interacts_with DB09280?
Disease-dependent reciprocal phosphorylation of serine and tyrosine residues of c- DB00134 / P08581 contributes disease retardation of a transgenic mouse model of P35858 . Amyotrophic lateral sclerosis ( P35858 ) is a fatal disease characterized by progressive degeneration of motoneurons . We have demonstrated that hepatocyte growth factor ( P14210 ) attenuates loss of both spinal and brainstem motoneurons of P35858 model mice expressing mutated human P00441 (G93A) ( G93A ) . This study was designed to assess disease-dependent regulatory mechanisms of c- DB00134 / P08581 ( c- DB00134 ) activation in the facial motoneurons of G93A mice . Using double transgenic mice expressing P14210 and mutated P00441 (G93A) ( G93A/ P14210 ) , we showed that phosphorylation of c- DB00134 tyrosine residues at positions 1230 , 1234 and 1235 ( phospho- DB00135 ) , and thereby its activation , was slightly evident in G93A and highly obvious in G93A/ P14210 mice ( but absent in WT and P14210 -Tg mice ) . Phosphorylation of the c- DB00134 serine residue at position 985 ( phospho- DB00133 ) , a residue involved in the negative regulation of its activation , was evident in WT and P14210 -Tg mice . Protein phosphatase 2A ( PP2A ) , which is capable of dephosphorylating c- DB00134 phospho-serine , is upregulated in the facial motoneurons of G93A and G93A/ P14210 mice compared with WT and P14210 -Tg mice . Thus , c- DB00134 activation is reciprocally regulated by phosphorylation between c- DB00134 serine and tyrosine residues through PP2A induction in the presence or absence of mutant P00441 expression , and P14210 functions more efficiently in P35858 and P35858 -related diseases . High doses of intravenous immunoglobulin do not affect the recognition phase of the classical complement pathway . We have recently found that intravenous immunoglobulin ( DB00028 ) prevents deposition of P01024 and C4 fragments onto antibody sensitized erythrocytes . To find out if such an effect results from the blockade of the recognition phase of the classical complement cascade , we investigated the ability of human serum containing high concentrations of DB00028 to deposit the recognition subunit of the first complement component ( C1q ) onto targets . Normal human serum supplemented in vitro with DB00028 did not demonstrate reduced C1q binding to targets as determined by radiolabeled antihuman C1q antibody uptake . Similarly , methylamine-treated normal human serum to which DB00028 was added was equally effective in terms of C1q binding as the same serum without DB00028 . At increasing doses of sensitizing antibody , C1q uptake decreased proportionally ; however , at all antibody dilution points C1q uptake was not significantly different in the serum with DB00028 in comparison with normal serum . Serum from a patient treated with DB00028 did not differ in its capacity to deposit C1q from the same patient 's serum before therapy . Our data suggest that DB00028 does not interfere with the recognition step of classical complement pathway . This is a US government work . There are no restrictions on its use . Drugs targeting nitric oxide synthase for migraine treatment . INTRODUCTION : Ample evidence that nitric oxide ( NO ) is a causative molecule in migraine has encouraged research to develop drugs that target the NO-cGMP cascade for migraine treatment . NO synthase ( NOS ) inhibition is an innovative therapeutic principle . AREAS COVERED : This paper reviews the rationale underlying NOS inhibition in migraine treatment . It also provides a review on the efficacy and safety data for NOS inhibitors ( nonselective NOS inhibitor L-N(G)-methyl-arginine hydrochloride [ L-NMMA ] , selective inducible NOS [ P35228 ] inhibitors GW273629 and GW274150 , combined neuronal NOS [ P29475 ] inhibitor and P28222 /1D receptor agonist DB06096 ) in acute or preventive migraine treatment . EXPERT OPINION : The data highlighted herein , from four placebo-controlled trials and 1 open-labeled clinical trial using 4 different NOS inhibitors on a total of 705 patients , provide convincing efficacy data only for the nonselective NOS inhibitor L-NMMA . Unfortunately , this NOS inhibitor raises cardiovascular safety concerns and has an unfavorable pharmacokinetic profile . As experimental studies predicted , P35228 inhibitors are ineffective in migraine . Still , upcoming selective P29475 inhibitors are a hope for migraine treatment , with the P29475 isoform being most clearly involved in trigeminovascular transmission and central sensitization . Future studies should help to clarify whether NOS inhibition is equally fruitful in acute and preventive treatment . It should also clarify if P29475 inhibition holds promise as a therapeutic tool for the treatment of chronic migraine and other forms of headache . p38 Q96HU1 kinase regulates stem cell apoptosis in human hematopoietic failure . Myelodysplastic syndromes ( P43034 ) are clonal stem cell disorders that lead to ineffective hematopoiesis and are common causes of low blood counts in the elderly . The exact molecular mechanisms regulating increased stem apoptosis in these disorders are not well defined . p38 MAPK activation is important in regulating the growth inhibitory signals of P01375 , TGF-beta and Interferons on human hematopoiesis . Our findings show that p38 MAPK is overactivated in myelodysplasia bone marrows and regulates hematopoietic stem cell apoptosis . Inhibition of p38 MAPK by genetic or pharmacologic means decreases apoptosis and stimulates in vitro hematopoiesis from primary P43034 hematopoietic progenitors . These studies point to the potential efficacy of selective p38alpha inhibitor , DB05412 , in human bone marrow failure . P01375 polymorphisms as a potential modifier gene in the cystic fibrosis . Modifier genes , as the P01375 -α gene , can modulate the cystic fibrosis ( CF ) severity . Thus , -238G > A and -308G > A polymorphisms of P01375 -α gene were analyzed as modifiers of CF . In this context , the present study enrolled 49 CF patients ( diagnosis performed by sweat test and complete P13569 screening ) . The -238G > A polymorphism analysis was performed by Q9ULH0 -PCR , and -308G > A , by PCR-RFLP . In our data , the -238G > A polymorphism was not associated with clinical variability . The AA genotype for -308G > A polymorphism was a risk factor for early gastrointestinal symptoms ( OR=5.98 , 95 % CI=1.06-49.68 ) and protection for the first Pseudomonas aeruginosa ( OR=0.05 , 95 % CI=0.0003-0.007 ) . For the first P. aeruginosa , GA genotype was a risk factor ( OR=10.2 , 95 % CI=1.86-84.09 ) ; for the same genotype , the diagnosis was made in minor time than the AA genotype ( p=0.031 ) . Considering the -308G > A polymorphism alleles , the G allele was a risk factor for early pulmonary symptoms ( OR=3.81 , 95 % CI=1.13-12.97 ) and P. aeruginosa ( OR=66.77 , 95 % CI=15.18-482.7 ) ; however , the same allele showed better transcutaneous oxygen saturation ( OR=9.24 , 95 % CI=1.53-206.1 ) . The A allele was a protective factor for early pulmonary symptoms ( OR=12.26 , 95 % CI=0.08-0.89 ) and P. aeruginosa ( OR=12.15 , 95 % CI=0002-0007 ) , however , the same allele was a risk factor for worst transcutaneous oxygen saturation ( OR=7.01 , 95 % CI=1.14-157.4 ) . As conclusion , the -308G > A polymorphism of the P01375 -α gene was associated with the CF severity . Molecular physiology of glucagon-like peptide-1 insulin secretagogue action in pancreatic β cells . P01308 secretion from pancreatic β cells is stimulated by glucagon-like peptide-1 ( P0C6A0 ) , a blood glucose-lowering hormone that is released from enteroendocrine L cells of the distal intestine after the ingestion of a meal . P0C6A0 mimetics ( e.g. , DB01276 ) and P0C6A0 analogs ( e.g. , DB06655 ) activate the β cell P43220 ( P43220 ) , and these compounds stimulate insulin secretion while also lowering levels of blood glucose in patients diagnosed with type 2 diabetes mellitus ( T2DM ) . An additional option for the treatment of T2DM involves the administration of dipeptidyl peptidase-IV ( DPP-IV ) inhibitors ( e.g. , Januvia , DB04876 ) . These compounds slow metabolic degradation of intestinally released P0C6A0 , thereby raising post-prandial levels of circulating P0C6A0 substantially . Investigational compounds that stimulate P0C6A0 secretion also exist , and in this regard a noteworthy advance is the demonstration that small molecule Q8TDV5 agonists ( e.g. , AR231453 ) stimulate L cell P0C6A0 secretion while also directly stimulating β cell insulin release . In this review , we summarize what is currently known concerning the signal transduction properties of the β cell P43220 as they relate to insulin secretion . Emphasized are the cyclic AMP , protein kinase A , and Epac2-mediated actions of P0C6A0 to regulate DB00171 -sensitive K⁺ channels , voltage-dependent K⁺ channels , O94759 cation channels , intracellular Ca⁺ release channels , and Ca⁺-dependent exocytosis . We also discuss new evidence that provides a conceptual framework with which to understand why P43220 agonists are less likely to induce hypoglycemia when they are administered for the treatment of T2DM . A DNA hypermethylation profile reveals new potential biomarkers for prostate cancer diagnosis and prognosis . BACKGROUND : DNA hypermethylation has emerged as a novel molecular biomarker for the evaluation of prostate cancer diagnosis and prognosis . Defining the specific gene hypermethylation profile for prostate cancer could involve groups of genes that specifically discriminate patients with indolent and aggressive tumors . METHODS : Genome-wide methylation analysis was performed on 83 tumor and 10 normal prostate samples using the GoldenGate Methylation Cancer Panel I ( Illumina , Inc. ) . All clinical stages of disease were considered . RESULTS : We found 41 genes hypermethylated in more than 20 % of the tumors analyzed ( P < 0.01 ) . Of these , we newly identified P28161 and P01210 as being genes that are hypermethylated in prostate cancer and that were simultaneously methylated in 40.9 % of the tumors analyzed . We also identified panels of genes that are more frequently methylated in tumor samples with clinico-pathological indicators of poor prognosis : a high Gleason score , elevated Ki-67 , and advanced disease . Of these , we found simultaneous hypermethylation of P13569 and P28222 to be common in patients with a high Gleason score and high Ki-67 levels ; this might indicate the population at higher risk of therapeutic failure . The DNA hypermethylation profile was associated with cancer-specific mortality ( log-rank test , P = 0.007 ) and biochemical recurrence-free survival ( log-rank test , P = 0.0008 ) . CONCLUSIONS : Our findings strongly indicate that epigenetic silencing of P28161 and P01210 is a common event in prostate cancer that could be used as a molecular marker for prostate cancer diagnosis . In addition , simultaneous P28222 and P13569 hypermethylation could help discriminate aggressive from indolent prostate tumors . Drosophila Answers to Q13148 Proteinopathies . Initially implicated in the pathogenesis of P13569 and HIV-1 transcription , nuclear factor Q13148 was subsequently found to be involved in the origin and development of several neurodegenerative diseases . In 2006 , in fact , it was reported for the first time the cytoplasmic accumulation of Q13148 in ubiquitin-positive inclusions of P35858 and FTLD patients , suggesting the presence of a shared underlying mechanism for these diseases . Today , different animal models of Q13148 proteinopathies are available in rodents , nematodes , fishes , and flies . Although these models recapitulate several of the pathological features found in patients , the mechanisms underpinning the progressive neuronal loss observed in Q13148 proteinopathies remain to be characterized . Compared to other models , Drosophila are appealing because they combine the presence of a sophisticated brain with the possibility to investigate quickly and massively phenotypic genetic modifiers as well as possible therapeutic strategies . At present , the development of Q13148 -related Drosophila models has further strengthened the hypothesis that both Q13148 " loss-of-function " and " gain-of-function " mechanisms can contribute to disease . The aim of this paper is to describe and compare the results obtained in a series of transgenic and knockout flies , along with the information they have generated , towards a better understanding of the mechanisms underlying Q13148 proteinopathies . Cystic fibrosis modifier genes related to Pseudomonas aeruginosa infection . Cystic fibrosis ( CF ) is one of the most common life-shortening genetic disorders , and the CF transmembrane conductance regulator ( P13569 ) is the major causal gene . However , a substantial clinical variability among patients with identical P13569 genotypes suggests the presence of modifier genes . We tested the effect of four genes involved in Pseudomonas aeruginosa infection . Analysis of a primary cohort detected eight candidate polymorphisms that were genotyped in the secondary cohort of 1579 patients ; lung function and age at first infection with P. aeruginosa were considered as the phenotypes . Both additive and codominant models were considered , adjusting for confounding variables but not for multiple comparisons . In the secondary cohort , heme oxygenase-1 ( P09601 ) rs2071749 had the most significant effect on lung function in the pediatric group ( P=0.01 ; P(corrected)=0.03 ) , and complement factor 3 ( P01024 ) rs11569393 and P09601 rs2071746 in the adult groups ( P=0.03 for both variants ; P(corrected)=0.16 , 0.09 ) . No polymorphism of complement factor B ( P00751 ) or toll-like receptor 4 ( O00206 ) had a significant modifying effect on lung function in either group . We have identified two genes that showed nominal association with disease severity among CF patients . However , because of the multiple comparisons made , further studies are required to confirm the interaction between these modifying genes and P13569 . Interplay between inhibitory ferric and stimulatory curcumin regulates phosphorylation-dependent human cystic fibrosis transmembrane conductance regulator and ΔF508 activity . Curcumin potentiates cystic fibrosis transmembrane conductance regulator ( P13569 ) activation in an DB00171 -independent but phosphorylation-dependent manner . The underlying molecular mechanisms are unclear . Here , P29320 -293T cells cultured in an Fe(3+)-containing medium were transiently transfected with P13569 constructs , and the role of the inhibitory Fe(3+) bridge between intracellular loop 3 and the regulatory domain of P13569 in this pathway was investigated . The results showed that ethylenediaminetetraacetic acid ( DB00974 ) stimulated phosphorylation-dependent P13569 activation and the stimulation was suppressed by the deletion of the regulatory domain or the insertion of a C832A mutation that removes the Fe(3+)-binding interface . Furthermore , curcumin potentiation of P13569 was significantly weakened not only by Fe(3+)-insensitive mutations at the interface between the regulatory domain and intracellular loop 3 but also by N-ethylmaleimide or DB00974 pretreatment that removes Fe(3+) . More importantly , potentiation of P13569 was completely suppressed by sufficient Fe(3+) . Finally , the insertion of Fe(3+)-insensitive H950R/S768R increased the curcumin-independent activity of ΔF508 but weakened its curcumin potentiation . Thus , Fe(3+) homeostasis in epithelia may play a critical role in regulating P13569 activity , and targeting Fe(3+)-chelating potentiators may direct new therapies for cystic fibrosis . P01308 is involved in transcriptional regulation of NKCC and the P13569 Cl(-) channel through PI3K activation and P29323 inactivation in renal epithelial cells . It is is well known that insulin stimulates glucose transport and epithelial Na(+) channel ( ENaC ) -mediated Na(+) reabsorption ; however , the action of insulin on Cl(-) secretion is not fully understood . In this study , we investigated the action of insulin on Na(+)-K(+)-2Cl(-) cotransporter ( NKCC ) -mediated Cl(-) secretion in epithelial A6 cells . Interestingly , insulin treatment remarkably enhanced the forskolin-stimulated Cl(-) secretion associated with an increase in apical Cl(-) conductance by upregulating mRNA expression of both P13569 and NKCC , although insulin treatment alone had no effect on the basal Cl(-) secretion or apical Cl(-) conductance without forskolin application . We next elucidated a role of phosphoinositide 3-kinase ( PI3K ) in the insulin-induced enhancement of the Cl(-) secretion , since insulin actually activated PI3K , resulting in activation of Akt , a downstream molecule of PI3K . LY294002 ( a PI3K inhibitor ) reduced the Cl(-) secretion by suppressing mRNA expression of NKCC , whereas insulin still had a stimulatory action on mRNA expression of P13569 even in the presence of LY294002 . On the other hand , we found that a MEK inhibitor ( PD98059 ) further enhanced the insulin-stimulated P13569 mRNA expression and the Cl(-) secretion in forskolin-stimulated A6 cells and that insulin induced slight , transient activation of P29323 followed by significant inactivation of P29323 . These observations suggest that : ( 1 ) insulin respectively upregulates mRNA expression of NKCC and P13569 through activation of PI3K and inactivation of P29323 ; ( 2 ) insulin signals on mRNA expression of NKCC and P13569 are not enough to stimulate transepithelial Cl(-) secretion , but enhance the stimulatory action of DB02527 on transepithelial Cl(-) secretion . First intracellular loop of the human cholecystokinin-A receptor is essential for cyclic AMP signaling in transfected P29320 -293 cells . Cholecystokinin ( CCK ) -A and CCK-B receptors are highly homologous members of the seven transmembrane domain G-protein-coupled receptor superfamily . Genes of both receptors contain five exons and share a similar exon-intron organization . To determine the structural basis of P32238 ( P32238 ) functionally coupled to Gs , a series of chimeric mutants were constructed by replacing exons of human P32239 ( P32239 ) , from the second to the fifth ( last ) exon , with human P32238 counterparts . Binding and signal transduction properties of wild-type and chimeric receptors were examined in stably transfected P29320 -293 cells . Chimeric receptors that maintained high affinity binding to CCK exhibited dose-dependent increases in intracellular calcium mobilization similar to both wild-type receptors . However , only the wild-type P32238 and chimeric mutants containing the second exon of P32238 were able to mediate significantly greater increases in intracellular DB02527 content and adenylyl cyclase activity compared with wild-type P32239 . A P32239 mutant was further constructed by replacing five amino acids , DB00145 - DB00149 - DB00133 - DB00125 -( DB00125 )- DB00149 , in the first intracellular loop with the corresponding five P32238 specific amino acids , DB00167 - DB00125 - DB00174 -Lys-( DB00125 )- DB00134 . The resultant receptor maintained high affinity binding to both CCK and gastrin and dose-dependent calcium responses similar to wild-type P32239 . However , this first intracellular loop mutant also gained positive DB02527 responses to both sulfated CCK-8 and gastrin-17 with EC50 values of 8.5 +/- 1 nM and 23 +/- 7 nM , respectively . These data suggest that the first intracellular loop of P32238 is essential for coupling to Gs and activation of adenylyl cyclase signal transduction cascade . Sensitivity of a renal K+ channel ( ROMK2 ) to the inhibitory sulfonylurea compound glibenclamide is enhanced by coexpression with the DB00171 -binding cassette transporter cystic fibrosis transmembrane regulator . We demonstrate here that coexpression of ROMK2 , an inwardly rectifying DB00171 -sensitive renal K+ channel ( Q14654 ) with cystic fibrosis transmembrane regulator ( P13569 ) significantly enhances the sensitivity of ROMK2 to the sulfonylurea compound glibenclamide . When expressed alone , ROMK2 is relatively insensitive to glibenclamide . The interaction between ROMK2 , P13569 , and glibenclamide is modulated by altering the phosphorylation state of either ROMK2 , P13569 , or an associated protein , as exogenous MgATP and the catalytic subunit of protein kinase A significantly attenuate the inhibitory effect of glibenclamide on ROMK2 . Thus P13569 , which has been demonstrated to interact with both Na+ and Cl- channels in airway epithelium , modulates the function of renal ROMK2 K+ channels . P09917 pathway promotes cell proliferation in human glioma cell lines . OBJECTIVE : P09917 ( P09917 ) is a key enzyme in the synthesis of leukotrienes ( LTs ) , that might promote carcinogenesis . We investigated P09917 expression and examined whether the P09917 pathway is associated with the proliferation of human brain tumors . METHODS : We immunohistochemically evaluated the profile of P09917 expression in various types of brain tumors obtained from 42 patients , and examined the proliferative effects of the P09917 pathway in human glioma cell lines using a proliferation assay . RESULTS : Immunohistochemistry of glioblastomas , astrocytomas , meningiomas , medulloblastomas , craniopharyngiomas , ependymomas , neurinomas , oligodendrogliomas , malignant lymphomas , dysembryoplastic neuroepithelial and metastatic brain tumors revealed P09917 expression in the cytoplasm and nuclei or nuclear envelopes of tumor cells . The P09917 inhibitor A861 and the P09960 hydrolase inhibitor DB03424 dose-dependently suppressed the proliferation of A172 cells , a glioma cell line . CONCLUSIONS : We confirmed the expression of P09917 in various human brain tumors and demonstrated the partial suppression of tumor growth by inhibitors of the P09917 - P09960 hydrolase pathway in human glioma cell lines . The P09917 - P09960 pathway might play roles in the proliferation of human glioma cells . Genomic structure of murine methylmalonyl- DB01992 mutase : evidence for genetic and epigenetic mechanisms determining enzyme activity . Methylmalonyl- DB01992 mutase ( P22033 ) is a nuclear-encoded mitochondrial matrix enzyme . We have reported characterization of murine P22033 and cloning of a murine P22033 cDNA and now describe the murine Mut locus , its promoter and evidence for tissue-specific variation in P22033 mRNA , enzyme and holo-enzyme levels . The Mut locus spans 30 kb and contains 13 exons constituting a unique transcription unit . A B1 repeat element was found in the 3' untranslated region ( exon 13 ) . The transcription initiation site was identified and upstream sequences were shown to direct expression of a reporter gene in cultured cells . The promoter contains sequence motifs characteristic of : ( 1 ) TATA-less housekeeping promoters ; ( 2 ) enhancer elements purportedly involved in co-ordinating expression of nuclear-encoded mitochondrial proteins ; and ( 3 ) regulatory elements including CCAAT boxes , cyclic AMP-response elements and potential P05549 -binding sites . Northern blots demonstrate a greater than 10-fold variation in steady-state mRNA levels , which correlate with tissue levels of enzyme activity . However , the ratio of holoenzyme to total enzyme varies among different tissues , and there is no correlation between steady-state mRNA levels and holoenzyme activity . These results suggest that , although there may be regulation of P22033 activity at the level of mRNA , the significance of genetic regulation is unclear owning to the presence of epigenetic regulation of holoenzyme formation . DB00640 regulation of cystic fibrosis transmembrane conductance regulator through prostenoids in airway epithelia . Cystic fibrosis is caused by dysfunction of the cystic fibrosis transmembrane conductance regulator ( P13569 ) protein , leading to altered ion transport , chronic infection , and excessive inflammation . Here we investigated regulation of P13569 in airway cell monolayers by adenosine , adenosine receptors , and arachidonic acid . Our studies demonstrate that the A2B adenosine receptor is expressed at high levels relative to the other adenosine receptor subtypes , with a characteristic low-affinity profile for adenosine-stimulated P13569 Cl- currents in both Calu-3 cells and CFBE41o- airway cell monolayers stably transduced with wild-type P13569 . The levels of adenosine found in sputum from patients with cystic fibrosis with moderate to severe lung disease stimulated apical prostaglandin release in Calu-3 and CFBE41o- cells , implicating adenosine regulation of phospholipase A2 ( P04054 ) activity . A2B adenosine receptor and arachidonic acid stimulation produced P13569 -dependent currents in airway monolayers and increased DB02527 levels that were sensitive to cyclooxygenase inhibition . Arachidonic acid demonstrated dual regulation of P13569 , stimulating P13569 and Cl- currents in intact airway monolayers , and potently inhibiting PKA-activated Cl- currents in excised membrane patches . Cl- currents produced by arachidonic acid were sensitive to inhibition of PKA , cyclooxygenase , and P09917 . Together , the results provide a converging mechanism to link regulation of P13569 and airway cell inflammation through adenosine and adenosine receptors . Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed " correctors " such as DB09280 ( VX-809 ) that improve P13569 maturation and trafficking and " potentiators " such as ivacaftor ( VX-770 ) that enhance channel activity may provide important advances in CF therapy . Although VX-770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX-770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX-770 administration caused a dose-dependent reversal of VX-809-mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX-770 , markedly increasing its turnover rate . Chronic VX-770 treatment also reduced mature wild-type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short-term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and/or development of new potentiator compounds that do not interfere with P13569 stability . Improved diabetic control during oral sulfonylurea treatment in two children with permanent neonatal diabetes mellitus . Permanent neonatal diabetes mellitus ( P01160 ) , defined as diabetes diagnosed in the first 6 months of age and requiring life-long insulin therapy , is a rare disorder of unknown etiology . Activating mutations of the Q14654 gene , which encodes the Kir6.2 subunit of the DB00171 -dependent potassium channel in beta-cells , have been found to cause 30-58 % of cases of P01160 . Sulfonylurea treatment in theses patients reduces or eliminates the need for exogenous insulin . We report two Taiwanese boys who were diagnosed with P01160 at 1 and 4.5 months of age . They had been treated with exogenous insulin for 6 and 15 years , respectively . In September 2006 , they were both found to have a Q14654 mutation ( valine-to-methionine at codon 59 ; V59M ) . DB01016 successfully increased the basal C-peptide level , lowered HbA(1c) , and reduced blood sugar excursions . In one patient , the insulin dose was reduced to 0.2 U/kg/day , and the other was able to discontinue insulin altogether . These two cases from Taiwan add to the experience with similar mutations reported in Caucasians . 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 . Possible role of cholecystokinin-A receptors in regulation of thyrotropin ( DB00024 ) secretion in male rats . We studied the importance of cholecystokinin ( CCK ) system in the regulation of thyrotropin ( DB00024 ) and prolactin ( PRL ) secretion in male rats . To this end , we tested the effects of both unselective CCK agonists CCK-8 and caerulein , and CCK-B selective agonists Q13308 and pentagastrin as well as the selective CCK antagonists ( devazepide and L-365,260 ) at wide dose-ranges on the cold-stimulated and TRH-induced DB00024 and PRL secretion . DB00403 , given s.c . 15 min before sacrifice , decreased DB00024 levels at 5 micrograms/kg . In time course-studies , the maximum inhibition was seen at 15 min but the effect lasted at least 30 , but less than 60 min . Also CCK-8 decreased DB00024 levels at the doses of 20 and 50 micrograms/kg at 15 min . Devazepide and L-365,260 did not affect DB00024 or PRL levels at any dose . The effect of caerulein ( 5 micrograms/kg ) was antagonized by devazepide , a CCK-A antagonist , at 100 micrograms/kg , but not by a CCK-B antagonist L-365,260 tested at a wide dose range . PRL levels were not affected by any treatment . DB00403 ( 5 micrograms/kg ) , given at the same time as TRH ( 500 ng/kg ) , inhibited the TRH-induced DB00024 levels at 15 min , but not at 30 or 60 min . CCK-8 ( 50 micrograms/kg ) , Q13308 ( 100 micrograms/kg ) and pentagastrin ( 500 micrograms/kg ) did not affect the TRH-induced DB00024 secretion . The results probably indicate that P32238 stimulation inhibits DB00024 secretion at the level of the anterior pituitary gland . PRL levels in male rats are not affected by CCK system . [ Diagnosis and treatment of isolated methylmalonic acidemia ] . OBJECTIVE : To explore the clinical feature , therapeutic effect and prognosis of isolated methylmalonic acidemia . METHODS : The clinical characteristics , laboratory findings , treatment and outcome of 40 patients were retrospectively analyzed . The main treatment was a low-protein diet supplemented with L-carnitine and special milk free of leucine , valine , threonine and methionine . DB00115 was also given to cobalamin responders . The patients were followed up every 1-3 months . RESULTS : Mutations in the P22033 gene were identified in 30 of 33 patients who had accepted DNA testing . Thirty cases were treated and followed up regularly for from 1 month to 8 years . Eight cases had died , 8 had developed normal intelligence , among whom 4 from newborn screening were asymptomatic . Psychomotor developmental delay and mental retardation were present in 14 cases . The propionylcarnitine level , ratio of propionylcarnitine/acetylcarnitine in blood , methylmalonic acid and methylcitric acid levels in urine have decreased significantly , with the median values reduced respectively from 24.15 ( 7.92-81.02 ) μmol/L , 1.08 ( 0.38-6.01 ) , 705.34 ( 113.79-3078.60 ) and 7.71 ( 0.52-128.21 ) to 10.50 ( 3.00-30.92 ) μmol/L , 0.63 ( 0.25-2.89 ) , 166.23 ( 22.40-3322.21 ) and 3.96 ( 0.94-119.13 ) ( P < 0.05 ) . CONCLUSION : The prognosis of isolated methylmalonic acidemia may be predicted with the enzymatic subgroup , age at onset and cobalamin responsiveness . Outcome is unfavorable in neonatal patients and those who were non-responsive to cobalamin . Multiple endocytic signals in the C-terminal tail of the cystic fibrosis transmembrane conductance regulator . The cystic fibrosis transmembrane conductance regulator ( P13569 ) is a DB02527 -dependent protein kinase ( PKA ) -activated chloride channel that is localized to the plasma membrane and endosomal compartment . Endosomal targeting of P13569 is attributed to the DB00135 (1424)-based internalization signal , identified in the C-terminal tail of the channel . Mutation of the DB00135 (1424) residue could partly inhibit the endocytosis of P13569 and its association with the adapter protein P05549 . To reveal additional endosomal targeting signals , site-directed mutagenesis of both a chimaera , composed of a truncated form of interleukin 2 receptor alpha chain ( TacT ) and the C-terminal tail of P13569 ( Ct ) , and the full-length P13569 was performed . Morphological and functional assays revealed the presence of multiple internalization motifs at the C-terminus , consisting of a phenylalanine-based motif ( DB00120 (1413) ) and a bipartite endocytic signal , comprising a tyrosine ( DB00135 (1424) ) and a di- DB00149 -based ( DB00149 (1430)- DB00149 ) motif . Whereas the replacement of any one of the three internalization motifs with alanine prevented the endocytosis of the TacT-Ct chimaera , mutagenesis of DB00120 (1413)- DB00149 impaired the biosynthetic processing of P13569 , indicating that DB00120 (1413) is indispensable for the native structure of P13569 . In contrast , replacement of DB00149 (1430)- DB00149 - and DB00135 (1424)-based signals with alanine increased the cell-surface density of both the chimaeras and P13569 in an additive manner . These results suggest that the internalization of P13569 is regulated by multiple endocytic sorting signals .