interacts_with DB01229?
Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5-hydroxytryptamine ; 5-HT ) , 5-HT receptors 1A ( 5-HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel-allergic patients , at 72 h post-challenge with the antigen . In addition , the effects of 5-HT2AR agonist 2,5-dimethoxy-4-iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel-stimulated peripheral blood mononuclear cells from nickel-allergic patients , regarding their proliferation and interleukin ( IL ) -2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell-like line ( XS52 ) , regarding its IL-1beta production . Serotonin-positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0.01 ) in 5-HT1AR-positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5-HT2AR- and P31645 -positive cells were increased ( p < 0.001 for both ) in the eczematous skin . Treatment of nickel-stimulated peripheral blood mononuclear cells with 5x10(-5) mol/l of DOI inhibited ( p < 0.01 ) the proliferation of nickel-stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . DB00215 at 10(-6) mol/l tended to inhibit the production of IL-1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction . Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury-associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng/ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs. P09038 ( 10 ng/ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease . Linkage of cytokine genes to rheumatoid arthritis . Evidence of genetic heterogeneity . OBJECTIVE : To investigate linkage of candidate disease susceptibility genes to rheumatoid arthritis ( RA ) in affected sibling pair families stratified for specific clinical features . METHOD : Two hundred RA affected sibling pair families were genotyped for informative microsatellite markers mapping within or less than 3cM from : P27352 alpha , P27352 gamma , P27352 beta , IL1 alpha , IL1 beta , P14778 , P60568 , P05231 , Q01344 , IL8R , P10415 , P29965 , NOS3 , P49279 , alpha 1 anti-trypsin , and alpha 1 anti-chymotrypsin , using fluorescence based automated technology . Linkage was examined by defining allele sharing sibling pairs . This was assessed by maximum likelihood-inheritance by descent methods . RESULTS : An increase in allele sharing was seen for Q01344 in female sibling pairs ( LOD 0.91 , p = 0.03 ) , for P27352 gamma in sibling pairs with an affected male ( LOD 0.96 , p = 0.03 ) and most significantly for P60568 in sibling pairs where one or both were persistently seronegative ( LOD 1.05 , p = 0.02 ) . CONCLUSION : Weak evidence of linkage of RA to Q01344 , IFN gamma , and P60568 has been detected in clinical subsets of sibling pairs suggesting that RA is a genetically heterogeneous disease . Statin Modulation of Human T-Cell Proliferation , IL-1β and Q16552 Production , and IFN-γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune-mediated disease and in experimental models . The aim of this study was to compare statin-mediated immunosuppressive effects on human T-cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T-cell proliferation . At concentrations that inhibited anti-CD3/28-stimulated T-cell proliferation ( P < 0.01 ) , simvastatin significantly decreased intracellular P01730 (+) T-cell expression of IFN-γ ( P < 0.01 ) to levels similar to those induced by conventional immunosuppressives . DB01076 and lovastatin also decreased IFN-γ expression , although to a lesser degree ( P < 0.05 ) . All three statins reduced levels of Q16552 production ( P < 0.01 ) . However , in response to anti-CD3/28 stimulation , simvastatin significantly upregulated IL-1β production ( P < 0.05 ) . The profile of cytokines produced in response to anti-CD3/28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin-mediated immunomodulatory effects on human immune cells . Porcine O60603 and Q9Y2C9 : identification and their involvement in Mycoplasma hyopneumoniae infection . We successfully cloned and sequenced porcine toll-like receptor ( O60603 ) and Q9Y2C9 cDNA from porcine alveolar macrophages stimulated with 10 microg/ml lipopolysaccharide ( LPS ) . The open reading frames ( ORFs ) of the porcine O60603 and Q9Y2C9 cDNA were shown to be 2358 and 2391 bp in length and to encode 785 and 796 amino acids , respectively . The predicted amino acid sequence of porcine O60603 was 72.3 % homologous to human O60603 and 61.0 % homologous to murine O60603 . That of porcine Q9Y2C9 was 74.4 % homologous to human Q9Y2C9 and 66.1 % homologous to murine Q9Y2C9 . Porcine O60603 and Q9Y2C9 genes were both mapped to porcine chromosome 8 ( O60603 : SSC8q21.1 --> 21.5 ; Q9Y2C9 : SSC8p11.1 --> P38936 .1 ) by fluorescence in situ hybridization ( Q5TCZ1 ) and radiation hybrid mapping . Western blot analysis confirmed that O60603 and Q9Y2C9 proteins were both expressed in porcine alveolar macrophages . Further , antiporcine O60603 and Q9Y2C9 antibodies synergistically blocked tumor necrosis factor-alpha ( P01375 ) production by porcine alveolar macrophages stimulated with Mycoplasma hyopneumoniae . These results indicated that both O60603 and Q9Y2C9 are important in the recognition of M. hyopneumoniae in porcine alveolar macrophages and will be useful in understanding innate immunity against M. hyopneumoniae . Telomere shortening and decreased replicative potential , contrasted by continued proliferation of telomerase-positive CD8+ P10747 (lo) T cells in patients with systemic lupus erythematosus . To evaluate whether the immune system of systemic lupus erythematosus ( SLE ) patients shows features of premature aging , we compared telomere length and proliferative potential of SLE peripheral blood mononuclear cells ( PBMC ) ( N = 90 ) to those of controls ( N = 64 ) . SLE samples showed accelerated loss of telomeric DNA ( P = 0.00008 ) and higher levels of senescent ( < or =5 kb ) telomeric DNA ( P = 0.00003 ) . Viability cell counts and CFSE tracking in 6-week-old cell cultures indicated that SLE PBMC ( CD8+ and P01730 + T cells ) underwent fewer mitotic cycles and had shorter telomeres than controls ( P = 0.04 ) . However , a CD8(+) P10747 (lo) T cell subset expanded preferentially in SLE-derived bulk cultures ( P = 0.0009 ) , preserved telomeric DNA ( P = 0.01 vs entire CD8+ ) , and displayed telomerase activity [ 2.1 telomerase arbitrary units ( P10636 ) vs 0.5 P10636 in CD8+ P10747 (hi) cells and 0.3 P10636 in bulk PBMC ; P = 0.05 ] . These T cell anomalies could be due to chronic in vivo stimulation of the immune system and may contribute to the immune dysregulation found in SLE . Internet-based behavioral activation -- treatment for postnatal depression ( Netmums ) : a randomized controlled trial . BACKGROUND : Despite the high prevalence of postnatal depression ( P01160 ) , few women seek help . The internet may increase timely access to treatment . We report a randomized controlled trial of a minimal intervention internet Behavioral Activation ( iBA ) treatment modified to address postnatal specific concerns ( Postnatal-iBA ) . METHODS : Women ( n=910 ) recruited via a popular UK parenting site , Netmums.com , scoring above 12 on the Edinburgh Postnatal Depression Scale ( EPDS ) were randomly assigned to receive either Postnatal-iBA delivered or treatment-as-usual ( P10636 ) . We investigated the feasibility ( recruitment , trial and treatment adherence ) and effectiveness ( depression status EPDS > 12 ) of the intervention . RESULTS : Recruitment was excellent ; 1261 women , 961 of whom met inclusion criteria , signed up to the trial within two 2-week recruitment periods . Thirty-eight percent ( 343/910 ) of women completed the 15-week outcome assessment . Of those who completed 15-week assessment , fewer exceeded the depression cutoff in the Postnatal-iBA group ( n=66/181 ) compared to P10636 ( n=91/162 ) . Assuming all non-respondents remained depressed , the Postnatal-iBA effect was reduced . LIMITATIONS : The study suffered from high attrition and future trials need to consider strategies for improving outcome completion . Some women reported struggles " keeping up " with the treatment . CONCLUSIONS : A minimal support , widely accessible internet Behavioral Activation program for P01160 is feasible to deliver to community populations when embedded within popular parenting sites . For women who provide outcome data , postnatal-iBA offers promise as an effective treatment for P01160 . The addition of support may reduce women 's struggles to keep pace with the treatment . P00797 inhibition reduces atherosclerotic plaque neovessel formation and regresses advanced atherosclerotic plaques . OBJECTIVE : The interaction between the renin-angiotensin system and toll-like receptors ( TLRs ) in the pathogenesis of advanced atherosclerotic plaques is not well understood . We studied the effects of the renin inhibitor aliskiren on the progression of advanced atherosclerotic plaque in apolipoprotein E-deficient ( ApoE(-/-) ) mice with a special focus on plaque neovessel formation . METHODS AND RESULTS : Four-wk-old ApoE(-/-) mice were fed a high-fat diet for 8 wks , and the mice were randomly assigned to one of three groups and administered a vehicle , hydralazine , or aliskiren for an additional 12 wks . DB09026 reduced the atherosclerotic plaque area and plaque neovessel density . It increased the plaque collagen and elastin contents , and reduced plasma angiotensin II levels and plaque macrophage infiltration and cathepsin S ( CatS ) protein . DB09026 also decreased the levels of AT1R , gp91phox , O60603 , monocyte chemotactic protein-1 , and CatS mRNAs in the aortic roots . DB01275 had no beneficial vascular effects , although its administration resulted in the same degree of blood pressure reduction as aliskiren . CatS deficiency mimicked the aliskiren-mediated vasculoprotective effect in the ApoE(-/-) mice , but aliskiren showed no further benefits in ApoE(-/-) CatS(-/-) mice . In vitro , O60603 silencing reduced CatS expression induced by angiotensin II . Moreover , aliskiren or the inhibition of CatS impaired the endothelial cell angiogenic action in vitro or/and ex vivo . CONCLUSION : P00797 inhibition appears to inhibit advanced plaque neovessel formation in ApoE(-/-) mice and to decrease the vascular inflammatory action and extracellular matrix degradation , partly by reducing AT1R/ O60603 -mediated CatS activation and activity , thus regressing advanced atherosclerosis . An association analysis of circadian genes in anxiety disorders . BACKGROUND : The mammalian circadian system is responsible for controlling daily oscillations in physiology and behavior . Circadian genes contribute to the sleep-wake cycle and mood , and because patients with anxiety disorder often suffer from sleep disturbances , we hypothesized that variants in circadian-clock-related genes might predispose to human anxiety disorders as well . We tested this hypothesis with a genetic association analysis . METHODS : We analyzed 131 single nucleotide polymorphisms from 13 circadian-clock-related genes . The study sample consisted of 321 individuals diagnosed with an anxiety disorder and 653 matched healthy controls from a Finnish population-based cohort . RESULTS : Single nucleotide polymorphisms in two genes showed some evidence for association to social phobia : in Q8WYA1 rs2306073 ( p = .0099 ) and in P14416 rs7131056 ( p = .0084 ) . P10415 rs12454712 ( p = .0029 ) and P14416 rs4245146 ( p = .0010 ) showed evidence for association to generalized anxiety disorder , whereas rs2463107 ( p = .0064 ) in Q96IZ0 and rs4245146 ( p = .0029 ) in P14416 showed evidence for association to the pooled group of all anxiety disorders . Findings in P14416 became stronger when only anxiety disorder cases with comorbid alcohol use disorder were considered . CONCLUSIONS : Genes contributing to circadian rhythms might also play a role in the genetic predisposition to anxiety disorders . In addition , our study provides further support for the association of P14416 to comorbid anxiety and alcohol use disorder . Dopamine agonist-induced hypothermia and disruption of prepulse inhibition : evidence for a role of D3 receptors ? The dopamine D3/D2 receptor agonists 7-OH-DPAT , quinpirole , quinelorane , and PD128907 , the mixed dopamine agonist apomorphine , the D2 agonist bromocriptine , and the D1/D5 agonist SKF38393 were examined in models of hypothermia and prepulse inhibition ( PPI ) in Wistar rats . As dopamine agonist-induced hypothermia has been proposed as a model of D3 receptor function , and dopamine agonists are known to disrupt PPI , drug potencies to induce hypothermia were established and compared with doses necessary to disrupt PPI . 7-OH-DPAT , quinpirole , quinelorane , PD128907 , and apomorphine , reduced body temperature and disrupted PPI with a similar rank order of potency ( quinelorane > quinpirole = 7-OH-DPAT > PD128907 = apomorphine ) . DB01200 and SKF38393 were ineffective in both models . In a separate study , the dopamine reuptake inhibitors cocaine and GBR 12909 had no effect on PPI . In a final set of studies , the D2/D3 antagonist raclopride blocked both 7-OH-DPAT-induced hypothermia and 7-OH-DPAT-induced PPI disruption . The P08908 antagonist WAY 100,135 , and the peripheral D2-like antagonist domperidone had no effect . These findings suggest that the hypothermia and PPI disruptions seen with some of these dopamine agonists may be mediated by central D3 receptors ; however , only studies using more selective dopamine receptor ligands can definitively rule out effects at the D2 or D4 receptors . Akt/ P31749 kinase phosphorylates separately Thr212 and Ser214 of tau protein in vitro . P10636 contains a consensus motif for protein kinase B/Akt ( Akt ) , which plays an essential role in anti-apoptotic signaling . The motif encompasses the AT100 double phospho-epitope ( Thr212/Ser214 ) , a specific marker for Alzheimer 's disease ( AD ) and other neurodegenerations , raising the possibility that it could be generated by Akt . We studied Akt-dependent phosphorylation of tau protein in vitro . We found that Akt phosphorylated both Thr212 and Ser214 in the longest and shortest tau isoforms as determined using phospho site-specific antibodies against tau . Akt did not phosphorylate other tau epitopes , including Tau-1 , AT8 , AT180 , 12E8 and PHF-1 . The Akt-phosphorylated tau retained its initial electrophoretic mobility . Immunoprecipitation studies with phospho-specific Thr212 and Ser214 antibodies revealed that only one of the two sites is phosphorylated per single tau molecule , resulting in tau immunonegative for AT100 . Mixed kinase studies showed that prior Ser214 phosphorylation by Akt blocked protein kinase A but not GSK3beta activity . On the other hand , GSK3beta selectively blocked Ser214 phosphorylation , which was prevented by lithium . The results suggest that Akt may be involved in AD-specific phosphorylation of tau at the AT100 epitope in conjunction with other kinases . Our data suggest that phosphorylation of tau by Akt may play specific role(s) in Akt-mediated anti-apoptotic signaling , particularly relevant to AD and other neurodegenerations . P00797 angiotensin system modulates P42345 pathway through AT2R in HIVAN . P42345 ( P42345 ) has been reported to contribute to the development of HIV-associated nephropathy ( HIVAN ) . We hypothesized that HIV may be activating renal tissue P42345 pathway through renin angiotensin system ( DB01367 ) via Angiotensin Receptor Type II receptor ( AT2R ) . Renal tissues of Vpr transgenic and Tg26 ( HIVAN ) mice displayed enhanced phosphorylation of P42345 and p70S6K . DB09026 , a renin inhibitor attenuated phosphorylation of both P42345 and p70S6K in renal tissues of HIVAN mice . Interestingly , Angiotensin Receptor Type I ( AT1R ) blockade did not modulate renal tissue phosphorylation of P42345 in HIVAN mice ; on the other hand , AT2R blockade attenuated renal tissue phosphorylation of P42345 in HIVAN mice . In vitro studies , both renin and Ang II displayed enhanced mouse tubular cell ( P04629 ) phosphorylation of p70S6K in a dose dependent manner . HIV/ P04629 also displayed enhanced phosphorylation of both P42345 and p70S6K ; interestingly this effect of HIV was further enhanced by losartan ( an AT1R blocker ) . On the other hand , AT2R blockade attenuated HIV-induced tubular cell phosphorylation of P42345 and p70S6K , whereas , AT2R agonist enhanced phosphorylation of P42345 and p70S6K . These findings indicate that HIV stimulates P42345 pathway in HIVAN through the activation of renin angiotensin system via AT2R . DB00563 induces apoptosis through p53/ P38936 -dependent pathway and increases P12830 expression through downregulation of HDAC/ Q15910 . DB00563 ( MTX ) is a dihydrofolate reductase ( P00374 ) inhibitor widely used as an anticancer drug in different kinds of human cancers . Here we investigated the anti-tumor mechanism of MTX against non-small cell lung cancer ( NSCLC ) A549 cells . MTX not only inhibited in vitro cell growth via induction of apoptosis , but also inhibited tumor formation in animal xenograft model . RNase protection assay ( RPA ) and RT-PCR demonstrated its induction of p53 target genes including DR5 , P38936 , Puma and Noxa . Moreover , MTX promoted p53 phosphorylation at Ser15 and acetylaion at Lys373/382 , which increase its stability and expression . The apoptosis and inhibition of cell viability induced by MTX were dependent on p53 and , partially , on P38936 . In addition , MTX also increased P12830 expression through inhibition of histone deacetylase ( HDAC ) activity and downregulation of polycomb group protein enhancer of zeste homologue 2 ( Q15910 ) . Therefore , the anticancer mechanism of MTX acts through initiation of p53-dependent apoptosis and restoration of P12830 expression by downregulation of HDAC/ Q15910 . Accumulation of cyclin-dependent kinase 5 ( cdk5 ) in neurons with early stages of Alzheimer 's disease neurofibrillary degeneration . P12004 -dependent kinase 5 ( cdk5 ) is one of the candidate kinases involved in the abnormal hyperphosphorylation of tau . To have a direct effect on tau hyperphosphorylation , cdk5 protein levels and enzyme activity should be upregulated in especially those neurons that develop neurofibrillary tangles ( NFTs ) . We studied the distribution of cdk5 immunoreactivity in neurons with or without early- and late-stage NFTs in hippocampal , entorhinal , transentorhinal , temporal and frontal cortices , and cerebellum of Alzheimer 's disease ( AD ) and control brain . The immunocytochemical localisation of cdk5 was compared with that obtained using antibodies to P10636 ( tau in paired helical filaments of NFTs , mAb AT8 ) and ubiquitin as markers of early and late stage NFTs , respectively . Immunoreactivities of cdk5 and P10636 were found in neuronal perikarya and processes of hippocampal , entorhinal , transentorhinal , temporal and frontal , and cerebellar cortices . An apparent increase of cdk5 immunoreactivity was seen in pretangle neurons and in neurons bearing early stage NFTs . These findings suggest that this kinase might be involved in the formation of NFTs at a relatively early stage in the neocortex . A brief cognitive-behavioural social skills training for stabilised outpatients with schizophrenia : a preliminary study . Achieving social functioning and achieving social competence are two main objectives of psychosocial interventions for people suffering from schizophrenia . The present preliminary study presents a novel approach of social skills training ( P61278 ) based on the proposals of Kopelowicz et al . ( Kopelowicz , A. , Liberman , R. P. , and Zarate , R. , 2006. Schizophr. Bull. 32 ( 1 ) : P28222 -23 ) that link the treatment to seven specific target behaviours : social perception , social information processing , responding and sending skills , affiliative skills , interactional skills , and behaviour governed by social norms . Thirty-one stabilised outpatients were randomly assigned to one of two groups , P61278 ( n=13 ) or treatment-as-usual ( n=18 ) ( P10636 ; case management , medication adherence , psychotherapy , leisure engagement , and family support ) and were assessed at baseline in cognitive performance , clinical symptomatology , social cognition , and psychosocial functioning . These outcomes were evaluated across post-treatment and at the 6-month follow-up appointment . P61278 subjects showed improvements in psychopathology , social discomfort , social cognition ( self-regulation statements during interactions ) , social withdrawal , interpersonal communication , and quality of life compared with the P10636 group . At the 6-month follow-up , results were maintained for negative symptoms , social discomfort , and some functioning outcomes . Neuropsychological variables were also examined , as mediators of benefit from skills training . Results support the efficacy of the brief P61278 for outpatients with schizophrenia and show the need to implement empirically supported interventions in mental health services to enhance patients ' social functioning and quality of life . Telomere shortening is associated with reduced duodenal HCOFormula secretory but normal gastric acid secretory capacity in aging mice . The incidence of duodenal ulcer , especially Helicobacter pylori-negative duodenal ulcer , strongly increases with age . In humans , telomere length shortening is considered to be one critical factor in cellular senescence and organ survival . In this study , we compared basal and stimulated gastric acid and duodenal HCO(3)(-) secretory rates in aged late-generation ( G(3) ) telomerase-deficient ( mTERC(-/-) ) mice , which are characterized by severe telomere dysfunction due to the inability to elongate telomeres during cell division . We found that basal and forskolin-stimulated HCO(3)(-) secretion and short-circuit current ( I(sc) ) in isolated duodenal mucosa of G(3) mTERC(-/-) mice were markedly reduced compared with age-matched wild-type mice . In contrast , basal and forskolin-stimulated acid secretory rates in isolated G(3) mTERC(-/-) gastric mucosa were not significantly altered . Correspondingly , duodenal mucosa of G(3) mTERC(-/-) mice showed slimming and shortening of villi , whereas gastric mucosal histology was not significantly altered . However , the ratios of cystic fibrosis transmembrane conductance regulator ( P13569 ) and solute-linked carrier 26 gene family ( Slc26a6 ) mRNA expression in relation to cytokeratin-18 were not altered in duodenal mucosa . The further knockout of P38936 , which is a downstream effector of telomere shortening-induced senescence , rescued villus atrophy of duodenal mucosa , and basal and forskolin-stimulated duodenal HCO(3)(-) secretion and I(sc) in mTERC(-/-) P38936 (-/-) double-knockout mice were not different from wild-type controls . In conclusion , genetic ablation of telomerase resulted in P38936 -dependent duodenal mucosal atrophy and reduced duodenal HCO(3)(-) secretory capacity , whereas gastric morphology and acid secretory function were preserved . This suggests that telomere shortening during aging may result in an imbalance between aggressive and protective secretions against duodenal mucosa and thus predispose to ulcer formation . Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism (PE). tPA has not been replaced by third generation plasminogen activators , e.g. DB00015 ( Ret ) and DB00031 ( TNK ) that circulate with longer life-spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor-1 ( e.g. P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility . Novel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-beta(1)-dependent pathway . Nonsteroidal anti-inflammatory drugs ( NSAIDs ) reduce the risk of gastrointestinal cancers . Recently , a similar protective effect has been demonstrated by the specific cyclo-oxygenase-2 ( P35354 ) inhibitors . However , the exact mechanism that accounts for the anti-proliferative effect of specific P35354 inhibitors is still not fully understood , and it is still controversial whether these protective effects are predominantly mediated through the inhibition of P35354 activity and prostaglandin synthesis . Identification of molecular targets regulated by P35354 inhibitors could lead to a better understanding of their pro-apoptotic and anti-neoplastic activities . In the present study , we investigated the effect and the possible molecular target of a P35354 -specific inhibitor SC-236 on gastric cancer . We showed that SC-236 induced apoptosis in gastric cancer cells . However , this effect was not dependent on P35354 inhibition . SC-236 down-regulated the protein expression and kinase activity of P05771 (1) , increased the expression of PKCdelta and PKCeta , but did not alter the expression of other PKC isoforms in AGS cells . Moreover , exogenous prostaglandins or PGE(2) receptor antagonists could not reverse the inhibition effect on PKCbeta(1) by SC-236 , which suggested that this effect occurred through a mechanism independent of cyclo-oxygenase activity and prostaglandin synthesis . Overexpression of PKCbeta(1) attenuated the apoptotic response of AGS cells to SC-236 and was associated with overexpression of P38936 (waf1/cip1) . Inhibition of PKCbeta(1)-mediated overexpression of P38936 (waf1/cip1) partially reduced the anti-apoptotic effect of PKCbeta(1) . The down-regulation of PKCbeta(1) provides an explanation for P36551 -independent apoptotic effects of specific P35354 inhibitor in cultured gastric cancer cells . We also suggest that PKCbeta(1) act as survival mediator in gastric cancer , and its down-regulation by P35354 inhibitor SC-236 may provide new target for future treatment of gastric cancer . DB00563 in pediatric osteosarcoma : response and toxicity in relation to genetic polymorphisms and dihydrofolate reductase and reduced folate carrier 1 expression . OBJECTIVE : To determine the influence of the genotype and the level of expression of different enzymes involved in folate metabolism on the response to and toxicity of high-dose methotrexate treatment in pediatric osteosarcomas . STUDY DESIGN : P00374 and Reduced folate carrier 1 ( RFC1 ) semiquantitative expression was analyzed in 34 primary and metastatic osteosarcoma tissues by real-time polymerase chain reaction . The following polymorphisms were also analyzed in peripheral blood from 96 children with osteosarcoma and 110 control subjects : C677T , A1298C ( P42898 ) , G80A ( RFC1 ) , A2756G ( Q99707 ) , C1420T ( SHMT ) , the 28bp-repeat polymorphism , and 1494del6 of the P04818 gene . Treatment toxicity was scored after each cycle according to criteria from the World Health Organization . RESULTS : P00374 and RFC1 expression was lower in initial osteosarcoma biopsy specimens than in metastases ( P = .024 and P = .041 , respectively ) . RFC1 expression was moderately decreased in samples with poor histologic response to preoperative treatment ( P = .053 ) . Patients with osteosarcoma with P46379 /G4 hematologic toxicity were more frequently TT than CT/CC for C677T/ P42898 ( P = .023 ) and GG for A2756G/ Q99707 ( P = .048 and P = .057 for gastrointestinal and hematologic toxicity , respectively ) . CONCLUSIONS : The role of C677T/ P42898 and A2756G/ Q99707 on chemotherapy-induced toxicity should be further investigated in pediatric osteosarcomas receiving high-dose methotrexate . Altered expression of P00374 and RFC1 is a feasible mechanism by which osteosarcoma cells become resistant to methotrexate . Overexpression of SnoN/SkiL , amplified at the 3q26.2 locus , in ovarian cancers : a role in ovarian pathogenesis . High-resolution array comparative genomic hybridization of 235 serous epithelial ovarian cancers demonstrated a regional increase at 3q26.2 encompassing SnoN/SkiL , a coregulator of SMAD/TGFbeta signaling . SnoN RNA transcripts were elevated in approximately 80 % of advanced stage serous epithelial ovarian cancers . In both immortalized normal ( TIOSE ) and ovarian carcinoma cell lines ( OVCA ) , SnoN RNA levels were increased by TGFbeta stimulation and altered by LY294002 and JNK II inhibitor treatment suggesting that the PI3K and JNK signaling pathways may regulate TGFbeta-induced increases in SnoN RNA . In TIOSE , SnoN protein levels were reduced 15min post TGFbeta-stimulation , likely by proteosome-mediated degradation . In contrast , in OVCA , SnoN levels were elevated 3h post-stimulation potentially as a result of inhibition of the proteosome . To elucidate the role of SnoN in ovarian tumorigenesis , we explored the effects of both increasing and decreasing SnoN levels . In both TIOSE and OVCA , SnoN siRNA decreased cell growth between 20 and 50 % concurrent with increased P38936 levels . In TIOSE , transient expression of SnoN repressed TGFbeta induction of P05121 promoters with little effect on the P38936 promoter or resultant cell growth . In contrast to the effects of transient expression , stable expression of SnoN in TIOSE led to growth arrest through induction of senescence . Collectively , these results implicate SnoN levels in multiple roles during ovarian carcinogenesis : promoting cellular proliferation in ovarian cancer cells and as a positive mediator of cell cycle arrest and senescence in non-transformed ovarian epithelial cells . Mer receptor tyrosine kinase is a therapeutic target in pre-B-cell acute lymphoblastic leukemia . Acute lymphoblastic leukemia ( ALL ) is currently treated with an intense regimen of chemotherapy yielding cure rates near 85 % . However , alterations to treatment strategies using available drugs are unlikely to provide significant improvement in survival or decrease therapy-associated toxicities . Here , we report ectopic expression of the Mer receptor tyrosine kinase in pre-B-cell ALL ( B-ALL ) cell lines and pediatric patient samples . Inhibition of Mer in B-ALL cell lines decreased activation of AKT and MAPKs and led to transcriptional changes , including decreased expression of antiapoptotic P05771 gene and increase in proapoptotic Q07812 and BBC3 genes . Further , Mer inhibition promoted chemosensitization , decreased colony-forming potential in clonogenic assays , and delayed disease onset in a mouse xenograft model of leukemia . Our results identify Mer as a potential therapeutic target in B-ALL and suggest that inhibitors of Mer may potentiate lymphoblast killing when used in combination with chemotherapy . This strategy could reduce minimal residual disease and/or allow for chemotherapy dose reduction , thereby leading to improved event-free survival and reduced therapy-associated toxicity for patients with B-ALL . Additionally , Mer is aberrantly expressed in numerous other malignancies suggesting that this approach may have broad applications . Gene network profiling before and after transplantation in alcoholic cirrhosis liver transplant recipients . The main objective of this study was to define a gene network profile network in liver transplant recipients with alcoholic cirrhosis before and after liver transplantation . Genes were selected from data obtained in a previous study of liver transplant recipients with alcoholic cirrhosis . Selected up-regulated genes were further validated by quantitative real-time polymerase chain reaction in different groups of liver transplant recipients with alcoholic cirrhosis ( n=5 ) . Selected genes up-regulated before transplantation were : Q07011 ( tumor necrosis factor [ P01375 ] receptor superfamily , member 9 ) ; P14784 ( interleukin-2 receptor beta ) ; Q92843 ( P10415 -like 2 ) ; Q96PH1 ( NADPH ) oxidase , EF-hand calcium binding domain 5 ) ; P50542 ( peroxisomal biogenesis factor 5 ) ; P37231 ( peroxisome proliferator-activated receptor gamma ) ; Q96Q05 ( O14920 binding protein ) ; Q9NYR9 ( NFKappaBeta inhibitor interacting Ras-like 2 ) ; P05112 ( interleukin-4 ) ; IL-4R ( interleukin 4 receptor ) ; P07327 ( alcohol dehydrogenase 1A , class 1 ) ; O75891 ( aldehyde dehydrogenase 1 family , member Q9NUQ9 ) ; P05164 ( myeloperoxidase ) ; P01160 ( natriuretic peptide precursor A ) ; Q16548 ( P10415 -related protein A1 ) ; P24522 ( growth arrest and DNA-damage-inducible alpha ) ; P55061 ( P55061 ) ; P42336 ( phosphoinositide-3-kinase , catalytic , alpha polypeptide ) ; P38484 ( interferon gamma receptor 2 ) ; O60674 ( Janus Kinase 2 ) ; FAS ( Fas , P01375 receptor superfamily , member 6 ) ; Q92844 ( TRAF family member-associated NFKB activator ) ; O95551 ( O95551 ) ; and P08758 ( annexin A5 ) . P40763 regulates proliferation and survival of CD8+ T cells : enhances effector responses to HSV-1 infection , and inhibits P22301 + regulatory CD8+ T cells in autoimmune uveitis . P40763 regulates P01730 + T cell survival and differentiation . However , its effects on CD8+ T cells are not well understood . Here , we show that in comparison to WT CD8+ T cells , P40763 -deficient CD8+ T cells exhibit a preactivated memory-like phenotype , produce more P60568 , proliferate faster , and are more sensitive to activation-induced cell death ( AICD ) . The enhanced proliferation and sensitivity to AICD correlated with downregulation of class-O forkhead transcription factors ( FoxO1 , FoxO3A ) , P38936 (waf1) , p27( P46527 ) , Bcl-2 , OX-40 , and upregulation of P48023 , Bax , and Bad . We examined whether P40763 -deficient CD8+ T cells can mount effective response during herpes simplex virus ( HSV-1 ) infection and experimental autoimmune uveitis ( EAU ) . Compared to WT mice , HSV-1-infected P40763 -deficient mice ( STAT3KO ) produced less IFN-γ and virus-specific KLRG-1+ CD8+ T cells . STAT3KO mice are also resistant to EAU and produced less Q16552 -producing Tc17 cells . Resistance of STAT3KO to EAU correlated with marked expansion of P22301 -producing regulatory CD8+ T cells ( CD8-Treg ) implicated in recovery from autoimmune encephalomyelitis . Thus , increases of P05231 -induced P40763 activation observed during inflammation may inhibit expansion of CD8-Tregs , thereby impeding recovery from uveitis . These results suggest that P40763 is a potential therapeutic target for upregulating CD8+ T cell-mediated responses to viruses and suggest the successful therapeutic targeting of P40763 as treatment for uveitis , derived , in part , from promoting CD8-Treg expansion . Molecular response of HL-60 cells to mitotic inhibitors vincristine and taxol visualized with apoptosis-related gene expressions , including the new member Q9HB09 . DB01229 and vincristine belong to a group of anticancer drugs that target microtubules , subsequently arresting cells at the mitotic phase of the cell cycle and inducing programmed cell death . The P10415 ( bcl-2 ) family of genes is of known implication in apoptosis induced by various stimuli , among which Q9HB09 , a new member of the family , cloned by our group . For further insights into the mechanisms and molecular targets implicated and modified as a result of apoptosis induced by these two mitosis-arresting drugs , we studied the possible alterations , at the mRNA level , of various apoptosis-related genes ( P10415 , Q07812 , Q9HB09 , CASPASE-3 , FAS ) after leukemia cell ( HL-60 ) treatment with these drugs . The kinetics of cell toxicity were evaluated by the MTT [ 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide ] method , trypan blue staining , and cell proliferation efficiency ; apoptosis induction was assayed by endonucleosomal cleavage of DNA ( DNA laddering ) ; and the expression levels of the genes were analysed by RT-PCR , using gene-specific primers . The percentage of nonviable cells was upregulated with increasing cell exposure time and drug concentrations to both taxol and vincristine . Distinct modulations of apoptosis-related genes at the mRNA level were also observed , mainly concerning P10415 and Q9HB09 along apoptosis induction . Our results indicate and support the hypothesis that the apoptosis-related genes P10415 and Q9HB09 respond similarly to treatment of the human , acute , myelocytic leukemia HL60 cells with the anticancer drugs vincristine and taxol though in a drug-specific and time-dependent manner . Glutathione levels and Q07812 activation during apoptosis due to oxidative stress in cells expressing wild-type and mutant cystic fibrosis transmembrane conductance regulator . Cystic fibrosis is characterized by chronic inflammation and an imbalance in the concentrations of alveolar and lung oxidants and antioxidants , which result in cell damage . Modifications in lung glutathione concentrations are recognized as a salient feature of inflammatory lung diseases such as cystic fibrosis , and glutathione plays a major role in protection against oxidative stress and is important in modulation of apoptosis . The cystic fibrosis transmembrane conductance regulator ( P13569 ) is permeable to Cl(-) , larger organic ions , and reduced and oxidized forms of glutathione , and the DeltaF508 P13569 mutation found in cystic fibrosis patients has been correlated with impaired glutathione transport in cystic fibrosis airway epithelia . Because intracellular glutathione protects against oxidative stress-induced apoptosis , we studied the susceptibility of epithelial cells ( HeLa and IB3-1 ) expressing normal and mutant P13569 to apoptosis triggered by H(2)O(2) . We find that cells with normal P13569 are more sensitive to oxidative stress-induced apoptosis than cells expressing defective P13569 . In addition , sensitivity to apoptosis could be correlated with glutathione levels , because depletion of intracellular glutathione results in higher levels of apoptosis , and glutathione levels decreased faster in cells expressing normal P13569 than in cells with defective P13569 during incubation with H(2)O(2) . The pro-apoptotic BCL-2 family member , Q07812 , is also activated faster in cells expressing normal P13569 than in those with mutant P13569 under these conditions , and artificial glutathione depletion increases the extent of Q07812 activation . These results suggest that glutathione-dependent Q07812 activation in cells with normal P13569 represents an early step in oxidative stress-induced apoptosis of these cells . Increased exchange rate of histone H1 on chromatin by exogenous myogenin expression . To explore the molecular mechanism of chromatin remodeling involved in the regulation of transcriptional activation of specific genes by a myogenic regulatory factor P15173 , we used NIH3T3 fibroblasts with a stably integrated H1.1-GFP fusion protein to monitor histone H1 movement directly by fluorescence recovery after photobleaching ( P42345 ) in living cells . The observation from P42345 experiments with myogenin transfected fibroblasts showed that the exchange rate of histone H1 in chromatin was obviously increased , indicating that forced expression of exogenous P15173 can induce chromatin remodeling . The hyperacetylation of histones H3 and H4 from myogenin transfected fibroblasts was detected by triton-acid-urea ( P10636 ) /SDS ( 2-D ) electrophoresis and Western blot with specific antibodies against acetylated N-termini of histones H3 and H4 . RT-PCR analysis indicated that the nAChR alpha-subunit gene was expressed in the transfected fibroblasts . These results suggest that the expression of exogenous P15173 can induce chromatin remodeling and activate the transcription of P15173 -targeted gene in non-muscle cells . Transcriptional response to ionizing radiation in lymphocyte subsets . Human lymphocyte subpopulations differ in their cellular responses to ionizing radiation . To shed light on the molecular basis of this effect , we characterized the transcriptional response to 1 Gy X-rays of P01730 + T lymphocytes . Of 18,433 genes tested , 102 were modulated more than 1.5-fold . The majority of the strongly activated genes were p53 targets involved in DNA repair and apoptosis . The expression of three of these genes was further tested by quantitative RT-PCR in lymphocyte subpopulations [ P01730 + and CD8+ T , P15391 + B , CD56+ natural killer cells and peripheral blood lymphocytes ( PBLs ) ] from ten adult donors . In contrast to Q92466 , O14763 and Q07812 were differentially modulated among the subpopulations and the PBLs , being more activated in irradiated P15391 + B and CD8+ T lymphocytes . The level of Q07812 activation in the various subpopulations correlated with the sensitivity of the cells to radiation , suggesting its possible role in the differential radiosensitivity of hematopoietic cell subsets . Genetics of idiopathic disseminated bronchiectasis . Bronchiectasis is an abnormal dilation of bronchi , consequent to the destruction of their walls . It is included in the category of obstructive pulmonary diseases , along with chronic obstructive pulmonary disease ( P48444 ) , asthma , and cystic fibrosis . In approximately 50 % of cases , bronchiectasis is associated with underlying conditions ; in the remainder , known causes are not ascertainable ( idiopathic bronchiectasis ) . A search for genetic determinants of this phenotype , with the cystic fibrosis gene as a candidate , has been performed by three independent groups . The results of this search agreed on the association of bronchiectasis with cystic fibrosis gene mutations and polymorphisms . The cystic fibrosis gene is also associated with bronchiectasis due to rheumatoid arthritis and allergic bronchopulmonary aspergillosis . A few other genes have been investigated in idiopathic bronchiectasis , with negative results . Idiopathic bronchiectasis is , therefore , to be considered as an obstructive multifactorial disorder belonging to the category of cystic fibrosis monosymptomatic diseases ( or P13569 -opathies ) , whose pathogenesis is influenced by environmental factors and other undetermined genes . Dissociable fronto-striatal effects of dopamine D2 receptor stimulation on cognitive versus motor flexibility . Genetic and pharmacological studies suggest an important role of the dopamine D2 receptor ( P14416 ) in flexible behavioral adaptation , mostly shown in reward-based learning paradigms . Recent evidence from imaging genetics indicates that also intentional cognitive flexibility , associated with lateral frontal cortex , is affected by variations in P14416 signaling . In the present functional magnetic resonance imaging ( Q9BWK5 ) study , we tested the effects of a direct pharmacological manipulation of P14416 stimulation on intentional flexibility in a task-switching context , requiring switches between cognitive task rules and between response hands . In a double blind , counterbalanced design , participants received either a low dose of the P14416 agonist bromocriptine or a placebo in two separate sessions . DB01200 modulated the blood-oxygen-level-dependent ( BOLD ) signal during rule switching : rule-switching-related activity in the left posterior lateral frontal cortex and in the striatum was increased compared to placebo , at comparable performance levels . Fronto-striatal connectivity under bromocriptine was slightly increased for rule switches compared to rule repetitions . Hand-switching-related activity , in contrast , was reduced under bromocriptine in sensorimotor regions . Our results provide converging evidence for an involvement of P14416 signaling in fronto-striatal mechanisms underlying intentional flexibility , and indicate that the neural mechanisms underlying different types of flexibility ( cognitive vs motor ) are affected differently by increased dopaminergic stimulation . Mutation analyses in amyotrophic lateral sclerosis/parkinsonism-dementia complex of the Kii peninsula , Japan . To clarify the genetic background of amyotrophic lateral sclerosis ( P35858 ) /parkinsonism-dementia complex ( P20941 ) of the Kii peninsula , Japan ( Kii P35858 / P20941 ) , we performed extended mutation analyses of three patients with pathologically diagnosed Kii P35858 / P20941 . Direct sequencing analyses were performed in 19 genes , including P35858 /frontotemporal lobar degeneration ( FTLD ) -related genes ( P04179 , P08294 , Q96Q42 /alsin , Q16637 , PGRN , P03950 , P15692 , P55072 , O95292 , Q14203 , Q9UQN3 , and Q13148 or Q13148 ) , tauopathy-related gene ( GSK3beta ) , and parkinsonism-related genes ( alpha-synuclein , Q5S007 , parkin , Q99497 , Q9BXM7 , and Q9NQ11 ) . Gene dosage analyses were conducted in screening of P10636 , alpha-synuclein , Q13148 ( or Q13148 ) , GSK3beta , and parkin . We found no mutation in the 19 genes . We found a homozygous nonsynonymous SNP ( Q96Q42 /alsin V368M ) shared by all the three patients . Gene dosage was normal in P10636 , alpha-synuclein , Q13148 , GSK3beta , and parkin . The present findings , together with a previous negative study on P10636 and P00441 mutation , further elucidated the lack of causative mutations in all exons , exon-intron boundaries , or some rearrangements of the reported major causative or susceptible genes related to P35858 , FTLD , parkinsonism , synucleinopathy , Q13148 proteinopathy , and tauopathy . However , the familial aggregation and lack of any environment factors suggest that Kii P35858 / P20941 is caused by other yet unidentified genetic factors . Reduced folate carrier and dihydrofolate reductase expression in acute lymphocytic leukemia may predict outcome : a Children 's Cancer Group Study . PURPOSE : DB00563 is a major component of current treatment regimens for children with acute lymphocytic leukemia ( ALL ) . Potential mechanisms of methotrexate resistance include impaired drug uptake , decreased drug retention , and dihydrofolate reductase ( P00374 ) amplification . The purpose of this study was to assess whether reduced folate carrier ( P41440 ) and P00374 expression in untreated leukemic blasts correlated with outcome . METHODS : Quantitative real-time RT-PCR was used to measure P41440 and P00374 mRNA expression in leukemic blasts from 40 newly diagnosed patients with ALL obtained in a blinded fashion from Children 's Cancer Group studies . RESULTS : Low P41440 expression at diagnosis correlated significantly with an unfavorable event free survival . Surprisingly , low , not high , P00374 expression correlated significantly with an unfavorable event-free survival . Proliferative cell nuclear antigen ( P12004 ) expression demonstrated a weak inverse relationship between sample P12004 and P00374 or P41440 expression , suggesting that P00374 and P41440 expression may be markers for factors other than drug resistance . CONCLUSIONS : These results suggest that impaired transport may be an important mechanism of intrinsic methotrexate resistance in ALL , and P00374 expression also may be an important prognostic factor in ALL . Additional studies are necessary to clarify the mechanism for the correlation of low P00374 expression with poor outcome . Tp53-associated growth arrest and DNA damage repair gene expression is attenuated in mammary epithelial cells of rats fed whey proteins . Dietary protection from mammary cancer is likely coordinated through multiple signaling pathways , based on the known heterogeneity of the disease and the distinct origins of mammary tumor cells . The present study examined the modulatory effects of dietary intake of whey protein hydrolysate ( WPH ) relative to casein ( CAS ) , on mammary epithelial cell resistance to endogenous DNA damage using Tp53 gene expression and signaling as a read-out , and on systemic proapoptotic and immune surveillance activity , in young adult female Sprague-Dawley rats . Rats were fed AIN-93G diets made with CAS or WPH as the sole protein source beginning at gestation d 4 . At postnatal day ( P01160 ) 50 , mammary glands of rats fed WPH had lower levels of activated Tp53 and p38 mitogen-activated protein kinase proteins , and reduced transcript levels for Tp53-associated DNA damage repair , growth arrest , and proapoptotic genes than those of CAS-fed rats . Serum from WPH-fed rats had greater apoptotic activity in MCF-7 tumor cells than that from rats fed CAS . Serum levels of monocyte chemoattractant protein ( MCP ) -1 were higher in WPH- than in CAS-fed rats . MCF-7 cells treated with CAS serum + recombinant rat P13500 had apoptotic activity and Tp53 and P38936 gene expression levels comparable to those treated with WPH serum or recombinant P13500 . Results indicate that mammary glands of rats fed a WPH diet are more protected from endogenous DNA damage than are those of CAS-fed rats , and identify P13500 as a potential serum biomarker for the positive effects of healthy diets . Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 -induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen-activated protein kinase ( MAPK ) or nuclear factor-kappaB ( NF-kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] -thymidine incorporation into DNA . Activation of PKC , MAPK and NF-kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal-regulated protein kinase 1/2 and NF-kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N-acetyl-l-cysteine resulted in a significant decrease in P51606 -induced activation of PKC- , MAPK- and NF-kappaB-signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF-kappaB in P51606 -induced BREC proliferation and P15692 expression . DB01120 inhibits BREC proliferation by interfering with these intracellular signal transduction pathways . DB09280 - DB08820 in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 . Personalised intervention for people with depression and severe P48444 . Chronic obstructive pulmonary disease ( P48444 ) is often complicated by depression and exemplifies the challenge in managing chronic illnesses that require active patient participation in care . In a clinical trial ( NCT00151372 ) , we compared a novel personalised intervention for depression and P48444 ( PID-C ) targeting treatment adherence with treatment as usual ( P10636 ) . In 138 patients with major depression and severe P48444 , PID-C led to a higher remission rate and a greater reduction in depressive symptoms and in dyspnoea-related disability than P10636 over 28 weeks and 6 months after the last session . If replicated , PID-C may serve as a care model for patients with both depression and medical illnesses with a deteriorating course . 3-Hydroxy-3-methylglutaryl coenzyme a reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture . Recent evidence suggests that apoptosis may be involved in the control of vascular smooth muscle cell ( VSMC ) number in atherosclerotic lesions . 3-Hydroxy-3-methylglutaryl coenzyme A ( HMG- DB01992 ) reductase inhibitors have been reported to induce apoptosis in a variety of tumor cell lines . To evaluate whether these agents also induce apoptosis of VSMCs , cultured rat VSMCs were treated with increasing doses of atorvastatin in the presence of FBS as a survival factor . The presence of apoptosis was evaluated by morphological criteria , annexin V binding , and DNA fragmentation and quantified as the proportion of hypodiploid cells by flow cytometry . DB01076 induced apoptosis in a dose-dependent manner , an effect also seen with simvastatin and lovastatin , but not with the hydrophilic drug pravastatin . The proapoptotic effect of statins was seen only when the inhibition of acetate incorporation into sterols was > 95 % and was fully reversed by mevalonate , farnesyl pyrophosphate , and geranylgeranyl pyrophosphate but not by isopentenyl adenosine , ubiquinone , or squalene , suggesting a role for prenylated proteins in the regulation of VSMC apoptosis . To further assess the role of protein prenylation , VSMCs were exposed to the prenyl transferase inhibitors perillic acid and manumycin A . Both agents induced VSMC apoptosis as evaluated by the above-mentioned criteria . Finally , VSMC treatment with lipophilic statins was associated with decreased prenylation of P38936 -Rho B , further supporting the role of protein prenylation inhibition in statin-induced VSMC apoptosis . The present data suggest that interference with protein prenylation by P04035 inhibitors or other agents may provide new strategies for the prevention of neointimal thickening . The presence and function of dopamine type 2 receptors in boar sperm : a possible role for dopamine in viability , capacitation , and modulation of sperm motility . Several studies have shown that dopamine and other catecholamines are present in oviduct luminal fluid . We recently reported that dopamine type 2 receptors ( P14416 ) are present in a wide range of mammalian sperm , suggesting a role for dopaminergic signaling in events such as fertilization , capacitation , and sperm motility . In the present study , we used Western blot analysis to show that boar sperm express P14416 and that their activation with dopamine ( 100 nM ) has a positive effect on cell viability that can be correlated with AKT/ P31749 phosphorylation . DB01200 ( 100 nM ) and dopamine ( 100 nM and 10 muM ) increased tyrosine phosphorylation during the capacitation period . Immunofluorescence analysis indicated that P14416 localization is dynamic and depends on the capacitation stage , colocalizing with tyrosine phosphorylated proteins in the acrosome and midpiece region of capacitated boar sperm . This association was confirmed by coimmunoprecipitation analysis . We also showed that bromocriptine ( 100 nM ) and low-concentration dopamine ( 100 nM and 10 muM ) increased total and progressive motility of sperm . However , high concentrations of dopamine ( 1 mM ) decreased tyrosine phosphorylation and motility in in vitro sperm capacitation assays . This can be explained by the presence of the dopamine transporters ( Q01959 , official symbol Q01959 ) in sperm , as demonstrated by Western blot analysis and immunocytochemistry . Taken together , our results support the idea that dopamine may have a fundamental role during sperm capacitation and motility in situ in the female upper reproductive tract . Q03135 tyrosine phosphorylation enhances paclitaxel-mediated cytotoxicity . Q03135 ( Q03135 ) , a highly conserved membrane-associated protein , is a putative regulator of cellular transformation . Q03135 is localized in the plasmalemma , secretory vesicles , Golgi , mitochondria , and endoplasmic reticulum membrane and associates with the microtubule cytoskeleton . Taxanes such as paclitaxel ( DB01229 ) are potent anti-tumor agents that repress the dynamic instability of microtubules and arrest cells in the G(2)/M phase . Src phosphorylation of DB00135 -14 on Q03135 regulates its cellular localization and function . We report that phosphorylation of Q03135 on DB00135 -14 regulates paclitaxel-mediated apoptosis in MCF-7 breast cancer cells . Befitting its role as a multitasking molecule , we show that Q03135 sensitizes cells to apoptosis by regulating cell cycle progression and activation of the apoptotic signaling molecules P10415 , p53 , and P38936 . We demonstrate that phosphorylated Q03135 triggers apoptosis by inactivating P10415 and increasing mitochondrial permeability more efficiently than non-phosphorylated Q03135 . Furthermore , expression of P38936 , which correlates with taxane sensitivity , is regulated by Q03135 phosphorylation in a p53-dependent manner . Collectively , our findings underscore the importance of Q03135 phosphorylation in apoptosis and suggest that events that negate Q03135 tyrosine phosphorylation may contribute to anti-microtubule drug resistance . Xaliproden ( SR57746A ) induces P08908 receptor-mediated Q96HU1 kinase activation in PC12 cells . Neurotrophic growth factors are involved in cell survival . However , natural growth factors have a very limited therapeutic use because of their short half-life . In the present study , we investigated the mechanism of action of a non-peptidic neurotrophic drug , Xaliproden , a potential molecule for the treatment of motoneuron diseases , since the transduction pathways of this synthetic P08908 agonist are very poorly understood . Xaliproden does not activate the Trk receptor but causes a rapid increase in the activities of the P27361 and P28482 isoforms of Q96HU1 kinase , which then rapidly decrease to the basal level . We demonstrate that isoforms of the P29353 adapter protein are phosphorylated independently of each other and are probably not the source of the Xaliproden-induced Q96HU1 kinases activation . The inhibitor of Ras farnesylation , FPT-1 , and the protein kinase C inhibitors , GF 109203X and chelerythrine , inhibited the Xaliproden-induced Q96HU1 kinase activation , suggesting p21Ras and PKC involvement . Moreover , the observations that the P08908 antagonist , pindobind , and pertussis toxin abolished the Xaliproden-induced P29323 stimulation suggested that Xaliproden activates the Q96HU1 kinase pathways by stimulating the G protein-coupled receptor , P08908 . These results demonstrate clearly that the non-peptidic compound , Xaliproden , exerts its neurotrophic effects through a mechanism of action differing from that of neurotrophins . These findings suggest that this compound does not involve MAPK activation by TrkA receptor stimulation but acts by Q96HU1 kinase pathway by a pertussis toxin-sensitive mechanism involving P08908 receptors , P38936 Ras and MEK-1 and by PKC and Akt pathways . In vivo effects of a combined P28222 receptor/ P31645 antagonist in experimental pulmonary hypertension . AIMS : A mechanism for co-operation between the serotonin ( 5-hydroxytryptamine , 5-HT ) transporter and P28222 receptor in mediating pulmonary artery vasoconstriction and proliferation of pulmonary artery smooth muscle cells has been demonstrated in vitro . Here we determine , for the first time , the in vivo effects of a combined P28222 receptor/serotonin transporter antagonist ( LY393558 ) with respect to the development of pulmonary arterial hypertension ( PAH ) and its in vitro effects in human pulmonary artery smooth muscle cells ( hPASMCs ) derived from idiopathic PAH ( IPAH ) patients . METHODS AND RESULTS : We determined the effects of LY393558 as well as a selective serotonin transporter inhibitor , citalopram , on right ventricular pressure , right ventricular hypertrophy , and pulmonary vascular remodelling in wildtype mice and mice over-expressing serotonin transporter ( P31645 + mice ) before and after hypoxic exposure . We also compared their effectiveness at reversing PAH in P31645 + mice and hypoxic mice . Further , we examined the proliferative response to serotonin in IPAH hPASMCs . We also clarified the pharmacology of serotonin-induced vasoconstriction and P28222 receptor/serotonin transporter interactions in mouse isolated pulmonary artery . DB00215 had a moderate effect at preventing and reversing experimental PAH in vivo whereas LY393558 was more effective . LY393558 was more effective than citalopram at reversing serotonin-induced proliferation in IPAH hPASMCs . There is synergy between P28222 receptor and serotonin transporter inhibitors against serotonin-induced vasoconstriction in mouse pulmonary arteries . CONCLUSION : P28222 receptor and serotonin transporter inhibition are effective at preventing and reversing experimental PAH and serotonin-induced proliferation of PASMCs derived from IPAH patients . Targeting both the serotonin transporter and P28222 receptor may be a novel therapeutic approach to PAH . Genetic variants and multiple myeloma risk : IMMEnSE validation of the best reported associations -- an extensive replication of the associations from the candidate gene era . BACKGROUND : Genetic background plays a role in multiple myeloma susceptibility . Several single-nucleotide polymorphisms ( SNP ) associated with genetic susceptibility to multiple myeloma were identified in the last years , but only a few of them were validated in independent studies . METHODS : With the aim to conclusively validate the strongest associations so far reported , we selected the polymorphisms rs2227667 ( P05121 ) , rs17501108 ( P14210 ) , rs3136685 ( P32248 ) , rs16944 ( P01584 ) , rs12147254 ( Q13114 ) , rs1805087 ( Q99707 ) , rs1800629 ( P01375 -α ) , rs7516435 ( P55211 ) , rs1042265 ( Q07812 ) , rs2234922 ( mEH ) , and rs1801133 ( P42898 ) . We genotyped them in 1,498 multiple myeloma cases and 1,934 controls ascertained in the context of the International Multiple Myeloma rESEarch ( IMMEnSE ) consortium , and meta-analyzed our results with previously published ones . RESULTS : None of the selected SNPs were significantly associated with multiple myeloma risk ( P value range , 0.055-0.981 ) , possibly with the exception of the SNP rs2227667 ( P05121 ) in women . CONCLUSIONS : We can exclude that the selected polymorphisms are major multiple myeloma risk factors . Q9P2X3 : Independent validation studies are crucial to identify true genetic risk factors . Our large-scale study clarifies the role of previously published polymorphisms in multiple myeloma risk . Production of paired helical filament , tau-like proteins by PC12 cells : a model of neurofibrillary degeneration . Neuron-like cells derived from a rat pheochromocytoma cell line ( PC12 ) and differentiated with nerve growth factor produce a paired helical filament ( PHF ) -like antigen when they are subjected to heat shock ( Wallace et al. : Mol Brain Res 19:149-155 , 1993 ) . It accumulates in a localized region of the perinuclear cytoplasm and reacts with monoclonal antitau antibodies , which identify epitopes in the N- and C-terminal halves and the microtubule-binding domain of tau protein . The observed profile of immunoreactivity suggests the presence of full-length and C-terminally truncated tau in a region of perinuclear cytoplasm in which no structurally intact PHFs could be demonstrated by conventional transmission electron microscopy . The accumulated tau protein colocalized with antibodies raised against mitochondrial outer membrane proteins and was associated with the presence of numerous mitochondrial profiles that were demonstrated with electron microscopy . Because differentiated PC12 cells pretreated with colcemid or DB01229 prior to heat shock fail to exhibit perinuclear PHF-like immunoreactivity , the reported response to heat shock appears to require an intact system of intracellular microtubules . This PC12 system provides a model in which the metabolic and molecular biological underpinnings of neuronal degeneration in Alzheimer 's disease can be manipulated . The system may eventually be applicable to the development of pharmaceutical agents that interfere with formation and/or degeneration of P10636 in Alzheimer 's disease . 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 . Neuroprotective gene expression profiles in ischemic cortical cultures preconditioned with DB01277 or P09038 . The mechanisms underlying growth factor preconditioning of neurons are only partially elucidated , and no studies have been conducted in this area using a gene profiling approach . We used cDNA microarrays to compare the transcriptional profiles of cells preconditioned either with insulin-like growth factor I ( DB01277 ) or basic fibroblast growth factor ( P09038 ) , to identify differentially regulated genes that may function in growth factor signaling , response to oxygen-glucose deprivation ( OGD ) , and most importantly , cell survival . Primary rat cortical cultures were treated with P09038 or DB01277 for 2 , 24 , or 24 h followed by OGD for 90 min , and compared with cells that were subject to OGD without growth factor pretreatment . Although the majority of surveyed genes were unchanged in all experimental treatments , 175 genes ( 10 % of the cDNAs on the chip ) were found to be differentially regulated in at least one of the treatment conditions . Hierarchical clustering of these 175 genes was used to identify four expression clusters : DB01277 regulated , P09038 regulated , OGD regulated , and putative neuroprotective genes . Further analysis using realtime RT-PCR confirmed that we had identified genes that are regulated by single growth factors , as well as several more that are co-regulated by both DB01277 and P09038 . These genes can influence neuronal survival by affecting diverse pathways such as growth factor signal transduction ( P16070 , Q99075 , Q16828 , Q12929 , P17936 ) , DNA repair and transcription ( Q92949 ) , metabolic homeostasis ( P20936 , P34897 ) , cytoskeletal stability ( P26038 , P10636 ) and cholesterol biosynthesis ( P37268 , P14324 ) . Extracellular P10415 proteins are danger-associated molecular patterns that reduce tissue damage in murine models of ischemia-reperfusion injury . BACKGROUND : Ischemia-reperfusion ( I/R ) injury contributes to organ dysfunction in a variety of clinical disorders , including myocardial infarction , stroke , organ transplantation , and hemorrhagic shock . Recent investigations have demonstrated that apoptosis as an important mechanism of cell death leading to organ dysfunction following I/R . Intracellular danger-associated molecular patterns ( DAMPs ) released during cell death can activate cytoprotective responses by engaging receptors of the innate immune system . METHODOLOGY/PRINCIPAL FINDINGS : Ischemia was induced in the mouse hind limb by tourniquet or in the heart by coronary artery ligation . Reperfusion injury of skeletal or cardiac muscle was markedly reduced by intraperitoneal or subcutaneous injection of recombinant human (rh) P10415 protein or rhBCL2-related protein A1 ( Q16548 ) ( 50 ng/g ) given prior to ischemia or at the time of reperfusion . The cytoprotective activity of extracellular rhBCL2 or rhBCL2A1 protein was mapped to the BH4 domain , as treatment with a mutant P10415 protein lacking the BH4 domain was not protective , whereas peptides derived from the BH4 domain of P10415 or the BH4-like domain of Q16548 were . Protection by extracellular rhBCL2 or rhBCL2A1 was associated with a reduction in apoptosis in skeletal and cardiac muscle following I/R , concomitant with increased expression of endogenous mouse P10415 ( mBCL2 ) protein . Notably , treatment with rhBCL2A1 protein did not protect mice deficient in toll-like receptor-2 ( O60603 ) or the adaptor protein , myeloid differentiation factor-88 ( MyD88 ) . CONCLUSIONS/SIGNIFICANCE : Treatment with cytokine-like doses of rhBCL2 or rhBCL2A1 protein or BH4-domain peptides reduces apoptosis and tissue injury following I/R by a O60603 -MyD88-dependent mechanism . These findings establish a novel extracellular cytoprotective activity of P10415 BH4-domain proteins as potent cytoprotective DAMPs .