literature on childhood-onset inherited disorders associated with impaired cytokine-mediated immunity . RECENT FINDINGS : Cytokine-mediated immunity defects can be classified into seven different groups : defects in the interleukin ( IL ) -7 receptor ( IL7RA ) , in the common cytokine receptor gamma chain ( gammac ) of the P60568 , -4 , -7 , -15 , and -21 , and in Jak3 ( P52333 ) downstream of the gamma chain ; mutation in the P60568 receptor alpha ( IL-2RA ) and defective expression of the IL-2Rbeta chain ; mutations in the gene encoding for a chemokine receptor , P61073 ; mutations in five genes involved in the IL-12/23-interferon-gamma axis ( P29460 , P42701 , P15260 , P38484 , P42224 ) ; mutations in three genes involved in the nuclear factor-kappaB signaling pathway ( Q9NWZ3 , Q9Y6K9 , IkappaBA ) ; mutations in the tumor necrosis factor receptor signaling pathway ( P19438 ) ; and mutations in the transforming growth factor-1 gene ( P01137 ) . SUMMARY : Genetic cytokine-mediated immunity defects are associated with a highly heterogeneous group of clinical features , ranging from susceptibility to infections to developmental defects . This heterogeneity highlights the diversity and pleiotropy of cytokines . It is likely that many more cytokine defects and their responsive pathways will be discovered in the coming years , expanding further the heterogeneity associated with this group of childhood-onset illnesses . P38398 transcriptionally regulates genes involved in breast tumorigenesis . Loss of function of P38398 caused by inherited mutation and tissue-specific somatic mutation leads to breast and ovarian cancer . Nearly all P38398 germ-line mutations involve truncation or loss of the C-terminal BRCT transcriptional activation domain , suggesting that transcriptional regulation is a critical function of the wild-type gene . The purpose of this project was to determine whether there is a link between the role of P38398 in transcriptional regulation and its role in tumor suppression . We developed a cell line ( in which P38398 can be induced ) and used microarray analysis to compare transcription profiles of epithelial cells with low endogenous levels of P38398 vs. transcription profiles of cells with 2-4-fold higher induced levels of expression of P38398 . At these levels of expression , P38398 did not induce apoptosis . Undirected cluster analysis of six paired experiments revealed 373 genes , the expression of which was altered significantly and consistently by P38398 induction . Expression of 62 genes was altered more than 2-fold . P38398 -regulated genes associated with breast tumorigenesis included the estrogen-responsive genes MYC and cyclin D1 , which are overexpressed in many breast tumors ; P42224 and P23458 , key components of the cytokine signal transduction pathway ; the extracellular matrix protein laminin 3A ; P47928 , an inhibitor of DNA-binding transcriptional activators , which in turn negatively regulates P38398 expression ; and the prohormone stanniocalcin , expression of which is lost in breast tumor cells . Coordinated expression of P38398 with P47928 and with stanniocalcin was confirmed in primary breast and ovarian tumors . DB01645 potentiates the P01160 effect on a K(+)-conductance in P29320 -293 cells . P29320 -293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 . RT-PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 receptor ( P16066 , P16066 ) could be amplified , the P09543 -specific receptor P20594 ( P20594 ) and the receptor specific for guanylins , P25092 , could not be detected . In patch clamp experiments the effects of P01160 ( 10 nM ) on membrane voltage ( V(m) ) were monitored and P29320 -293 cells depolarized by 2.3 +/- 0.5 mV ( n=14 ) . In the presence of the P01133 receptor blocker genistein ( 10 microM ) the effect of P01160 was increased by 65 % to 3.9 +/- 0.8 mV ( n=14 ) . After removal of genistein the P01160 -mediated depolarization further increased by 147 % to 5.7 +/- 1.0 mV ( n=14 ) . P01160 given repetitively without genistein had no increasing depolarizing effect in P29320 -293 cells with time . The P01160 effect could be fully blocked by 1 mM Ba(2+) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 inhibits a K(+)-conductance via a cGMP-dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 -293 cells by -3.9 +/- 0.6 mV ( n=11 ) and this effect could also be fully blocked by Ba(2+) ( -0.3 +/- 0.1 mV , n=5 ) , indicating that genistein activates a K(+)-conductance which contributes significantly to the membrane potential of P29320 -293 cells . Pressure overload-induced cardiac hypertrophy response requires janus kinase 2-histone deacetylase 2 signaling . Pressure overload induces cardiac hypertrophy through activation of O60674 ( Jak2 ) , however , the underlying mechanisms remain largely unknown . In the current study , we tested whether histone deacetylase 2 ( Q92769 ) was involved in the process . We found that angiotensin II ( Ang-II ) -induced re-expression of fetal genes ( Atrial natriuretic peptide ( P01160 ) and brain natriuretic peptide ( DB04899 ) ) in cultured cardiomyocytes was prevented by the Jak2 inhibitor AG-490 and Q92769 inhibitor Trichostatin-A ( P32119 ) , or by Jak2/ Q92769 siRNA knockdown . On the other hand , myocardial cells with Jak2 or Q92769 over-expression were hyper-sensitive to Ang-II . In vivo , pressure overload by transverse aorta binding ( AB ) induced a significant cardiac hypertrophic response as well as re-expression of P01160 and DB04899 in mice heart , which were markedly reduced by AG-490 and P32119 . Significantly , AG-490 , the Jak2 inhibitor , largely suppressed pressure overload-/Ang-II-induced Q92769 nuclear exportation in vivo and in vitro . Meanwhile , P32119 or Q92769 siRNA knockdown reduced Ang-II-induced P01160 / DB04899 expression in Jak2 over-expressed H9c2 cardiomyocytes . Together , these results suggest that Q92769 might be a downstream effector of Jak2 to mediate cardiac hypertrophic response by pressure overload or Ang-II . DB08895 in kidney transplantation . INTRODUCTION : This review will discuss the mechanism of action and important kidney transplant clinical trial data for the small molecule Janus kinase ( JAK ) 3 inhibitor tofacitinib , formerly known as CP-690,550 and tasocitinib . AREAS COVERED : Successful kidney transplantation requires adequate immunosuppression . Current maintenance immunosuppressive protocols which rely on calcineurin inhibitors have long-term nephrotoxicity and negative impact on cardiometabolic risk factors . JAKs are cytoplasmic tyrosine kinases that participate in the signaling of a broad range of cell surface receptors , particularly members of the cytokine receptor common gamma ( cγ ) chain family . P52333 inhibition has immunosuppressive effects and treatment with tofacitinib in clinical trials has demonstrated efficacy in autoimmune disorders such as psoriasis and rheumatoid arthritis . Nonhuman primate models of renal transplantation demonstrated prolonged graft survival with tofacitinib compared to control . Renal transplant clinical trials in humans have demonstrated tofacitinib to be noninferior to cyclosporine in terms of rejection rates and graft survival . There was also a lower rate of new onset diabetes after transplant . However , there was a trend toward more infections , including cytomegalovirus and BK virus nephritis . EXPERT OPINION : DB08895 may be a promising alternative to calcineurin inhibitors . The optimal therapeutic window is still being determined . Comparison of gene expression profiles and related pathways in chronic thromboembolic pulmonary hypertension . Chronic thromboembolic pulmonary hypertension ( CTEPH ) is one of the main causes of severe pulmonary hypertension . However , despite treatment ( pulmonary endarterectomy ) , in approximately 15-20 % of patients , pulmonary vascular resistance and pulmonary arterial pressure continue to increase . To date , little is known about the changes that occur in gene expression in CTEPH . The identification of genes associated with CTEPH may provide insight into the pathogenesis of CTEPH and may aid in diagnosis and treatment . In this study , we analyzed the gene expresion profiles of pulmonary artery endothelial cells from 5 patients with CTEPH and 5 healthy controls using oligonucleotide microarrays . Bioinformatics analyses using the Gene Ontology ( GO ) and KEGG databases were carried out to identify the genes and pathways specifically associated with CTEPH . Signal transduction networks were established to identify the core genes regulating the progression of CTEPH . A number of genes were found to be differentially expressed in the pulmonary artery endothelial cells from patients with CTEPH . In total , 412 GO terms and 113 pathways were found to be associated with our list of genes . All differential gene interactions in the Signal-Net network were analyzed . P52333 , P30679 , O15264 , P32121 and P25116 were the most significantly altered . Bioinformatics analysis may help gather and analyze large amounts of data in microarrays by means of rigorous experimental planning , scientific statistical analysis and the collection of complete data . In this study , a novel differential gene expression pattern was constructed . However , further studies are required to identify novel targets for the diagnosis and treatment of CTEPH . Janus kinase inhibition with tofacitinib : changing the face of inflammatory bowel disease treatment . The advent of anti-Tumor Necrosis Factor ( P01375 ) therapy has changed the way of treating inflammatory bowel disease ( Q9UKU7 ) . However , primary and secondary failure are relatively frequent with all anti- P01375 agents , which are available only as parenteral agents . DB08895 is an oral janus kinase ( JAK ) inhibitor that inhibits JAK family kinase members , in particular P23458 and P52333 , achieving a broad limitation of inflammation by interfering with several cytokine receptors . It first proved its efficacy as an immunosuppressive regimen after renal transplantation , and was recently approved by the FDA for rheumatoid arthritis . First data in Q9UKU7 are promising , especially in ulcerative colitis . Ongoing clinical trials in both UC and Crohn 's disease ( CD ) are needed to further explore its efficacy in CD and to better assess its safety profile . Tofacitinab in renal transplantation . DB08895 ( tositinib , CP-690,550 ) is a small molecule inhibitor of Janus associated kinases , primarily P52333 and O60674 , which inhibits cytokine signaling through the IL-2Rγ chain . In this article , we review the mechanism of action of tofacitinib , and pre-clinical and clinical data regarding its use in solid organ transplantation thus far . It is hoped that tofacitinib may form the basis for calcineurin-free immunosuppression , improving renal function while eliminating calcineurin inhibitor renal toxicity . Current studies suggest that tofacitinib is an effective immunosuppressive agent for renal transplantation , but it 's use in current protocols carries an increased risk of CMV , BK , and EBV viral infection , anemia and leukopenia , and post-transplant lymphoproliferative disorder . Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1 . The trace amine-associated receptor 1 ( Q96RJ0 ) is a G protein-coupled receptor that is functionally activated by amphetamine-based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild-type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to DB01576 or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine-induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine-induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine-based psychostimulants . That methamphetamine-but not morphine-induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling . Targeting P52333 in kidney transplantation : current status and future options . PURPOSE OF REVIEW : This review will discuss the mechanism of action and important clinical trial data in renal transplantation for the small molecule Janus kinase ( JAK ) 3 inhibitor tofacitinib , formerly known as CP-690,550 and tasocitinib . RECENT FINDINGS : JAKs are cytoplasmic tyrosine kinases that participate in the signaling of a broad range of cell surface receptors , particularly members of the cytokine receptor common gamma ( cγ ) chain family . P52333 inhibition has immunosuppressive effects and treatment with tofacitinib in clinical trials has demonstrated efficacy in autoimmune disorders such as psoriasis and rheumatoid arthritis . Nonhuman primate models of renal transplantation demonstrated prolonged graft survival with tofacitinib compared with vehicle control . Renal transplant clinical trials in humans have demonstrated tofacitinib to be noninferior to cyclosporine in terms of rejection rates and graft survival . There was also a lower rate of new-onset diabetes after transplant . However , there was a trend toward more infections , including cytomegalovirus and BK virus nephritis . SUMMARY : DB08895 may be a promising alternative to calcineurin inhibitors . The optimal therapeutic window is still being determined . Clinical utility of the oral JAK inhibitor tofacitinib in the treatment of rheumatoid arthritis . Immune/inflammatory cells act in rheumatoid arthritis ( RA ) -affected patients by synthesizing several inflammatory mediators , including cytokines that initiate intracellular signaling . Recently , small molecule inhibitors of transduction and transcription signals that influence the intracellular pathways ( such as the Janus kinase [ JAK ] family of tyrosine kinases ) have been tested for RA treatment . Four members of the JAK family are known : P23458 , O60674 , P52333 , and TyK2 . P23458 / P52333 constitutively binds to the cytoplasmic portion of the cytokine receptor - the common gamma chain - that represents a common subunit of several cytokines involved in T-cell and natural killer cell development , as well as in B-cell activation . DB08895 is an oral JAK inhibitor that is now available and effective in RA treatment , as shown in multiple Phase II and Phase III clinical trials . However , long-term safety data and comparisons with other disease-modifying antirheumatic drugs and small molecule inhibitors are necessary to better determine the role of tofacitinib in RA . The influence of non-HLA gene polymorphisms and interactions on disease risk in a Western Australian multiple sclerosis cohort . Non-Human Leukocyte Antigen ( HLA ) genes have concomitant , although modest , effects on multiple sclerosis ( MS ) susceptibility ; however findings have varied in different populations . Here we present the results of an association study of 16 single nucleotide polymorphisms ( SNPs ) in 10 non-HLA genes ( P16871 , P01589 , CLEC-16A , P29597 , P19256 , Q13568 , P40763 , P16410 , P02649 , P05362 ) in a Western Australian cohort of 350 MS patients and 498 population control subjects . Our results indicate that in this population , SNPs in P16871 , P29597 , Q13568 and P02649 have modifying effects on MS susceptibility . We also found evidence of interactive protective effects between polymorphisms in the P16871 / P19256 , CLEC-16A/ P16410 , and P29597 / Q13568 genes , which in some instances are restricted within HLA- or gender-defined groups . Multifaceted link between cancer and inflammation . Increasing evidence from epidemiological , preclinical and clinical studies suggests that dysregulated inflammatory response plays a pivotal role in a multitude of chronic ailments including cancer . The molecular mechanism(s) by which chronic inflammation drives cancer initiation and promotion include increased production of pro-inflammatory mediators , such as cytokines , chemokines , reactive oxygen intermediates , increased expression of oncogenes , P35354 ( cyclo-oxygenase-2 ) , 5- P28300 ( P09917 ) and MMPs ( matrix metalloproteinases ) , and pro-inflammatory transcription factors such as NF-κB ( nuclear factor κB ) , P40763 ( signal transducer and activator of transcription 3 ) , AP-1 ( activator protein 1 ) and HIF-1α ( hypoxia-inducible factor 1α ) that mediate tumour cell proliferation , transformation , metastasis , survival , invasion , angiogenesis , chemoresistance and radioresistance . These inflammation-associated molecules are activated by a number of environmental and lifestyle-related factors including infectious agents , tobacco , stress , diet , obesity and alcohol , which together are thought to drive as much as 90 % of all cancers . The present review will focus primarily on the role of various inflammatory intermediates responsible for tumour initiation and progression , and discuss in detail the critical link between inflammation and cancer . Mycoepoxydiene , a fungal polyketide inhibits MCF-7 cells through simultaneously targeting p53 and NF-κB pathways . Mycoepoxydiene ( Q9UQD0 ) is a cytotoxic polyketide that is isolated from the marine fungal strain Diaporthe sp . HLY-1 , which is associated with mangroves ; however , the mechanism of action of Q9UQD0 remains unknown . Here , we report the molecular mechanisms of apoptosis activation and growth inhibition induced by Q9UQD0 in MCF-7 cells . The present results show that Q9UQD0 induces DNA damage through the production of reactive oxygen species ( ROS ) , which resulted in the phosphorylation of P16104 and the activation of the Q13315 kinase ( Q13315 ) and p53 signaling pathways . In addition , Q9UQD0 increases the accumulation of IκBα and enhances the association between IKKγ and Hsp27 via the activation of Hsp27 , which eventually resulted in the inhibition of P01375 -α-induced NF-κB transactivation . Therefore , we conclude that Q9UQD0 inhibits MCF-7 cells by simultaneously activating p53 to induce apoptosis and suppressing NF-κB to disrupt cell proliferation . Because small molecules having both of these effects are rare , further exploration of Q9UQD0 as an antitumor lead compound is needed . DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( DB00293 ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45-fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4-fold following TS inhibition in the Ugi-expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 -inhibited cells to folate or nucleotide-based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 -inhibited cells arrested in early S-phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma- P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S-phase arrest . Although gamma- P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 -inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model . DB00188 prevents the expression of P45452 and the degradation of collagen type 2 in human chondrocytes . The structural backbone of extracellular matrix in cartilage is the collagen fibril , which is mainly composed of type II collagen . A measurable increase in type II collagen denaturation and degradation has been found in early Osteoarthritis ( OA ) . Pro-inflammatory cytokine such as P01375 -α produced in OA cartilage induced the expression of matrix metalloproteinase-13 ( P45452 ) , which targets and degrades type II collagen . DB00188 is a proteasome inhibitor approved by the FDA for treatment of multiple myeloma and mantel cell lymphoma . The effects of bortezomib in OA have not been reported before . In this study , we found that bortezomib is able to suppress the degradation of type II collagen induced by P01375 -α in human chondrocytes . Mechanistically , bortezomib treatment inhibits the expression of P10914 through blunting O60674 / P42224 pathway , thereby prevents the induction of P45452 as well as the degradation of type II collagen . Our findings suggest the therapeutic potentials of bortezomib in patients with OA . Molecular targets and regulators of cardiac hypertrophy . Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli . It enables myocytes to increase their work output , which improves cardiac pump function . Although cardiac hypertrophy may initially represent an adaptive response of the myocardium , ultimately , it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world . A number of signaling modulators that influence gene expression , apoptosis , cytokine release and growth factor signaling , etc. are known to regulate heart . By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed . This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy . In this review , we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin , cGMP , NFAT , natriuretic peptides , histone deacetylase , P05231 cytokine family , Gq/ P49842 signaling , PI3K , MAPK pathways , Na/H exchanger , DB01367 , polypeptide growth factors , P01160 , NO , P01375 , Q07869 and JAK/ P35610 pathway , microRNA , Cardiac angiogenesis and gene mutations in adult heart . Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy . The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy , with special emphasis on novel researches and investigations . Changes in gene expression in atherosclerotic plaques analyzed using DNA array . A better understanding of atherogenesis at the level of gene expression could lead to the identification of new therapeutic strategies for vascular diseases . With DNA array technology , it is possible to identify multiple , simultaneous changes in gene expression in small tissue samples from atherosclerotic arteries . We analyzed gene expression in normal arteries and in immunohistologically characterized human advanced atherosclerotic lesions using an array of 18376 cDNA fragments . The array method was first validated by detecting a group of genes ( n=17 ) that were already known to be connected to atherogenesis . These genes included e.g. P02649 , P34810 , P01033 and phospholipase D . Next we detected 75 differentially expressed genes that were previously not connected to atherogenesis . A subgroup of genes involved in cell signaling and proliferation was selected for further analyzes with in situ hybridization and RT-PCR which confirmed array results by showing induction in advanced lesions of P23458 ( P23458 ) which is an important signaling molecule in activated macrophages ; P15692 receptor-2 which mediates angiogenic and vasculoprotective effects of P15692 ; and an unknown gene , which mapped on chromosome 19 . It is concluded that DNA array technology enables fast screening of gene expression in small samples of atherosclerotic lesions . The technique will be useful for the identification of new factors , such as P23458 and P15692 receptor-2 , which may play an important role in atherogenesis . Transcriptional regulation of the major HIV-1 coreceptor , P61073 , by the kappa opioid receptor . Previous studies have demonstrated that KOR activation results in decreased susceptibility to infection by HIV-1 in human PBMCs . In the present studies , we have found this effect is , in part , a result of down-regulation of the major HIV-1 coreceptor , P61073 . Using a combination of biochemical approaches , our results show that P61073 protein and mRNA levels were reduced significantly following KOR activation . We evaluated the nature of the signaling pathway(s) , which were induced by KOR activation , using transcription factor-binding array analysis and comparing extracts from control and KOR-activated cells . We determined that the IRFs and STATs were induced following KOR activation , and these events were important for the inhibition of P61073 expression . Using chemical inhibitors and siRNA constructs , we determined that O60674 , P40763 , and P14316 were critical members of this signal transduction pathway . Immediately following KOR activation , O60674 was phosphorylated , and this was required for the phosphorylation/activation of P40763 . Moreover , P14316 mRNA and protein expression were also up-regulated , and further studies using ChIP analysis showed that P14316 was induced to bind in vivo to the P61073 promoter . This is the first report detailing the initiation of a KOR-induced O60674 / P40763 and P14316 signaling cascade , and these pathways result in substantial down-regulation of P61073 expression . The capacity of KOR to down-regulate P61073 expression may provide a strategy for the development of novel therapeutics for the inhibition of HIV replication . Polymorphisms in genes implicated in dopamine , serotonin and noradrenalin metabolism suggest association with cerebrospinal fluid monoamine metabolite concentrations in psychosis . BACKGROUND : Homovanillic acid ( HVA ) , 5-hydroxyindoleacetic acid ( 5-HIAA ) and 3-methoxy-4-hydroxyphenylglycol ( MHPG ) are the major monoamine metabolites in the central nervous system ( CNS ) . Their cerebrospinal fluid ( P04141 ) concentrations , reflecting the monoamine turnover rates in CNS , are partially under genetic influence and have been associated with schizophrenia . We have hypothesized that P04141 monoamine metabolite concentrations represent intermediate steps between single nucleotide polymorphisms ( SNPs ) in genes implicated in monoaminergic pathways and psychosis . METHODS : We have searched for association between 119 SNPs in genes implicated in monoaminergic pathways [ tryptophan hydroxylase 1 ( P17752 ) , Q8IWU9 , tyrosine hydroxylase ( TH ) , P20711 ( DDC ) , dopamine beta-hydroxylase ( P09172 ) , catechol-O-methyltransferase ( P21964 ) , monoamine oxidase A ( P21397 ) and P27338 ] and monoamine metabolite concentrations in P04141 in 74 patients with psychotic disorder . RESULTS : There were 42 nominally significant associations between SNPs and P04141 monoamine metabolite concentrations , which exceeded the expected number ( 20 ) of nominal associations given the total number of tests performed . The strongest association ( p = 0.0004 ) was found between P27338 rs5905512 , a SNP previously reported to be associated with schizophrenia in men , and MHPG concentrations in men with psychotic disorder . Further analyses in 111 healthy individuals revealed that 41 of the 42 nominal associations were restricted to patients with psychosis and were absent in healthy controls . CONCLUSIONS : The present study suggests that altered monoamine turnover rates in CNS reflect intermediate steps in the associations between SNPs and psychosis . Immunohistochemical analysis in ethinylestradiol-treated breast cancers after prior long-term estrogen-deprivation therapy . BACKGROUND : P03372 ( ER ) positive breast cancer can often be treated by hormone therapy ; however a certain population of ER-positive patients become resistant to hormone therapy after long-term hormone treatment . DB00977 ( EE2 ) is a derivative of estrogen , which has shown promising effects in these patients . METHODS : We successfully obtained tissue samples from 6 patients undergoing EE2 treatment and examined 13 well-known breast cancer-related factors by immunohistochemistry . Of the 6 patients , 5 responded but one patient did not . RESULTS : Before EE2 treatment , staining for both ER and androgen receptor ( AR ) was strong in the nucleus , and the progesterone receptor ( PgR ) was almost no staining . EE2 treatment significantly down-regulated ER and up-regulated PgR while nuclear and cytosolic AR were oppositely down- and up-regulated , respectively . Cytosolic staining of P38398 was significantly up-regulated by EE2 whereas nuclear staining tended to decrease . Individual comparisons suggested less induction of PgR and decreasing AKT but increasing pAKT in the non-responder following EE2 treatment . CONCLUSIONS : Our observations revealed that EE2 activated ER downstream genes ; however it did not stimulate cell growth . This suggests that hormone resistant cells might receive growth signals from a non-genomic pathway and this may be reflected in their sensitivity to EE2 treatment . Human cardiomyocyte hypertrophy induced in vitro by P40189 stimulation . OBJECTIVES : Recent in vivo and in vitro studies in animals have demonstrated that cytokines of the P05231 family are involved in cardiac hypertrophy and in protection of cardiomyocytes against apoptosis . The present study aims to analyse the capacity of human atrial cardiac cells ( i.e. , cardiomyocytes and fibroblasts ) to display the P40189 receptor subunit , and to evaluate its functionality . METHODS : Twenty human atrial biopsies were used for immunohistochemistry , in situ hybridisation , and western blot analysis or dissociated for isolation and primary culture of cardiac cells . RESULTS : Fibroblasts present in tissue or maintained in primary culture clearly express P40189 whereas the signal in cardiomyocytes is weaker . Culture of cardiac cells with a P40189 agonist antibody enhances atrial natriuretic peptide ( P01160 ) , beta myosin heavy chain ( beta-MHC ) expression in cardiomyocytes , and significantly increases the cell surface area microm(2) ) . This process could involve P40763 ( signal transducer and activator of transcription 3 ) phosphorylation . CONCLUSIONS : These results demonstrate that P40189 activation in human cardiac cells leads to cardiomyocyte hypertrophy . We discuss several hypotheses on the role of P05231 -type cytokines on cardiomyocyte functions . T cell lines established from multiple sclerosis cerebrospinal fluid T cells using human retroviruses . Cerebrospinal fluid ( P04141 ) lymphocytes from patients with multiple sclerosis ( MS ) were transformed with human T cell leukemia/lymphoma virus ( HTLV I and HTLV II ) and the resulting cell lines characterized by cell surface phenotyping and functional assessment . The lines were predominantly of the P01730 helper/induce phenotype although the HTLV II lines contained 10-20 % CD8+ cells . The lines appeared to be activated cells ; the majority were Q96RJ0 + , HLA-DR+ , and TAC+ ( CD25+ ) . Interestingly , they were OKT10- ( P28907 - ) . Functionally , the lines contained no natural killer ( NK ) activity and were modestly cytotoxic in the antibody-dependent cellular cytotoxicity ( ADCC ) assay . They were poor proliferative responders to antigens and mitogens though the HTLV II lines did respond to interleukin 2 ( P60568 ) . The HTLV I lines were either nonresponsive to or were suppressed by P60568 . Early passages of two of the lines produced P60568 but this was lost as the cells were passed in culture . The cell lines were capable of either directly or indirectly suppressing pokeweed mitogen ( PWM ) -driven immunoglobulin production by normal B cells . In addition , the lines were capable of producing gamma-interferon ( P01579 ) , lymphotoxin ( LT ) , an interleukin 1 ( IL1 ) -like factor , glial growth promoting factor ( GGPF ) , and P05231 . The advantage of these lines over clones or cell lines developed using other techniques is their growth in the absence of feeder layers or P60568 and their ability to be cloned and to grow in culture indefinitely . The JAK inhibitor , tofacitinib , reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells . OBJECTIVE : DB08895 , which is a Janus kinase ( JAK ) inhibitor , has shown clinical effects in the treatment of rheumatoid arthritis . JAKs are important kinases in lymphocyte differentiation ; however , their function in dendritic cells ( DCs ) is unknown . In this study , the function of JAKs in DCs was investigated with tofacitinib . METHODS : The effects of tofacitinib on the maturation of human monocyte-derived DCs induced by lipopolysaccharide ( LPS ) stimulation were investigated . In addition , its effects on T cell stimulatory capability was investigated by coculturing with naïve CD45RA-positive T cells . RESULTS : DB08895 decreased expression of P33681 / P42081 in a concentration-dependent manner in LPS-stimulated DCs ; however , it did not affect HLA-DR expression . DB08895 suppressed tumour necrosis factor , interleukin ( IL ) -6 and IL-1β production without affecting transforming growth factor ( TGF ) -β and P22301 production . Meanwhile , P33681 / P42081 expression in DCs was enhanced by type I interferon ( IFN ) stimulation , and the LPS-induced P33681 / P42081 expression was inhibited by an antibody to type I IFN receptor . Furthermore , tofacitinib suppressed production of type I IFN and activation of interferon regulatory factor ( Q969Q1 ) -7 , which is a transcription factor involved in P33681 / P42081 and type I IFN expression . DB08895 also decreased the T cell stimulatory capability of DCs and increased expression of indoleamine 2,3-dioxygenase ( P14902 ) -1 and Q6ZQW0 . CONCLUSIONS : DB08895 , a P23458 / P52333 inhibitor , affected the activities of human DCs . It decreased P33681 / P42081 expression and T cell stimulatory capability through suppression of type I IFN signalling . These results suggest a novel mode of action for tofacitinib and a pivotal role for JAKs in the differentiation of DCs . P52333 activity is necessary for phosphorylation of cytosolic phospholipase A2 and prostaglandin E2 synthesis by macrophages infected with Francisella tularensis live vaccine strain . Francisella tularensis , the causative agent of tularemia , modulates the host immune response to gain a survival advantage within the host . One mechanism of immune evasion is the ability of F. tularensis to induce the synthesis of the small lipid mediator prostaglandin E2 ( DB00917 ) , which alters the host T cell response making the host more susceptible to Francisella growth . DB00917 is synthesized by a tightly regulated biosynthetic pathway following stimulation . The synthesis of DB00917 begins with the liberation of arachidonic acid ( AA ) from membrane phospholipids by cytosolic phospholipase A2 ( P47712 ) . AA is subsequently converted to the unstable intermediate PGH2 by cyclooxygenase-2 ( P35354 ) , and PGH2 undergoes an isomerization reaction to generate DB00917 . Our objective was to identify F. tularensis-activated host signaling pathways that regulate the activity of the enzymes in the DB00917 -biosynthetic pathway . In this study , we show that P47712 , p38 mitogen-activated protein kinase ( MAPK ) , and P52333 ( P52333 ) signaling are necessary for F. tularensis-induced DB00917 production . Inhibition of P52333 activity reduced the phosphorylation of P47712 and P35354 protein levels . In addition , P52333 regulates P47712 phosphorylation independent of transcription . Moreover , p38 MAPK activity is required for F. tularensis-induced P35354 protein synthesis , but not for the phosphorylation of P47712 . This research highlights a unique signaling axis in which P52333 and p38 MAPK regulate the activity of multiple enzymes of the DB00917 -biosynthetic pathway in macrophages infected with F. tularensis . Resistance to killing by tumor necrosis factor in an adipocyte cell line caused by a defect in arachidonic acid biosynthesis . We have found that Q96RJ0 -R6 , which are resistant to the cytotoxic effects of tumor necrosis factor ( P01375 ) in the presence of cycloheximide ( Reid , T. R. , Torti , F. , and Ringold , G. M. ( 1989 ) J. Biol. Chem. 264 , 4583-4589 ) , have reduced ability to release arachidonic acid ( 20:4 ) from membrane phospholipids in response to either P01375 or the calcium ionophore A23187 treatment . However , no defect in the activity of phospholipase A2 , the principal enzyme responsible for the release of 20:4 from phospholipids , was observed in these cells . Detailed biochemical characterization of these P01375 -resistant cells has revealed that these cells are unable to synthesize 20:4 endogenously because of a defect in delta 6-desaturase , the rate-limiting enzyme of 20:4 biosynthesis . This deficiency leads to a marked decrease in the steady-state levels of 20:4 present in choline-containing phospholipid ( PC ) and ethanolamine-containing phospholipid ( PE ) . The Q96RJ0 -R6 cells , however , are capable of incorporating exogenous 20:4 into PC and PE , and when loaded in such manner they become significantly more sensitive to the cytotoxic effects of P01375 in the presence of cycloheximide . Therefore , the release of arachidonic acid from phospholipids appears to be a critical element in the signaling pathway utilized by P01375 and is essential to the rapid cytotoxic response elicited by P01375 in the absence of protein synthesis in wild-type Q96RJ0 cells . High loading dose of clopidogrel is unable to satisfactorily inhibit platelet reactivity in patients with glycoprotein IIIA gene polymorphism : a genetic substudy of PRAGUE-8 trial . The study aimed to assess the impact of nine polymorphisms of genes encoding platelet receptors , enzymes , and hemostatic factors on clopidogrel efficacy to inhibit platelet reactivity in patients with stable coronary artery disease undergoing elective coronary angiography either with or without ad hoc percutaneous coronary intervention . The study was performed as a genetic substudy of the PRAGUE-8 trial . Ninety-five patients pretreated with 600 mg clopidogrel at least 6 h prior to coronary angiography were tested . Baseline platelet reactivity to ADP was assessed before the drug was administered . DB00758 efficacy was tested again at 12 and 28 h after administration . Polymorphisms of platelet receptors , glycoprotein ( GP ) Ia ( 807C/T ) , Q9HCN6 ( 13254C/T ) , P05106 ( PlA1/PlA2 ) , P25116 ( IVSn-14A/T ) , Q9H244 ( 32C/T ) , Q9H244 ( H1/H2 ) haplotype , gene variations of cyclooxygenase-1 , Leiden , and factor II mutations were studied . Flow cytometric tests of vasodilator-stimulated phosphoprotein phosphorylation states were used as a measure of drug efficacy . None of the gene polymorphisms influenced baseline ADP-induced platelet reactivity significantly . Twenty-eight hours after drug administration , differences in suppression of ADP-induced platelet reactivity were observed between polymorphism-positive and polymorphism-negative patients . Inhibition of platelet reactivity , after 600 mg of clopidogrel , was significantly less in carriers of PlA2 ( P=0.009 ) for mean decrease in platelet reactivity index . The proportion of clopidogrel nonresponders ( platelet reactivity index > 50 % ) was apparently higher in PlA2 carriers in comparison with PlA1/PlA1 patients ( 54 vs. 24 % , P=0.082 ) . A 600 mg loading dose of clopidogrel failed to acceptably inhibit platelet reactivity in patients who were positive for the PlA2 polymorphism . A common single nucleotide polymorphism can exacerbate long-QT type 2 syndrome leading to sudden infant death . BACKGROUND : Identification of infants at risk for sudden arrhythmic death remains one of the leading challenges of modern medicine . We present a family in which a common polymorphism ( single nucleotide polymorphism ) inherited from the father , combined with a stop codon mutation inherited from the mother ( both asymptomatic ) , led to 2 cases of sudden infant death . METHODS AND RESULTS : P51787 , Q12809 , Q14524 , P15382 , Q9Y6J6 , CACNA1c , CACNB2b , and P63252 genes were amplified and analyzed by direct sequencing . Functional electrophysiological studies were performed with the single nucleotide polymorphism and mutation expressed singly and in combination in Chinese ovary ( CHO- P04264 ) and COS-1 cells . An asymptomatic woman presenting after the death of her 2-day-old infant and spontaneous abortion of a second baby in the first trimester was referred for genetic analysis . The newborn infant had nearly incessant ventricular tachycardia while in utero and a prolonged QTc ( 560 ms ) . The mother was asymptomatic but displayed a prolonged QTc . Genetic screening of the mother revealed a heterozygous nonsense mutation ( P926AfsX14 ) in Q12809 , predicting a stop codon . The father was asymptomatic with a normal QTc but had a heterozygous polymorphism ( K897T ) in Q12809 . The baby who died at 2 days of age and the aborted fetus inherited both K897T and P926AfsX14 . Heterologous coexpression of K897T and P926AfsX14 led to loss of function of Q12809 current much greater than expression of K897T or P926AfsX14 alone . CONCLUSIONS : Our data suggest that a common polymorphism ( K897T ) can markedly accentuate the loss of function of mildly defective Q12809 channels , leading to long-QT syndrome-mediated arrhythmias and sudden infant death . P60568 regulates expression of C- O75444 in human P01730 T cells . Blockade of IL-2R with humanized anti-CD25 Abs , such as daclizumab , inhibits Th2 responses in human T cells . Recent murine studies have shown that P60568 also plays a significant role in regulating Th2 cell differentiation by activated P42229 . To explore the role of activated P42229 in the Th2 differentiation of primary human T cells , we studied the mechanisms underlying P60568 regulation of C- O75444 expression . Chromatin immunoprecipitation studies revealed that P60568 induced P42229 binding to specific sites in the C- O75444 promoter . These sites corresponded to regions enriched for markers of chromatin architectural features in both resting P01730 and differentiated Th2 cells . Unlike P05231 , P60568 induced C- O75444 expression in P01730 T cells with or without prior TCR stimulation . TCR-induced C- O75444 expression was significantly inhibited by treatment with daclizumab or a P52333 inhibitor , R333 . Furthermore , P60568 and P05231 synergistically induced C- O75444 expression in TCR-activated T cells , suggesting functional cooperation between these cytokines . Finally , both TCR-induced early P05112 mRNA expression and P05112 cytokine expression in differentiated Th2 cells were significantly inhibited by IL-2R blockade . Thus , our findings demonstrate the importance of P60568 in Th2 differentiation in human T cells and support the notion that IL-2R-directed therapies may have utility in the treatment of allergic disorders . Genotype frequencies of 50 polymorphisms for 241 Japanese non-cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL-1A , IL-1B , IL-1RN , IL-1R1 , P05231 , P10145 , P22301 , P41159 , Le , L-myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF-B , P01375 -A , P01375 -B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non-cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C/T at intron 2 and G2502T , IL-1A 46-bp VNTR , IL-1R1 C-116T , P05231 Ins/Del 17C , P10145 A-278T and C74T , IL- 10 T-819C , P41159 A-2548G , P31213 2-bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL-1B C-31T and IL-1A C-889T , IL-1B C-31T and IL-1RN 86-bp VNTR , IL-1B C-31T and IL-1R1 C-116T , P01375 -A G-308A and P01375 -B A252G , P31213 Val89Leu and 2-bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype/allele frequencies among Japanese for an archival purpose . The low-potency , voltage-dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high-affinity human ether-a-go-go-related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower-affinity Q12809 blockers may be different . In this study , alanine-substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . DB01182 's blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open-channel model ) . These findings are supported by very slow recovery of wild-type Q12809 channels from block at -120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open-state propafenone binding-site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi-stacking interactions with two or more Phe656 side-chains ) is either perturbed or becomes less accessible because of closed-channel gating . This provides further evidence for the existence of gating-induced changes in the spatial location of Phe656 side chains . Very early-onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early-onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 -3B , P01160 , and P36382 from 192 early-onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7.6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0.1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4.1 % ; with minor allele frequency < 0.1 ; P = .0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early-onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF . Characterization of the aggregation responses of camel platelets . BACKGROUND : Despite evidence of active hemostasis , camel platelets barely respond to common aggregating agents at standard doses used for human platelet aggregation . OBJECTIVES : The purpose of the study was to find out whether camel platelets can be activated by high doses or combinations of aggregation agonists , and to characterize the receptor that mediates the aggregation response to adenosine diphosphate ( ADP ) , the most potent agonist for camel platelets known so far . METHODS : Aggregation studies were performed with platelet-rich plasma ( PRP ) in response to multiple doses or combinations of ADP , epinephrine ( P08473 ) , collagen , and arachidonic acid ( AA ) . Aggregation responses to ADP were performed before and after the addition of the ADP receptor ( Q9H244 ) antagonist DB00758 . RESULTS : Camel platelets responded to ADP at doses higher than the standard dose for human platelets , and to combinations of P08473 and other agonists , while no aggregation was elicited with P08473 or AA alone . DB00758 blocked the ADP-induced aggregation responses in a dose-dependent fashion in vitro . CONCLUSIONS : Camel platelet aggregation can be activated by increasing the dose of some agonists such as ADP , but not AA or P08473 . Irreversible aggregation of camel platelets could also be triggered by a combination of P08473 and ADP , and collagen and AA . Inhibition with clopidogrel suggests that camel platelets express the ADP receptor , Q9H244 . Understanding platelet function in camels will add to the understanding of platelet function in health and disease . DB00452 -arginine conjugate , a novel HIV-1 Tat antagonist : synthesis and anti-HIV activities . HIV-1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV-1 Tat stimulates transactivation by binding to HIV-1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T-cells for productive HIV-1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV-1 Tat antagonist , a neomycin B-hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3-activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) -labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV-1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M- and T-tropic HIV-1 laboratory isolates ( EC(50) = 0.8-5.3 microM ) . A putative model structure for the TAR-NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV-1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV-1 binding to cells , partially by blocking the P61073 HIV-1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis . A pharmacokinetic and clinical assessment of tofacitinib for the treatment of rheumatoid arthritis . INTRODUCTION : Rheumatoid arthritis ( RA ) is a chronic painful and debilitating autoimmune disease . Although the outcome for patients with RA has improved markedly in the past decades , driven largely by the advent of biological disease-modifying antirheumatic drugs ( DMARDs ) and updated management strategies , adequate disease control can not be achieved in a substantial proportion of patients . Since RA is a syndrome with different biological subsets , DMARDs , with a novel mechanism of action , may represent a valuable addition to the current armamentarium . DB08895 is a novel synthetic DMARD that selectively inhibits Janus kinases ( JAKs ) , particularly P23458 and P52333 . AREAS COVERED : This review describes the pharmacokinetics of tofacitinib . Furthermore , the article summarizes and comments the drug 's efficacy and safety profile in RA patients . The authors furthermore assess data derived from the FDA 's RA development program . EXPERT OPINION : DB08895 is an oral synthetic DMARD displaying linear pharmacokinetics . Metabolism , primarily mediated by P08684 , accounts for 70 % of the total clearance of the drug ; the remaining 30 % are renally excreted . DB08895 monotherapy , or in combination with traditional DMARDs , has demonstrated its efficacy while having an acceptable safety profile in RA patients who have responded inadequately to current DMARDs , including P01375 antagonists . In view of its undetermined benefit to risk ratio , in the real-world population , tofacitinib should , for now , only be prescribed to selected patients . Novel path to P05231 trans-signaling through thrombin-induced soluble P05231 receptor release by platelets . Interleukin ( IL ) -6 is a multifunctional cytokine with a critical role in inflammatory , immunoregulatory and haemopoietic responses . Its receptor consists of an ubiquitously expressed membrane transducing element ( P40189 ) and of the specific element P08887 ( P08887 ) , present only on hepatocytes and some leukocyte subsets . P08887 also exists as soluble protein ( sIL-6R ) that , in the presence of P05231 , forms a complex able to bind P40189 and , thanks to the mechanism called trans-signaling , transduces P05231 effect through tyrosine phosphorylation and activation of the signal transducer and transcription activator ( P35610 ) -3 . The aim of this study was to analyze the bidirectional relationships between platelet aggregation and P05231 -dependent effects . While platelets do not produce P05231 , we found that resting platelets express P40189 , but not P08887 , on their membranes . Upon activation by thrombin or calcium ionophore A23187 , but not by ADP , the P08887 is released in soluble form , while cangrelor , the specific inhibitor of Q9H244 receptor , can partially inhibit sIL-6R release . This sIL-6R is biologically active and , in the presence of P05231 , can trigger P05231 trans-signaling , inducing an autocrine activation loop ( as measured by an increase in P08887 and P40189 content ) and P40763 phosphorylation . On the other hand , P05231 trans-signaling has no effect on platelet degranulation or aggregation by itself , nor on thrombin-induced platelet aggregation . Our data add an important piece to the puzzle of thrombosis and inflammation : in the presence of P05231 , which can be produced by stressed endothelial cells , the platelet-derived P05231 trans-signaling could be crucial for the evolution of inflammation within a damaged vessel . Kinase inhibitors : a new class of antirheumatic drugs . The outlook for patients with rheumatoid arthritis has improved significantly over the last three decades with the use of disease-modifying antirheumatic drugs . However , despite the use of methotrexate , cytokine inhibitors , and molecules targeting T and B cells , a percentage of patients do not respond or lose their response over time . The autoimmune process in rheumatoid arthritis depends on activation of immune cells , which utilize intracellular kinases to respond to external stimuli such as cytokines , immune complexes , and antigens . In the past decade , small molecules targeting several kinases , such as p38 MAPK , Syk , and JAK have been developed . Several p38 MAPK inhibitors proved ineffective in treating rheumatoid arthritis . The Syk inhibitor , fostamatinib , proved superior to placebo in Phase II trials and is currently under Phase III investigation . DB08895 , a P23458 /3 inhibitor , was shown to be efficacious in two Phase III trials , while VX-509 , a P52333 inhibitor , showed promising results in a Phase II trial . Fostamatinib and tofacitinib were associated with increased rates of infection , elevation of liver enzymes , and neutropenia . Moreover , fostamatinib caused elevations of blood pressure and diarrhea , while tofacitinib was associated with an increase in creatinine and elevation of lipid levels . 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 . Modulatory effects of heparin and short-length oligosaccharides of heparin on the metastasis and growth of LMD MDA-MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short-chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I(125) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0.001 ) . These oligosaccharides also significantly inhibited P48061 -induced migration of P61073 -expressing LMD MDA-MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , DB06822 . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0.05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0.001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin-derived oligosaccharides in the inhibition of tumour growth and metastases . P52333 inhibition significantly attenuates psoriasiform skin inflammation in P05107 mutant PL/J mice . P52333 , a member of the Janus kinase family , is predominantly expressed in hemopoietic cells and binds specifically to the common gamma chain of a subfamily of cytokine receptors that includes P60568 , P05112 , P13232 , P15248 , P40933 , and Q9HBE4 . Previous studies suggest that this tyrosine kinase plays key roles in mediating T cell functions , and inhibition of P52333 has been shown to prevent graft rejection and decrease the severity of arthritis in rodent models . However , the functions of P52333 in the development of skin immune responses and diseases such as psoriasis have not been determined . P05107 mutant PL/J mice develop spontaneous T cell-dependent psoriasiform skin disease with several similarities to human psoriasis . In this study , we treated mice with established skin disease with R348 , a small molecule inhibitor of P52333 , and observed a marked attenuation of skin lesions following 6 wk of treatment . Histological analyses revealed major reductions of both epidermal and dermal lesion severity scores in R348-treated P05107 -deficient PL/J mice compared with vehicle controls , which was associated with decreased P01730 (+) T cell infiltration . In addition , systemic levels of Q16552 , Q9GZX6 , IL-23 , and P01375 were significantly lower in mice receiving the compound , and T cells isolated from R348-treated mice also showed reduced phosphorylation of Stat5 after stimulation with P60568 . These findings suggest that small-molecule inhibitors of P52333 may be useful in the treatment of inflammatory skin diseases such as psoriasis and strongly implicate JAK signaling events as important in the pathogenesis of this disease . 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 . Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol-A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER-labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER-labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER-labelled neurons in the VMH . EE and Q03001 increased ER-labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats . Selective JAK/ P40763 signalling regulates transcription of colony stimulating factor-2 and -3 in Concanavalin-A-activated mesenchymal stromal cells . Human bone marrow-derived mesenchymal stromal cells ( MSCs ) express Toll-like receptors ( TLRs ) and produce cytokines and chemokines , all of which contribute to these cells ' immunomodulatory and proangiogenic properties . Among the secreted cytokines , colony-stimulating factors ( CSFs ) regulate angiogenesis through activation of endothelial cell proliferation and migration . Since O60682 are recruited within hypoxic tumors where they signal paracrine-regulated angiogenesis , the aim of this study was to evaluate which P04141 members are expressed and are inducible in activated O60682 . Furthermore , we investigated the JAK/ P35610 signal transducing pathway that may impact on P04141 transcription . O60682 were activated with Concanavalin-A ( ConA ) , a TLR-2/6 agonist as well as a membrane type-1 matrix metalloproteinase ( P50281 ) inducer , and we found increased transcription of granulocyte macrophage- P04141 ( GM- P04141 , P04141 -2 ) , granulocyte P04141 ( DB00099 , P04141 -3 ) , and P50281 . Gene silencing of either P40763 or P50281 prevented ConA-induced phosphorylation of P40763 , and reversed ConA effects on P04141 -2 and P04141 -3 . Treatment with the Janus Kinase (JAK)2 inhibitor AG490 antagonized the ConA induction of P50281 and P04141 -2 , while the pan-JAK inhibitor DB08895 reversed ConA-induced P04141 -2 and -3 gene expression . Silencing of O60674 prevented the ConA-mediated increase of P04141 -2 , while silencing of P23458 , P52333 and P29597 prevented the increase in P04141 -3 . Given that combined TLR-activation and locally-produced P04141 -2 and P04141 -3 could regulate immunomodulation and neovascularization , pharmacological targeting of TLR-2/6-induced P50281 /JAK/ P40763 signalling pathway may prevent O60682 contribution to tumor development .