interacts_with DB08865?
[ c- DB00134 signaling pathway participating in the gefitinib resistance of different gene types of non-small cell lung cancer cells induced by P14210 in vitro ] . BACKGROUND AND OBJECTIVE : It has been known that hepatocyte growth factor ( P14210 ) induces gefitinib resistance in non-small cell lung cancer ( NSCLC ) cells . The possible mechanism may be related to the activation of the P08581 c- DB00134 . The aim of this study is to investigate the involvement of c- DB00134 and its downstream signaling pathway in the P14210 -induced gefitinib resistance of NSCLC cells with different epidermal growth factor receptor ( P00533 ) gene types . METHODS : NSCLC cell lines with different P00533 genes ( PC-9 , Q8NBP7 /R , H292 , and A549 ) were selected and induced by P14210 . Cell survival was determined by MTT assay and the expression of DB00134 and downstream signaling proteins were examined by Western blot . RESULTS : Gefitinib inhibited the cell growth of Q8NBP7 , H292 , and A549 cell lines in a dose-dependent manner . The concentration-survival curve notably shifted to the right when induced by P14210 . The apoptotic rate was lower when the cells were treated with P14210 and gefitinib than when these cells were treated with gefitinib alone ( P < 0.05 ) , particularly in Q8NBP7 , H292 , and A549 cells , but not in Q8NBP7 /R . P14210 stimulated the phosphorylation of DB00134 and downstream signaling proteins in Q8NBP7 , H292 , Q8NBP7 /R , and A549 cell lines . p- DB00134 , p-Akt , p-Stat3 , and p-Erk1/2 expressions were higher when the cells were treated with P14210 and gefitinib than when these cells were treated with gefitinib alone , particularly in Q8NBP7 , H292 , and A549 cells , but not in Q8NBP7 /R . CONCLUSIONS : c- DB00134 and its downstream signaling pathway possibly participated in the P14210 -induced gefitinib resistance in NSCLC cells with different P00533 gene types . Suppression of parathyroid hormone-related protein messenger RNA expression by medroxyprogesterone acetate in breast cancer tissues . The level of parathyroid hormone-related protein ( P12272 ) expressed in breast cancer tissue is closely related to the incidence of bone metastasis . We examined the P12272 mRNA expression in breast cancer tissues by coamplification polymerase chain reaction ( PCR ) in mole ratio to internal standard beta-actin mRNA . The P12272 expression was higher in premenopausal patients than in postmenopausal patients ( P < 0.05 ) . More pronounced difference by menopause found in estrogen receptor ( ER ) positive groups ( P < 0.001 ) indicated that the P12272 expression in breast cancer tissue is hormonally regulated and might be altered by endocrine agents . To clarify the changes of P12272 expression by endocrine therapy of breast cancer , we measured P12272 expression in the breast cancer tissue incubated for 24 h with 1 x 10(-8) M of estradiol ( E2 ) , 1 x 10(-6) M of tamoxifen ( TAM ) and 1 x 10(-5) M of medroxyprogesterone acetate ( DB00603 ) . The P12272 expression was decreased significantly by DB00603 ( P < 0.005 ) , while E2 and TAM did not change the P12272 expression . P06401 ( PgR ) mRNA expression was also examined to confirm that the breast cancer tissue responds to E2 and TAM . The results were well compatible with the better therapeutic effect of DB00603 reported for the treatment of breast cancer with bone metastases . As a potential candidate for the receptor that mediates the suppressive effect of DB00603 , androgen receptor ( AR ) is suggested most probable . Present results also demonstrated that the clinical response of individual tumors is closely associated with the early in vitro changes of gene expression detected in the cancer specimen . A Hepatocyte Growth Factor ( P14210 ) /receptor autocrine loop regulates constitutive self-renewal of human periodontal ligament cells but reduces sensitivity to exogenous P14210 . BACKGROUND : In addition to its prominent role in liver regeneration , hepatocyte growth factor ( P14210 ) is now generally thought to be produced by mesenchymal cells to promote the regeneration of epithelial tissue by a paracrine mechanism . However , it is not known how or if P14210 could be involved in the regeneration of periodontal tissues . The purpose of this study was to characterize the ability of normal human periodontal ligament ( PDL ) cells to produce or respond to P14210 . METHODS : PDL cells derived from healthy young volunteers were used from passages four through 10 . P14210 receptors were detected both by immunocytochemical staining and Western-blotting analysis . Both DNA synthesis ( by bromo-deoxyuridine [ BrdU ] -incorporation ) and secreted P14210 were quantified by enzyme-linked immunosorbent assays . Mitogen-activated protein kinase ( MAPK ) phosphorylation was also analyzed by Western blot . RESULTS : Despite the immunocytochemical demonstration of P08581 protein in the cytoplasm and on the plasma membrane of PDL cells , exogenous recombinant human P14210 did not exert the mitogenic effects expected . As reported for other mesenchymal cells , PDL cells were found to secrete P14210 . Treatments with neutralizing anti- P14210 antibody significantly suppressed constitutive PDL cell proliferation and sustained the receptor protein at higher levels than in non-treated cells . Under these conditions , exogenous P14210 rapidly phosphorylated extracellular signal-regulated kinase ( P29323 ) , an action linked to the cell proliferation and downregulation of cell-surface receptors . CONCLUSIONS : Unlike other known mesenchymal or epithelial cells , these findings suggest that normal PDL cells from young donors possess a constitutive P14210 /receptor autocrine loop that normally regulates their replacement self-proliferation but reduces sensitivity to exogenously applied P14210 by acute receptor downregulation . Molecular mechanisms of cell proliferation induced by low power laser irradiation . Low power laser irradiation ( LPLI ) promotes proliferation of multiple cells , which ( especially red and near infrared light ) is mainly through the activation of mitochondrial respiratory chain and the initiation of cellular signaling . Recently , the signaling proteins involved in LPLI-induced proliferation merit special attention , some of which are regulated by mitochondrial signaling . P08581 ( c- DB00134 ) , a member of tyrosine protein kinase receptors ( TPKR ) , is phosphorylated during LPLI-induced proliferation , but tumor necrosis factor alpha ( P01375 ) receptor has not been affected . Activated TPKR could activate its downstream signaling elements , like Ras/Raf/MEK/ P29323 , PI3K/Akt/ P06730 , PI3K/Akt/ P29474 and P98160 -gamma/PKC pathways . Other two pathways , DeltaPsim/ DB00171 / DB02527 /JNK/AP-1 and ROS/Src , are also involved in LPLI-induced proliferation . LPLI-induced cell cycle progression can be regulated by the activation or elevated expressions of cell cycle-specific proteins . Furthermore , LPLI induces the synthesis or release of many molecules , like growth factors , interleukins , inflammatory cytokines and others , which are related to promotive effects of LPLI . DB08865 for the treatment of patients with advanced non-small cell lung cancer . DB08865 is a potent small-molecule inhibitor of Q9UM73 ( anaplastic lymphoma kinase ; Q9UM73 ) and hepatocyte growth factor receptor ( P08581 , proto-oncogene c- DB00134 ) . A range of tumors , including subsets of non-small cell lung cancer ( NSCLC ) , anaplastic large cell lymphoma and inflammatory myofibroblastic tumors harbor an Q9UM73 rearrangement that leads to oncogenic activation of Q9UM73 . DB08865 has demonstrated preclinical and clinical activity against such malignancies through inhibition of Q9UM73 , and patients harboring Q9UM73 - rearranged NSCLC have demonstrated high response rates and prolonged progression-free survival in phase I and II studies . In August 2011 , crizotinib was approved for the treatment of advanced Q9UM73 -positive NSCLC . Interferon-gamma upregulates the c- DB00134 /hepatocyte growth factor receptor expression in alveolar epithelial cells . In the repair process after lung injury , the regeneration of alveolar epithelial cells plays an important role by covering the damaged alveolar wall and preventing the activated fibroblasts from invading the intra- alveolar spaces . P14210 ( P14210 ) is a potent mitogen for alveolar epithelial cells and has been reported to be capable of repressing the fibrosing process by connecting to the c- DB00134 / P08581 on alveolar epithelial cells . However , it has been reported that the c- DB00134 expression was downregulated in an acute phase of lung injury , which may limit the effect of P14210 for therapeutic use . In the present study we observed that interferon ( IFN ) -gamma upregulates the c- DB00134 messenger RNA ( mRNA ) and protein expression in A549 alveolar epithelial cells . We analyzed the mechanism of this upregulation and found that P01579 enhances the transcription of the c-met proto-oncogene , and that it does not prolong the stability of the c- DB00134 mRNA . P14210 is known to act as a motogen as well as a mitogen for epithelial cells . We also found that the migratory activity of A549 cells induced by P14210 is strongly enhanced by preincubation with P01579 . Finally , we administered recombinant P01579 to C57BL/6 mice and confirmed that this upregulation is also observed in vivo . These results suggest that the combination of P14210 and P01579 could be a new therapeutic approach for fibrosing pulmonary diseases . Desmopressin ( DB00035 ) induces NO production in human endothelial cells via V2 receptor- and DB02527 -mediated signaling . The hemostatic agent desmopressin ( DB00035 ) also has strong vasodilatory effects . DB00035 is a selective agonist for the vasopressin V2 receptor ( P30518 ) , which is coupled to DB02527 -dependent signaling . DB00035 -induced vasodilation may be due to endothelial NO synthase ( P29474 ) activation . This hypothesis implies DB02527 -mediated P29474 activation . It also implies wide extrarenal , endothelial P30518 expression . We show that in human umbilical vein endothelial cells ( HUVECs ) the DB02527 -raising agents forskolin and epinephrine increase NO production , as measured by a l-NMMA-inhibitable rise in cellular cGMP content . They also increase P29474 enzymatic activity , in a partly calcium-independent manner . DB02527 -mediated P29474 activation is associated with phosphorylation of residue Ser1177 , in a phosphatidyl inositol 3-kinase ( PI3K ) -independent manner . HUVECs do not express P30518 . However , after heterologous P30518 expression , DB00035 induces DB02527 -dependent P29474 activation via Ser1177 phosphorylation . We have previously found P30518 expression in cultured lung endothelial cells . By real time quantitative RT-PCR , we now find a wide P30518 distribution notably in heart , lung and skeletal muscle . These results indicate that DB00035 and other DB02527 -raising agents can activate P29474 via PI3K-independent Ser1177 phosphorylation in human endothelial cells . This mechanism most likely accounts for DB00035 -induced vasodilation . DB00452 -arginine conjugate , a novel HIV-1 Tat antagonist : synthesis and anti-HIV activities . HIV-1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV-1 Tat stimulates transactivation by binding to HIV-1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T-cells for productive HIV-1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV-1 Tat antagonist , a neomycin B-hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3-activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) -labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV-1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M- and T-tropic HIV-1 laboratory isolates ( EC(50) = 0.8-5.3 microM ) . A putative model structure for the TAR-NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV-1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV-1 binding to cells , partially by blocking the P61073 HIV-1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis . DB00502 induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist/coagonist sites , other modulator sites , including butyrophenone site may regulate the N-methyl-D-aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co-immunoprecipitated by anti-Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol-binding proteins , P29475 and Ras- P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras- P01286 from membranes and activation of c-Jun-kinase . Inclusion of insulin prevented relocalization of Ras- P01286 and subsequent neuronal death . DB00502 -induced dissociation of Ras- P01286 leads to inhibition of membrane-bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway . 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 . P14210 / P24001 , a four-kringle antagonist of hepatocyte growth factor , is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice . We reported that P24001 , composed of the N-terminal hairpin and subsequent four kringle domains of hepatocyte growth factor ( P14210 ) , acts as the competitive antagonist for P14210 . We now provide the first evidence that P24001 inhibits tumor growth and metastasis as an angiogenesis inhibitor as well as an P14210 antagonist . Administration of P24001 suppressed primary tumor growth and lung metastasis of Lewis lung carcinoma and Jyg-MC(A) mammary carcinoma s.c. implanted into mice , although neither P14210 nor P24001 affected proliferation and survival of these tumor cells in vitro . P24001 treatment resulted in a remarkable decrease in microvessel density and an increase of apoptotic tumor cells in primary tumors , which suggests that the inhibition of primary tumor growth by P24001 may be achieved by suppression of tumor angiogenesis . In vivo , P24001 inhibited angiogenesis in chick chorioallantoic membranes and in rabbit corneal neovascularization induced by basic fibroblast growth factor ( P09038 ) . In vitro , P24001 inhibited growth and migration of human microvascular endothelial cells induced by P09038 and vascular endothelial growth factor ( P15692 ) as well as by P14210 . P14210 and P15692 activated the DB00134 / P08581 and the P35968 / P15692 receptor , respectively , whereas P24001 inhibited P14210 -induced DB00134 tyrosine phosphorylation but not P15692 -induced P35968 phosphorylation . P24001 inhibited P14210 -induced P27361 /2 ( Q8TCB0 /42 mitogen-activated protein kinase ) activation , but allowed for P09038 - and P15692 -induced P27361 /2 activation . These results indicate that P24001 is an angiogenesis inhibitor as well as an P14210 antagonist , and that the antiangiogenic action of P24001 is independent of its activity as P14210 antagonist . The bifunctional properties of P24001 to act as an angiogenesis inhibitor and as an P14210 antagonist raises the possibility that P24001 may prove therapeutic for cancer patients . A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 /5 and Q9BQB6 genes polymorphisms . DB00946 is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non-genetic factors . DB00946 metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms -1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 *2 and/or P11712 *3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 *1B , P20815 *3 and P20815 *6 polymorphisms . Among non-genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β-blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3.92 mg/week and 3.54 mg/week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm . Effect of valproic acid through regulation of DB01221 receptor- P29323 signaling in sleep deprivation rats . Although the effect of mood stabilizer valproic acid ( DB00313 ) through multiple signaling pathways has been shown , its therapeutic mechanism is still largely unknown . We investigated the effect of DB00313 ( 200 mg/kg , every 12 h ) in sleep deprivation ( SD ) rats ( 72 h ) , the manic-like animal model , focusing on the N-methyl-D : -aspartic acid ( DB01221 ) receptor and signaling mediators of synaptic plasticity such as extracellular signal-regulated protein kinase ( P29323 ) , DB02527 response element-binding protein ( CREB ) , B cell chronic lymphocytic leukemia/lymphoma 2 ( P10415 ) , and brain-derived neurotrophic factor ( P23560 ) . SD reduced the expression of the Q13224 subunit of the DB01221 receptor in the frontal cortex and hippocampus but did not affect the expression of Q9UHB4 and Q12879 subunits . In comparison , DB00313 inhibited the SD-induced reduction of Q13224 expression in both brain regions . In addition , SD attenuated P29323 phosphorylation in the frontal cortex and hippocampus , whereas DB00313 prevented the attenuation . DB00313 also protected the SD-induced decrease of CREB phosphorylation , P10415 expression , and P23560 expression in the frontal cortex but not in the hippocampus . These results indicate that DB00313 could regulate DB01221 receptor- P29323 signaling in SD rats , preventing the SD-induced decrease of the expression of Q13224 subunit and the activation of P29323 signaling mediators such as P29323 , CREB , P10415 , and P23560 . Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with DB01259 and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 -positive breast cancer . We report a patient with breast cancer overexpressing HER-2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine . Prevention of acute ischemic renal failure by targeted delivery of growth factors to the proximal tubule in transgenic mice : the efficacy of parathyroid hormone-related protein and hepatocyte growth factor . Treatment of acute renal failure ( Q8N726 ) would be enhanced by identification of factors that accelerate renal recovery from injury . P12272 ( P12272 ) and hepatocyte growth factor ( P14210 ) have been shown to stimulate proliferation in proximal nephron-derived cells . For studying the pathophysiologic roles and therapeutic potential of these two factors in Q8N726 , transgenic mice overexpressing P12272 or P14210 in the proximal tubule under the direction of the gamma-glutamyl transpeptidase-I promoter were developed . These mice display ( 1 ) abundant expression of the respective transgenes in the kidney ; ( 2 ) similar PTH type I receptor and P08581 ( c-met ) expression levels in the proximal tubule compared with control littermates ; and ( 3 ) normal renal morphology , function , and tubule cell proliferation under basal conditions . However , in contrast to control mice , when acute ischemic renal injury was induced , renal function rapidly and dramatically recovered in P14210 -overexpressing mice . In addition , 48 h after ischemia , P14210 -overexpressing transgenic mice displayed a fourfold increase in tubule cell proliferation and a threefold decrease in apoptotic tubule cell death compared with control mice . In contrast , P12272 -overexpressing mice responded to either ischemic or folic acid-induced renal damage similarly to control mice . These studies demonstrate that overexpression of P12272 in the proximal nephron of mice does not seem to provide protection against acute renal injury . In marked contrast , P14210 overexpression results in dramatic protection from ischemia-induced Q8N726 , without inducing any apparent alteration in the physiology of the kidney under normal conditions . These studies suggest that P14210 , when targeted specifically to the proximal tubule , may have therapeutic potential in providing protection against ischemia-induced renal failure . P08581 tyrosine kinase met is a substrate of the receptor protein-tyrosine phosphatase Q12913 . The receptor protein-tyrosine phosphatase ( PTP ) Q12913 ( CD148/PTP-eta ) has been implicated in the regulation of cell growth , differentiation , and transformation , and most recently has been identified as a potential tumor suppressor gene mutated in colon , lung , and breast cancers . We have generated constructs comprising the cytoplasmic segment of Q12913 fused to the maltose-binding protein to identify potential substrates and thereby suggest a physiological function for Q12913 . We have shown that the substrate-trapping mutant form of Q12913 interacted with a small subset of tyrosine-phosphorylated proteins from lysates of the human breast tumor cell lines MDA-MB-231 , T-47D , and T-47D/ DB00134 and have identified the hepatocyte growth factor/scatter factor receptor DB00134 , the adapter protein Gab1 , and the junctional component O60716 as potential substrates . Following ligand stimulation , phosphorylation of specific tyrosyl residues in DB00134 induces mitogenic , motogenic , and morphogenic responses . When co-expressed in 293 cells , the full-length substrate-trapping mutant form of Q12913 formed a stable complex with the chimeric receptor colony stimulating factor 1 ( P04141 ) - DB00134 and wild type Q12913 dephosphorylated P04141 - DB00134 . Furthermore , we observed that Q12913 preferentially dephosphorylated a Gab1 binding site ( DB00135 (1349) ) and a COOH-terminal tyrosine implicated in morphogenesis ( DB00135 (1365) ) , whereas tyrosine residues in the activation loop of DB00134 ( DB00135 (1230) , DB00135 (1234) , and DB00135 (1235) ) were not preferred targets of the PTP . The ability of Q12913 preferentially to dephosphorylate particular tyrosine residues that are required for DB00134 -induced signaling suggests that Q12913 may function in controlling the specificity of signals induced by this PTK , rather than as a simple " off-switch " to counteract PTK activity . P14210 and P04626 /neu downregulate expression of apoptosis-inducing factor in non-small cell lung cancer . Our previous study showed that patients with advanced stages of non-small cell lung cancer ( NSCLC ) were frequently detected with upregulation of hepatocyte growth factor ( P14210 ) . In vitro , P14210 reduced expression of apoptosis-inducing factor ( O95831 ) and cisplatin sensitivity in NSCLC cells . The effect of P14210 was via P08581 ( c-MET ) and the downstream effector , focal adhesion kinase ( Q05397 ) . In this study , we determined the prognostic value of O95831 in NSCLC patients . O95831 expression was determined by immunohistochemistry and immunoblotting . Our data show that O95831 expression was associated with better prognosis . Expression of O95831 inversely correlated with that of positive NSCLC markers , e.g. , dihydrodiol dehydrogenase ( Q04828 ) , c-MET , short oncostatin M receptor ( OSMRs ) , matrix metalloproteinase ( MMP ) -1 , and P04626 /neu , which were closely associated with drug resistance , tumor recurrence , metastasis and poor prognosis . Noteworthy , silence of P04626 /neu gene expression increases O95831 level and drug sensitivity . Addition of P14210 inhibits O95831 expression in P04626 /neu-silenced cells . These results suggested that both P14210 and P04626 /neu affect drug resistance by regulating O95831 expression in NSCLC . Role of Q14116 in overt pain-like behaviour in mice . There are evidences that targeting Q14116 might be beneficial to inhibit inflammatory symptoms , including hypernociception ( decrease in nociceptive threshold ) . The mechanism of Q14116 mechanical hypernociception depends on endothelin in rats and mice . However , the role of Q14116 in overt pain-like behaviour remains undetermined . Therefore , we addressed the role of Q14116 in writhing response induced by intraperitoneal ( i.p. ) injection of phenyl-p-benzoquinone ( PBQ ) and acetic acid in mice . Firstly , it was detected that PBQ and acetic acid i.p. injection induced a dose-dependent number of writhes in Balb/c mice . Subsequently , it was observed that the PBQ - but not the acetic acid-induced writhes were diminished in Q14116 deficient ( ( -/- ) ) mice . Therefore , considering that P01579 , endothelin and prostanoids mediate Q14116 -induced mechanical hypernociception , we also investigated the role of these mediators in the same model of writhing response in which Q14116 participates . It was noticed that PBQ-induced writhes were diminished in P01579 (-/-) mice and by the treatment with DB00559 ( mixed endothelin P25101 /ETB receptor antagonist ) , BQ 123 ( cyclo[DTrp-DAsp-Pro-DVal- DB00149 ] , selective endothelin P25101 receptor antagonist ) , BQ 788 ( N-cys-2,6 dimethylpiperidinocarbonyl-l-methylleucyl-d-1-methoxycarboyl-d-norleucine , selective endothelin ETB receptor antagonist ) or indomethacin ( cycloxigenase inhibitor ) . Thus , Q14116 , P01579 , endothelin acting on endothelin P25101 and ETB receptors , and prostanoids mediate PBQ-induced writhing response in mice . To conclude , these results further advance the understanding of the physiopathology of overt pain-like behaviour , and suggest for the first time a role for Q14116 in writhing response in mice . Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis/metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long-term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 *4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P=0.003 and P=0.007 ) and were 2.2- and 2.5-fold more likely to develop P42126 and CND ( P=0.039 and P=0.041 ) , respectively . P34913 55Arg , P51589 *7 , P10632 *1B , and P10632 g.36785A allele carriers had lower EET and DHET P04141 levels . P10632 g.25369T and P10632 g.36755A allele carriers had higher EET levels . Patients with P10632 *2C and P34913 404del variants had worse long-term outcomes while those with P34913 287Gln , P51589 *7 , and P11712 g.816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3-month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis/metabolic pathway and the pathophysiology of aSAH . P48061 and [N33A] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin/calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G-protein-dependent and β-arrestin-dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 /2 phosphorylation . In contrast , the structural variant [N33A] P48061 triggered no β-arrestin-dependent phosphorylation of P27361 /2 , and signaled via G protein-dependent pathways alone . Both P48061 and [N33A] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 -positive 5637 or HeLa cells with P48061 modified the HB- P01133 -dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [N33A] P48061 , while preserving P61073 -related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β-arrestin 2 , P48061 induced a full inhibition of P00533 like [N33A] P48061 in non-silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [N33A] P48061 may transinhibit P00533 via G-proteins/calmodulin/calcineurin , but [N33A] P48061 does not activate β-arrestin-dependent P27361 /2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [N33A] P48061 activates preferentially G-protein-dependent pathways and is an inhibitor of P00533 .