interacts_with DB00266?
Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines/patients ' bone marrow samples ) untreated/treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 /proteosome dependent fragmentation ) ( WB , DB00266 , qPCR ) and targets (WB). eIF4GI was inhibited by knockdown and 4EGI-1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 /proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 /ERα/HIF1α/c-Myc ) . Finally , we showed that the small molecule 4EGI-1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention . Altered growth factor expression in the aging penis : the Brown-Norway rat model . The objective of the present study was to evaluate age-related changes in the protein and gene expression of modulators of erectile function ( nitric oxide [ NO ] and endothelin-1 [ ET-1 ] ) and growth factors such as transforming growth factor ( TGF-beta1 ) and vascular endothelial growth factor ( P15692 ) in the penile tissue of Brown-Norway ( BN ) rats . Young and old BN male rats were euthanized , and the penile tissue was processed for immunohistochemical and molecular analyses . Total RNA was extracted , and an Access reverse transcription-polymerase chain reaction ( RT-PCR ) system was used for messenger RNA ( mRNA ) expression analysis . Immunohistochemical studies showed a decreased expression of endothelial nitric oxide synthase ( P29474 ) protein and an increased staining for ET-1 . Quantitative analysis of PCR products revealed decreased levels of P15692 mRNA expression in the old population of rats . The most significant decrease was detected between bands corresponding to splice forms 164 ( 21 % ) and 120 ( 18 % ) . The observed alterations in the gene expression of growth factors such as P15692 may contribute to the abnormal age-related morphological and physiological alterations in the erectile tissue . P20711 inhibition does not influence the diuretic and natriuretic response to exogenous alpha-atrial natriuretic peptide in man . The role of dopamine synthesis in the renal actions of human alpha-atrial natriuretic peptide ( alpha P01160 ) was investigated in six dehydrated volunteers using the P20711 inhibitor carbidopa . Each subject received oral placebo or carbidopa ( 100 mg ) followed by an infusion of alpha P01160 10 pmol.kg-1.min-1 for 1 h . The responses to placebo alone and to carbidopa alone were investigated on separate occasions. alpha P01160 produced a similar increase in plasma immunoreactive alpha P01160 whether placebo or carbidopa pretreatment had been given . Urinary dopamine excretion was increased by alpha P01160 . DB00190 pretreatment substantially attenuated this increase without affecting the natriuretic or water-diuretic response to alpha P01160 . DB00190 also failed to alter the change in filtration fraction produced by alpha P01160 . The results suggest that increased synthesis of intrarenal dopamine is not required for the renal effects of alpha P01160 in man . Gene expression by PBMC in primary sclerosing cholangitis : evidence for dysregulation of immune mediated genes . Primary sclerosing cholangitis ( PSC ) is a chronic disease of the bile ducts characterized by an inflammatory infiltrate and obliterative fibrosis . The precise role of the immune system in the pathogenesis of PSC remains unknown . We used RNA microarray analysis to identify immune-related genes and pathways that are differentially expressed in PSC . Messenger RNA ( mRNA ) from peripheral blood mononuclear cells ( PBMC ) was isolated from both patients with PSC and age and sex matched healthy controls . Samples from 5 PSC patients and 5 controls were analyzed by microarray and based upon rigorous statistical analysis of the data , relevant genes were chosen for confirmation by RT-PCR in 10 PSC patients and 10 controls . Using unsupervised hierarchical clustering , gene expression in PSC was statistically different from our control population . Interestingly , genes within the P60568 receptor beta , P05231 and Q96HU1 Kinase pathways were found to be differently expressed in patients with PSC compared to controls . Further , individual genes , P01375 induced protein 6 ( TNFaip6 ) and membrane-spanning 4-domains , subfamily A ( ms4a ) were found to be upregulated in PSC while similar to Q99717 ( Q99717 ) was downregulated . In conclusion , several immune-related pathways and genes were differentially expressed in PSC compared to control patients , giving further evidence that this disease is systemic and immune-mediated . Transient estrogen exposure from birth affects uterine expression of developmental markers in neonatal gilts with lasting consequences in pregnant adults . Disruption of estrogen-sensitive , estrogen receptor ( ER ) -dependent events during porcine uterine development between birth ( postnatal day= P01160 0 ) and P01160 14 affects patterns of uterine morphoregulatory gene expression in the neonate with lasting consequences for reproductive success . Uterine capacity for conceptus support is reduced in pregnant adult gilts exposed to estradiol valerate ( EV ) for 14 days from birth . Objectives here were to determine effects of EV exposure from birth through P01160 13 on neonatal uterine and adult endometrial markers of growth , patterning , and remodeling . Targets included the relaxin receptor ( Q9HBX9 ) , estrogen receptor-alpha ( P03372 ) and vascular endothelial growth factor ( P15692 ) , morphoregulatory markers P31260 and O00755 , and the matrix metalloproteinases (MMP)2 and P14780 . Gilts were treated daily with EV ( 50 microg/kg body weight per day , i.m. ) or corn oil vehicle from birth through P01160 13 . Uteri were obtained from neonates on P01160 14 and from adults on pregnancy day 12 ( PxD 12 ) . In neonates , EV exposure from birth increased uterine Q9HBX9 gene expression , and both P03372 and P15692 proteins . At PxD 12 , endometrial Q9HBX9 mRNA remained elevated , while P03372 protein was reduced . Early EV treatment decreased neonatal uterine O00755 , but increased P31260 expression . O00755 expression was reduced in EV-treated adults . Transient EV exposure increased P14780 transcripts at P01160 14 , whereas both latent and active P14780 activity was increased due to early EV treatment in adults on PxD 12 . Results support the hypothesis that transient , estrogen-induced disruption of porcine uterine development from birth alters early programming events that lead to functional consequences in the adult . Global gene expression profiles of subcutaneous adipose and muscle from glucose-tolerant , insulin-sensitive , and insulin-resistant individuals matched for BMI . OBJECTIVE : To determine altered gene expression profiles in subcutaneous adipose and skeletal muscle from nondiabetic , insulin-resistant individuals compared with insulin-sensitive individuals matched for BMI . RESEARCH DESIGN AND METHODS : A total of 62 nondiabetic individuals were chosen for extremes of insulin sensitivity ( 31 insulin-resistant and 31 insulin-sensitive subjects ; 40 were European American and 22 were African American ) and matched for age and obesity measures . Global gene expression profiles were determined and compared between ethnic groups and between insulin-resistant and insulin-sensitive participants individually and using gene-set enrichment analysis . RESULTS : African American and European American subjects differed in 58 muscle and 140 adipose genes , including many inflammatory and metabolically important genes . Peroxisome proliferator-activated receptor γ cofactor 1A ( Q9UBK2 ) was 1.75-fold reduced with insulin resistance in muscle , and fatty acid and lipid metabolism and oxidoreductase activity also were downregulated . Unexpected categories included ubiquitination , citrullination , and protein degradation . In adipose , highly represented categories included lipid and fatty acid metabolism , insulin action , and cell-cycle regulation . Inflammatory genes were increased in European American subjects and were among the top Kyoto Encyclopedia of Genes and Genomes pathways on gene-set enrichment analysis . O60427 , P15692 , P26045 , Q9UIH9 , P56645 , Q687X5 , and P30556 were among genes expressed differentially in both adipose and muscle . CONCLUSIONS : Adipose tissue gene expression showed more differences between insulin-resistant versus insulin-sensitive groups than the expression of genes in muscle . We confirm the role of Q9UBK2 in muscle and show some support for inflammation in adipose from European American subjects but find prominent roles for lipid metabolism in insulin sensitivity independent of obesity in both tissues . Phase I study of matuzumab in combination with 5-fluorouracil , leucovorin and cisplatin ( PLF ) in patients with advanced gastric and esophagogastric adenocarcinomas . BACKGROUND : To evaluate the safety and tolerability of two different weekly doses of the fully humanized epidermal growth factor receptor ( P00533 ) -targeting monoclonal antibody matuzumab combined with high-dose 5-fluorouracil , leucovorin and cisplatin ( PLF ) in the first-line treatment of patients with P00533 -positive advanced gastric and esophagogastric adenocarcinomas . METHODS : Patients were treated in two matuzumab dose groups with the first cohort of patients receiving 400 mg matuzumab in combination with PLF . Based on the safety observations the next cohort of patients received 800 mg matuzumab . The study was conducted in two parts , with phase A , designed to assess the safety and tolerability of the combination , and phase B designed to be a treatment continuation for those patients benefiting from treatment . Treatment cycles were 7 weeks each . Each patient received the dose of matuzumab they were assigned to at study entry for the duration of the study . RESULTS : Fifteen P00533 -positive patients were enrolled into the two matuzumab dose groups ; 400 mg dose n=7 ; 800 mg dose n=8 . All patients experienced at least one adverse event ( AE ) . No patient experienced any serious AE which was considered to be related to matuzumab . Two grade 3 AEs possibly related to matuzumab occurred in 2 different patients ( 13.3 % ) , both in the 800 mg dose group . No dose-limiting toxicity ( DLT ) was observed in the 400 mg group . The maximum tolerated dose of matuzumab was not reached . The best confirmed overall response rate was 26.7 % . CONCLUSION : DB05101 , in combination with PLF , demonstrated an acceptable safety profile with modest anti-tumor activity . Polymorphisms of dopamine receptor/transporter genes and risk of non-small cell lung cancer . BACKGROUND : The dopaminergic pathway may be of interest in assessing risk of non-small cell lung cancer ( NSCLC ) . Dopamine receptors are expressed in alveolar epithelial cells and human lung tumours , and dopamine inhibits both cell proliferation in vitro and growth of lung tumour xenografts in nude mice . Moreover , dopamine selectively inhibits the vascular permeability and angiogenic activity of vascular endothelial growth factor ( P15692 / P15692 ) . The bioavailability of dopamine is regulated by dopamine receptors D2 ( P14416 ) , D4 ( P21917 ) and dopamine transporter 1 ( Q01959 / Q01959 ) genes . METHODS : We have analysed 10 single nucleotide polymorphisms in P14416 , P21917 and Q01959 / Q01959 genes in relation to lung cancer risk in a case-control study of smoking subjects . The study subjects were 413 healthy individuals from general population and 335 NSCLC cases . Both cases and controls were Caucasians of Norwegian origin . RESULTS : We demonstrate that P14416 polymorphisms -141Cdel , 3208G > T , TaqIB ; P21917 -521C > T and Q01959 / Q01959 -1476T > G are associated with a two- to five-fold increased NSCLC risk . The variant alleles of P14416 1412A > G and 960C > G had protective effects . CONCLUSION : The dopamine receptor/transport gene polymorphisms are associated with the risk of NSCLC among smokers . The data show that the polymorphisms resulting in lower dopamine bioavailability were associated with increased risk of NSCLC . Comparison of effects of olmesartan and telmisartan on blood pressure and metabolic parameters in Japanese early-stage type-2 diabetics with hypertension . P30556 blockers ( ARBs ) are regarded as first-line treatments for type-2 diabetes with hypertension . Despite the availability of various types of ARBs , there are no comparative studies of their effects on patients with diabetes . In this open-label prospective crossover study , we compared the effects of olmesartan ( 20 mg/day ) and telmisartan ( 40 mg/day ) . Twenty Japanese early-stage type-2 diabetes patients with hypertension treated with valsartan ( 80 mg/day ) for at least 8 weeks were recruited to this study . At study entry , valsartan was changed to olmesartan ( 20 mg/day ) or telmisartan ( 40 mg/day ) and administered for 8 weeks . The drugs were then switched and treatment was continued for another 8 weeks . We analyzed the blood pressure lowering effects of each drug by 24-h ambulatory blood pressure monitoring at 0 , 8 , and 16 weeks . Simultaneously , we measured metabolic parameters and inflammation markers . DB00275 lowered mean systolic and diastolic blood pressure more significantly than did telmisartan . While there were no differences between the groups in metabolic parameters , including HbA1c and adiponectin , the decreases in serum interleukin-6 and highly sensitive P02741 were more significant by olmesartan treatment . Our results indicate that olmesartan has more potent arterial blood pressure lowering and anti-inflammatory effects than telmisartan . DB05229 sodium , a stable prostacyclin analogue , elicits dilation of isolated porcine retinal arterioles : roles of P29474 and potassium channels . PURPOSE : DB01240 ( DB01240 ) is usually described as an endoEDRFsthelium-derived relaxing factor , but the vasoreactivity to DB01240 in the retinal arterioles and the underlying mechanisms are not fully understood . We examined the effects of DB01240 on the retinal microcirculation using beraprost sodium ( BPS ) , a stable DB01240 analogue , and the signaling mechanisms involved in this vasomotor activity . METHODS : Porcine retinal arterioles were isolated , cannulated , and pressurized without flow in vitro . Video microscopic techniques recorded the diametric responses to BPS . RESULTS : DB05229 sodium elicited dose-dependent ( 0.1 pM-0.1 μM ) vasodilation of the retinal arterioles that was abolished by the P43119 ( IP ) antagonist CAY10441 . DB05229 sodium-induced vasodilation decreased by 50 % after the endothelium was removed and was inhibited by the nitric oxide ( NO ) synthase inhibitor N(G)-nitro-L-arginine methyl ester ( L-NAME ) comparable with denudation . Inhibition of soluble guanylyl cyclase by 1H-1,2,4-oxadiazolo[4,3-a]quinoxalin-1-one ( ODQ ) and blockage of protein kinase A ( PKA ) by Rp-8-Br-cAMPS were comparable to L-NAME . DB05229 sodium-induced vasodilation was also inhibited by the nonselective potassium channel inhibitor , tetraethylammonium , and the adenosine triphosphate-sensitive potassium ( KATP ) channel blocker , glibenclamide . Residual vasodilation in the presence of glibenclamide decreased further with subsequent application of ODQ . CONCLUSIONS : DB05229 sodium , a stable DB01240 analogue , causes vasodilation of the retinal arterioles mediated via the IP receptor . The current findings suggest that BPS elicits endothelium-dependent and -independent dilation of the retinal arterioles mediated by NO induced by activation of PKA in the endothelium and the KATP channel activation in the vascular smooth muscle , respectively . Uptake and incorporation of pinolenic acid reduces n-6 polyunsaturated fatty acid and downstream prostaglandin formation in murine macrophage . Many reports have shown the beneficial effects of consumption of pine seeds and pine seed oil . However , few studies have examined the biological effect of pinolenic acid ( PNA ; 5,9,12-18:3 ) , the main fatty acid in pine seed oil . In this study , using murine macrophage RAW264.7 cells as a model , we examined the effect of PNA on polyunsaturated fatty acid ( PUFA ) metabolism , prostaglandin ( PG ) biosynthesis and cyclooxygenase-2 ( P35354 ) expression . Results showed that PNA was readily taken up , incorporated and elongated to form eicosatrienoic acid ( ETrA , 7,11,14-20:3 ) in macrophage cells . A small portion of this elongated metabolite was further elongated to form 9,13,16-22:3 . The degree of incorporation of PNA and its metabolites into cellular phospholipids varied with the length of incubation time and the concentration of PNA in the medium . Incubation of PNA also modified the fatty acid profile of phospholipids : the levels of 18- and 20-carbon PUFA were significantly decreased , whereas those of 22-carbon fatty acids increased . This finding suggests that PNA enhances the elongation of 20-carbon fatty acids to 22-carbon fatty acids . The syntheses of PGE(1) from dihomo-gamma-linolenic acid ( DB00154 , 8,11,14-20:4 ) and PGE(2) from arachidonic acid ( O95255 , 5,8,11,14-20:4 ) were also suppressed by the presence of PNA and its metabolite . As the expression of P35354 was not suppressed , the inhibitory effect of PNA on PG activity was attributed in part to substrate competition between the PNA metabolite ( i.e. , 7,11,14-20:3 ) and DB00154 ( or O95255 ) . A microRNA signature for a P12643 -induced osteoblast lineage commitment program . Bone morphogenetic proteins ( BMPs ) are potent morphogens that activate transcriptional programs for lineage determination . How BMP induction of a phenotype is coordinated with microRNAs ( miRNAs ) that inhibit biological pathways to control cell differentiation , remains unknown . Here , we show by profiling miRNAs during P12643 induced osteogenesis of C2C12 mesenchymal cells , that 22 of 25 miRNAs which significantly changed in response to P12643 are down-regulated . These miRNAs are each predicted to target components of multiple osteogenic pathways . We characterize two representative miRNAs and show that miR-133 directly targets Runx2 , an early BMP response gene essential for bone formation , and miR-135 targets Q99717 , a key transducer of the P12643 osteogenic signal , controlled through their 3'UTR sequences . Both miRNAs functionally inhibit differentiation of osteoprogenitors by attenuating Runx2 and Q99717 pathways that synergistically contribute to bone formation . Although miR-133 is known to promote Q9P2K5 -dependent myogenesis , we have identified a second complementary function to inhibit Runx2-mediated osteogenesis . Our key finding is that P12643 controls bone cell determination by inducing miRNAs that target muscle genes but mainly by down-regulating multiple miRNAs that constitute an osteogenic program , thereby releasing from inhibition pathway components required for cell lineage commitment . Thus , our studies establish a mechanism for BMP morphogens to selectively induce a tissue-specific phenotype and suppress alternative lineages . Hsp27 regulates epithelial mesenchymal transition , metastasis , and circulating tumor cells in prostate cancer . Defining the mechanisms underlying metastatic progression of prostate cancer may lead to insights into how to decrease morbidity and mortality in this disease . An important determinant of metastasis is epithelial-to-mesenchymal transition ( EMT ) , and the mechanisms that control the process of EMT in cancer cells are still emerging . Here , we report that the molecular chaperone Hsp27 ( P04792 ) drives EMT in prostate cancer , whereas its attenuation reverses EMT and decreases cell migration , invasion , and matrix metalloproteinase activity . Mechanistically , silencing Hsp27 decreased P05231 -dependent P40763 phosphorylation , nuclear translocation , and P40763 binding to the Twist promoter , suggesting that Hsp27 is required for P05231 -mediated EMT via modulation of P40763 /Twist signaling . We observed a correlation between Hsp27 and Twist in patients with prostate cancer , with Hsp27 and Twist expression each elevated in high-grade prostate cancer tumors . Hsp27 inhibition by DB06094 , an antisense therapy currently in phase II trials , reduced tumor metastasis in a murine model of prostate cancer . More importantly , DB06094 treatment decreased the number of circulating tumor cells in patients with metastatic castration-resistant prostate cancer in a phase I clinical trial . Overall , this study defines Hsp27 as a critical regulator of P05231 -dependent and P05231 -independent EMT , validating this chaperone as a therapeutic target to treat metastatic prostate cancer . Marker gene polymorphisms in hyperkinetic disorder -- predictors of clinical response to treatment with methylphenidate ? Gene polymorphisms of the dopamine D4 receptor ( P21917 ) and serotonin transporter ( 5-HTT ) are under discussion as potential genetic risk factors for hyperkinetic disorder ( HD ) . In this disorder , treatment with the psychostimulant methylphenidate ( DB00422 ; Ritalin ) induces calming effects and amelioration in only 70 % of the patients . DB00422 blocks the reuptake of dopamine , thus enhancing synaptic dopamine which in turn antagonizes the release of prolactin ( PL ) . Genotyping HD patients for P21917 and 5-HTT polymorphisms and measuring PL concentrations , we report on an association between the combination P21917 *7/ P31645 LL genotype and a reduced improvement in general functioning accompanied by different PL levels upon DB00422 treatment . Thus , our study supports the hypothesis that marker gene polymorphism may be helpful in identifying DB00422 non-responders . Ca2+ response of rat mesangial cells to DB00171 analogues . The aim of this investigation was to characterise the effects of DB00171 analogues and UTP on the single cell intracellular Ca2+ concentration ( [Ca2+]i ) in cultured rat mesangial cells . Typically , there were two phases in the Ca2+ response to the agonists , an initial fast transient peak and a subsequent slower decline , or plateau , phase . For the peak amplitude in [Ca2+]i the agonists had about equal effect . But when taking in consideration the percentage of responding cells and the integrated Ca2+ response over 1 min , the order of efficacy of nucleotide agonists ( 100 microM ) was UTP = DB00171 > ATPgammaS > ADP = 2MeS- DB00171 ( 2-methylthio- DB00171 ) . DB00640 , AMP and beta,gamma-Me- DB00171 ( 100 microM ) had no effect . DB04786 ( 100 microM ) and reactive blue ( 50 microM ) decreased the number of responding cells . Removing Ca2+ from the bath diminished neither the peak in [Ca2+]i nor the percentage of responding cells , but the average [Ca2+]i increase in 1 min was significantly reduced . The results indicate that P41231 receptors are present in rat mesangial cells but it can not be excluded that there are receptors distinct from P41231 which also mediate a rise in [Ca2+]i . Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals . In diabetic P01130 -/- mice , an ectopic P12643 -Msx2 gene regulatory program is upregulated in association with vascular calcification . We verified the procalcific actions of aortic Msx2 expression in vivo . CMV-Msx2 transgenic ( CMV-Msx2Tg(+) ) mice expressed 3-fold higher levels of aortic Msx2 than nontransgenic littermates . On high-fat diets , CMV-Msx2Tg(+) mice exhibited marked cardiovascular calcification involving aortic and coronary tunica media . This corresponded to regions of Msx2 immunoreactivity in adjacent adventitial myofibroblasts , suggesting a potential paracrine osteogenic signal . To better understand Msx2-regulated calcification , we studied actions in 10T1/2 cells . We found that conditioned media from Msx2-transduced 10T1/2 cells ( Msx2-CM ) is both pro-osteogenic and adipostatic ; these features are characteristic of Wnt signaling . Msx2-CM stimulated Wnt-dependent TCF/LEF transcription , and Msx2-transduced cells exhibited increased nuclear beta-catenin localization with concomitant alkaline phosphatase induction . Msx2 upregulated Wnt3a and Wnt7a but downregulated expression of the canonical inhibitor Dkk1 . Dkk1 treatment reversed osteogenic and adipostatic actions of Msx2 . DB06285 , a Q03431 agonist that inhibits murine vascular calcification , suppressed vascular P12643 -Msx2-Wnt signaling . Analyses of CMV-Msx2Tg(+) mice confirmed that Msx2 suppresses aortic Dkk1 and upregulates vascular Wnts ; moreover , TOPGAL(+) ( Wnt reporter ) ; CMV-Msx2Tg(+) mice exhibited augmented aortic LacZ expression . Thus , Msx2-expressing cells elaborated an osteogenic milieu that promotes vascular calcification in part via paracrine Wnt signals . P00533 -AKT-Smad signaling promotes formation of glioma stem-like cells and tumor angiogenesis by Q02535 -driven cytokine induction . Aberrant activation of receptor tyrosine kinases ( RTK ) is causally linked to the pathobiological traits of glioblastoma and genesis of glioma stem-like cells ( P56915 ) , but the underlying mechanism is still unknown . Here , we show that epidermal growth factor receptor ( P00533 ) signaling regulates the proliferation , angiogenesis , and acquisition of P56915 characteristics by inducing inhibitor of differentiation 3 ( Q02535 ) and Q02535 -regulated cytokines [ P09341 and interleukins ( IL ) -6 and 8 ] induction . We found that P00533 -mediated Q02535 expression was regulated by Q99717 , which was directly phosphorylated by AKT . Furthermore , Q02535 alone imparted P56915 features to primary astrocytes derived from Ink4a/Arf-deficient mouse , and P00533 - Q02535 - P05231 signaling axis gave rise to tumor cell heterogeneity . Conversely , P00533 inhibitors suppressed P00533 -AKT- Q99717 -driven induction of Q02535 , which led to a decrease in the tumorsphere forming ability of GSCs and U87MG cells that possess an active mutant P00533 , EGFRvIII , without obvious cytotoxic effects . However , these cells seemed to regain colonogenic ability after removal of the P00533 inhibitors . Together , the results delineate a novel integrative molecular mechanism in which the RTK-ID signaling pathway governs genesis and maintenance of GBM histopathologic features , such as GSCs-based tumor initiation , progression , and angiogenesis . Regulated catalysis of extracellular nucleotides by vascular P49961 / P49961 is required for liver regeneration . BACKGROUND & AIMS : Little is known about how endothelial cells respond to injury , regulate hepatocyte turnover and reconstitute the hepatic vasculature . We aimed to determine the effects of the vascular ectonucleotidase P49961 on sinusoidal endothelial cell responses following partial hepatectomy and to dissect purinergic and growth factor interactions in this model . METHODS : Parameters of liver injury and regeneration , as well as the kinetics of hepatocellular and sinusoidal endothelial cell proliferation , were assessed following partial hepatectomy in mice that do not express P49961 , that do not express DB00171 /UTP receptor P41231 , and in controls . The effects of extracellular DB00171 on vascular endothelial growth factor ( P15692 ) , hepatocyte growth factor ( P14210 ) , and interleukin-6 responses were determined in vivo and in vitro . Phosphorylation of the endothelial P15692 receptor in response to extracellular nucleotides and growth factors was assessed in vitro . RESULTS : After partial hepatectomy , expression of the vascular ectonucleotidase P49961 increased on sinusoidal endothelial cells . Targeted disruption of P49961 impaired hepatocellular regeneration , reduced angiogenesis , and increased hepatic injury , resulting in pronounced vascular endothelial apoptosis , and decreased survival . Decreased P14210 release by sinusoidal endothelial cells , despite high levels of P15692 , reduced paracrine stimulation of hepatocytes . Failure of P15692 receptor-2/ P35968 transactivation by extracellular nucleotides on P49961 -null endothelial cells was associated with P41231 receptor desensitization . CONCLUSIONS : Regulated phosphohydrolysis of extracellular nucleotides by P49961 coordinates both hepatocyte and endothelial cell proliferation following partial hepatectomy . Lack of P49961 activity is associated with decreased hepatic regeneration and failure of vascular reconstitution . Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) -1 and P35354 , were measured using real-time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0.05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .