interacts_with DB01268?
Heterogeneous expression of cyclooxygenase-2 and inducible nitric oxide synthase within colorectal tumors : correlation with tumor angiogenesis . BACKGROUND : Recent studies have shown that the cyclooxygenase ( P36551 ) and the inducible nitric oxide synthase ( P35228 ) pathways are involved in the development of tumor angiogenesis in human cancers . AIMS : To investigate whether a different pattern of P35354 and P35228 expression/activity exists within different areas of colorectal tumors and to analyze the relationship between these two enzymes and tumor angiogenesis . METHODS : Microvessel density ( P53602 ) and P35354 , P35228 , vascular endothelial growth factor ( P15692 ) and P15692 receptor-2 ( P35968 ) protein expression were evaluated at both the invasive front ( IF ) and the tumor center ( TC ) in 46 human colorectal cancer specimens . We also investigated the concentration of DB00917 and NO at the same sites . RESULTS : P35354 and P35228 protein expression and activity were significantly higher within the IF than the TC of the tumor specimens . Similarly , P53602 and P15692 / P35968 expression significantly increased from the TC to the IF . Only P35354 expression was significantly correlated with P53602 and P15692 / P35968 expression at both the TC and the IF . CONCLUSION : Our study shows a heterogeneous expression of P35354 and P35228 in colorectal cancer . The up-regulation of P35354 at the IF parallels an increase in vessel density and P15692 / P35968 expression , thus supporting the hypothesis that the tumor periphery is the most aggressive portion of a colorectal tumor . Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene-environment studies on cancer : data from population-based Japanese random samples . Knowledge of genetic polymorphisms in gene-environment studies may contribute to more accurate identification of avoidable risks and to developing tailor-made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene-environment studies on cancer in Japan . SNP typing was performed on middle-aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples . Reinvestigation of carrier transport properties in liquid crystalline 2-phenylbenzothiazole derivatives . We have reinvestigated the charge carrier transport properties in a liquid crystal of 2-(4'-heptyloxyphenyl)-6-dodecylthiobenzothiazole ( 7O- P10721 - P28222 ) , for which the electronic conduction was first established in rodlike liquid crystals and for which the highest hole mobility in the smectic A ( SmA ) phase ever achieved was reported . We found that 7O- P10721 - P28222 exhibited three crystal phases , one of which appeared in a limited temperature range of 10 degrees just below the phase transition temperature from the SmA phase . In this crystal phase , nondispersive transient photohole currents were observed in time-of-flight experiments , and its hole mobility was determined to be 8 x 10(-3) cm(2)/Vs , slightly higher than that reported previously in the SmA phase . For the SmA phase , however , the hole mobility was 1 x 10(-4) cm(2)/Vs . Furthermore , we established the electron transport in the SmA phase of purified 7O- P10721 - P28222 , whose mobility was the same as the hole mobility in that phase . In order to confirm generality of the new findings in 7O- P10721 - P28222 , we investigated the carrier transport properties of its derivative having a short hydrocarbon chain , 2-(4'-heptyloxyphenyl)-6-butylthiobenzothiazole ( 7O- P10721 -S4 ) , and obtained comparable results . The present results correct a mistake in the previous report and give an idea of what a typical mobility in the SmA phase is . On the basis of these results , we discuss what determines the charge carrier mobility in smectic mesophases . Ex vivo binding of flibanserin to serotonin P08908 and 5- Q13049 receptors . DB04908 has been reported to be an agonist at P08908 -receptors and an antagonist at 5- Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5- Q13049 antagonism at doses ( 4-5 mg kg-1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5- Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [3H]8-OH-DPAT and [3H]ketanserin to label P08908 and 5- Q13049 receptors , respectively . DB04908 was given at 1 , 10 and 30 mg kg-1 intraperitoneally . The dose of 1 mg kg-1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg-1 reduced the binding of both radioligands in all the three brain regions non-selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0.5 h and was reduced or not evident after 3 h . We conclude that 5-HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor-mediated effects . Synergistic growth inhibition in HL-60 cells by the combination of acyclic retinoid and vitamin K2 . PURPOSE : The aim of this study was to assess the effects of acyclic retinoid ( P10323 ) and vitamin K(2) ( VK(2) ) in HL-60 cells . METHODS : We used HL-60 cells , and the Trypan Blue dye exclusion method was used for cell proliferation assays . For detection of apoptosis , the P08758 -binding capacity of treated cells was examined by flow cytometry . To evaluate the cell cycle , we used a FITC BrdU Flow P10721 and flow cytometry . Total extracted and equivalent amounts of protein were examined by Western blotting using specific antibodies . RESULTS : P10323 and VK(2) dose dependently inhibited the proliferation of HL-60 cells . These two agents in combination synergistically inhibited cell growth and induced apoptosis . VK(2) inhibited activation of the Ras/MAPK signaling pathway , and P10323 plus VK(2) cooperatively inhibited phosphorylation of RXRα and the growth of HL-60 cells . Moreover , P10323 and VK(2) induced increases in G0/ P55008 phase HL-60 cells , alone and synergistically in combination . CONCLUSION : The synergistic effects of P10323 and VK(2) on HL-60 cells may provide a novel strategy for treating leukemia . DB00435 and superoxide inhibit platelet-derived growth factor receptor phosphotyrosine phosphatases . Platelet derived growth factor receptor ( P09619 ) became tyrosine autophosphorylated in rat mesangial cells shortly after platelet derived growth factor ( PDGF ) ligation in a tyrosine kinase inhibitor ( tyrphostin AG 1296 ) sensitive manner . Ligand-independent , massive tyrosine P09619 phosphorylation was achieved by diverse NO releasing compounds . Phosphorylation was slow compared to PDGF , revealed a concentration- and time-dependency , and was not mimicked by lipophilic cyclic-GMP analogues . P01584 / DB02527 activated mesangial cells released NO and in turn showed P09619 phosphorylation . A NO-synthase involvement was assured by L-NG-nitroarginine methyl ester inhibition . P09619 phosphorylation was also achieved by the redox cycler 2,3-dimethoxy-1,4-naphthoquinone . NO- and O2(.-)-evoked PGDFR phosphorylation was DB06151 reversible . Cell free dephosphorylation assays revealed P09619 dephosphorylation by tyrosine phosphatases . Receptor dephosphorylation by cytosolic phosphatases was completed within 30 min and was sensitive to the readdition of NO donors or orthovanadate . In addition , phosphatase activity determined in a direct dephosphorylation assay using the substrate para-nitrophenyl phosphate was attenuated by NO or vanadate . We conclude that cytosolic protein tyrosine phosphatases are targeted by exogenously supplied or endogenously generated NO in mesangial cells . Radical ( NO. or O2.- ) formation shifts the phosphorylation -- dephosphorylation equilibrium towards phosphorylation , thus integrating redox-mediated responses into established signal transducing pathways . 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 . Suppression of proliferation and migration in highly-metastatic lung cancer cells as well as tumor growth by a new synthesized compound TBrC and its molecular mechanisms of action . To develop new anticancer agents has been considered as a useful and necessary strategy to suppress highly-metastatic lung cancer , the leading cause of cancer-related deaths in the world . In this study , we synthesized a new compound ethyl 6-bromocoumarin-3-carboxylyl L-theanine ( TBrC ) and studied the anticancer activity of TBrC and its molecular mechanisms of action . Our results show that TBrC remarkably inhibits the proliferation and migration in highly-metastatic lung cancer cells by inducing apoptosis and cell cycle arrest as well as regulating related protein expressions . Further study indicated that TBrC not only enhances the protein levels of Bax , cytosolic cytochrome c , caspase-3 and P09874 but also reduces the protein expressions of Bcl-2 , cyclin D1 , P17948 and NF-κB as well as inhibits the phosphorylation and expressions of P35968 and Akt in the cancer cells . More importantly , TBrC displays strong suppression of highly-metastatic tumor growth and reduces the tumor weight by 61.6 % in tumor-bearing mice without toxicity to the mice . Our results suggest that TBrC suppresses the proliferation and migration of lung cancer cells via VEGFR-Akt-NF-κB signaling pathways ; TBrC may have a wide therapeutic and/or adjuvant therapeutic application in the treatment of lung cancer . Pleiotropic stromal effects of vascular endothelial growth factor receptor 2 antibody therapy in renal cell carcinoma models . The benefits of inhibiting vascular endothelial growth factor ( P15692 ) signaling in cancer patients are predominantly attributed to effects on tumor endothelial cells . Targeting non-endothelial stromal cells to further impact tumor cell growth and survival is being pursued through the inhibition of additional growth factor pathways important for the survival and/or proliferation of these cells . However , recent data suggest that P15692 receptor ( VEGFR ) -specific inhibitors may target lymphatic vessels and pericytes in addition to blood vessels . Here , in fact , we demonstrate that DC101 ( 40 mg/kg , thrice a week ) , an antibody specific to murine P35968 , significantly reduces all three of these stromal components in subcutaneous ( SKRC-29 ) and orthotopic ( 786-O-LP ) models of renal cell carcinoma ( RCC ) established in nu/nu athymic mice . DB01268 ( 40 mg/kg , once daily ) , a receptor tyrosine kinase inhibitor of P35968 and other growth factor receptors , also caused significant loss of tumor blood vessels in RCC models but had weaker effects than DC101 on pericytes and lymphatic vessels . In combination , sunitinib did not significantly add to the effects of DC101 on tumor blood vessels , lymphatic vessels , or pericytes . Nevertheless , sunitinib increased the effect of DC101 on tumor burden in the SKRC-29 model , perhaps related to its broader specificity . Our data have important implications for combination therapy design , supporting the conclusion that targeting P35968 alone in RCC has the potential to have pleiotropic effects on tumor stroma . DB01268 treatment in pediatric patients with advanced GIST following failure of imatinib . BACKGROUND : DB01268 inhibits P10721 and other members of the split-kinase-domain family of receptor tyrosine kinases . DB01268 prolongs survival in adult patients with imatinib-resistant gastrointestinal stromal tumor ( GIST ) . We report the experience with sunitinib in pediatric patients with advanced GIST following failure of imatinib . PROCEDURE : DB01268 therapy was provided through a treatment-use protocol . Patients were 10-17 years old at enrollment . All patients had GIST resistant to imatinib therapy . DB01268 was administered daily for 4 weeks in 6-week treatment cycles . P10721 and platelet-derived growth factor receptor alpha ( P16234 ) genotyping of tumor tissue were performed . RESULTS : One patient achieved a partial response , five patients had stable disease and one patient had progressive disease on sunitinib . The duration of disease stabilization was between 7 and 21+ months , with a mean of 15 months . Time to tumor progression was longer on sunitinib than on prior imatinib treatment for five of six patients . Two patients experienced grade 3 adverse events . All other adverse events were grade 1-2 . None of the five patients tested had mutations in P10721 or P16234 . CONCLUSION : DB01268 treatment was associated with substantial initial antitumor activity and acceptable tolerability in this group of pediatric patients with imatinib-resistant GIST . An online coupled cell membrane chromatography with LC/MS method for screening compounds from Aconitum carmichaeli Debx. acting on P35968 . An online analytical method coupling high expression vascular endothelial growth factor receptor ( VEGFR ) cell membrane chromatography ( VEGFR-CMC ) with high performance liquid chromatography mass spectrometry ( LC/MS ) for screening and identification of active component from traditional Chinese herb Aconitum carmichaeli Debx. acting on P35968 was established . Through a 10-port column switcher , factions separated by VEGFR-CMC column ( first dimension ) were transferred and were adsorbed on an enrichment column . Then , these fractions were sent into LC/MS system ( second dimension ) immediately and directly for separation and preliminary identification , respectively . DB01268 malate ( SN ) was used as positive control , while nifedipine ( NF ) , dexamethasone acetate ( DX ) , methoxyamine hydrochloride ( MT ) and atenolol ( AT ) as negative controls . The specification of this VEGFR-CMC-online-LC/MS method was validated by competitive displacement test . As a result , mesaconitine ( O60682 ) , aconitine ( AC ) , and hypaconitine ( HPC ) were identified as the active constituents acting on P35968 . The in vitro inhibition activity of starting extract of Aconitum carmichaeli Debx. , O60682 , AC , and HPC on HEK293/VEGFR cell viability by MTT test , separately . The in vitro inhibition activity of O60682 , AC , and HPC on vascular endothelial growth factor ( P15692 ) secretion of HEK293/VEGFR cell was tested by P15692 -ELISA assay . The screening results given by the system offered additional exemplification supporting this online coupling method and gave new evidence to the development of anti-tumor drug from natural products . Guggulsterone inhibits angiogenesis by blocking P40763 and P15692 expression in colon cancer cells . The plant sterol guggulsterone has been shown to exert anti-tumor effects , making it a candidate chemotherapeutic agent . We investigated the anti-tumor effects of guggulsterone on colon cancer cells and elucidated the underlying molecular mechanisms related to angiogenesis . The apoptotic effects of guggulsterone were examined by cell survival assay . Western blot analysis was used to determine the levels of various down-stream intracellular proteins involved in angiogenesis , including signal transducer and activator of transcription 3 ( P40763 ) , vascular endothelial growth factor ( P15692 ) , hypoxia-inducible factor-1alpha ( HIF-1alpha ) and aryl hydrocarbon receptor nuclear translocator ( P27540 ) . Using chromatin immunoprecipitation assay , we tested whether guggulsterone affects the recruitment of P40763 , P27540 and HIF-1alpha to the human P15692 promoter . To investigate the effect of guggulsterone on vascular endothelial cell migration and invasion , tube formation and migration assays were conducted using human umbilical vein endothelial cells ( HUVECs ) . Matrix metalloproteinase ( MMP ) -2 and -9 activities were measured by gelatin zymography . Guggulsterone significantly reduced cell viability in colon cancer cells in a dose-dependent manner and blocked P15692 , P27540 and P40763 expression prominently in hypoxic conditions . The recruitment of P40763 and P27540 , but not HIF-1alpha , to the P15692 promoter was inhibited by guggulsterone treatment . HUVECs produced much foreshortened and severely broken tubes and showed decreased migration activity under guggulsterone effects . In addition , zymography revealed that P08253 and -9 enzyme activities were markedly lower in the presence of guggulsterone . The results of this study suggest that guggulsterone not only induces apoptosis , but also inhibits angiogenesis and metastasis in colon cancer cells by blocking P40763 and P15692 expression , suggesting its therapeutic potential in the treatment of colorectal cancer . [ GIST refractory to imatinib treatment ] . After the introduction of imatinib , the outcome for patients with advanced gastro-intestinal stromal tumor ( GIST ) was vastly improved . However , resistance to imatinib has become a new problem . The cause of resistance to imatinib is the low sensitivity of gene mutations in the P10721 gene or PDGFRα , or an acquisition of additional mutations , and a low plasma level of imatinib . DB01268 is the first drug that showed an effectiveness for treating GIST refractory to imatinib . New molecular target drugs for overcoming imatinib resistance are being developed now . Pharmacological management of gastrointestinal stromal tumours : an update on the role of sunitinib . The efficacy and tolerability of the receptor tyrosine kinase inhibitor , sunitinib malate , have been demonstrated in phase I-III clinical trials of patients with imatinib-resistant or imatinib-intolerant gastrointestinal stromal tumours ( GIST ) as well as in a worldwide expanded-access study and in a continuous daily dosing ( CDD ) trial . Tumour genotype may have a significant influence on the activity of sunitinib in patients with imatinib-resistant GIST . DB01268 activity was observed across different GIST genotypes and particularly in patients with wild-type and P10721 exon 9 mutations ( all relatively resistant to standard-dose imatinib ) and in patients with secondary P10721 exons 13 and 14 mutations . Adverse events with sunitinib were generally mild to moderate and easily managed by dose reduction , dose interruption or standard supportive measures . Treatment discontinuation can be avoided in most patients by close monitoring before and during treatment with appropriate adverse event management as necessary . The correlation between treatment exposure and clinical response is prompting the search for new approaches to treatment optimisation to ensure that patients derive maximum benefit from sunitinib therapy , including dose adjustments based on blood testing to ensure optimal drug exposure , and the use of the alternative CDD regimen to avoid treatment interruption . Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8-OH-DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p-chlorophenylalanine ( p- P15085 , 300 mg/kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0.5 mg/kg ) or 8-OH-DPAT ( 0.5 mg/kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5,7-dihydroxytryptamine ( 5,7- DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0.5 mg/kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5,7- DB02901 treated rats . In lesioned animals 8-OH-DPAT ( 0.5 mg/kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8-OH-DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour . Membrane P48023 kills human peripheral blood T lymphocytes , and soluble P48023 blocks the killing . It has been believed that the Fas expressed on human peripheral blood T cells ( P10721 ) is nonfunctional , because these cells are insensitive to agonistic anti-Fas/Apo-1 mAbs that efficiently kill in vitro-activated T cells and many Fas-expressing cell lines . Here , we demonstrate that membrane-bound P48023 ( P48023 ) kills both fresh and in vitro-activated P10721 , indicating that the Fas expressed on fresh P10721 is functional . In contrast , soluble P48023 kills only the latter . Naive T cells in umbilical cord blood do not express Fas , but can be induced to express Fas by P01579 or by a combination of P60568 and anti- P10747 mAb , after which they acquire sensitivity to membrane but not to soluble P48023 . Soluble P48023 inhibited the killing of fresh P10721 by membrane P48023 . These results indicate that the shedding of P48023 from the membrane is a mechanism for downregulating at least part of its killing activity . Inhibition of proliferation and migration of luminal and claudin-low breast cancer cells by P09619 inhibitors . BACKGROUND : Platelet-derived growth factors ( PDGFs ) bind to two receptors , PDGFRα and PDGFRβ to mediate cell proliferation , migration and survival . Although epithelial cells typically do not express high levels of PDGFRs , their expression has been reported to increase in breast cancer cells that have undergone epithelial to mesenchymal transition . METHODS : P09619 signaling was inhibited using DB01268 malate , Imatinib mesylate or DB08896 in murine and human luminal-like and claudin-low mammary tumor cell lines or Masitinib in only the human cell lines . A scratch wound assay was used to assess tumor cell migration while immunofluorescence for phosphorylated histone H3 or cleaved caspase 3 was used to determine tumor cell proliferation and apoptosis , respectively . RESULTS : DB01268 and DB08896 , but not Imatinib , were capable of significantly inhibiting the migration of both murine and human luminal-like and claudin-low breast cancer cells while Masitinib inhibited migration in both human breast cancer cell lines . DB01268 but not DB08896 or Imatinib also significantly suppressed tumor cell proliferation in all four cell lines tested while Masitinib had no significant effect on human breast cancer cell proliferation . None of the P09619 inhibitors consistently regulated mammary tumor cell apoptosis . CONCLUSION : DB01268 , DB08896 and Masitinib may prove clinically useful in inhibiting breast cancer cell migration and metastasis while only DB01268 ( and possibly DB08896 in some breast cancer subtypes ) is effective at inhibiting both migration and proliferation of breast cancer cells . P35372 and P20813 gene variants as risk factors in methadone-related deaths . DB00333 is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro-opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 *4,*9 , and *6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 *4 , *9 , and *6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0.05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0.39 ) . In these methadone-related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0.04 ) , a finding not associated with morphine-related deaths . The risk of a methadone-related fatality during treatment may be evaluated in part by screening for P20813 *6 and A118G . Gastrointestinal stromal tumor . Gastrointestinal stromal tumors ( GISTs ) are the most common mesenchymal tumors of the gastrointestinal tract . These form a distinct category of tumors characterized by oncogenic mutations of the P10721 receptor tyrosine kinase in a majority of patients . P10721 is used not only for diagnosis but also for targeted therapy of GISTs . Imatinib , a tyrosine kinase inhibitor , is widely used in the treatment of advanced and metastatic GISTs and has been recently employed in the neo adjuvant and adjuvant set-up with encouraging results . Certain specific mutations in an exon ( such as in exon 9 ) of the P10721 gene result in GISTs that are relatively unresponsive to the Imatinib treatment . New therapeutic agents like DB01268 have now been approved for the treatment of Imatinib-resistant GIST . This review summarizes the salient features of GIST along with a detailed review of targeted multi-disciplinary approach to the treatment of these special tumors . New perspectives : role of sunitinib in breast cancer . DB01268 malate ( SU11248 ) is a multitarget oral tyrosine kinase receptor ( RTKs ) inhibitor which was approved by FDA in renal cells carcinoma ( RCC ) and imatinib-resistant or imatinib-intollerant gastrointestinal stromal tumour ( GIST ) . DB01268 is able to inhibit RTKs such as receptors for platelet-derived growth factor ( PDGF-R alpha and beta ) and for vascular endothelial growth factor ( VEGFRs ) . It is able to inhibit P10721 receptor , colony stimulating factor type 1 receptor ( P04141 - 1R ) , glial cell line neutrophic factor receptor ( P07949 ) , fms-like tyrosine kinase receptor-3 ( P36888 or P36888 ) , signal transducer and activator of transcription 3 ( P40763 ) and AKT ( protein kinase B ) in tumour cells . Many sunitinib targets play important roles in growth and survival of human breast cancer ( BC ) . The " rationale " of sunitinib in BC ( with or without others antiagiogenetic therapy ) is its ability to block simultaneously intracellular portion of RTKs inhibiting many downstream signals . We overviewed the most relevant studies concerning sunitinib in metastatic BC . DNA microarray reveals different pathways responding to paclitaxel and docetaxel in non-small cell lung cancer cell line . The wide use of paclitaxel and docetaxel in NSCLC clinical treatment makes it necessary to find biomarkers for identifying patients who can benefit from paclitaxel or docetaxel . In present study , NCI-H460 , a NSCLC cell line with different sensitivity to paclitaxel and docetaxel , was applied to DNA microarray expression profiling analysis at different time points of lower dose treatment with paclitaxel or docetaxel . And the complex signaling pathways regulating the drug response were identified , and several novel sensitivity-realted markers were biocomputated.The dynamic changes of responding genes showed that paclitaxel effect is acute but that of docetaxel is durable at least for 48 hours in NCI-H460 cells . Functional annotation of the genes with altered expression showed that genes/pathways responding to these two drugs were dramatically different . Gene expression changes induced by paclitaxel treatment were mainly enriched in actin cytoskeleton ( P68032 , P10916 and Q9UKX2 ) , tyrosine-protein kinases ( ERRB4 , P10721 and P35590 ) and focal adhesion pathway ( P10916 , IGF1 and P17948 ) , while the expression alterations responding to docetaxel were highly co-related to cell surface receptor linked signal transduction ( SHH , P21918 and Q7Z4H4 ) , cytokine-cytokine receptor interaction ( P01583 and P05231 ) and cell cycle regulation ( P14635 , O96020 and P12004 ) . Moreover , we also confirmed some different expression patterns with real time PCR . Our study will provide the potential biomarkers for paclitaxel and docetaxel-selection therapy in clinical application . Ca2+-calmodulin and janus kinase 2 are required for activation of sodium-proton exchange by the Gi-coupled 5-hydroxytryptamine 1a receptor . The type 1 sodium-proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5-hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2+/calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist-induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G(i2)alpha and/or G(i3)alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton-sensing and/or proton-transporting region of P19634 --> activation of P19634 . The G(i/o)-coupled P08908 receptor now joins a handful of Gq-coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2+ . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process . In-silico screening and in-vitro validation of Vascular Endothelial Growth Factor Receptor-2 ( P35968 ) inhibitors . P35968 tyrosine kinase receptor draws attention of the scientific fraternity in drug discovery for its important role in cancer , cardiopulmonary , cardiovascular diseases etc . Hence there is a need for novel P35968 inhibitors screening and testing for their biological activities . The 3D-structure was collected from PDB and stability was checked by using WHATIF and PROCHECK programs and subjected for virtual screening on Zinc database . We used virtual screening method to screen new P35968 blocker molecules based on their binding energies and then docked with active site on the receptor with the help of AUTODOCK software . Based on the results obtained top three molecules ( VRB1-3 ) were selected and tested in Cardiomyocytes H9c2 cells for cell viability under hypoxic condition . The invitro studies showed VRB2 as the best molecule among the selected three molecules as well as with a standard commercial drug DB01268 . DB01268 and periodic hair depigmentation due to temporary c- P10721 inhibition . A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue-specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two-hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 's DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull-down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co-immunoprecipitation of Q9Y6X2 . Co-transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP-6 promoter-luciferase reporter demonstrated up to 94 % inhibition of O75030 -mediated transcriptional activation . Using a gel-shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development . Nonclinical safety evaluation of sunitinib : a potent inhibitor of P15692 , PDGF , P10721 , P36888 , and P07949 receptors . DB01268 malate ( SUTENT ) is a multitargeted receptor tyrosine kinase ( RTK ) inhibitor that is approved multinationally for the treatment of imatinib-resistant/-intolerant gastrointestinal stromal tumor and advanced renal cell carcinoma . This paper characterizes the organ toxicity of sunitinib in Sprague-Dawley rats and cynomolgus monkeys , and the reversibility of any treatment-induced effects . Rats and monkeys received sunitinib ( 0-15 and 0-20 mg/kg/day , respectively ) orally on a consecutive daily dosing schedule for thirteen weeks or on an intermittent daily dosing schedule for up to nine months . Clinical observations and laboratory parameters were recorded . Necropsy was conducted following treatment/recovery periods , and histologic examinations were performed . In rats , sunitinib was generally tolerated at 0.3 and 1.5 mg/kg/day , and findings were reversible . In monkeys , the level at which there were no observed adverse effects was 1.5 mg/kg/day , and findings were similarly reversible ( except for uterine/ovarian weight changes and skin pallor ) . Data suggest that inhibition of multiple RTK pathways may induce pharmacologic effects on organ systems in nonclinical species . Key pharmacologic effects of sunitinib included reversible inhibition of neovascularization into the epiphyseal growth plate , and impaired corpora lutea formation and uterine development during estrus . Similar observations have been noted with this class of RTK signaling inhibitors and are consistent with pharmacologic perturbations of physiologic/angiogenic processes associated with the intended molecular targets . Phase II testing of sunitinib : the National Cancer Institute of Canada Clinical Trials Group IND Program Trials IND.182-185 . DB01268 ( SU11248 ) is an orally bioavailable inhibitor that affects the receptor tyrosine kinases involved in tumour proliferation and angiogenesis , including vascular endothelial growth factor ( P15692 ) receptors 1 , 2 , 3 , and platelet-derived growth factor receptors alpha ( P16234 ) and beta ( P09619 ) . Because angiogenesis is necessary for the growth and metastasis of solid tumours , and P15692 is believed to have a pivotal role in that process , SUNITINIB treatment may have broad-spectrum clinical utility . In the present article , we discuss the biologic and clinical rationales that have recently led the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group to initiate four phase ii trials testing this agent in the following four different tumour types : relapsed diffuse large cell lymphoma , malignant pleural mesothelioma , locally advanced or metastatic cervical cancer and recurrent epithelial ovarian , fallopian tube , or primary peritoneal carcinoma . [ The role of matrix metalloproteinases and their inhibitors in pathogenesis of pancreatic pseudocysts ] . The investigation was conducted in 47 patients , operated on for pancreatic pseudocysts ( PP ) . Activity of matrix metalloproteinases ( P14780 ) and content of their tissue inhibitor ( P16035 ) were determined in the blood serum for estimation of inflammatory factors , hypoxia severity and state of the pancreatic tissue reconstruction . High activity of P14780 and P16035 in presence of PP types I and II was noted in patients , what , probably , is caused by compensation reaction , directed towards inhibition of the collagen system destruction ( predominantly of collagen type IV ) and prevention of further reconstruction of pancreatic connective tissue . While progressing of pancreatic fibrosis the P14780 activity and the P16035 level have lowered in comparison with these indices while its absence . In PP type III the P14780 activity was by 83.6 % higher , than in a control group , but , by 51.4 and 35.1 % lower , than in PP types I and IV . In all the patients endothelial dysfunction with endothelial injury was observed , witnessed by significant rising of the P15692 content in the blood serum . It have created favorable conditions for pancreatic tissue remodeling while parenchymal defect have been constituted by tissue , owing lower level of organization , including a cicatricial one . In cases of cellular repeated affection more activation of pancreatic stellate cells and enhancement of production of extracellular matrix component were noted . Blockade of MEK/ P29323 signaling enhances sunitinib-induced growth inhibition and apoptosis of leukemia cells possessing activating mutations of the P36888 gene . The P07333 -like tyrosine kinase 3 ( P36888 ) is a cell surface receptor tyrosine kinase . Activating mutations of this gene occur in nearly 30 % of acute myelogenous leukemia ( AML ) patients . These mutations , in part , result in activation of mitogen-activated protein kinase ( MEK ) /extracellular signal-regulated kinase ( P29323 ) signaling pathways . In this study , we found that AZD6244 ( ARRY-142886 ) , a novel inhibitor of Q02750 /2 kinases , effectively inhibited the proliferation of acute biphenotypic leukemia MV4-11 and acute monocytic leukemia MOLM13 cells . The concentrations that inhibited 50 % growth were approximately 0.3 and 1.2 microM , respectively , as measured by thymidine uptake on day 2 of culture . AZD6244 potently down-regulated the levels of phospho- P27361 /2 and its downstream effector , p-p70S6K , in the MV4-11 and MOLM13 cells as measured by Western blot analysis . Interestingly , when AZD6244 was combined with sunitinib , a P36888 kinase inhibitor , growth inhibition and apoptosis of both MV4-11 and MOLM13 cells were synergistically enhanced in association with further down-regulation of phospho- P27361 /2 and p-p70S6K in these cells . Taken together , concomitant blockade of P36888 and MEK signaling represents a promising treatment strategy for individuals with leukemia who possess activating mutations of P36888 . Targeting PIM kinases impairs survival of hematopoietic cells transformed by kinase inhibitor-sensitive and kinase inhibitor-resistant forms of P36888 and P11274 / P00519 . Previous studies have shown that activation of the signal transducer and activator of transcription 5 ( P42229 ) plays an essential role in leukemogenesis mediated through constitutive activated protein tyrosine kinases ( PTK ) . Because PIM-1 is a P42229 target gene , we analyzed the role of the family of PIM serine/threonine kinases ( PIM-1 to PIM-3 ) in PTK-mediated transformation of hematopoietic cells . Ba/ P13726 cells transformed to growth factor independence by various oncogenic PTKs ( P41212 / O60674 , P41212 / Q16288 , P41212 / P00519 , P11274 / P00519 , P36888 -ITD , and H4/PDGFbetaR ) show abundant expression of PIM-1 and PIM-2 . Suppression of PIM-1 activity had a negligible effect on transformation . In contrast , expression of kinase-dead PIM-2 mutant ( PIM-2KD ) led to a rapid decline of survival in Ba/ P13726 cells transformed by P36888 -ITD but not by other oncogenic PTKs tested . Coexpression of PIM-1KD and PIM-2KD abrogated growth factor-independent growth of Ba/ P13726 transformed by several PTKs , including P11274 / P00519 . Targeted down-regulation of PIM-2 by RNA interference ( RNAi ) selectively abrogated survival of Ba/ P13726 cells transformed by various P36888 ( P36888 ) -activating mutants [ internal tandem duplication ( ITD ) and kinase domain ] and attenuated growth of human cell lines containing P36888 mutations . Interestingly , cells transformed by P36888 and P11274 / P00519 mutations that confer resistance to small-molecule tyrosine kinase inhibitors were still sensitive to knockdown of PIM-2 , or PIM-1 and PIM-2 by RNAi . Our observations indicate that combined inactivation of PIM-1 and PIM-2 interferes with oncogenic PTKs and suggest that PIMs are alternative therapeutic targets in PTK-mediated leukemia . Targeting the PIM kinase family could provide a new avenue to overcome resistance against small-molecule tyrosine kinase inhibitors . Strategic combination therapy overcomes tyrosine kinase coactivation in adrenocortical carcinoma . BACKGROUND : Coactivation of tyrosine kinase limits the efficacy of tyrosine kinase inhibitors . We hypothesized that a strategic combination therapy could overcome tyrosine kinase coactivation and compensatory oncogenic signaling in patients with adrenocortical carcinoma ( ACC ) . METHODS : We profiled 88 tyrosine kinases before and after treatment with sunitinib in H295R and SW13 ACC cells . The effects of monotherapy and strategic combination regimens were determined by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium ( ie , MTS ) assay . RESULTS : The minimum inhibitory concentrations ( IC(min) ) of sunitinib quenched its primary targets : P36888 , P35968 , and P07949 . In contrast , P29323 , P08631 , Chk2 , P07947 , CREB , MEK , MSK , p38 , P09769 , and P30530 were hyperactivated . Monotherapy with sunitinib or PD98059 at their IC(min) reduced proliferation by 23 % and 19 % , respectively , in H295R cells and by 25 % and 24 % , respectively , in SW13 cells . DB01268 and PD98059 in combination decreased proliferation by 68 % and 64 % in H295R and in SW13 cells , respectively ( P < .05 versus monotherapy ) . The effects of combination treatment exceeded the sum of the effects observed with each individual agent alone . CONCLUSION : We describe the first preclinical model to develop strategic combination therapy to overcome tyrosine kinase coactivation in ACC . Because many tyrosine kinase inhibitors are readily available , this model can be immediately tested in clinical trials for patients with advanced ACC . Comparison of two polymer-based immunohistochemical detection systems : ENVISION+ and ImmPRESS . The non-specific background reaction produced in avidin-biotin-based immunohistochemistry , particularly after harsh antigen retrieval procedures , has promoted the use of non-avidin-biotin systems , yet there are few reports comparing the performance of non-avidin-biotin , polymer-based methods . In this study we compare two of these methods , ENVISION+trade mark and ImmPRESS , in animal tissues . We examined the immunoreactivity of 18 antigens in formalin-fixed , paraffin-embedded tissues . Antigens were located in the cytoplasmic membrane ( CD11d , P05107 and CD79a ) , cytoplasm ( calretinin , P23219 , P35354 , Glut-1 , HepPar 1 , P10721 , Melan A , tryptase and uroplakin III ) or nucleus ( Q2TAK8 , P09936 and thyroid transcription factor 1 ) . We also evaluated three infectious agents ( Aspergillus , calicivirus and West Nile virus ) . The staining with ENVISION+ or ImmPRESS was performed simultaneously for each antigen . The intensity of the reaction and background staining were scored . ImmPRESS yielded similar or higher reaction intensity than ENVISION+trade mark in 16/18 antigens . ImmPRESS produced abundant background with the other two antigens ( calretinin and P35354 ) , which hindered interpretation of the specific reaction . The cost of ImmPRESS was 25 % lower than for ENVISION+trade mark . Based on these results , ImmPRESS is a good polymer-based detection system for routine immunohistochemistry . CREB inhibits AP-2alpha expression to regulate the malignant phenotype of melanoma . BACKGROUND : The loss of AP-2alpha and increased activity of DB02527 -responsive element binding ( CREB ) protein are two hallmarks of malignant progression of cutaneous melanoma . However , the molecular mechanism responsible for the loss of AP-2alpha during melanoma progression remains unknown . METHODOLOGY/PRINCIPAL FINDINGS : Herein , we demonstrate that both inhibition of PKA-dependent CREB phosphorylation , as well as silencing of CREB expression by shRNA , restored AP-2alpha protein expression in two metastatic melanoma cell lines . Moreover , rescue of CREB expression in CREB-silenced cell lines downregulates expression of AP-2alpha . Loss of AP-2alpha expression in metastatic melanoma occurs via a dual mechanism involving binding of CREB to the AP-2alpha promoter and CREB-induced overexpression of another oncogenic transcription factor , Q01094 . Upregulation of AP-2alpha expression following CREB silencing increases endogenous P38936 (Waf1) and decreases P43121 / P43121 , both known to be downstream target genes of AP-2alpha involved in melanoma progression . CONCLUSIONS/SIGNIFICANCE : Since AP-2alpha regulates several genes associated with the metastatic potential of melanoma including c- P10721 , P15692 , P25116 , P43121 / P43121 , and P38936 (Waf1) , our data identified CREB as a major regulator of the malignant melanoma phenotype . P35372 mutant , T394A , abolishes opioid-mediated adenylyl cyclase superactivation . This study was to characterize the effects of a point-mutant at C-terminal of mu opioid receptor ( MOR ) , namely MOR T394A , in chronic opioid-induced cellular responses . After 18 h of exposure to [ D-Ala , N-Me- DB00120 , DB00145 -ol ] enkephalin ( DAMGO ) , adenylyl cyclase ( AC ) superactivation , a hallmark for the cellular adaptive response after chronic opioid stimulation , was observed in the cells expressing wild-type receptor , but was totally abolished in the cells expressing MOR T394A . Receptor phosphorylation was also attenuated in cells with MOR T394A after prolonged preexposure to agonist . Furthermore , Q96HU1 kinase kinase-1 ( Q02750 ) overexpression was able to rescue AC superactivation in cells with MOR T394A , but showed no effect in the wild-type MOR-expressing cells . These results indicated that the amino acid T394 at C-terminus of MOR played a critical role in chronic agonist-induced AC superactivation and receptor phosphorylation . Gastrointestinal stromal tumors : a review of case reports , diagnosis , treatment , and future directions . Gastrointestinal stromal tumor ( GIST ) is a nonepithelial , mesenchymal tumor first described by Mazur and Clark in 1983 . Since then , its molecular biology has been studied in great detail . Special interest in the role of tyrosine kinase in its regulation has been the target by different drug research . Mutation in c-kit exons 9 , 11 , 13 , 17 and P16234 mutation in exons 12 , 14 , 18 are responsible for activation of gene signaling system resulting in uncontrolled phosphorylation and tissue growth . However , 5 to 15 % of GISTs does not harbor these mutations , which raises additional questions in another alternate signaling pathway mutation yet to be discovered . Diagnosis of GISTs relies heavily on P10721 /CD117 immunohistochemical staining , which can detect most GISTs except for a few 3 % to 5 % that harbors P16234 mutation . Newer staining against PKC theta and DOG-1 genes showed promising results but are not readily available . Clinical manifestation of GISTs is broad and highly dependent on tumor size . Surgery still remains the first-line treatment for GISTs . The advancement of molecular biology has revolutionized the availability of newer drugs , Imatinib and DB01268 . Together with its advancement is the occurrence of Imatinib/ DB01268 drug resistance . With this , newer monoclonal antibody drugs are being developed and are undergoing clinical trials to hopefully improve survival in patients with GISTs . Synthetic delivery system for tuberculosis vaccines : immunological evaluation of the M. tuberculosis 38 kDa protein entrapped in biodegradable P00747 microparticles . Tuberculosis remains a major public health burden which could be ameliorated by effective and well-defined subunit vaccines , particularly because the protective efficacy of current M. bovis BCG vaccines is both unpredictable and variable . The immunodominant 38 kDa antigen from Mycobacterium tuberculosis was entrapped in biodegradable poly ( DL-lactide co-glycolide ) ( P00747 ) microparticles which served as a delivery system . Both cellular and humoral immune responses were assessed and compared with those obtained after immunization with the 38 kDa protein emulsified in incomplete Freund 's adjuvant ( IFA ) . Vaccination of mice with a single dose of antigen-loaded microparticles resulted in specific IgG titres peaking after five weeks comparable to those achieved after vaccination with protein emulsified in incomplete Freund 's adjuvant ( IFA ) . T-cell responses were found to be superior to those induced with antigen/IFA . The T- and B-cell epitope specificities ad judged with synthetic peptides were identical following immunization with antigen in microparticles or IFA . Differences in adjuvanticity were revealed by measuring antigen-specific IgG1 , IgG2a and antigen-induced P01579 secretion in vitro : substantially higher titres of IgG2a were observed following immunization with antigen/microparticles than with 38 kDa protein/IFA . This was paralleled by a tenfold higher secretion of P01579 in mice injected with antigen/microparticles . Reduction in colony-forming units was not consistent in mice immunized with 38 kDa protein entrapped in microparticles which were subsequently infected with live tubercle bacilli . Taken together these results indicate that biodegradable P00747 microparticles constitute a favorable candidate vaccine delivery system worthy of further assessment in the quest to develop better and defined agents protecting against tuberculosis . DB01268 malate . Recently , there has been a growing interest in understanding the role of receptor tyrosine kinases ( RTK ) , such as vascular endothelial growth factor receptor ( VEGFR ) , platelet-derived growth factor receptor ( P09619 ) , stem cell factor receptor ( P10721 ) , and fms-like tyrosine kinase 3 ( P36888 ) , in promoting tumor angiogenesis , tumor growth and metastasis . DB01268 ( sunitinib malate ; SU11248 ; SUTENT ; Pfizer Inc , New York , NY , USA ) is a novel , orally bio-available , oxindole , multi-targeted tyrosine kinase inhibitor with high binding affinity for VEGFR and P09619 which has shown anti-tumor and anti-angiogenic activities . This drug recently received approval from the US Food and Administration ( FDA ) in two indications simultaneously : advanced renal cell carcinoma ( adRCC ) and gastrointestinal stromal tumors ( GIST ) , in patients who are resistant or intolerant to the treatment with imatinib . The present article reviews the recent pharmacologic and clinical data related to the use of this new promising drug in the field of oncology . DB08879 -- an anti- Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . DB08879 is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up-to-date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat-B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . DB08879 was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 )20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti- P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA . Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9-hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 -arg144 , P11712 -cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH-generating system . DB01267 was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9-hydroxyrisperidone , with activities of 7.5 , 0.4 and 0.2 pmol pmol(-1) CYP min(-1) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9-hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9-hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9-hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9-hydroxyrisperidone in rat . The formation of 9-hydroxyrisperidone is highly correlated with testosterone 6beta-hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat . Analyses of cross species polymerase chain reaction products to infer the ancestral state of human polymorphisms . In numerous population genetic and disease association studies decisions about the ancestry of polymorphic alleles are often made based on the relative frequency of the alleles in the extant populations with the most frequent allele being deemed as ancestral . However , the frequency of an allele in a population is generally not a perfect indicator of its ancestral status . A more accurate method to assess ancestral/derived status of polymorphic alleles involves identification of shared alleles between species . We used this strategy to examine genomic regions homologous to several human polymorphisms in four species of non-human primates . Cross species polymerase chain reaction ( CS-PCR ) , with primers designed from human sequence , was used to investigate regions of interest . Nineteen polymorphisms at six loci ( P14416 , HOXB@ , PAH , D4S10 , P10745 , and P07949 ) were examined either by restriction fragment length analysis of PCR products ( PCR-RFLP ) or by direct sequencing . At seventeen of the eighteen PCR-RFLPs , non-human primates were monomorphic and identical to each other for either lack of restriction enzyme site or presence of the site . Thus , at these seventeen polymorphic sites the shared alleles are most likely to be the ancestral ones in humans . In several cases we have used sequence data to further demonstrate that the nucleotide at the site of the polymorphism is conserved between species confirming the hypothesis of a single ancestral allele . However , not all human alleles can be simply resolved into ancestral and derived ; sequence data from one PCR-RFLP ( in an intron of the PAH locus ) and a single strand conformational polymorphism ( SSCP ) in the 3' untranslated region ( UTR ) of the P14416 gene illustrate this point . Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase-2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long-term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( DB00461 ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti-inflammatory drugs ( NSAIDs ) , and the meta-analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10-fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared . Cytokines as targets in chronic obstructive pulmonary disease . Chronic obstructive pulmonary disease [ P48444 ] is characterised by airflow limitation of peripheral airways that is not fully reversible and progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases . There is also intense airway wall remodelling and evidence of systemic inflammation . Increased interleukin [ IL ] -6 , IL-1beta , tumor necrosis factor-alpha [ P01375 ] , P09341 -alpha , P13500 and P10145 levels are measured in sputum , with further increases during exacerbations . The bronchiolar epithelium over-expresses P13500 , MIP-1alpha and P10145 . P10145 can account for sputum neutrophil chemotactic activity . TNFalpha and IL-1beta stimulate macrophages to produce matrix metalloproteinase-9 [ P14780 ] , and bronchial epithelial cells to produce extracellular matrix glycoproteins . Increased expression of transforming growth factor-beta [ TGFbeta ) and epidermal growth factor [ P01133 ] occurs in the epithelium and submucosal cells ; gene array studies reveal an excess of TGFbeta1 , P29279 and P16234 in P48444 . TGFbeta and P01133 activate proliferation of fibroblasts , while activation of the P01133 receptor leads to mucin gene expression . Anti-cytokine therapy could be in the form of soluble receptors or by neutralising antibodies , small compounds blocking cytokine receptors or incomplete and non-activating cytokines , inhibitors of protein activation and inhibitors of signal transduction and transcription such as via inhibition of mitogen-activated protein kinases [ MAPK ] and of transcription factor , nuclear factor kappaB . Anti- P10145 therapy has been tried with little effect on P48444 , and current trials are on-going with P01375 inhibitors . Other treatments such as phosphodiesterase 4 inhibitors have anti-cytokine effects that may underlie their beneficial effects in P48444 . The secondary P36888 -ITD F691L mutation induces resistance to DB05213 in P36888 -ITD+ AML but retains in vitro sensitivity to PKC412 and DB01268 . DB00338 , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . DB00338 is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P-type H+/K+ ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . DB00338 topically applied to the skin of UV-irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . DB00338 had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P-type ATPase in the trans-Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans-Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . DB00338 treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase . Second line therapies for the treatment of gastrointestinal stromal tumor . PURPOSE OF REVIEW : Most gastrointestinal stromal tumors eventually acquire resistance to imatinib mesylate . This review focuses on recent progress on management of patients whose disease progresses on the standard dose of imatinib . RECENT FINDINGS : Approximately 30 % of patients failing standard-dose imatinib achieve disease stabilization with high-dose imatinib , but objective responses are few and the clinical benefit usually short-lived . Patients receiving enzyme-inducing drugs may need high imatinib doses to achieve therapeutic blood concentrations . Surgical excision of a single growing metastasis leads to a median progression-free survival time of 7-11 months . DB01268 malate is effective following imatinib failure . The median time to disease progression is approximately 6 months with sunitinib therapy versus 6 weeks with placebo following discontinuation of imatinib , but few ( 5 % ) patients achieve objective response . Patients with gastrointestinal stromal tumor with P10721 exon 9 mutation may benefit more from sunitinib than those with exon 11 mutation . DB01268 frequently causes abnormal thyroid function . SUMMARY : DB01268 is now the approved second line therapy following imatinib failure and for patients intolerant to imatinib . The clinical benefit is only moderate , and thyroid function monitoring is required . Several investigational agents are being evaluated for imatinib-resistant gastrointestinal stromal tumor . Palliative procedures , such as hepatic arterial embolization , also require study . DB05039 inhibits tumor cell invasiveness and P14780 expression by suppressing IKK/NF-κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein-coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra-long-acting inhaled β2-agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β-arrestin-2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor-α ( P01375 -α ) -induced NF-κB activity by reducing levels of both phosphorylated-IKK and -IκBα , thereby decreasing NF-κB nuclear translocation and the expression of P14780 , an NF-κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 -α/NF-κB-induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF-κB activity in a β-arrestin2-dependent manner , preventing further lung damage and improving lung function in P48444 patients . Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35-year-old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0.9 mg/kg of Recombinant Tissue P00747 Activator ( rtPA , DB00009 ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a " neurological dose " of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra-arterial catheter-directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis . A phase I/II study of sunitinib and intensive chemotherapy in patients over 60 years of age with acute myeloid leukaemia and activating P36888 mutations . Acute myeloid leukaemia ( AML ) with P36888 mutation has a dismal prognosis in elderly patients . Treatment with a combination of P36888 inhibitors and standard chemotherapy has not been extensively studied . Therefore , we instigated a phase I/II clinical trial of chemotherapy with cytosine arabinoside ( DB00987 ) /daunorubicin induction ( 7+3 ) followed by three cycles of intermediate-dose DB00987 consolidation in 22 AML patients with activating P36888 mutations . DB01268 was added at predefined dose levels and as maintenance therapy for 2 years . At dose level 1 , sunitinib 25 mg daily continuously from day 1 onwards resulted in two cases with dose-limiting toxicity ( DLT ) , prolonged haemotoxicity and hand-foot syndrome . At dose level -1 , sunitinib 25 mg was restricted to days 1-7 of each chemotherapy cycle . One DLT was observed in six evaluable patients . Six additional patients were treated in an extension phase . Thirteen of 22 patients ( 59 % ; 8/14 with P36888 -internal tandem duplication and 5/8 with P36888 -tyrosine kinase domain ) achieved a complete remission/complete remission with incomplete blood count recovery . For the 17 patients included at the lower dose level , median overall , relapse-free and event-free survival were 1·6 , 1·0 and 0·4 years , respectively . Four out of five analysed patients with relapse during maintenance therapy lost their initial P36888 mutation , suggesting outgrowth of P36888 wild-type subclones . P00747 /plasmin regulates c-fos and egr-1 expression via the MEK/ P29323 pathway . In this study , we showed that plasminogen ( Plg ) and plasmin ( Pla ) bind to lysine-binding sites on cell surface and trigger a signaling pathway that activates the mitogen-activated protein kinase ( MAPK ) MEK and P27361 /2 , which in turn leads to the expression of the primary response genes c-fos and early growth response gene egr-1 . Our data show that the Plg/Pla-stimulated steady-state mRNA levels of both genes reached a maximum by 30 min and then returned to basal levels by 1h . The gene induction was sensitive to both pharmacological and genetic inhibition of MEK . Leupeptin , a serine protease inhibitor , suppressed Pla but not Plg-induced c-fos and egr-1 expression , emphasizing the role played by the serine protease activity associated with Pla . Pre-incubation with cholera toxin completely blocked the Plg/Pla-induced gene expression , suggesting that another signaling pathway , which recruits G protein-coupled receptors , may also be involved . Furthermore , Plg/Pla also stimulated AP-1 and P18146 DNA-binding activities , which were abrogated by pharmacological inhibition of MEK . Altogether , these results suggest that Plg/Pla stimulates c-fos and egr-1 expression via activation of the MEK/ P29323 pathway . Poly( DB02059 )polymerase-1 signalling of the DNA damage induced by P11387 poison in D54(p53wt) and U251(p53mut) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor-mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor DB01030 and the poly( DB02059 )polymerase-1 inhibitor DB02690 in D54(p53wt) and U251(p53mut) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti-proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2/M block of the cell cycle . We also evaluated , the influence of TPT+/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT-dependent increase of P09874 auto-modification level in both the cells . Moreover , in the D54(p53wt) cells we found that in co-treatments DB02690 incremented the TPT-dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251(p53mut) cells we found that DB02690 incremented the TPT-dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .