interacts_with DB01067?
P01308 /FGF-binding ciliary membrane glycoprotein from Tetrahymena . Triton X-100 extracted ciliary membrane protein from isolated cilia , prepared from the protozoon Tetrahymena thermophila , were fractionated by affinity chromatography on columns with covalently bound fibroblast growth factor ( FGF ) , insulin , or concanavalin A ( ConA ) , respectively . The eluted proteins were further analyzed by electrophoresis on sodium dodecyl sulfate polyacrylamide gels , isoelectric focusing , and by immunoblotting techniques using antibodies against the FGF receptor , platetelet derived growth factor ( PDGF ) receptor alpha-subunit , and insulin receptor beta-subunit . The particular antibodies were chosen because the peptides PDGF , FGF , insulin , and ConA are chemoattractants in this organism and corresponding binding ( receptor ) proteins could be expected to be identified . A 66 kDa protein fraction was eluted from the FGF-MiniLeak agarose , insulin-MiniLeak agarose and ConA sepharose . This fraction responded in Western immunoblots to an antibody against the beta-subunit of the human insulin receptor , to an antibody against the PDGF receptor ( P09619 ) and also to an antibody against the bovine FGF receptor ( FGFR ) that is known , in other systems , to inhibit FGF binding to its receptor . When analyzed by SDS-PAGE and stained with Coomassie blue the 66 kDa fraction appeared as a single component . However , in some experiments it appeared more heterogeneous when stained with silver indicating the presence of minor components that may be a procedural artifact or isoforms of the same glycoprotein . The 66 kDa protein(s) migrated in isoelectric focusing with a pI of 7.4 . The results are discussed in terms of the possible role of the 66 kDa glycoprotein as a protein involved in peptide-mediated cell signalling . Pharmacologic modulation of niche accessibility via tyrosine kinase inhibition enhances marrow and thymic engraftment after hematopoietic stem cell transplantation . Essential survival signals within hematopoietic stem cell ( P19526 ) and thymic niches are mediated by receptor tyrosine kinases , which can be reversibly inhibited using clinically available drugs . We studied whether sunitinib , a multityrosine kinase inhibitor that inhibits P10721 , enhances engraftment after bone marrow transplantation ( BMT ) in mice . DB01268 diminished hematopoietic progenitor cell numbers , and sunitinib enhanced marrow , peripheral myeloid , and lymphoid engraftment after BMT in Rag1(-/-) mice . DB01268 augmented P19526 engraftment because recipients displayed increased myeloid and lymphoid engraftment and because sunitinib-treated recipients of purified HSCs showed enhanced engraftment of secondary hosts . However , sunitinib preferentially augmented T-cell engraftment with lesser effects on myeloid and P19526 engraftment . Consistent with this , sunitinib preferentially depleted the early thymic progenitor subset in the thymus . DB01268 did not increase engraftment in mice with deficient P10721 signaling , and the pattern of more potent effects on T cell compared with P19526 engraftment observed in sunitinib-treated hosts was also observed after BMT into P10721 (W/Wv) mice . These results implicate P10721 as a critical modulator of thymic niches . We conclude that transient , pharmacologic inhibition of P10721 enhances accessibility of marrow and thymic niches , and provides a novel , noncytotoxic approach to accomplish engraftment after stem cell transplantation . PDE10 inhibition increases P42261 and CREB phosphorylation and improves spatial and recognition memories in a Huntington 's disease mouse model . Huntington 's disease ( HD ) causes motor disturbances , preceded by cognitive impairment , in patients and mouse models . We showed that increased hippocampal DB02527 -dependent protein kinase ( PKA ) signaling disrupts recognition and spatial memories in R6 HD mouse models . However , unchanged levels of hippocampal phosphorylated ( p ) DB02527 -responsive element-binding protein ( CREB ) suggested unaltered nuclear PKA activity in R6 mice . Here , we extend this finding by showing that nuclear pPKA catalytic subunit ( Thr197 ) and pPKA substrate levels were unaltered in the hippocampus of R6/1 mice . Phosphodiesterases ( PDEs ) play an important role in the regulation of PKA activity . Q9Y233 , a DB02527 /cGMP dual-substrate PDE , was reported to be restricted to the nuclear region in nonstriatal neurons . Using cell fractionation we confirmed that Q9Y233 was enriched in nuclear fractions , both in wild-type and R6/1 mice hippocampus , without differences in its levels or intracellular distribution between genotypes . We next investigated whether inhibition of PDE10 with papaverine could improve cognitive function in HD mice . DB01113 treatment improved spatial and object recognition memories in R6/1 mice , and significantly increased pGluA1 and pCREB levels in R6/1 mice hippocampus . DB01113 likely acted through the activation of the PKA pathway as the phosphorylation level of distinct cGMP-dependent kinase ( cGK ) substrates was not modified in either genotype . Moreover , hippocampal DB02527 , but not cGMP , levels were increased after acute papaverine injection . Our results show that inhibition of PDE10 improves cognition in R6 mice , at least in part through increased P42261 and CREB phosphorylation . Thus , PDE10 might be a good therapeutic target to improve cognitive impairment in HD . [ Drugs stimulating insulin release. Importance of their use for improving glycemia , safety and quality of life in diabetes mellitus type 2 ] . Etiopathogenesis of diabetes mellitus is bipolar . On one hand there occurs impairment in beta-cell function caused by genetic factors or abnormal development during fetal period . On the other hand defects of peripheral insulin action are also of significant importance . The bipolarity is also expressed by changing relationship between genetic and environmental factors . P01308 release is connected with closing DB00171 -dependent kalium channel , a structure closely connected with sulfonylurea receptors . Several receptors may be distinguished : Q09428 in Langerhans isles and SUR2 in heart ( SUR2A ) and vessel smoot muscles ( SUR2B ) . In the treatment of insulin release disorders sulfonylureas are still of significant importance though repaglinid and phenyloalanine derivates also have some clinical importance . Within sulfonylurea derivates there have been developed some preparations of slow drug release ( DB01067 GITS , Diaprel MR ) . One daily dose of DB01067 GITS and lower tendency to hypoglycaemia favour acceptation of the therapy by the patients what is also important for their quality of life . Quality of life is now regarded as important as obtaining good indices of diabetes control . The increase of memory T cell subsets in children with idiopathic nephrotic syndrome . Two-color and three-color flow cytometry was carried out to determine whether the memory T cells ( CD45RO+ T cells ) play a major role in lymphocyte dysfunction of 26 children with idiopathic nephrotic syndrome ( P01308 ) . The P01308 patients were divided into three groups : ( 1 ) 10 patients who were not receiving glucocorticoid hormone ( P30793 ) and were suffering from acute nephrotic state were referred to as N1 ; ( 2 ) 8 patients who were in remission maintained by P30793 therapy alone were referred to as N2 ; ( 3 ) 8 patients who were free of P30793 therapy for at least 4 months were referred to as N3 . Group N1 demonstrated a significant increase in the percentage of CD45RO+ P01730 + T cells and CD45RO+CD8+ T cells ( p < 0.05 ) compared with 11 controls , and these subsets were noted to have a tendency to decrease to control levels in groups N2 and N3 . Furthermore , interleukin-2 receptor-alpha expressed subsets in CD45RO+ P01730 + T cells ( CD45RO+ P01730 +CD25+ T cells ) were also increased only in group N1 ( p < 0.02 ) . A similar tendency of absolute counts was observed in these subsets . These results suggest that activated memory T cells reflect lymphocyte dysfunction at initial onset or relapse in P01308 children . Immunoaffinity purification of the functional 20S proteasome from human cells via transient overexpression of specific proteasome subunits . The proteasome is a multi-subunit proteolytic complex that plays a central role in protein degradation in all eukaryotic cells . It regulates many vital cellular processes therefore its dysfunction can lead to various pathologies including cancer and neurodegeneration . Isolation of enzymatically active proteasomes is a key step to the successful study of the proteasome regulation and functions . Here we describe a simple and efficient protocol for immunoaffinity purification of the functional 20S proteasomes from human P29320 293T cells after transient overexpression of specific proteasome subunits tagged with 3xFLAG . To construct 3xFLAG-fusion proteins , DNA sequences encoding the 20S proteasome subunits P28074 , P28066 , and P25788 were cloned into mammalian expression vector pIRES-hrGFP-1a . The corresponding recombinant proteins P28074 -3xFLAG , P28066 -3xFLAG , or P25788 -3xFLAG were transiently overexpressed in human P29320 293T cells and were shown to be partially incorporated into the intact proteasome complexes . 20S proteasomes were immunoprecipitated from P29320 293T cell extracts under mild conditions using antibodies against FLAG peptide . Isolation of highly purified 20S proteasomes were confirmed by SDS-PAGE and Western blotting using antibodies against different proteasome subunits . Affinity purified 20S proteasomes were shown to possess chymotrypsin- and trypsin-like peptidase activities confirming their functionality . This simple single-step affinity method of the 20S proteasome purification can be instrumental to subsequent functional studies of proteasomes in human cells . Potent and selective activation of the pancreatic beta-cell type K( DB00171 ) channel by two novel diazoxide analogues . AIMS/HYPOTHESIS : We investigated the pharmacological properties of two novel DB00171 sensitive potassium ( K( DB00171 ) ) channel openers , 6-Chloro-3-isopropylamino-4 H-thieno [ 3,2- e ] -1,2,4-thiadiazine 1,1-dioxide ( NNC 55-0118 ) and 6-chloro-3-(1-methylcyclopropyl)amino-4 H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide ( NN414 ) , on the cloned cardiac ( Kir6.2/SUR2A ) , smooth muscle ( Kir6.2/SUR2B ) and pancreatic beta cell ( Kir6.2/ Q09428 ) types of K( DB00171 ) channel . METHODS : We studied the effects of these compounds on whole-cell currents through cloned K( DB00171 ) channels expressed in Xenopus oocytes or mammalian cells ( HEK293 ) . We also used inside-out macropatches excised from Xenopus oocytes . RESULTS : In P29320 293 cells , NNC 55-0118 and NN414 activated Kir6.2/ Q09428 currents with EC(50) values of 0.33 micromol/l and 0.45 micromol/l , respectively , compared with that of 31 micro mol/l for diazoxide . Neither compound activated Kir6.2/SUR2A or Kir6.2/SUR2B channels expressed in oocytes , nor did they activate Kir6.2 expressed in the absence of Q09428 . Current activation was dependent on the presence of intracellular MgATP , but was not supported by MgADP . CONCLUSION/INTERPRETATION : Both NNC 55-0118 and NN414 selectively stimulate the pancreatic beta-cell type of K( DB00171 ) channel with a higher potency than diazoxide , by interaction with the Q09428 subunit . The high selectivity and efficacy of the compounds could prove useful for treatment of disease states where inhibition of insulin secretion is beneficial . Further evidence for a functional role of the glutamate receptor gene Q14832 in schizophrenia . In recent years , evidence has been accumulating indicating a major role of glutamate in the pathogenesis and pathophysiology of schizophrenia . Of particular importance in this regard are the metabotropic glutamate receptors ( GRM ) . Thus , a recently published trial of the amino acid analogue DB05096 , which exerts its effects through the activation of the glutamate receptors Q14832 / Q14416 , showed an improvement of positive and negative symptoms comparable to treatment with olanzapine . A functional variant of Q14832 has been described which modulates synaptic glutamate levels . We assessed whether this functional variant rs6465084 is related to schizophrenia in a large sample of patients and controls . We found an increased frequency of the A allele ( p=0.027 ) and the AA genotype ( p=0.024 ) in schizophrenia patients . Moreover , in an assessment of schizophrenia endophenotypes , patients of the AA genotype performed poorly in the digit symbol test , a measure of attention ( p=0.008 ) . Our results provide further evidence for the potential importance of the glutamate receptor Q14832 in schizophrenia , and indicate that the novel antipsychotic DB05096 may actually be targeting a pathogenic pathway of schizophrenia . DB00501 enhances antigen-specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti-ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti-ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB/c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA-specific IgG(1) , IgG(2a) and/or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA-sensitized BALB/c mice promoted Th2 cytokine secretion by OVA-stimulated spleen cells in vitro and increased serum levels of OVA-specific IgE , IgG(1) and IgG(2a) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies . A critical role for P01344 in memory consolidation and enhancement . We report that , in the rat , administering insulin-like growth factor II ( P01344 , also known as P01344 ) significantly enhances memory retention and prevents forgetting . Inhibitory avoidance learning leads to an increase in hippocampal expression of P01344 , which requires the transcription factor CCAAT enhancer binding protein β and is essential for memory consolidation . Furthermore , injections of recombinant P01344 into the hippocampus after either training or memory retrieval significantly enhance memory retention and prevent forgetting . To be effective , P01344 needs to be administered within a sensitive period of memory consolidation . P01344 -dependent memory enhancement requires P01344 receptors , new protein synthesis , the function of activity-regulated cytoskeletal-associated protein and glycogen-synthase kinase 3 ( GSK3 ) . Moreover , it correlates with a significant activation of synaptic GSK3β and increased expression of GluR1 ( also known as P42261 ) α-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid receptor subunits . In hippocampal slices , P01344 promotes P11717 -dependent , persistent long-term potentiation after weak synaptic stimulation . Thus , P01344 may represent a novel target for cognitive enhancement therapies . No evidence of mutations of the P28074 ( beta-5 subunit of proteasome ) in a case of myeloma with clinical resistance to DB00188 . Rindopepimut , a 14-mer injectable peptide vaccine against EGFRvIII for the potential treatment of glioblastoma multiforme . Celldex Therapeutics is developing rindopepimut ( DB05374 ) , a 14-mer injectable peptide vaccine for the potential treatment of glioblastoma multiforme ( GBM ) . Rindopepimut specifically targets a novel junctional epitope of the P00533 deletion mutant EGFRvIII , which is a constitutively active receptor that is expressed in approximately 60 to 70 % of patients with GBM . EGFRvIII expression is correlated with worse prognosis and reduced overall survival . Importantly , EGFRvIII is not expressed in normal brain tissue , making it an excellent therapeutic target . Preclinical studies demonstrated lasting tumor regression and increased survival times , as well as efficient generation of EGFRvIII-specific humoral and cellular immune responses , in animals expressing EGFRvIII and vaccinated with rindopepimut . Phase I and II clinical trials in patients with GBM demonstrated significantly increased median time to progression and overall survival time in those vaccinated with rindopepimut compared with matched historical controls . Only limited side effects have been observed in patients . Given these results , rindopepimut is an extremely promising therapy for patients with GBM . Phase I and II clinical trials in patients with GBM were ongoing at the time of publication . In the future , it may be beneficial to combine rindopepimut with other treatment modalities to further prolong survival . [ Activation of coagulation cascade in children during an idiopathic nephrotic syndrome relapse ] . The objective of this study was to assess concentrations of selected markers of coagulation in children with relapse of idiopathic nephrotic syndrome during a 6-week therapy . Study groups : 22 subjects ( 32 relapses ) -- 14 males , 8 females ( mean age 7.15 +/- 1.5 y. ) with no thrombotic complications were included into the study . All children were clinically steroid-sensitive . METHODS : Coagulation markers ( platelet count , thrombin time , APTT , INR , fibrinogen 1 + 2 fragments ( F1 + 2 ) , thrombin-antithrombin complexes ( TAT ) , serum levels of D-dimer ( DD ) , fibrin monomers ( FM ) and antithrombin activity ( P01008 ) ) were measured three times : on admission , after 2 and 6 weeks . The control group consisted of 13 healthy children . RESULTS : Serum concentration of TAT or F1 + 2 did not differ between 3 stages ( p > 0.05 ) . However , values at 0 and 2 weeks were significantly higher than in control group ( p < 0.05 ) . We found no correlation between TAT or F1 + 2 and FBG , ALB , TCH , TG levels . [ table : see text ] CONCLUSIONS : The coagulation cascade in relapse of NS was activated during first 6 weeks of therapy whereas metabolic disturbances ( low ALB , high P02675 , TCH , TG , high platelets ) normalized . It is speculative whether it was caused by active immunological process but definitely it resulted in " prothrombotic state " in P01308 patients . The regulation of rotenone-induced inflammatory factor production by DB00171 -sensitive potassium channel expressed in BV-2 cells . Our previous studies have demonstrated that activating DB00171 -sensitive potassium channel ( K( DB00171 ) channel ) , not only improved Parkinsonian behavior and neurochemical symptoms , but also reduced P35228 activity and mRNA levels in striatum and nigra of rotenone rat model of Parkinson 's disease ( PD ) . In this study , it was first shown that the subunits of K( DB00171 ) channels are expressed in BV-2 cells , and then it was investigated whether K( DB00171 ) channel was involved in regulating inflammatory factor production from BV-2 cells activated by rotenone . It was found that K( DB00171 ) channel was expressed in BV-2 cell and formed by the combination of Kir 6.1 and Q09428 2A/2B . K( DB00171 ) channel openers ( KCOs ) including pinacidil , diazoxide and iptakalim ( Ipt ) exerted beneficial effects on rotenone-induced morphological alterations of BV-2 cells , decreased tumor necrosis factor alpha ( P01375 ) production and the expression and activity of inducible isoform of nitric oxide synthase ( P35228 ) . Either glibenclamide or 5-hydroxydecanoate acid ( a selective mitochondrial K( DB00171 ) channel blocker ) could abolish the effects of KCOs , suggesting that K( DB00171 ) channels , especially mitochondrial DB00171 -sensitive potassium channels ( mitoK( DB00171 ) channels ) , played a crucial role in preventing the activation of BV-2 cells , and subsequently the production of a variety of proinflammatory factors . Therefore , activation of K( DB00171 ) channel might be a new therapeutic strategy for treating neuroinflammatory and neurodegenerative disorders . Arachidonic acid signaling is involved in the mechanism of imidazoline-induced KATP channel-independent stimulation of insulin secretion . The mechanism by which the novel , pure glucose-dependent insulinotropic , imidazoline derivative BL11282 promotes insulin secretion in pancreatic islets has been investigated . The roles of KATP channels , alpha2-adrenoreceptors , the I1-receptor-phosphatidylcholine-specific phospholipase ( PC- P98160 ) pathway and arachidonic acid signaling in BL11282 potentiation of insulin secretion in pancreatic islets were studied . Using Q09428 (-/-) deficient mice , the previous notion that the insulinotropic activity of BL11282 is not related to its interaction with KATP channels was confirmed . Insulinotropic activity of BL11282 was not related to its effect on alpha2-adrenoreceptors , I1-imidazoline receptors or PC- P98160 . BL11282 significantly increased [3H]arachidonic acid production . This effect was abolished in the presence of the iPLA2 inhibitor , bromoenol lactone . The data suggest that potentiation of glucose-induced insulin release by BL11282 , which is independent of concomitant changes in cytoplasmic free Ca2+ concentration , involves release of arachidonic acid by iPLA2 and its metabolism to epoxyeicosatrienoic acids through the cytochrome P-450 pathway . Genetically rescued tetrahydrobiopterin-depleted mice survive with hyperphenylalaninemia and region-specific monoaminergic abnormalities . One of the possibly mutated genes in DOPA-responsive dystonia ( DRD , Segawa 's disease ) is the gene encoding P30793 , which is the rate-limiting enzyme for tetrahydrobiopterin ( BH4 ) biosynthesis . Based on our findings on 6-pyruvoyltetrahydropterin synthase ( Q03393 ) gene-disrupted ( Pts(-/-) ) mice , we suggested that the amount of tyrosine hydroxylase ( TH ) protein in dopaminergic nerve terminals is regulated by the intracellular concentration of BH4 . In this present work , we rescued Pts(-/-) mice by transgenic introduction of human Q03393 cDNA under the control of the dopamine beta-hydroxylase promoter to examine regional differences in the sensitivity of dopaminergic neurons to BH4-insufficiency . The DPS-rescued ( Pts(-/-) , DPS ) mice showed severe hyperphenylalaninemia . Human Q03393 was efficiently expressed in noradrenergic regions but only in a small number of dopaminergic neurons . DB03886 and dopamine contents , and TH activity in the striatum were poorly restored compared with those in the midbrain . TH-immunoreactivity in the lateral region of the striatum was far weaker than that in the medial region or in the nucleus accumbens . We concluded that dopaminergic nerve terminals projecting to the lateral region of the striatum are the most sensitive to BH4-insufficiency . Biochemical and pathological changes in DPS-rescued mice were similar to those in human malignant hyperphenylalaninemia and DRD . DB00501 in elective Caesarean section . Effect on gastric acidity . Aspiration pneumonitis , Mendelson 's syndrome , continues to be an important cause of maternal morbidity and mortality in obstetric anaesthesia , despite widespread adoption of the practice of routine administration of alkalis . P25021 blocking drugs have been shown to reduce gastric secretion in non-obstetric patients . DB00501 was given intravenously to fasting patients before elective Caesarean section . In all 10 patients who received cimetidine 200 mg intravenously at 60 -- 80 minutes before anaesthesia , the pH of gastric contents at the time of induction was above 2.5 . When the interval between administration of the drug and induction of anaesthesia was only 30 -- 40 minutes ( six patients ) or was over 90 minutes ( 20 patients ) then the pH was raised to above this value in only two-thirds of patients . By contrast eight of 10 untreated patients were found to have a gastric pH of less than 2.5 . No adverse effects of cimetidine were seen in mothers or infants . Genetic and epigenetic markers in the evaluation of pancreatic masses . BACKGROUND : Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma . The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with P01116 mutation detection in the evaluation of pancreatic masses . EXPERIMENTAL DESIGN : Sixty-one fine needle aspirates of pancreatic masses ( 43 pancreatic adenocarcinomas and 18 chronic pancreatitis ) were studied . Methylation status of P25021 , Q05925 , P09486 , P55290 and P25054 were analysed using melting curve analysis after DNA bisulfite treatment . P01116 mutations were also analysed . RESULTS : The methylation panel had a sensitivity of 73 % ( 27 of 37 , CI 95 % 56 to 86 % ) and a specificity of 100 % whenever two or more promoters were found hypermethylated . P01116 mutations showed a sensitivity of 77 % ( 33 of 43 , CI 95 % 62 to 88 % ) and a specificity of 100 % . Both molecular analyses added useful information to cytology by increasing the number of informative cases . When genetic and epigenetic analyses were combined sensitivity was 84 % ( 36 of 43 CI 95 % 69 to 93 % ) maintaining a 100 % specificity . CONCLUSIONS : Analysis of hypermethylation status of a panel of genes and P01116 mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses . The combined molecular analysis increases the number of informative cases without diminishing specificity . Expression and possible role of IGF-IR in the mouse gastric myenteric plexus and smooth muscles . P01308 -like growth factor-I ( P05019 ) and its receptor ( IGF-IR ) have tremendous trophic effects on the central , peripheral and enteric neurons . The loss of IGF-IR contributes to the development of diabetic gastroparesis . However , the nature and the function of the IGF-IR(+) cells in the gastric myenteric plexus remain unclear . In this study , anti- P28329 , anti-S100β or anti-c- P10721 antibodies were used to co-label IGF-IR(+) cells and neurons , glial cells or interstitial cells of Cajal ( ICCs ) , respectively . We also generated type 1 diabetic mice ( DM ) to explore the influence of impaired P05019 /IGF-IR in the myenteric neurons . Results showed that IGF-IR was expressed in the epithelium , smooth muscles and myenteric plexi of the mouse stomach . Most of the IGF-IR(+) cells in the myenteric plexi were P28329 (+) cholinergic neurons , but not enteric glial cells and there were more IGF-IR(+) neurons and fibers in the gastric antrum than in the corpus . The IGF-IR(+)/ P28329 (+) neurons and ICCs were closely juxtaposed , but distinctly distributed in the myenteric plexus , indicating a possible role for the IGF-IR(+)/ P28329 (+) neurons in the mediation of gastric motility through ICCs . Moreover , the decrease of IGF-IR and cholinergic neurons in the myenteric plexi and smooth muscles of DM mice suggested that P05019 /IGF-IR signaling might play a role in neuron survival and neurite outgrowth , as well as stem cell factor ( P21583 ) production , which is required for the development of ICCs . Our results provide insights into the effects of P05019 /IGF-IR signaling on the development of gastrointestinal motility disorders . Novel multiplex method to assess insulin , leptin and adiponectin regulation of inflammatory cytokines associated with colon cancer . The role of altered levels of insulin , leptin and adiponectin in contributing to the observed increased risk of colon cancer associated with obesity remains to be determined . Elevated insulin and leptin associated with obesity are linked to inflammatory responses . Conversely , adiponectin levels are reduced in obese individuals and this hormone is generally associated with anti-inflammatory responses . Inflammatory cytokines are key components of processes linked with carcinogenesis . P01308 , leptin and adiponectin receptor expression profiles were assessed in human normal , adenomatous polyp and tumour tissue . P01308 , leptin and adiponectin regulation of inflammatory cytokines previously identified as being associated with early events in colon carcinogenesis were further investigated here using a surrogate colon epithelial cell line and a custom designed GeXP assay of the inflammatory cytokines ( P78556 , P09341 , P19875 , P19876 , O14625 , P18510 , P02776 , P10145 , Q99731 , O00585 , P55773 , P13501 , Q08334 and P19438 ) . Mean insulin , leptin and adiponectin receptor expression levels were lower in adenomatous polyp samples in comparison with normal and tumour tissue . In contrast to leptin , insulin significantly reduced P78556 and O14625 and increased P19876 expression . Q8N1N2 length adiponectin , but not globular adiponectin , induced P13501 , P09341 , P19876 and P78556 gene expression . GeXP assay permitted measurement of changes in gene expression of cytokines in response to insulin and adiponectin , indicating the potential for insulin and adiponectin regulation of mediators of inflammation associated with early events in colon carcinogenesis . The diagnosis of fasting hypoglycemia due to an islet-cell tumor obscured by a highly specific insulin assay . The work-up of fasting hypoglycemia may be difficult but is crucially important because a wrong diagnosis can lead to either unnecessary pancreatectomy or a missed pancreatic tumor . We describe a patient with severe fasting hypoglycemia [ 22-32 mg/dl ( 1. P35326 .8 mmol/liter ) after 6-10 h of fasting ] in which the diagnosis of a secretory islet-cell tumor was obscured , rather than facilitated , by use of a new , highly specific serum insulin assay . P01308 measured by the specific assay suppressed normally during fasting hypoglycemia [ undetectable at < 2.0-3.8 micro IU/ml ( 26.4 pmol/liter ) ] , whereas insulin measured by older , less specific assays was diagnostically elevated [ 34 , 73 micro IU/ml ( 236.1 , 507.0 pmol/liter ) ] . Serum proinsulin and C-peptide levels were abnormal , and further work-up revealed an islet-cell tumor that secreted predominantly proinsulin . The tumor was surgically removed , relieving the fasting hypoglycemia . We conclude that insulin levels as measured by new , highly specific insulin assays may obscure the diagnosis of a functional , proinsulin-secreting islet-cell tumor . Because proinsulin cross-reacts with insulin in older insulin assays , C-peptide or proinsulin should be measured to rule out a proinsulin-secreting islet-cell tumor . Normative values for new insulin assays must be established during prolonged fasting . Potentiation of P01138 -induced neurite outgrowth in PC12 cells by papaverine : role played by P98160 -γ , IP3 receptors . DB01113 , an inhibitor of phosphodiesterase ( PDE ) 10A , is gaining attention for its potential in the treatment of neuropsychiatric diseases such as schizophrenia . However , the precise mechanisms underlying the putative neuroprotective/neurotrophic actions of papaverine remain unclear . Thus , we investigated the effects of papaverine on nerve growth factor ( P01138 ) -induced neurite outgrowth in PC12 cells . DB01113 potentiated P01138 -induced neurite outgrowth in PC12 cells in a concentration-dependent manner . In contrast , the selective Q9Y233 inhibitor MP-10 had no effect on P01138 -induced neurite outgrowth . The potentiation of P01138 -induced neurite outgrowth by papaverine was blocked by the P98160 -γ inhibitor U73122 . Furthermore , papaverine 's potentiation of P01138 -induced neurite outgrowth was also blocked by the co-administration of inositol 1,4,5-trisphosphate ( IP(3) ) receptor antagonists ( xestospongin C and 2-aminoethoxydiphenyl borate ( 2- Q9H4A4 ) ) and by reduced expression of IP(3) receptor gene ( i.e. , itpr1 and itpr3 ) by siRNA . Our findings suggest that papaverine could potentiate P01138 -induced neurite outgrowth , and that activation of P98160 -γ and IP(3) receptors might be involved in the mechanism underlying papaverine 's potentiation of neurite outgrowth in PC12 cells . DB03886 -dependent hyperphenylalaninemia due to deficiency of 6-pyruvoyl tetrahydropterin synthase . We describe the clinical , neurologic , and biochemical findings in 10 patients with 6-pyruvoyl tetrahydropterin synthase ( 6- Q03393 ) deficiency from seven families , all of whom originate from one large tribe in Saudi Arabia . This deficiency presents with severe , early onset of failure to thrive , neurologic deterioration , and morbidity and mortality secondary to repeated episodes of bronchopneumonia or cardiorespiratory abnormalities . The urinary pterin excretion pattern indicates deficient activity of 6- Q03393 , which has been confirmed by direct enzyme assay in red blood cells of three patients . We treated our patients with combined use of tetrahydrobiopterin 20 mg/kg/d , L-dihydroxyphenylalanine 15 mg/kg/d , carbidopa 3.75 mg/kg/d , and L-5-hydroxytryptophan 5 mg/kg/d . Neurologic findings improved significantly in all after 5 to 24 months . Although head circumference and weight returned to the lower limit of normal in four , height normalized only in one of seven patients . Despite an unrestricted diet during combined therapy , blood phenylalanine and urinary excretion of neopterin and biopterin returned to normal . [ Localization of pancreatic insulinomas by combined radiographic methods ] . Seventeen cases with a total of eighteen insulinomas were examined by ultrasonography ( US ) , computed tomography ( CT ) , angiography , percutaneous transhepatic portal and pancreatic venous sampling ( Q03393 ) and intraoperative ultrasonography ( IOUS ) . We discussed about diagnostic accuracy of insulinomas on these diagnostic modalities . Tumor localization was achieved by US in 39 % , CT in 72 % and angiography in 81 % . Although total 15 tumors ( 83 % ) can be correctly detected , multiple lesions were not completely ruled out . We recommended the criteria in Q03393 as follows : P01308 concentration level above 200 mu U/ml . Or , both of insulin concentration ratio ( step-up site/control ) above three and elevation of the P16435 concentration level on the Q03393 . According to these criteria , the accuracy rate was 91 % . Overall preoperative diagnostic accuracy was 100 % . IOUS allowed us to detect the localization of the tumors completely . DNA hypomethylation , transient neonatal diabetes , and prune belly sequence in one of two identical twins . One known genetic mechanism for transient neonatal diabetes is loss of methylation at 6q24 . The etiology of prune belly sequence is unknown but a genetic defect , affecting the mesoderm from which the triad abdominal muscle hypoplasia , urinary tract abnormalities , and cryptorchidism develop , has been suggested . We investigated a family , including one twin , with transient neonatal diabetes and prune belly sequence . Autoantibody tests excluded type 1 diabetes . Microsatellite marker analysis confirmed the twins being monozygotic . We identified no mutations in Q9NU63 , Q14654 , Q09428 , GCK , P20823 , P35680 , Q9Y261 , P52945 , O43316 , or O60481 . The proband had loss of methylation at the 6q24 locus TNDM and also at the loci P11717 , O95661 , and Q5EB52 , while the other family members , including the healthy monozygotic twin , had normal findings . The loss of methylation on chromosome 6q24 and elsewhere may indicate a generalized maternal hypomethylation syndrome , which accounts for both transient neonatal diabetes and prune belly sequence . The PEPvIII-KLH ( DB05374 ) vaccine in glioblastoma multiforme patients . Conventional therapies for glioblastoma multiforme ( GBM ) fail to target tumor cells exclusively , resulting in non-specific toxicity . Immune targeting of tumor-specific mutations may allow for more precise eradication of neoplastic cells . P00533 variant III ( EGFRvIII ) is a tumor-specific mutation that is widely expressed in GBM and other neoplasms and its expression enhances tumorigenicity . This in-frame deletion mutation splits a codon , resulting in a novel glycine at the fusion junction producing a tumor-specific epitope target for cellular or humoral immunotherapy . We have previously shown that vaccination with a peptide that spans the EGFRvIII fusion junction ( PEPvIII-KLH/ DB05374 ) is an efficacious immunotherapy in syngeneic murine models . In this review , we summarize our results in GBM patients targeting this mutation in multiple , multi-institutional Phase II immunotherapy trials . These trials demonstrated that a selected population of GBM patients who received vaccines targeting EGFRvIII had an unexpectedly long survival time . Further therapeutic strategies and potential pitfalls of using this approach are discussed . P06401 modulator for emergency contraception : a randomized controlled trial . OBJECTIVE : Compare the efficacy and adverse effects of DB05366 , a new progesterone receptor modulator , to levonorgestrel for emergency contraception . METHODS : We performed a randomized , double-blinded noninferiority trial , enrolling healthy women seeking emergency contraception within 72 hours of unprotected intercourse . Participants were randomly assigned to receive a single dose of 50 mg of DB05366 , plus a placebo 12 hours later or two doses of 0.75 mg of levonorgestrel taken 12 hours apart . Follow-up was scheduled 5 to 7 days after the expected onset of the next menstrual period . Posttreatment pregnancy was established by a positive urine test at follow-up and confirmed by quantitative serum beta-hCG . Daily diaries were used from the time of emergency contraception use until next menses to record adverse effects and sexual activity . RESULTS : Product efficacy was evaluable in 775 of DB05366 users and 774 of levonorgestrel users . Pregnancies occurred in 7 ( 0.9 % , 95 % confidence interval 0. P35326 .6 % ) and 13 ( 1.7 % , 95 % confidence interval 0.8-2.6 % ) women , respectively . Based on the estimated cycle day of unprotected intercourse , 85 % and 69 % of anticipated pregnancies , respectively , were averted . Nausea was reported by a somewhat greater percentage of DB05366 than levonorgestrel users ( 29 % compared with 24 % , P=.03 ) , but the distribution of other adverse effects was similar in both groups . Women in both groups experienced considerable variation in menstrual cycle length as compared with their reported individual normal cycle lengths . CONCLUSION : DB05366 is at least as effective as levonorgestrel in preventing pregnancies after unprotected intercourse and has a similar side effect profile . LEVEL OF EVIDENCE : I . P01308 secretory defects and impaired islet architecture in pancreatic beta-cell-specific P40763 knockout mice . Normal islet formation and function depends on the action of various growth factors operating in pre- and postnatal development ; however , the specific physiological function of each factor is largely unknown . Loss-of-function analyses in mice have provided little information so far , perhaps due to functional redundancies of the growth factors acting on the pancreas . The present study focuses on the role of the transcription factor P40763 in insulin-producing cells . P40763 is one of the potential downstream mediators for multiple growth factors acting on the pancreatic beta-cells , including betacellulin , hepatocyte growth factor , growth hormone , and heparin-binding P01133 -like growth factor . To elucidate its role in the beta-cells , the P40763 gene was disrupted in insulin-producing cells in mice ( P40763 -insKO ) , using a cre-mediated gene recombination approach . Unexpectedly , P40763 -insKO mice exhibited an increase in appetite and obesity at 8 weeks of age or older . The mice showed partial leptin resistance , suggesting that expression of the RIP ( rat insulin promoter ) -cre transgene in hypothalamus partially inhibited the appetite-regulating system . Intraperitoneal glucose tolerance tests , performed in non-obese 5-week-old mice , showed that the P40763 -insKO mice were glucose intolerant . Islet perifusion experiments further revealed a deficiency in early-phase insulin secretion . Whereas islet insulin content or islet mass was not affected , expression levels of P11168 , Q09428 , and P15692 were significantly reduced in P40763 -insKO islets . Interestingly , P40763 -insKO mice displayed impaired islet morphology : alpha-cells were frequently seen in central regions of islets . Our present observations demonstrate a unique role of P40763 in maintaining glucose-mediated early-phase insulin secretion and normal islet morphology . Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk . The etiology of schizophrenia is thought to include both epistasis and gene-environment interactions . We sought to test whether a set of schizophrenia candidate genes regulated by hypoxia or involved in vascular function in the brain ( P31749 , P23560 , O75052 , P36544 , P21964 , Q96EV8 , Q99259 , Q14832 , Q99466 , Q02297 , O43272 , P49798 , P01375 ) interacted with serious obstetric complications to influence risk for schizophrenia . A family-based study of transmission disequilibrium was conducted in 116 trios . Twenty-nine probands had at least one serious obstetric complication ( OC ) using the McNeil-Sjostrom Scale , and many of the OCs reported were associated with the potential for fetal hypoxia . Analyses were conducted using conditional logistic regression and a likelihood ratio test ( LRT ) between nested models was performed to assess significance . Of the 13 genes examined , four ( P31749 ( three SNPs ) , P23560 ( two SNPs ) , Q96EV8 ( one SNP ) and Q14832 ( one SNP ) ) showed significant evidence for gene-by-environment interaction ( LRT P-values ranged from 0.011 to 0.037 ) . Although our sample size was modest and the power to detect interactions was limited , we report significant evidence for genes involved in neurovascular function or regulated by hypoxia interacting with the presence of serious obstetric complications to increase risk for schizophrenia . P06401 modulator DB05366 down-regulates vascular endothelial growth factor , adrenomedullin and their receptors and modulates progesterone receptor content in cultured human uterine leiomyoma cells . BACKGROUND : This study was conducted to evaluate the effects of graded concentrations ( 10(-8) , 10(-7) and 10(-6) M ) of progesterone receptor ( PR ) modulator DB05366 on the protein contents of PR , of vascular endothelial growth factor ( P15692 ) , adrenomedullin ( P35318 ) and their receptors in cultured human uterine leiomyoma and matching myometrial cells . METHODS : PR-A , PR-B , P15692 , P49765 , P15692 receptor ( VEGFR ) -1 , P35968 , P35318 and P35318 receptor ( O15218 ) contents were assessed by Western blot analysis . RESULTS : Treatment with 100 ng/ml progesterone increased P15692 , P49765 and P35318 contents in cultured leiomyoma cells and normal myometrial cells . The concomitant treatment with 10(-6) M DB05366 significantly decreased the progesterone-induced P15692 , P49765 and P35318 contents in cultured leiomyoma cells but not in normal myometrial cells . DB05366 treatment alone decreased P17948 , P35968 and O15218 contents in cultured leiomyoma cells but not in normal myometrial cells . DB05366 treatment increased PR-A and decreased PR-B contents in cultured leiomyoma cells in a dose-dependent manner compared with untreated cultures , whereas no significant changes in PR isoform contents were observed in normal myometrial cells . CONCLUSIONS : These results suggest that DB05366 down-regulates P15692 , P35318 and their receptor contents and modulates PR isoform contents in cultured leiomyoma cells in a cell-type-specific manner . A new approach in the study of the molecular and cellular events implicated in heparin-induced thrombocytopenia . Formation of leukocyte-platelet aggregates . DB01109 -induced thrombocytopenia ( HIT ) , a relatively common complication of heparin therapy , results of platelet activation , via the receptor for the Fc domain of IgG ( FcgammaRIIa ) , by heparin-dependent-antibodies , commonly directed against the heparin-platelet factor 4 ( H- P02776 ) antigenic complex . Our strategy was to use whole blood allowing the study of leukocyte-platelet interactions . Experiments were performed with blood from healthy donors incubated with HIT patients ' plasma and different concentrations of heparin . We showed that 75 % of the HIT patients ' plasma induced the formation of leukocyte-platelet-aggregates in a heparin-dependent-manner . The formation of leukocyte-platelet-aggregates induced by HIT plasma in the presence of heparin was ( i ) independent of the healthy blood donor FcgammaRIIa polymorphism , ( ii ) correlated with the levels of anti H- P02776 IgG antibodies contained in the patients ' plasma , and to a lesser extent to anti H- P02776 IgM antibodies , and ( iii ) was mediated by P16109 . This report opens new prospects in the study of the molecular and cellular events implicated in HIT . DB01268 in the treatment of advanced solid tumors . DB01268 is an oral multikinase inhibitor that blocks the vascular endothelial growth factor receptor ( VEGFR ) , platelet-derived growth factor receptor ( P09619 ) alpha and beta , c-kit , and other receptors . These attributes have proven to be efficacious in the treatment of metastatic renal cell carcinoma ( RCC ) , unresectable gastrointestinal stromal tumors ( GIST ) , and well-differentiated advanced pancreatic neuroendocrine tumors ( PNET ) . Though activity has been reported in other tumor types , phase III trials have not yet demonstrated improved survival outcomes in these cancers . Most side effects including hypertension , hand-foot syndrome , and diarrhea are generally well manageable . This review will detail the preclinical data leading up to the results of the pivotal phase III clinical trials that have led to the widespread use of sunitinib in advanced RCC , GIST , and PNET . [ Progress in locating the genetic causes of schizophrenia ] . Elucidation of the pathogenesis of schizophrenia is progressing rapidly . The importance of the glutamatergic system and the glutamate receptor Q14832 were shown in both genetic and pharmacological studies of the new drug DB05096 . The zinc finger domain-containing gene Q7Z570 could be identified as a new schizophrenia susceptibility gene , while large copy number variants at 1q21.1 and 15q13.3 now are seen as monogenic causes of schizophrenia . It is anticipated that the coming years will see further rapid progress in the unraveling of the causes of schizophrenia . Antithrombin replacement during extracorporeal membrane oxygenation . DB01109 remains the predominant anticoagulant during extracorporeal membrane oxygenation ( ECMO ) . DB01109 acts by potentiating the anticoagulant effect of antithrombin ( P01008 ) . Acquired P01008 deficiency , common in pediatric patients requiring ECMO , may result in ineffective anticoagulation with heparin . P01008 replacement may result in increased bleeding . Our objective is to determine P01008 's effect on anticoagulation and blood loss during ECMO . A retrospective chart review was performed of all patients at Children 's Hospital of Wisconsin who received P01008 while supported on ECMO in 2009 . P01008 activity levels , heparin drip rate , and activated clotting times ( ACT ) were compared before , 4 , 8 , and 24 h after P01008 administration . Chest tube output and packed red blood cell ( pRBC ) transfusion volume were compared from 24 h before P01008 administration to 24 h after . Twenty-eight patients received P01008 as a bolus dose during the course of 31 separate times on ECMO support . The median age of these patients was 0.3 years ( range 1 day-19.5 years ) . P01008 activity increased significantly at 8 and 24 h after administration . No significant difference was noted in heparin drip rate , ACT levels , chest tube output , or pRBC transfusion volume . P01008 administration resulted in higher P01008 activity levels for 24 h without a significant effect on heparin dose , ACT , or measures of bleeding . DB00171 -sensitive potassium channels ( K( DB00171 ) ) in retina : a key role for delayed ischemic tolerance . The objectives of the present study were to determine the localization of K( DB00171 ) channels in normal retina and to evaluate their potential roles in ischemic preconditioning ( IPC ) in a rat model of ischemia induced by increased intraocular pressure ( IOP ) . Brown Norway rats were subjected to sublethal 3- , lethal 20- and 40-min ischemia and the functional recovery was evaluated using electroretinography . The time interval between ischemic insults ranged from 1 to 72 h . The effects of K( DB00171 ) channel blockade on IPC protection were studied by treatment with 0.01 % glipizide . IPC was mimicked by injection of K( DB00171 ) channel openers of 0.01 % (-)cromakalim or 0.01 % P1060 72 h before 20-min ischemia . Co-expression of K( DB00171 ) channel subunits Kir6.2/ Q09428 was observed in the retinal pigment epithelium , inner segments of photoreceptors , outer plexiform and ganglion cell layers and at the border of the inner nuclear layer . In contrast to a 20- or 40-min ischemia , a 3-min ischemia induced no alteration of the electroretinogram ( ERG ) and constituted the preconditioning stimulus . An ischemic challenge of 40 min in preconditioned rats induced impairment of retinal function . However , animals preconditioned 24 , 48 and 72 h before 20-min ischemia had a significant improvement of the ERG . (-)Cromakalim and P1060 mimicked the effect of IPC . DB01067 significantly suppressed the protective effects of preconditioning . In conclusion , activation of K( DB00171 ) channels plays an important role in the mechanism of preconditioning by enhancing the resistance of the retina against a severe ischemic insult . Differences in transcript levels of ABC transporters between pancreatic adenocarcinoma and nonneoplastic tissues . OBJECTIVES : The aim of this study was to evaluate transcript levels of all 49 human DB00171 -binding cassette transporters ( ABCs ) in one of the most drug-resistant cancers , namely , the pancreatic ductal adenocarcinoma ( PDAC ) . Association of ABCs levels with clinical-pathologic characteristics and P01116 mutation status was followed as well . METHODS : Tumors and adjacent nonneoplastic tissues were obtained from 32 histologically verified PDAC patients . The transcript profile of ABCs was assessed using quantitative real-time polymerase chain reaction with a relative standard curve . P01116 mutations in exon 2 were assessed by high-resolution melting analysis and sequencing . RESULTS : Most ABCs were deregulated in PDAC and 10 ABCs were associated with clinical-pathologic characteristics . P01116 mutations did not change the global expression profile of ABCs . CONCLUSIONS : The expression of ABC transporters was significantly deregulated in PDAC tumors when compared to nonmalignant tissues . The observed up-regulation of P21439 , O95342 , P33527 , O15438 , O15440 , Q5T3U5 , and Q9UNQ0 in tumors may contribute to the generally poor treatment response of PDAC . The up-regulation of O95477 , Q8IZY2 , and P45844 implicates a serious impairment of cellular cholesterol homeostasis in PDAC . On the other hand , the observed down-regulation of Q99758 , O95255 , P13569 , and Q09428 suggests a possible role of stem cells in the development and progression of PDAC . C. elegans vulval development as a model system to study the cancer biology of P00533 signaling . Molecular genetic studies of C. elegans vulval development have helped to define an evolutionarily conserved signaling pathway from an P01133 -like ligand through P01133 -receptor , Ras and Q96HU1 kinase to the nucleus . Further studies have identified novel positive regulators such as Q8IVT5 -1 and Q09428 -8/ Q5T124 -2 and negative regulators such as cbl/SLI-1 . The many negative regulatory proteins might serve to prevent inappropriate signaling , and thus are analogous to tumor suppressor genes . Characterization of bortezomib-adapted I-45 mesothelioma cells . BACKGROUND : DB00188 , a proteasome-specific inhibitor , has emerged as a promising cancer therapeutic agent . However , development of resistance to bortezomib may pose a challenge to effective anticancer therapy . Therefore , characterization of cellular mechanisms involved in bortezomib resistance and development of effective strategies to overcome this resistance represent important steps in the advancement of bortezomib-mediated cancer therapy . RESULTS : The present study reports the development of I-45-BTZ-R , a bortezomib-resistant cell line , from the bortezomib-sensitive mesothelioma cell line I-45 . I-45-BTZ-R cells showed no cross-resistance to the chemotherapeutic drugs cisplatin , 5-fluorouracil , and doxorubicin . Moreover , the bortezomib-adapted I-45-BTZ-R cells had decreased growth kinemics and did not over express proteasome subunit beta5 ( P28074 ) as compared to parental I-45 cells . I-45-BTZ-R cells and parental I-45 cells showed similar inhibition of proteasome activity , but I-45-BTZ-R cells exhibited much less accumulation of ubiquitinated proteins following exposure to 40 nm bortezomib . Further studies revealed that relatively low doses of bortezomib did not induce an unfolded protein response ( UPR ) in the bortezomib-adapted cells , while higher doses induced UPR with concomitant cell death , as evidenced by higher expression of the mitochondrial chaperone protein Bip and the endoplasmic reticulum ( ER ) stress-related pro-apoptotic protein P35638 . In addition , bortezomib exposure did not induce the accumulation of the pro-apoptotic proteins p53 , Mcl-1S , and noxa in the bortezomib-adapted cells . CONCLUSION : These results suggest that UPR evasion , together with reduced pro-apoptotic gene induction , accounts for bortezomib resistance in the bortezomib-adapted mesothelioma cell line I-45-BTZ-R .