interacts_with DB00035?
Effects of phenacetin and its metabolite p-phenetidine on P23219 and P35354 activities and expression in vitro . The present study was aimed to test the possible cyclooxygenase ( P36551 ) -1/ P35354 selectivity of the old analgesic drug phenacetin and its metabolite p-phenetidine , which exhibits high renal toxicity . DB00316 ( acetaminophen ) , the main metabolite of phenacetin with low renal toxicity , and indomethacin were selected as reference compounds . Collagen-stimulated platelet thromboxane B2 ( TxB2 ) production and phorbol 12-myristate-13-acetate ( PMA ) -induced neutrophil prostaglandin E2 ( DB00917 ) synthesis were used as indicators for P23219 and P35354 activity , respectively . DB03783 was even less potent than paracetamol to reduce the production of both TxB2 and DB00917 , and no clear preference for either of the P36551 -enzymes was seen . P-phenetidine was a more potent inhibitor , already at nanomolar level , of the synthesis of these prostanoids than indomethacin and showed some preference to P35354 inhibition . Somewhat higher , micromolar , concentrations of p-phenetidine also reduced P35354 expression in neutrophils . We suggest that the very potent inhibitory activity of p-phenetidine on DB00917 synthesis combined with the reduction of P35354 expression could explain the renal papillary necrosis in phenacetin kidney . Induction of prostacyclin receptor expression in human erythroleukemia cells . We have identified both high-affinity ( KD = 36 +/- 3 nM ) and low-affinity ( KD = 2.1 +/- 0.8 microM ) prostacyclin ( DB01240 ) -receptor sites on human erythroleukemia ( HEL ) cells using the radiolabelled prostacyclin analogue . [3H]iloprost . The addition of the phorbol ester , TPA , to the culture medium caused a 5-10-fold increase in the number of both the low- and the high-affinity sites , without any change in their affinity constants . DB01088 stimulated HEL cell membrane adenylate cyclase activity 5-fold . This stimulation was potentiated in the presence of GTP , indicating a conventional P43119 -G2-adenylate cyclase system . HEL cells represent a source of prostacyclin receptor mRNA which may be of value in expression cloning of this receptor . Correlation between tumor volume response to radiotherapy and expression of biological markers in patients with cervical squamous cell carcinoma . OBJECTIVE : To determine the factors associated with tumor volume response to radiotherapy ( RT ) in cervical cancer patients , and the relationship between the tumor volume response and alteration of the expression of biological markers during RT . METHODS : Twenty consecutive patients with cervical squamous cell carcinoma who received definitive RT were enrolled . Tumor volumes were calculated by Q9BWK5 examinations performed at the start of RT ( pre-RT ) , at the fourth week of RT ( mid-RT ) , and 1 month after RT completion ( post-RT ) . Two serial punch biopsies were performed at pre- and mid-RT , and immunohistochemical staining was performed for cyclooxygenase ( P36551 ) -2 and epidermal growth factor receptor ( P00533 ) . RESULTS : For the pre-RT evaluation , fourteen ( 70 % ) and eleven ( 55 % ) patients showed positive immunoreactivity for P35354 and P00533 , respectively . Among the seven patients whose median percentage residual tumor at mid-RT ( P30518 ) was greater than 0.5 , seven ( 100 % , p=0.0515 ) and five ( 71.4 % , p=0.3742 ) patients showed positive immunoreactivity for P35354 and P00533 , respectively . The logistic regression analysis showed that positive immunoreactivity for both P35354 and P00533 at pre-RT were associated with P30518 ( p=0.0782 ) . For the mid-RT evaluation , eight cases showed an interval increase in the distribution of immunoreactivity for P35354 , and six out of the eight patients had a P30518 greater than 0.5 ( p=0.2222 ) . CONCLUSION : The poor mid-RT tumor response was associated with the coexpression of P35354 and P00533 . Q9GZV9 and its receptors . Q9GZV9 ( Q9GZV9 ) is a circulating factor that plays critical roles in phosphate and vitamin D metabolism , as evidenced by the fact that Q9GZV9 missense mutations cause autosomal dominant hypophosphatemic rickets ( P30518 ) . Autosomal dominant hypophosphatemic rickets is characterized by hypophosphatemia with inappropriately normal 1,25-dihydroxyvitamin D concentrations , as well as bone pain , fracture and rickets . This phenotype parallels that of patients with tumor induced osteomalacia ( TIO ) , X-linked hypophosphatemic rickets ( XLH ) , and fibrous dysplasia ( FD ) , in whom elevated serum Q9GZV9 levels are often observed . The fibroblast growth factor receptors ( P11362 -4 ) play key roles in skeletal development , as well as in normal metabolic processes . Several FGFR isoforms that potentially mediate the activity of Q9GZV9 have been implicated . In the short term , these findings will lead to further understanding of Q9GZV9 function , and potentially in the long term , to targeted therapies in disorders of hypo- and hyperphosphatemia that involve Q9GZV9 . Altered regulation of renal nitric oxide , atrial natriuretic peptide and cyclooxygenase systems in aldosterone escape in rats . The present study was aimed to determine whether there is an altered role of local nitric oxide ( NO ) , atrial natriuretic peptide ( P01160 ) and cyclooxygenase ( P36551 ) systems in the kidney in association with the aldosterone escape . Male Sprague-Dawley rats were used . DB04630 ( 200 microg/day ) was infused through entire time course . The control group was kept on a low sodium diet ( 0.02 mEq/day ) , and the experimental group was supplied with a higher sodium diet ( 2. /day ) . Four days after beginning the regimen , the kidneys were taken . The protein expression of NO synthase ( NOS ) and P36551 isoforms was determined by semiquantitative immunoblotting . The mRNA expression of components of P01160 system was determined by real-time polymerase chain reaction . The activities of soluble and particulate guanylyl cyclases were determined by the amount of cGMP generated in responses to sodium nitroprusside and P01160 , respectively . There developed aldosterone escape in the experimental group . Accordingly , the renal content and the urinary excretion of NO increased . The expression of P29475 was increased in the inner medulla . Neither the expression of P29474 nor that of P35228 was changed . The expression and the catalytic activity of soluble guanylyl cyclase remained unaltered . The mRNA expression of P01160 was increased . Neither the expression of P16066 or P17342 nor the activity of particulate guanylyl cyclase was altered in the papilla . The protein expression of P35354 was increased in the inner medulla , while that of P23219 remained unchanged . In conclusion , the upregulation of P29475 , P01160 , and P35354 may be causally related with the aldosterone escape . Pharmacogenomics of methadone maintenance treatment . DB00333 is the major opioid substitution therapy for opioid dependence . Dosage is highly variable and is often controlled by the patient and prescriber according to local and national policy and guidelines . Nevertheless many genetic factors have been investigated including those affecting its metabolism ( P20813 -consistent results ) , efflux transport ( P-gp-inconsistent results ) , target μ-opioid receptor ( μ-opioid receptor-inconsistent results ) and a host of other receptors ( P14416 ) and signaling elements ( P48051 and P32121 ; not replicated ) . None by themselves have been able to substantially explain dosage variation ( the major but not sole end point ) . When multiple genes have been combined such as P08183 , P20813 , P35372 and P14416 a greater contribution to dosage variation was found but not as yet replicated . As stabilization of dosage needs to be made rapidly , it is imperative that larger internationally based studies be instigated so that genetic contribution to dosage can be properly assessed , which may or may not tailor to different ethnic groups and each country 's policy towards an outcome that benefits all . Cellular mechanisms of the hemostatic effects of desmopressin ( DB00035 ) . The synthetic analog of vasopressin desmopressin ( DB00035 ) is widely used for the treatment of patients with von Willebrand disease ( VWD ) , hemophilia A , several platelet disorders , and uremic bleeding . DB00035 induces an increase in plasma levels of P04275 ( P04275 ) , coagulation factor VIII ( FVIII ) , and tissue plasminogen activator ( t-PA ) . It also has a vasodilatory action . In spite of its extensive clinical use , its cellular mechanism of action remains incompletely understood . Its effect on P04275 and t-PA as well as its vasodilatory effect are likely explained by a direct action on the endothelium , via activation of endothelial vasopressin P30518 receptor and DB02527 -mediated signaling . This leads to exocytosis from Weibel Palade bodies where both P04275 and t-PA are stored , as well as to nitric oxide ( NO ) production via activation of endothelial NO synthase . The mechanism of action of DB00035 on FVIII plasma levels remains to be elucidated . The hemostatic effect of DB00035 likely involves additional cellular effects that remain to be discovered . A novel mutation in P30518 causing congenital nephrogenic diabetes insipidus with complete resistance to antidiuretic hormone . A 6-month-old male infant presented with failure to thrive . Hypernatraemia and elevated serum osmolality in the presence of low urine sodium and osmolality led to the diagnosis of diabetes insipidus . Administration of DB00035 ( dDAVP ) neither decreased urine volume nor increased urine osmolality indicating congenital nephrogenic diabetes insipidus . Molecular analysis in the arginine-vasopressin receptor-2 gene ( P30518 ) located on chromosome Xq28 demonstrated a novel 5-base pair deletion ( c.962-966delACCCC ; g.1429-1433delACCCC ) leading to a shift of the reading frame ( p.Asn321fs ) and a premature termination codon implying an absent or non-functional protein . Treatment with hydrochlorothiazide , amiloride and indomethacin led to a favourable clinical course . DB00067 -induced P04275 secretion from endothelial cells involves V2 receptors and DB02527 . DB00067 and its analogue DB00035 ( DB00035 ) are known to raise plasma P04275 ( P04275 ) levels . DB00035 is used as a hemostatic agent for the treatment of von Willebrand 's disease . However , its cellular mechanisms of action have not been elucidated . DB00035 , a specific agonist for the vasopressin V2 receptor ( P30518 ) , exerts its antidiuretic effect via a rise in DB02527 in kidney collecting ducts . We tested the hypothesis that DB00035 induces P04275 secretion by binding to P30518 and activating DB02527 -mediated signaling in endothelial cells . P04275 secretion from human umbilical vein endothelial cells ( HUVECs ) can be mediated by DB02527 , but DB00035 is ineffective , presumably due to the absence of P30518 . We report that DB00035 stimulates P04275 secretion in a DB02527 -dependent manner in HUVECs after transfection of the P30518 . In addition , vasopressin and DB00035 induce P04275 secretion in human lung microvascular endothelial cells ( HMVEC-L ) . These cells ( but not HUVECs ) express endogenous P30518 , as shown by RT-PCR . DB00067 -induced P04275 secretion is mimicked by DB00035 and inhibited by the selective P30518 antagonist SR121463B . It is mediated by DB02527 , since it is inhibited by the protein kinase A inhibitor Rp-8CPT-cAMPS . These results indicate that vasopressin induces DB02527 -mediated P04275 secretion by a direct effect on endothelial cells . They also demonstrate functional expression of P30518 in endothelial cells , and provide a cellular mechanism for the hemostatic effects of DB00035 . 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 . Use of trifluoroperazine isolates a [(3)H] DB08954 binding site in rat brain membranes with the pharmacology of the voltage-independent ifenprodil site on N-methyl-D-aspartate receptors containing Q13224 subunits . The use of trifluoroperazine in a well washed rat brain membrane preparation revealed [(3)H]ifenprodil binding to a single high affinity state with the pharmacology of N-methyl-D-aspartate ( DB01221 ) receptors containing Q13224 subunits . Inhibition of [(3)H]ifenprodil binding in the presence of trifluoroperazine by 10 NR1a/ Q13224 selective agents was highly correlated with their inhibition at rat NR1a/ Q13224 receptors expressed in Xenopus ooctyes and [(3)H] DB01520 binding to rat brain Q13224 subunit containing DB01221 receptors but not with their inhibition of [(3)H]DTG binding . Allosteric interactions with polyamines , Mg(2+) , Zn(2+) , glutamate , glycine , and their antagonists were consistent with DB01221 receptors with Q13224 subtype pharmacology . The rank order of polyamine inhibition was spermine > spermidine > 1,5-(diethylamino)piperidine > arcaine > agmatine > putrescine . Both spermidine and MgCl(2) shifted the inhibition curve of ifenprodil to the right in a parallel manner , but Mg(2+) did not appear to be additive to spermidine . Glutamate increased and glycine decreased the binding . Conversely , CPP decreased the binding , and MDL 105,519 increased the binding in an agonist reversible manner . The increase with MDL 105,519 and glutamate appeared to be additive as did the decrease with glycine and CPP . Changes in the buffer pH between 6.5 and 8.0 did not affect the affinity of Q13224 agents . DB09202 but not clonidine inhibited the binding . MK-801 and agents from various other pharmacological classes did not significantly inhibit [(3)H]ifenprodil binding . [(3)H] DB08954 binding in the presence of trifluoroperazine appears to be selective for the voltage-independent ifenprodil site on DB01221 receptors containing the Q13224 subunit . Reaction of phenylglyoxal with arginine groups in P14920 from Rhodotorula gracilis . D-Amino-acid oxidase from Rhodotorula gracilis was irreversibly inactivated by phenylglyoxal in a biphasic process . The fast phase was completed in less than 1 min . Its extent was linearly dependent on phenylglyoxal concentration and was not influenced by the presence of DB03147 or benzoate , a pseudo-substrate . The second phase of inactivation was due to a simple second-order reaction . The presence of DB03147 exerted only partial protection ; the second-order rate constants of inactivation were 8.3 M-1 min-1 for holoprotein and 18.0 M-1 min-1 for apoprotein . The addition of benzoate completely protected against this second phase of inactivation . Efforts to isolate the enzyme modified at a single arginine residue at the end of the fast phase were unsuccessful , but analysis of the enzyme isolated at the end of the slow phase identified an arginine residue , protected by benzoate , that is highly conserved in all D-amino-acid oxidases and corresponds to Arg283 in the pig kidney enzyme . Modification of this residue is directly involved in the inactivation process during the slow phase . This arginine may represent the basic residue ion pairing with the carboxylate group of the substrate or the residue interacting with the flavin N1- P06681 = O locus . Ectopic DB01285 syndrome caused by bronchial carcinoid tumor indistinguishable from Cushing 's disease . A 75-year-old woman was admitted to our hospital because of a poor glycemic control . She was found to have Cushingoid feature and dynamic endocrine tests showed elevated plasma DB01285 and cortisol levels , lack of their circadian rhythm , non-suppressibility to high-dose dexamethasone , responsiveness to P06850 , but not to DB00035 , and suppression to octreotide . Pituitary Q9BWK5 showed an equivocal small lesion . CT scan of the chest showed two nodular lesions in the right lung ( S5 , S7 ) , while a mild uptake was noted only in S5 lesion by DB09150 -PET , but positive uptake was only in S7 lesion by somatostatin receptor scintigraphy ( SRS ) . Inferior petrosal sinus sampling revealed a gradient of plasma DB01285 after P06850 stimulation , consistent with the diagnosis of Cushing ' s disease . She underwent middle and inferior lobectomy of the right lung . The resected tumor in S7 was consistent with the diagnosis of a bronchial carcinoid tumor with positive DB01285 immunoreactivity , while that of S5 was cryptococcal granuloma . RT-PCR revealed abundant expressions of P01189 and SSTR ( -1 , -2 , -5 ) , but not of P34998 and P47901 . Postoperatively , abnormal endocrine data were normalized along with improvement of hypertension and diabetes . This was a diagnostic challenging case with ectopic DB01285 syndrome indistinguishable from Cushing ' s disease by various endocrine and imaging tests , among which SRS successfully localized the tumor responsible for ectopic DB01285 secretion . DB09079 , a triple angiokinase inhibitor , enhances cytotoxic therapy response in pancreatic cancer . Angiogenesis remains a sensible target for pancreatic ductal adenocarcinoma ( PDAC ) therapy . P15692 , PDGF , FGF and their receptors are expressed at high levels and correlate with poor prognosis in human PDAC . DB09079 is a triple angiokinase inhibitor that targets P17948 /2/3 , P11362 /2/3 and PDGFRα/β signaling . We investigated the antitumor activity of nintedanib alone or in combination with the cytotoxic agent gemcitabine in experimental PDAC . DB09079 inhibited proliferation of cells from multiple lineages found in PDAC , with gemcitabine enhancing inhibitory effects . DB09079 blocked PI3K/MAPK activity and induced apoptosis in vitro and in vivo . In a heterotopic model , net local tumor growth compared to controls ( 100 % ) was 60.8 ± 10.5 % in the gemcitabine group , -2.1 ± 9.9 % after nintedanib therapy and -12.4 ± 16 % after gemcitabine plus nintedanib therapy . Effects of therapy on intratumoral proliferation , microvessel density and apoptosis corresponded with tumor growth inhibition data . In a PDAC survival model , median animal survival after gemcitabine , nintedanib and gemcitabine plus nintedanib was 25 , 31 and 38 days , respectively , compared to 16 days in controls . The strong antitumor activity of nintedanib in experimental PDAC supports the potential of nintedanib-controlled mechanisms as targets for improved clinical PDAC therapy . Catalog of 178 variations in the Japanese population among eight human genes encoding G protein-coupled receptors ( GPCRs ) . We screened DNAs from 48 Japanese individuals for single-nucleotide polymorphisms ( SNPs ) in eight genes encoding G protein-coupled receptors ( GPCRs ) by directly sequencing the entire relevant genomic regions except for repetitive-sequence elements . This approach identified 147 SNPs and 31 insertion/deletion polymorphisms among the eight GPCR genes . On average , we identified one SNP in every 584 nucleotides . Of the 147 SNPs , 69 were identified in P30556 , 12 in P50052 , nine in P35414 , 20 in P37288 , nine in P30518 , 16 in P21728 , six in P08514 , and six in P43119 . Twenty-one SNPs were located in 5' flanking regions , 76 in introns , 32 in exons , and 18 in 3' flanking regions . These variants should contribute to investigations of possible correlations between genotypes and phenotypes as regards susceptibility to disease or responsiveness to drug therapy . Evolution of spatially coexpressed families of type-2 vomeronasal receptors in rodents . The vomeronasal organ ( VNO ) is an olfactory structure for the detection of pheromones . VNO neurons express three groups of unrelated G-protein-coupled receptors . Type-2 vomeronasal receptors ( V2Rs ) are specifically localized in the basal neurons of the VNO and are believed to sense protein pheromones eliciting specific reproductive behaviors . In murine species , V2Rs are organized into four families . Family-ABD V2Rs are expressed monogenically and coexpress with family-C V2Rs of either subfamily C1 ( V2RC1 ) or subfamily P06681 ( V2RC2 ) , according to a coordinate temporal diagram . Neurons expressing the phylogenetically ancient V2RC1 coexpress family-BD V2Rs or a specific group of subfamily-A V2Rs ( V2RA8-10 ) , whereas a second neuronal subset ( V2RC2-positive ) coexpresses a recently expanded group of five subfamily-A V2Rs ( V2RA1-5 ) along with vomeronasal-specific Major Histocompatibility Complex molecules ( H2-Mv ) . Through database mining and Sanger sequencing , we have analyzed the onset , diversification , and expansion of the P30518 -families throughout the phylogeny of Rodentia . Our results suggest that the separation of V2RC1 and V2RC2 occurred in a Cricetidae ancestor in coincidence with the evolution of the H2-Mv genes ; this phylogenetic event did not correspond with the origin of the coexpressing V2RA1-5 genes , which dates back to an ancestral myomorphan lineage . Interestingly , the evolution of receptors within the V2RA1-5 group may be implicated in the origin and diversification of some of the P30518 putative cognate ligands , the exocrine secreting peptides . The establishment of V2RC2 , which probably reflects the complex expansion and diversification of family-A V2Rs , generated receptors that have probably acquired a more subtle functional specificity . Fetal hypothalamic-pituitary adrenal ( Q9Y251 ) development and activation as a determinant of the timing of birth , and of postnatal disease . Birth in most animal species is triggered by the fetus through activation of the fetal hypothalamic-pituitary-adrenal ( Q9Y251 ) axis . Preterm birth , may be associated with precocious activation of fetal Q9Y251 function , reflecting the fetal response to an adverse intrauterine environment . There is a progressive and concurrent increase of ACTH1-39 and cortisol ( F ) in the circulation of fetal sheep during the last 15-20 days of pregnancy ( term , day 145-150 ) associated with increased expression of hypothalamic P06850 pituitary P01189 and adrenal Q01718 and steroidogenic enzymes , particularly P450 C17 . Similar changes occur with fetal hypoxemia . Negative feedback is ameliorated by decreased pituitary and hypothalamic glucocorticoid receptor , increased CBG , and altered fetal pituitary 11B-hydroxysteroid dehydrogenase type 1 . Repeated fetal hypoxemia , diminishes the fetal-pituitary DB01285 response , but increases fetal adrenal responsiveness . Fetuses exposed to maternal glucocorticoid in late gestation are growth restricted with altered postnatal Q9Y251 responsiveness and glycemic responses that reproduce the insulin resistance of type 2 diabetes . We conclude that the level of fetal Q9Y251 activity is crucial not only for determining gestation length , but also predicts pathophysiologic adjustment in later life . P14416 desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release . Neurons of the ventral tegmental area ( VTA ) are the source of dopaminergic ( DAergic ) input to important brain regions related to addiction . Prolonged exposure of these VTA neurons to moderate concentrations of dopamine ( DA ) causes a time-dependent decrease in DA-induced inhibition , a complex desensitization called DA inhibition reversal ( P30518 ) . P30518 is mediated by conventional protein kinase C ( cPKC ) through concurrent stimulation of D2 and D1-like DA receptors , or by D2 stimulation concurrent with activation of some Gq-linked receptors . DB01285 releasing factor ( CRF ) acts via Gq , and can modulate glutamater neurotransmission in the VTA . In the present study , we used brain slice electrophysiology to characterize the interaction of DA , glutamate antagonists , and CRF agonists in the induction and maintenance of P30518 in the VTA . Glutamate receptor antagonists blocked induction but not maintenance of P30518 . Putative blockers of neurotransmitter release and store-operated calcium channels blocked and reversed P30518 . CRF and the CRF agonist urocortin reversed inhibition produced by the D2 agonist quinpirole , consistent with our earlier work indicating that Gq activation reverses quinpirole-mediated inhibition . In whole cell recordings , the combination of urocortin and quinpirole , but not either agent alone , increased spontaneous excitatory postsynaptic currents ( sEPSCs ) in VTA neurons . Likewise , the combination of a D1-like receptor agonist and quinpirole , but not either agent alone , increased sEPSCs in VTA neurons . In summary , desensitization of D2 receptors induced by dopamine or CRF on DAergic VTA neurons is associated with increased glutamatergic signaling in the VTA . Predictive gene signatures : molecular markers distinguishing colon adenomatous polyp and carcinoma . Cancers exhibit abnormal molecular signatures associated with disease initiation and progression . Molecular signatures could improve cancer screening , detection , drug development and selection of appropriate drug therapies for individual patients . Typically only very small amounts of tissue are available from patients for analysis and biopsy samples exhibit broad heterogeneity that can not be captured using a single marker . This report details application of an in-house custom designed GenomeLab System multiplex gene expression assay , the hCellMarkerPlex , to assess predictive gene signatures of normal , adenomatous polyp and carcinoma colon tissue using archived tissue bank material . The hCellMarkerPlex incorporates twenty-one gene markers : epithelial ( P15311 , P05783 , Q9Y5S8 , Q9UBY0 ) , proliferation ( P12004 , P24385 , Q9NXJ0 ) , differentiation ( B4GANLT2 , P47902 , Q99626 ) , apoptotic ( P42574 , Q9Y5S8 , O95631 ) , fibroblast ( FSP1 , P02452 ) , structural ( P63267 , P51911 , DES ) , gene transcription ( Q13547 ) , stem cell ( O75473 ) , endothelial ( P04275 ) and mucin production ( Q02817 ) . Gene signatures distinguished normal , adenomatous polyp and carcinoma . Individual gene targets significantly contributing to molecular tissue types , classifier genes , were further characterised using real-time PCR , in-situ hybridisation and immunohistochemistry revealing aberrant epithelial expression of Q9NXJ0 , O75473 Q99626 , Q9Y5S8 and Q9UBY0 prior to development of carcinoma . Identified gene signatures identify aberrant epithelial expression of genes prior to cancer development using in-house custom designed gene expression multiplex assays . This approach may be used to assist in objective classification of disease initiation , staging , progression and therapeutic responses using biopsy material . Acute heat stress induces edema and nitric oxide synthase upregulation and down-regulates mRNA levels of the Q05586 , Q12879 and Q13224 subunits in the rat hippocampus . The influence of heat stress on constitutive isoform of neuronal nitric oxide synthase ( P29474 ) and DB01221 receptor gene expression in hippocampus was examined in a rat model . Subjection of animals to 4 h heat stress at 38 degrees C resulted in a marked upregulation of P29474 in the hippocampus accompanied with a marked general expansion and edematous cell changes . On the other hand DB01221 receptor messenger RNA encoding Q05586 , Q12879 and Q13224 subunits showed a marked downregulation in the hippocampus of heat stressed rats compared to the controls . Our results show that upregulation of P29474 is instrumental in heat stress associated edema and cell injury . Furthermore , an increased production of NO as evident with upregulation of P29474 appears to be a key factor in the downregulation of DB01221 receptor gene expression in heat stress . Reduction of burn scar formation by halofuginone-eluting silicone gel sheets : a controlled study on nude mice . Burn scar formations can cause disfiguration and loss of dermal function . The purpose of this study was to examine whether application of modified silicone gel sheets with an antifibrotic drug halofuginone-eluting hybrid surface produce an effect on scar development . There were a total of 2 animal groups . The athymic nude mice ( nu/nu ) of both groups underwent transplantation of full-thickness human skin grafts onto their backs and setting of partial thickness burn injury . The status of local scar development was observed over a period of 3 months after the application of silicone gel sheets and also after application of surface-modified halofuginone-eluting silicone gel sheets . Subsequently , via real-time polymerase chain reaction , the cDNA levels from key mediators of scar formation ( transforming growth factor beta , P02452 , connective tissue growth factor , fibroblast growth factor 2 , matrix metalloproteinase 2 , matrix metalloproteinase 9 ) were established and statistically evaluated . In comparison with uncoated silicone gel sheets , the application of halofuginone-eluting silicone gel sheets lead to a significant difference in gene expression activity in scar tissue . DB04866 -eluting hybrid surface silicone gel sheets significantly increase the antiscarring effect of adhesive silicone gel sheets by deceleration and downregulation of scar development by normalization of the expression activity . Ligand-mediated endocytosis and intracellular sequestration of guanylyl cyclase/natriuretic peptide receptors : role of GDAY motif . The guanylyl cyclase/natriuretic peptide receptor-A ( P16066 /NPRA ) , also referred to as P16066 , is a single polypeptide molecule having a critical function in blood pressure regulation and cardiovascular homeostasis . P16066 /NPRA , which resides in the plasma membrane , consists of an extracellular ligand-binding domain , a single transmembrane domain , and an intracellular cytoplasmic region containing a protein kinase-like homology domain ( KHD ) and a guanylyl cyclase ( GC ) catalytic domain . After binding with atrial and brain natriuretic peptides ( P01160 and DB04899 ) , P16066 /NPRA is internalized and sequestered into intracellular compartments . Therefore , P16066 /NPRA is a dynamic cellular macromolecule that traverses different subcellular compartments through its lifetime . This review describes the roles of short-signal sequences in the internalization , trafficking , and intracellular redistribution of P16066 /NPRA from cell surface to cell interior . Evidence indicates that , after internalization , the ligand-receptor complexes dissociate inside the cell and a population of P16066 /NPRA recycles back to the plasma membrane . Subsequently , the disassociated ligands are degraded in the lysosomes . However , a small percentage of the ligand escapes the lysosomal degradative pathway , and is released intact into culture medium . Using pharmacologic and molecular perturbants , emphasis has been placed on the cellular regulation and processing of ligand-bound P16066 /NPRA in terms of receptor trafficking and down-regulation in intact cells . The discussion is concluded by examining the functions of short-signal sequence motifs in the cellular life-cycle of P16066 /NPRA , including endocytosis , trafficking , metabolic processing , inactivation , and/or down-regulation in model cell systems . Activating mutations of GNAS in canine cortisol-secreting adrenocortical tumors . BACKGROUND : Cushing 's syndrome or hypercortisolism is a common endocrinopathy in dogs . In approximately 15 % of cases , the disorder is caused by adrenocorticotropin ( DB01285 ) -independent hypersecretion of cortisol by an adrenocortical tumor ( AT ) . Without other explanation , the cortisol hypersecretion has been referred to as autonomous . OBJECTIVES : To investigate whether DB01285 -independent hypersecretion of cortisol may be associated with aberrant activation of the melanocortin 2 receptor ( Q01718 ) -cyclic AMP ( DB02527 ) -protein kinase A ( PKA ) pathway . ANIMALS : All analyses were performed on 44 cortisol-secreting ATs ( 14 adenomas and 30 carcinomas ) derived from dogs diagnosed with DB01285 -independent hypercortisolism . METHODS : Mutation analysis was performed of genes encoding the stimulatory G protein alpha subunit ( GNAS ) , Q01718 , and PKA regulatory subunit 1A ( P10644 ) in all ATs . RESULTS : Approximately one-third of all ATs harbored an activating mutation of GNAS . Missense mutations , known to result in constitutive activation , were present in codon 201 in 11 ATs , in codon 203 ( 1 AT ) , and in codon 227 ( 3 ATs ) . No functional mutations were found in Q01718 and P10644 . CONCLUSIONS AND CLINICAL IMPORTANCE : Activation of DB02527 signaling is a frequent event in canine cortisol-secreting ATs and may play a crucial role in both DB01285 -independent cortisol production and tumor formation . To the best of our knowledge , this is the first report of potentially causative mutations in canine cortisol-secreting ATs .