interacts_with DB00863?
P25021 overexpression induces U937 cell differentiation despite triggered mechanisms to attenuate DB02527 signalling . Knowing that cell-surface receptors that recognize and respond to extracellular stimuli are key components for the regular communication between individual cells required for the survival of any living organism , the aim of the present work was to investigate the effect of P25021 overexpression on the U937 signal transduction pathway and its consequences on cell proliferation and differentiation . The overexpression of P25021 led to an increase in DB02527 basal levels , a leftward shift of agonist concentration-response curves , and similar maximal response to agonist treatment , suggesting that overexpressed H2Rs act as functional spare receptors . In this system cells triggered several mechanisms tending to restore DB02527 basal levels to those of the naïve cells . P25021 overexpression induced PDE activity stimulation and P25098 overexpression . In spite of the onset of these regulatory mechanisms , H2 agonist and rolipram treatments induced the terminal differentiation of the P25021 overexpressed clone , conversely to the naïve cells . Present findings show that stably P25021 overexpression alters DB02527 signalling as the result of not only the amounts of second messenger generated but also the activation or upregulation of various components of signalling cascade , leading to an adapted biologically unique system . This adaptation may represent an advantage or a disadvantage , depending on the biological system , but in any case , the existence of compensatory mechanisms should be considered when a clinical treatment is designed . Death receptors 4 and 5 activate Nox1 NADPH oxidase through riboflavin kinase to induce reactive oxygen species-mediated apoptotic cell death . Stimulation of the proapoptotic tumor necrosis factor ( P01375 ) -related apoptosis-inducing ligand ( P50591 ) receptors , death receptors 4 ( DR4 ) and 5 ( DR5 ) , conventionally induces caspase-dependent apoptosis in tumor cells . Here we report that stimulation of DR4 and/or DR5 by the agonistic protein KD548-Fc , an Fc-fused DR4/DR5 dual-specific Kringle domain variant , activates plasma membrane-associated Nox1 NADPH oxidase to generate superoxide anion and subsequently accumulates intracellular reactive oxygen species ( ROS ) , leading to sustained c-Jun N-terminal kinase activation and eventual apoptotic cell death in human HeLa and Jurkat tumor cells . KD548-Fc treatment induces the formation of a DR4/DR5 signaling complex containing riboflavin kinase ( Q969G6 ) , Nox1 , the Nox1 subunits ( Rac1 , Noxo1 , and Noxa1 ) , P01375 receptor-associated death domain ( Q15628 ) , and Q12933 ( TRAF2 ) . Depletion of Q969G6 , but not the Nox1 subunits , Q15628 and TRAF2 , failed to recruit Nox1 and Rac1 to DR4 and DR5 , demonstrating that Q969G6 plays an essential role in linking DR4/DR5 with Nox1 . Knockdown studies also reveal that Q969G6 , Q15628 , and TRAF2 play critical , intermediate , and negligible roles , respectively , in the KD548-Fc-mediated ROS accumulation and downstream signaling . Binding assays using recombinantly expressed proteins suggest that DR4/DR5 directly interact with cytosolic Q969G6 through Q969G6 -binding regions within the intracellular death domains , and Q15628 stabilizes the DR4/DR5- Q969G6 complex . Our results suggest that DR4 and DR5 have a capability to activate Nox1 by recruiting Q969G6 , resulting in ROS-mediated apoptotic cell death in tumor cells . Genetic and epigenetic markers in the evaluation of pancreatic masses . BACKGROUND : Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma . The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with P01116 mutation detection in the evaluation of pancreatic masses . EXPERIMENTAL DESIGN : Sixty-one fine needle aspirates of pancreatic masses ( 43 pancreatic adenocarcinomas and 18 chronic pancreatitis ) were studied . Methylation status of P25021 , Q05925 , P09486 , P55290 and P25054 were analysed using melting curve analysis after DNA bisulfite treatment . P01116 mutations were also analysed . RESULTS : The methylation panel had a sensitivity of 73 % ( 27 of 37 , CI 95 % 56 to 86 % ) and a specificity of 100 % whenever two or more promoters were found hypermethylated . P01116 mutations showed a sensitivity of 77 % ( 33 of 43 , CI 95 % 62 to 88 % ) and a specificity of 100 % . Both molecular analyses added useful information to cytology by increasing the number of informative cases . When genetic and epigenetic analyses were combined sensitivity was 84 % ( 36 of 43 CI 95 % 69 to 93 % ) maintaining a 100 % specificity . CONCLUSIONS : Analysis of hypermethylation status of a panel of genes and P01116 mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses . The combined molecular analysis increases the number of informative cases without diminishing specificity . Inhibitor of G protein-coupled receptor kinase 2 normalizes vascular endothelial function in type 2 diabetic mice by improving β-arrestin 2 translocation and ameliorating Akt/ P29474 signal dysfunction . In type 2 diabetes , although Akt/endothelial NO synthase ( P29474 ) activation is known to be negatively regulated by G protein-coupled receptor kinase 2 ( P25098 ) , it is unclear whether the P25098 inhibitor would have therapeutic effects . Here we examined the hypotensive effect of the P25098 inhibitor and its efficacy agonist both vascular ( aortic ) endothelial dysfunction ( focusing especially on the Akt/ P29474 pathway ) and glucose intolerance in two type 2 diabetic models ( ob/ob mice and nicotinamide+streptozotocin-induced diabetic mice ) . Mice were treated with a single injection of the P25098 inhibitor or vehicle , and the therapeutic effects were compared by examining vascular function and by Western blotting . The P25098 inhibitor lowered blood pressure in both diabetic models but not in their age-matched controls . The P25098 inhibitor significantly improved clonidine-induced relaxation only in diabetic ( ob/ob and DM ) mice , with accompanying attenuations of P25098 activity and translocation to the plasma membrane . These protective effects of the P25098 inhibitor may be attributable to the augmented Akt/ P29474 pathway activation ( as evidenced by increases in Akt phosphorylation at DB00133 (473) and at DB00156 (308) , and P29474 phosphorylation at DB00133 (1177) ) and to the prevention of the P25098 translocation and promotion of β-arrestin 2 translocation to the membrane under clonidine stimulation . Moreover , the P25098 inhibitor significantly improved the glucose intolerance seen in the ob/ob mice . Our work provides the first evidence that in diabetes , the P25098 inhibitor ameliorates vascular endothelial dysfunction via the Akt/ P29474 pathway by inhibiting P25098 activity and enhancing β-arrestin 2 translocation under clonidine stimulation , thereby contributing to a blood pressure-lowering effect . We propose that the P25098 inhibitor may be a promising therapeutic agent for cardiovascular complications in type 2 diabetes . DB11320 reduces susceptibility to natural killer cells via down-regulation of P26718 ligands on human monocytic leukaemia THP-1 cells . Natural killer ( NK ) group 2D ( P26718 ) is a key activating receptor expressed on NK cells , whose interaction with ligands on target cells plays an important role in tumorigenesis . However , the effect of histamine on P26718 ligands on tumour cells is unclear . Here we showed that human monocytic leukaemia THP-1 cells constitutively express MHC class I-related chain A ( Q29983 ) and Q9BZM6 on their surface , and incubation with histamine reduced the expression in a dose-dependent and time-dependent manner as assessed by flow cytometry . Interferon-γ augmented the surface expression of the P26718 ligands , and this augmentation was significantly attenuated by histamine . The histamine H1 receptor ( P35367 ) agonist 2-pyridylethylamine and P25021 agonist dimaprit down-regulated the expression of P26718 ligands , and activation of P35367 and P25021 signalling by A23187 and forskolin , respectively , had the same effect , indicating that the histamine-induced down-regulation of P26718 ligands is mediated by P35367 and P25021 . Quantitative reverse transcription-PCR showed that mRNA levels of the P26718 ligands and relevant microRNAs were not significantly changed by histamine . DB11320 down-regulated the surface expression of endoplasmic reticulum protein 5 , and inhibition of matrix metalloproteinases did not impair this down-regulation , indicating that proteolytic shedding was not involved . Instead , pharmacological inhibition of protein transport and proteasome abrogated it , and histamine enhanced ubiquitination of Q29983 . Furthermore , histamine treatment significantly reduced susceptibility to NK cell-mediated cytotoxicity . These results suggest that histamine down-regulates P26718 ligands through the activation of an P35367 - and P25021 -mediated ubiquitin-proteasome pathway and consequently reduces susceptibility to NK cells . Clinical and genetic factors associated with nausea and vomiting in cancer patients receiving opioids . BACKGROUND : This study investigates whether demographical , disease-related and genetic factors contribute to inter-individual differences in nausea and vomiting among patients receiving opioids for cancer pain . METHODS : Cancer patients receiving opioids were included from 17 centres in 11 European countries . Intensities of nausea and vomiting were reported by 1579 patients on four-point categorical scales . In stratified regression models including demographical and disease-related factors as covariates , 96 single nucleotide polymorphisms ( SNPs ) in 16 candidate genes related to opioid- or nausea/vomiting signalling pathways ( P08183 , P35372 , P41145 , P32121 , P42226 , P21964 , P20309 , P08912 , P35367 , P14416 , P35462 , P25103 , P46098 , O95264 , Q8WXA8 , P21554 ) were analysed for association with nausea and vomiting . FINDINGS : Age , body mass index , Karnofsky Performance Status , gender , use of antiemetics , type of opioid , type of cancer and eight SNPs were associated with the inter-individual differences in nausea and vomiting among cancer patients treated with opioids ( p < 0.01 ) . The SNPs were rs1176744 , rs3782025 and rs1672717 in O95264 ; rs165722 , rs4680 and rs4633 in P21964 ; rs10802789 and rs685550 in P20309 . Only the SNP rs1672717 in O95264 passed the Benjamini-Hochberg criterion for a 10 % false discovery rate . INTERPRETATION : Clinical characteristics and SNPs within the O95264 , P21964 and P20309 genes may be associated with the variability in nausea and vomiting among cancer patients receiving opioids . This knowledge may help to identify patients at particular risk for nausea and vomiting during treatment with opioids for cancer pain . Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4-methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol-HRP-H2O2 based CL ) . KEY FINDINGS : DB11320 , 4-methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP-activated whole blood CL in a dose-dependent manner . On the other hand , only VUF8430 was able to inhibit PMA-activated whole blood CL . DB00863 , but not JNJ10191584 , completely reduced the effects of histamine , 4-methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10(-6)M may also influence ROS production via binding to P25021 . Granulocyte macrophage-colony stimulating factor increases the expression of histamine and histamine receptors in monocytes/macrophages in relation to arteriosclerosis . OBJECTIVE : To study the effect of granulocyte macrophage-colony-stimulating factor ( GM- P04141 ) on histamine metabolism in arteriosclerosis , the expression of histidine decarboxylase ( HDC ; histamine-producing enzyme ) , histamine receptors 1 and 2 ( P35367 and P25021 ) , and GM- P04141 was investigated in human and mouse arteriosclerotic carotid arteries . Furthermore , the molecular mechanisms of GM- P04141 -induced HDC and P35367 expression in monocytic U937 cells were investigated . METHODS AND RESULTS : Immunohistochemistry showed that atherosclerotic human coronary and mouse ligated carotid arteries contained HDC-expressing macrophages . Gene expression of HDC , P35367 , P25021 , and GM- P04141 was also detected in the lesions . In U937 cells , GM- P04141 enhanced histamine secretion and gene expression of HDC and P35367 . A promoter assay showed that GM- P04141 enhanced gene transcription of HDC and P35367 but not P25021 . CONCLUSIONS : The present results indicate that HDC and HHR are expressed in arteriosclerotic lesion , and that GM- P04141 induces HDC and P35367 expression in monocytes . Locally produced histamine might participate in atherogenesis by affecting the expression of atherosclerosis-related genes in monocytes and smooth muscle cells . The presence of histamine-producing macrophages and gene expression of histamine receptors and GM- P04141 was demonstrated in arteriosclerotic lesions . In monocytic U937 cells , GM- P04141 upregulated the expression of histamine and P35367 . Coordinated expression of histamine and its receptors by GM- P04141 would participate in atherogenesis by affecting monocytic and SMC gene expression . Rectal antinociceptive properties of alverine citrate are linked to antagonism at the P08908 receptor subtype . Serotonin ( 5-HT ) is considered as a major mediator causing hyperalgesia and is involved in inflammatory reactions and irritable bowel syndrome . DB01616 citrate may possess visceral antinociceptive properties in a rat model of rectal distension-induced abdominal contractions . This study was designed to evaluate the pharmacological properties of alverine citrate in a rat model of rectal hyperalgesia induced by 5-HTP ( 5-HT precursor ) and by a selective P08908 agonist ( 8-OH-DPAT ) and to compare this activity with a reference P08908 antagonist ( WAY 100635 ) . At 4 h after their administration , 5-HTP and 8-OH-DPAT increased the number of abdominal contractions in response to rectal distension at the lowest volume of distension ( 0.4 mL ) . When injected intraperitoneally before 8-OH-DPAT and 5-HTP , WAY 100635 ( 1 mg kg(-1) ) blocked their nociceptive effect , but also reduced the response to the highest volume of distension ( 1.6 mL ) . Similarly , when injected intraperitoneally , alverine citrate ( 20 mg kg(-1) ) suppressed the effect of 5-HTP , but not that of 8-OH-DPAT . However , when injected intracerebroventricularly ( 75 microg/rat ) alverine citrate reduced 8-OH-DPAT-induced enhancement of rectal distension-induced abdominal contractions . In-vitro binding studies revealed that alverine citrate had a high affinity for P08908 receptors and a weak affinity for 5- Q9H205 and Q13639 subtypes . These results suggest that 5-HTP-induced rectal hypersensitivity involves 5-TH1A receptors and that alverine citrate acts as a selective antagonist at the P08908 receptor subtype to block both 5-HTP and 8-OH-DPAT-induced rectal hypersensitivity . Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders . Methylphenidate ( DB00422 ) reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders ( ASDs ) , however , response and tolerability varies widely . We hypothesized monoaminergic gene variants may moderate DB00422 effects in P51689 , as in typically developing children with attention-deficit/hyperactivity disorder . Genotype data were available for 64 children with P51689 and hyperactivity who were exposed to DB00422 during a 1-week safety/tolerability lead-in phase and 58 who went on to be randomized to placebo and three doses of DB00422 during a 4-week blinded , crossover study . Outcome measures included the Clinical Global Impression-Improvement ( CGI-I ) scale and the Aberrant Behavior Checklist ( ABC-hyperactivity index ) . A total of 14 subjects discontinued the study because of DB00422 side effects . Subjects were genotyped for variants in P21728 - P21918 , P08913 , Q01959 , P31645 , P21397 and P27338 , and P21964 . Forty-nine percent of the sample met positive responder criteria . In this modest but relatively homogeneous sample , significant differences by P21728 ( P=0.006 ) , P08913 ( P < 0.02 ) , P21964 ( P < 0.04 ) , P35462 ( P < 0.05 ) , P21917 ( P < 0.05 ) , Q01959 ( P < 0.05 ) and P31645 ( P < 0.05 ) genotypes were found for responders versus non-responders . Variants in P14416 ( P < 0.001 ) and P35462 ( P < 0.04 ) were associated with tolerability in the 14 subjects who discontinued the trial . For this first DB00422 pharmacogenetic study in children with P51689 , multiple monoaminergic gene variants may help explain individual differences in DB00422 's efficacy and tolerability . DB08896 for treatment of advanced gastrointestinal stromal tumors . INTRODUCTION : Gastrointestinal stromal tumors ( GISTs ) are abdominal sarcomas which are extremely refractory to chemotherapy treatment . The treatment of GISTs has been revolutionized by use of P10721 /platelet-derived growth factor receptor-α ( P16234 ) kinase inhibitors . Unfortunately , most tumors develop resistance to front-line ( imatinib ) or second-line ( sunitinib ) therapy . DB08896 , a P10721 / P16234 /vascular endothelial growth factor receptor ( VEGFR ) oral kinase inhibitor , has been shown to improve progression-free survival in the third- or fourth-line setting . AREAS COVERED : This review covers the preclinical and clinical studies of regorafenib for treatment of GIST . A literature search on regorafenib was carried out using the PubMed database up to October 2013 . EXPERT OPINION : Currently , imatinib and sunitinib represent the only proven first- and second-line therapies , respectively , for advanced GISTs . Based on the results of a Phase III study , regorafenib is now established as the only proven third-line therapy . DB08896 activity in this setting is believed to be due to its activity against oncogenic forms of P10721 / P16234 . Although side effects are common with this agent , they can be effectively managed with a combination of supportive care , dose interruptions/reductions . The toxicity profile is similar to other oral kinase inhibitors with anti-VEGFR activity . DB08896 is mainly metabolized by P08684 , and concomitant use of strong inducers/inhibitors of this enzyme should be avoided . Pharmacological profile of astemizole-derived compounds at the histamine H1 and H4 receptor -- H1/H4 receptor selectivity . DB00637 , a P35367 antagonist shows high affinity to the histamine H1 receptor but only a moderate affinity to the histamine H4 receptor . This study aims to modify the astemizole to keep high affinity to the histamine H1 receptor and to increase affinity to the histamine H4 receptor . Therefore , 13 astemizole-derived compounds and astemizole-JNJ7777120-derived hybrid compounds were synthesized and pharmacologically characterized at the histamine H1 and H4 receptors . The new compounds show affinity to the histamine H1 receptor in the pK i range from 5.3 to 8.8 , whereas the affinity of these compounds to the histamine H4 receptor was surprisingly rather low ( pK i from 4.4 to 5.6 ) . Three representative compounds were docked into the histamine H1 receptor and molecular dynamic studies were performed to explain the binding mode and the experimental results on a molecular level . Furthermore , taking into account the binding mode of compounds with high affinity to the histamine H4 receptor , a H1/H4-pharmacophore hypothesis was developed . Protective roles of epithelial cells in the survival of adult T-cell leukemia/lymphoma cells . Adult T-cell leukemia/lymphoma ( ATL ) is a highly invasive and intractable T-cell malignancy caused by human T-cell leukemia virus-1 infection . We demonstrate herein that normal tissue-derived epithelial cells ( NECs ) exert protective effects on the survival of leukemic cells , which may partially account for high resistance to antileukemic therapies in patients with ATL . Viral gene-silenced , ATL-derived cell lines ( ATL cells ) dramatically escaped from histone deacetylase inhibitor-induced apoptosis by direct co-culture with NECs . Adhesions to NECs suppressed P38936 (Cip1) expression and increased a proportion of resting G0/ P55008 phase cells in trichostatin A ( P32119 ) -treated ATL cells . ATL cells adhering to NECs down-regulated CD25 expression and enhanced vimentin expression , suggesting that most ATL cells acquired a quiescent state by cell-cell interactions with NECs . ATL cells adhering to NECs displayed highly elevated expression of the cancer stem cell marker P16070 . Blockade of P16070 signaling diminished the NEC-conferred resistance of ATL cells to P32119 -induced apoptosis . Co-culture with NECs also suppressed the expression of P26718 ligands on P32119 -treated ATL cells , resulting in decreased natural killer cell-mediated cytotoxicity . Combined evidence suggests that interactions with normal epithelial cells augment the resistance of ATL cells to P32119 -induced apoptosis and facilitate immune evasion by ATL cells . Pulmonary hypertension in the newborn P30793 -deficient mouse . DB00360 ( BH4 ) is a regulator of endothelial nitric oxide synthase ( P29474 ) activity . Deficient levels result in P29474 uncoupling , with a shift from nitric oxide to superoxide generation . The hph-1 mutant mouse has deficient P30793 ( GTPCH1 ) activity , resulting in low BH4 tissue content . The adult hph-1 mouse has pulmonary hypertension , but whether such condition is present from birth is not known . Thus , we evaluated newborn animals ' pulmonary arterial medial thickness , biopterin content ( BH4+BH2 ) , H(2)O(2) and P29474 , right ventricle-to-left ventricle+septum ( RV/LV+septum ) ratio , near-resistance pulmonary artery agonist-induced force , and endothelium-dependent and -independent relaxation . The lung biopterin content was inversely related to age for both types , but significantly lower in hph-1 mice , compared to wild-type animals . As judged by the RV/LV+septum ratio , newborn hph-1 mice have pulmonary hypertension and , after a 2-week 13 % oxygen exposure , the ratios were similar in both types . The pulmonary arterial agonist-induced force was reduced ( P < 0.01 ) in hph-1 animals and no type-dependent difference in endothelium-dependent or -independent vasorelaxation was observed . Compared to wild-type mice , the lung H(2)O(2) content was increased , whereas the P29474 expression was decreased ( P < 0.01 ) in hph-1 animals . The pulmonary arterial medial thickness , a surrogate marker of vascular remodeling , was increased ( P < 0.01 ) in hph-1 compared to wild-type mice . In conclusion , our data suggest that pulmonary hypertension is present from birth in the GTPCH1-deficient mice , not as a result of impaired vasodilation , but secondary to vascular remodeling . Regulation of the natural killer cell response to interferon-alpha by biogenic amines . Monocytes , recovered from human peripheral blood by counter-current centrifugal elutriation ( CCE ) , suppressed baseline natural killer ( NK ) cell cytotoxicity ( NKCC ) and rendered NK cells resistant to activation of cytotoxicity by human recombinant interferon-alpha ( IFN-alpha ) by a cell contact-dependent mechanism . Monocyte-induced suppression of resting and IFN-activated NK cells was abrogated by the biogenic amines histamine [ via H2-type receptors ( P25021 ) ] and serotonin [ via P08908 -type receptors ( 5-HT1AR ) ] . Our data are suggestive of a monocyte/NK cell interaction that is subject to regulation by biogenic amines . A novel inhibitory mechanism of nitrogen-containing bisphosphonate on the activity of Cl- extrusion in osteoclasts . DB09152 -containing bisphosphonates have been well known to be inhibited farnesyl diphosphate synthase ( P14324 ) , an enzyme in mevalonic acid metabolism , resulting in disturbance in polymerization of cytoskeleton structure in bone resorption and promotion of apoptosis in mature osteoclasts . Although bisphosphonates have been reported to activate ion transporters in native epithelium and Xenopus oocytes , little is known whether bisphosphonates affect acid hydrochronic acid extrusion in osteoclasts during bone resorption . The aim of this study was to determine the role of bisphosphonates on inhibition of hydrochronic acid extrusion in osteoclasts . Effects of zoledronic acid , a nitrogen-containing bisphosphonate , on the Cl(-) current activated by extracellular acidification were examined in two types of osteoclasts derived from RAW264.7 cells and mouse bone marrow macrophages ( BMMs ) . Extracellular acidification induced outwardly rectifying Cl(-) currents in mouse osteoclasts . DB00399 dose-dependently inhibited the acid-activated Cl(-) current . The non-nitrogen bisphosphonate etidronic acid had no effect on the acid-activated Cl(-) current . DB00759 -induced P14324 silencing caused a significant decrease in the Cl(-) current . The inhibitor of geranylgeranyl transferase suppressed the Cl(-) current . By contrast , the inhibitory action of zoledronic acid was rescued by addition of geranylgeranyl acid , a derivative of mevalonic acid . The activity of acid-activated Cl(-) currents was dependent on expression of P51798 during osteoclastogenesis . These results suggest that nitrogen-containing bisphosphonates suppress the activity of osteoclastic acid-activated Cl(-) currents through P14324 inhibition , suggesting the inhibition of Cl(-) extrusion activity . Key residues at the riboflavin kinase catalytic site of the bifunctional riboflavin kinase/ Q8NFF5 from Corynebacterium ammoniagenes . Many known prokaryotic organisms depend on a single bifunctional enzyme , encoded by the RibC of RibF gene and named DB03147 synthetase ( FADS ) , to convert DB00140 ( RF ) , first into Q68DA7 and then into DB03147 . The reaction occurs through the sequential action of two activities present on a single polypeptide chain where the N-terminus is responsible for the DB00171 : Q8NFF5 ( FMNAT ) activity and the C-terminus for the DB00171 : riboflavin kinase ( Q969G6 ) activity . Sequence and structural analysis suggest that T208 , N210 and E268 at the C-terminus Q969G6 module of Corynebacterium ammoniagenes FADS ( CaFADS ) might be key during RF phosphorylation . The effect of site-directed mutagenesis on the Q969G6 activity , as well as on substrates and products binding , indicates that T208 and N210 provide the Q969G6 active-site geometry for binding and catalysis , while E268 might be involved in the catalytic step as catalytic base . These data additionally suggest concerted conformational changes at the Q969G6 module of CaFADS during its activity . Mutations at the Q969G6 site also modulate the binding parameters at the FMNAT active site of CaFADS , altering the catalytic efficiency in the transformation of Q68DA7 into DB03147 . This observation supports the hypothesis that the hexameric assembly previously revealed by the crystal structure of CaFADS might play a functional role during catalysis . P04141 -1 ( P09603 ) delivers a proatherogenic signal to human macrophages . P09603 / P09603 supports the proliferation and differentiation of monocytes and macrophages . In mice , P09603 also promotes proinflammatory responses in vivo by regulating mature macrophage functions , but little is known about the acute effects of this growth factor on mature human macrophages . Here , we show that in contrast to its effects on mouse bone marrow-derived macrophages , P09603 did not induce expression of urokinase plasminogen activator mRNA , repress expression of apolipoprotein E mRNA , or prime LPS-induced P01375 and P05231 secretion in human monocyte-derived macrophages ( HMDM ) from several independent donors . Instead , we show by expression profiling that P09603 modulates the HMDM transcriptome to favor a proatherogenic environment . P09603 induced expression of the proatherogenic chemokines P02778 /IFN-inducible protein 10 , P13500 , and P80098 but repressed expression of the antiatherogenic chemokine receptor P61073 . P09603 also up-regulated genes encoding enzymes of the cholesterol biosynthetic pathway ( P04035 , P53602 , Q13907 , P14324 , Q14534 , Q16850 , EBP , Q15738 , Q9UBM7 , and Q15392 ) , and expression of P45844 , encoding a cholesterol efflux transporter , was repressed . Consistent with these effects , P09603 increased levels of free cholesterol in HMDM , and the selective P07333 kinase inhibitor GW2580 ablated this response . These data demonstrate that P09603 represents a further link between inflammation and cardiovascular disease and suggest two distinct mechanisms by which P09603 , which is known to be present in atherosclerotic lesions , may contribute to plaque progression . Expression and mutational status of treatment-relevant targets and key oncogenes in 123 malignant salivary gland tumours . BACKGROUND : Malignant tumours of the salivary glands ( MSGT ) are rare and pleomorphic entities . Patients with advanced disease may benefit from targeted therapy ; however , specific targets for optimising and personalising treatments are yet to be identified . DESIGN : Immunohistochemistry for C- P10721 , P00533 , P04626 , P15941 , phospho- P42345 , androgen/estrogens/progesterone receptors and Ki67 was carried out and evaluated in terms of progression-free and overall survival . High throughput molecular screening of key oncogenes was done in 107 patients using routine diagnostic methods and Sequenom technology . RESULTS : Several therapy leads were identified , including high levels of P04626 and androgen receptors in salivary duct carcinomas , C- P10721 in myoepithelial carcinomas and P00533 in mucoepidermoid carcinomas . Recurrent mutations involving downstream elements of the P00533 pathway were found in P01112 , notably in tumours with a myoepithelial component , and in other key oncogenes ( P01116 / P01111 /PI3KCA/ P15056 /MAP2K ) . On the other hand , < 1 % of samples had P00533 or P04626 mutations . CONCLUSION : Several tumour subtypes overexpressed targets of directed therapies suggesting potential therapy leads . Genotyping results suggest activation downstream of P00533 in 18 of the 107 samples that could be associated with low efficacy of P00533 inhibitors . Other molecules , such as PI3K/MEK or P42345 inhibitors , may have anti-tumour activity in this subgroup . The high mutation rate in P01112 highlights a novel key oncogenic event in MSGT . Enhanced goblet cell hyperplasia in HDC knockout mice with allergic airway inflammation . BACKGROUND : DB11320 is known to have immunoregulatory roles in allergic reactions through histamine receptor 1 ( P35367 ) , P25021 , Q9Y5N1 and Q9H3N8 . However , its role in goblet cell hyperplasia in the airways of asthma patients is yet to be clarified . OBJECTIVE : This study was designed to examine the role of histamine in goblet cell hyperplasia using histamine-deficient mice ( Hdc-/- mice ) with allergic airway inflammation . METHODS : Wild-type and Hdc-/- C57BL/6 mice were sensitized with ovalbumin ( OVA ) . After a 2-week exposure to OVA , goblet cell hyperplasia was evaluated . Cell differentials and cytokines in BALF were analyzed . The mRNA levels of P98088 and Gob-5 gene were determined quantitatively . RESULTS : The number of eosinophils in BALF increased in both the sensitized wild-type mice and Hdc-/- mice with OVA inhalation . In addition , the numbers of alveolar macrophages and lymphocytes in BALF increased significantly in the sensitized Hdc-/- mice with OVA inhalation compared to the wild-type mice under the same conditions . The concentrations of P05112 ( P05112 ) , P05113 , P35225 , Interferon-gamma ( P01579 ) , tumor necrosis factor-alpha ( P01375 ) and P60568 in the BALF all increased significantly in both groups compared to those exposed to saline . In particular , the concentration of P01375 in the Hdc-/- mice exposed to OVA was significantly higher than that in the wild-type mice under the same conditions . The mRNA levels of Gob-5 and P98088 , and the ratio of the goblet cells in the airway epithelium significantly increased in Hdc-/- mice exposed to OVA compared to wild-type mice . CONCLUSIONS : These results suggested that histamine may play a regulatory role in goblet cell hyperplasia in allergic airway inflammation . Serial changes in serum vitamin P04264 , triglyceride , cholesterol , osteocalcin and 25-hydroxyvitamin D3 in patients after hip replacement for fractured neck of femur or osteoarthritis . Serum vitamin P04264 concentrations were measured at presentation ( just before surgery ) and then at weekly intervals for 3 weeks in two groups of elderly patients requiring either hemiarthroplasty for fractured neck of femur ( FON , n = 13 ) or total hip replacement for osteoarthritis of the hip ( OA , n = 16 ) . In comparison with healthy elderly volunteers ( n = 25 ) , serum vitamin P04264 concentrations were significantly lower in both groups at presentation , and fell significantly within 24 h after surgery to concentrations approaching non-detectable , subsequently returning to pre-operative values within 3 weeks . Serum vitamin P04264 tended to be lower in the fracture group both before and after operation , although calculation of a vitamin P04264 -triglyceride ratio reduced the apparent difference as triglyceride concentrations were lower in the fracture group . P02818 concentrations were similar and fell significantly after operation in both groups , returning to pre-operative levels within 7 days . No differences in the two forms of osteocalcin ( carboxylated and undercarboxylated ) were observed either before or after operation in either group . DB00146 concentrations were not significantly different between the two groups at any time . DB01022 status may be lower than desirable in certain groups of the elderly population , and supplementation should be considered as prophylactic therapy . beta-Carotene induces apoptosis and up-regulates peroxisome proliferator-activated receptor gamma expression and reactive oxygen species production in MCF-7 cancer cells . Although the pharmacological role of beta-carotene in the prevention and treatment of many cancer cells has received increasing attention , the molecular mechanisms underlying such chemopreventive activity are not clear . Since peroxisome proliferator-activated receptor gamma ( P37231 ) has been implicated in regulating breast cancer cell differentiation and apoptosis , the effects of beta-carotene on the P37231 -mediated pathway and its association with reactive oxygen species production in MCF-7 cells were investigated in the present study . The results demonstrated that beta-carotene significantly increased P37231 mRNA and protein levels in time-dependent manner . In addition , beta-carotene increased the cyclin-dependent kinase inhibitor P38936 ( P38936 /CIP1) expression and decreased the prostanoid synthesis rate-limiting enzyme cyclooxygenase-2 expression . DB07863 ( GW9662 ) , an irreversible P37231 antagonist , partly attenuated the cell death caused by beta-carotene . Further , reactive oxygen species ( ROS ) production was induced by beta-carotene , resulting in mitochondrial dysfunction and cytochrome C release . DB00143 ( DB00143 ) treatment decreases the intracellular ROS and prevents cytochrome C release and cell apoptosis induced by beta-carotene . In total , these observations suggest that the synergistic effect of P37231 expression and ROS production may account for beta-carotene-mediated anticancer activities . A study of natural killer cell lectin-like receptor P04264 gene ( P26718 / P26718 ) region polymorphisms in a European population sample . Recent evidence has reinforced the belief in immunosurveillance as a powerful mechanism against cancer development . The natural killer ( NK ) cell has been recognized as a potent agent of cancer immunosurveillance . A Japanese cohort study correlated natural cytotoxic activity levels with subsequent cancer development and identified NK cell lectin-like receptor P04264 gene ( P26718 / P26718 ) polymorphisms as genetic markers of cancer predisposition . In the present study , we genotyped 82 reference cell lines and 388 newborn samples at 10 P26718 region variants by TaqMan ( ( R ) ) allelic discrimination assays and showed that the same polymorphisms occur at similar frequencies in Europeans . The same haplotype block that has been associated with lower natural cytotoxic activity also occurred with the highest frequency in our sample . We further detected evidence suggestive of natural selection at some of the loci analyzed and more importantly , sex specificity of this selection . It appeared that heterozygosity at loci forming a haplotype block was unfavorable for boys . Given the relevance of NK cells in fetal survival , this finding has potential implications in the study of genetics of maternofetal recognition . Our preliminary findings are of marginal statistical significance and should be replicated in a larger sample . We believe that our results will increase awareness of the involvement of P26718 in cancer immunosurveillance and possibly in prenatal selection .