interacts_with DB00072?
Q13639 receptors located on cholinergic nerves in human colon circular muscle . 5-Hydroxytryptamine 4 ( Q13639 ) receptor agonists promote colonic propulsion . The alteration of circular muscle ( CM ) motility underlying this involves inhibition of contractility via smooth muscle Q13639 receptors and proximal colonic motility stimulation , the mechanism of the latter not having been characterized . Our aim was to identify and characterize a Q13639 receptor-mediated stimulation of human colon CM contractile activity . Q13639 receptor ligands were tested on electrical field stimulation ( O43281 ) -induced contractions of human colonic muscle strips cut in the circular direction ( called ' whole tissue ' strips ) . Additionally , after incubation of tissues with [ 3H ] -choline these compounds were tested on O43281 -induced release of tritium in whole tissue strips and in ' isolated ' CM strips , obtained by superficial cutting in the CM layer . DB05232 and atropine blocked O43281 -induced contractions of whole tissue CM strips . DB06480 ( 0.3 micromol L-1 ) evoked a heterogenous response on O43281 -induced contraction , ranging from inhibition ( most frequently observed ) to enhancement . In the release experiments , O43281 -induced tritium efflux was blocked by tetrodotoxin . DB06480 increased O43281 -induced tritium and [ 3H ] -acetylcholine efflux in whole tissue and in isolated CM strips . All effects of prucalopride were antagonized by the selective Q13639 receptor antagonist GR113808 . The results obtained indicate the presence of excitatory Q13639 receptors on cholinergic nerves within the CM of human colon . DB06699 . DB06699 is a gonadotropin-releasing hormone ( DB00644 ) receptor antagonist that , in common with P30968 agonists ( e.g. leuprolide , goserelin and triptorelin ) , is indicated for use as an androgen-deprivation therapy in patients with advanced prostate cancer . In 1-year , randomized , open-label , phase II or III trials in patients with all stages of prostate cancer , subcutaneous degarelix was associated with rapid , profound and sustained suppression of serum testosterone and prostate-specific antigen ( PSA ) , without evidence of testosterone surges or microsurges . In the phase III trial , degarelix ( 240 mg initially followed by 80 mg every 28 days ) was considered to be effective and noninferior to intramuscular leuprolide ( 7.5 mg every 28 days ) with regard to inducing and maintaining suppression of serum testosterone to castrate levels ( i.e. < or=0.5 ng/mL ) . DB06699 induced testosterone suppression more rapidly than leuprolide . Median serum testosterone levels of < or=0.5 ng/mL were achieved by day 3 in degarelix recipients , but not until day 28 in leuprolide recipients . PSA suppression was also more rapid with degarelix than with leuprolide , with significant between-group differences in serum PSA levels favouring degarelix at 14 and 28 days . DB06699 treatment for 1 year was generally well tolerated ; the adverse events reported were mostly related to subcutaneous drug administration ( i.e. injection-site reactions ) and hormonal androgen deprivation ( e.g. hot flushes ) . Effect of axitinib ( AG-013736 ) on fatigue , thyroid-stimulating hormone , and biomarkers : a phase I study in Japanese patients . DB06626 is an oral , potent , and selective inhibitor of vascular endothelial growth factor receptor ( VEGFR ) 1 , 2 , and 3 . This phase I study evaluated the safety , pharmacokinetics , pharmacodynamics , antitumor activity , and recommended starting dose of axitinib in patients with advanced solid tumors . Twelve patients received single-dose axitinib 5 mg and were monitored for > or =48 h . Continuous 5 mg twice-daily dosing was then initiated . One patient had dose-limiting toxicity ( grade 3 proteinuria and fatigue ) . Common treatment-related adverse events were anorexia , fatigue , and diarrhea . Grade 3 treatment-related adverse events were fatigue and hypertension . Maximum axitinib plasma concentration occurred 1-4 h after steady-state dosing . Eleven patients experienced thyroid-stimulating hormone elevation ; time-course change and fatigue onset appeared to be related in some patients . Significant correlation was observed between thyroid-stimulating hormone change and area under the plasma concentration-time curve ( AUC ; r = 0.80 , P = 0.005 ) . DB06626 decreased plasma soluble vascular endothelial growth factor receptor 2 ( s- P35968 ) , with significant correlation between change in s- P35968 and AUC ( r = -0.92 , P < 0.0001 ) . Fluorodeoxyglucose positron emission tomography revealed a substantial decrease in tumor metabolic activity associated with axitinib . Tumor size decreased in nine patients . The time-course of thyroid-stimulating hormone change appeared correlated with fatigue . There were significant correlations between thyroid-stimulating hormone or s- P35968 and axitinib exposure . DB06626 5 mg twice-daily is the recommended starting dose for Japanese patients . This trial is registered with ClinicalTrials.gov , identifier NCT00447005 . Non-redundant roles of phosphoinositide 3-kinase isoforms alpha and beta in glycoprotein VI-induced platelet signaling and thrombus formation . Platelets are activated by adhesion to vascular collagen via the immunoglobulin receptor , glycoprotein VI ( Q9HCN6 ) . This causes potent signaling toward activation of phospholipase Cgamma2 , which bears similarity to the signaling pathway evoked by T- and B-cell receptors . Phosphoinositide 3-kinase ( PI3K ) plays an important role in collagen-induced platelet activation , because this activity modulates the autocrine effects of secreted ADP . Here , we identified the PI3K isoforms directly downstream of Q9HCN6 in human and mouse platelets and determined their role in Q9HCN6 -dependent thrombus formation . The targeting of platelet P42336 or -beta strongly and selectively suppressed Q9HCN6 -induced Ca(2+) mobilization and inositol 1,4,5-triphosphate production , thus demonstrating enhancement of phospholipase Cgamma2 by P42336 /beta . That P42336 and -beta have a non-redundant function in Q9HCN6 -induced platelet activation and thrombus formation was concluded from measurements of : ( i ) serine phosphorylation of Akt , ( ii ) dense granule secretion , ( iii ) intracellular Ca(2+) increases and surface expression of phosphatidylserine under flow , and ( iv ) thrombus formation , under conditions where P42336 /beta was blocked or p85alpha was deficient . In contrast , Q9HCN6 -induced platelet activation was insensitive to inhibition or deficiency of O00329 or -gamma . Furthermore , P42336 /beta , but not P48736 , contributed to Q9HCN6 -induced Rap1b activation and , surprisingly , also to Rap1b-independent platelet activation via Q9HCN6 . Together , these findings demonstrate that both P42336 and -beta isoforms are required for full Q9HCN6 -dependent platelet Ca(2+) signaling and thrombus formation , partly independently of Rap1b . This provides a new mechanistic explanation for the anti-thrombotic effect of PI3K inhibition and makes P42336 an interesting new target for anti-platelet therapy . Association of genetic polymorphisms with personality profile in individuals without psychiatric disorders . OBJECTIVE : Population-based twin studies demonstrate that approximately 40-50 % of the variability in personality dimensions results from genetic factors . This study assessed selected polymorphisms in the P21964 Val158Met , P21397 3'VNTR , 5HTTLPR , 102T/C 5- Q13049 , Q01959 3'VNTR and P14416 exon 8 genes and evaluated their association with personality profiles , anxiety levels , and depressiveness in healthy subjects . METHODS : This study included 406 unrelated ( mean age 38.51 years ) , mentally and somatically healthy Caucasian subjects of Polish origin . The prevalence of the gene variants mentioned above and their association with personality profiles , anxiety levels , and depressiveness was assessed using the Temperament and Character Inventory , NEO Five-Factor Inventory , Spielberger 's State-Trait Anxiety Inventory and Beck 's Depression Inventory . RESULTS : The effects of the 5HTTLPR gene on the s/s genotype and empathy ( P06681 ) were lowest in the entire group . The effects of gender , age and the Q13049 gene for the T/T genotype and attachment ( Q7Z3Z2 ) were highest in women . The effects of gender , age and the Q01959 gene on the 9/9 Q01959 genotype , compassion ( C4 ) and cooperativeness ( C ) were lowest in women . The effects of gender , age and the P21964 gene on the DB00134 / DB00134 genotype and neuroticism ( P04626 ) NEO-FFI were also lowest in women . CONCLUSIONS : Our results suggest considerable influence of individual genes on the formation of personality traits . P08637 -158 polymorphism influences the biological response to infliximab in Crohn 's disease through affecting the ADCC activity . An association between P08637 -158 V/F polymorphism and biological responses to infliximab has been reported in Crohn 's disease ( CD ) in Western countries . However , little is known about the mechanism by which gene polymorphism affects the responses to infliximab . The aims of this study were to confirm the association in Japanese CD patients and to reveal the effect of gene polymorphism on biological responses to infliximab . Japanese CD patients were examined retrospectively at weeks 8 and 30 . Clinical and biological responses were assessed by the Crohn 's disease activity index and P02741 levels , respectively . The infliximab-binding affinity of natural killer ( NK ) cells from P08637 -158 V/V , V/F and F/F donors was examined . DB00065 -mediated antibody-dependent cell-mediated cytotoxicity ( ADCC ) activities were also determined using transmembrane P01375 -α-expressing Jurkat T cells as target cells and peripheral blood mononuclear cells ( PBMCs ) from V/V , V/F and F/F donors as effector cells . Biological responses at week 8 were statistically higher in V/V patients , whereas no significant differences were observed in either clinical responses at weeks 8 and 30 or biological responses at week 30 among the three genotypes . NK cells and PBMCs from V/V patients also showed higher infliximab-binding affinity and infliximab-mediated ADCC activity , respectively . Our results suggest that P08637 -158 polymorphism is a predicting factor of biological responses to infliximab in the early phases . P08637 -158 polymorphism was also found to affect the infliximab-binding affinity of NK cells and infliximab-mediated ADCC activity in vitro , suggesting that an effect on ADCC activity influences biological responses to infliximab in CD patients . Role of chronic inhibition of dopamine-metabolizing enzymes in the regulation of renal sodium and phosphate excretion in the rat remnant kidney . BACKGROUND/AIMS : The present study examined the effects of chronic selective or combined inhibition of type A monoamine oxidase ( MAO ) and catechol-O-methyltransferase ( P21964 ) on daily urinary excretion of dopamine and metabolites and on natriuresis and phosphaturia in 3/4 nephrectomized ( 3/4nx ) and Sham rats . METHODS : The 3/4nx and Sham rats were placed in metabolic cages and received the P21397 -selective inhibitor Ro-411049 ( 7.5 mg x kg(-1) bid ) and/or the P21964 -selective inhibitor DB03336 3-202 ( 30 mg x kg(-1) bid ) orally for 3 days during high sodium diet . RESULTS : Selective P21964 inhibition increased the urinary excretion of the deaminated metabolite ( 3,4-dihydroxyphenylacetic acid , DOPAC ) and decreased the urinary excretion of the methylated ( 3-methoxytyramine , 3-MT ) and deaminated plus methylated metabolite ( homovanillic acid , HVA ) in both groups . Selective P21397 inhibition increased the urinary excretion of 3-MT and reduced the urinary excretion of both DOPAC and HVA in either 3/4nx or Sham rats . Combined inhibition of P21397 and P21964 did not significantly change the urinary excretion of DOPAC and markedly decreased the urinary excretion of 3-MT and HVA in both groups . Selective or combined inhibition of P21397 and P21964 did not alter the daily urinary excretion of dopamine , sodium or phosphate in either 3/4nx or Sham rats . CONCLUSIONS : Chronic selective or combined inhibition of P21397 and P21964 is not of major importance in regulating the dopamine-dependent natriuresis and phosphaturia in either 3/4nx or Sham rats . Agonists and antagonists of DB00644 and -II reduce metastasis formation by triple-negative human breast cancer cells in vivo . Metastasis to bone is a frequent problem of advanced breast cancer . Particularly breast cancers , which do not express estrogen and progesterone receptors and which have no overexpression/amplification of the P04626 -neu gene , so called triple-negative breast cancers , are considered as very aggressive and possess a bad prognosis . About 60 % of all human breast cancers and about 74 % of triple-negative breast cancers express receptors for gonadotropin-releasing hormone ( DB00644 ) , which might be used as a therapeutic target . Recently , we could show that bone-directed invasion of human breast cancer cells in vitro is time- and dose-dependently reduced by DB00644 analogs . In the present study , we have analyzed whether DB00644 analogs are able to reduce metastases of triple-negative breast cancers in vivo . In addition , we have evaluated the effects of DB00644 analogs on tumor growth . To quantify formation of metastasis by triple-negative MDA-MB-435 and MDA-MB-231 human breast cancers , we used a real-time PCR method based on detection of human-specific alu sequences measuring accurately the amount of human tumor DNA in athymic mouse organs . To analyze tumor growth , the volumes of breast cancer xenotransplants into nude mice were measured . We could demonstrate that DB00644 analogs significantly reduced metastasis formation by triple-negative breast cancer in vivo . In addition , we could show that DB00644 analogs significantly inhibited the growth of breast cancer into nude mice . Side effects were not detectable . In conclusion , DB00644 analogs seem to be suitable drugs for an efficacious therapy for triple-negative , P30968 -positive human breast cancers to prevent metastasis formation . Functional methionine synthase deficiency ( cblE and cblG ) : clinical and biochemical heterogeneity . Functional methionine synthase deficiency is generally characterized by homocystinuria and hypomethioninemia in the absence of methylmalonic aciduria . Patients are divided into two classes , cblE and cblG , on the basis of complementation analysis . Presentation has usually been in the first 2 years of life , but one patient came to medical attention at age 21 years with symptoms initially diagnosed as multiple sclerosis . Common findings among 11 patients ( 4 with cblE and 7 with cblG ) have included megaloblastic anemia ( all patients ) and various neurological deficits including developmental retardation ( 10 patients ) , cerebral atrophy ( 8 patients ) , hypotonia ( 7 patients ) , EEG abnormalities ( 6 patients ) , and nystagmus ( 5 patients ) . Hypertonia , seizures , blindness , and ataxia were less frequent . All patients have responded to therapy with cobalamin with resolution of anemia and biochemical abnormalities ; neurological deficits resolved more slowly and in some cases incompletely . DB00200 has been more effective than cyanocobalamin . Fibroblasts from patients with cblE ( 5 patients ) and cblG ( 6 patients ) all showed decreased intracellular levels of methylcobalamin ( DB03614 ) and decreased incorporation of label from 5-methyltetrahydrofolate into macromolecules , suggesting decreased activity of the DB03614 -dependent enzyme methionine synthase . Q99707 specific activity in extracts of all cblE fibroblasts was normal or near-normal under standard reducing conditions ; synthase specific activity in extracts of 5 cblG patients was low but was high in a 6th patient measured in another laboratory . Thus , there is heterogeneity among patients with functional methionine synthase deficiency both in clinical presentation and in the results of biochemical studies of cultured cells . Synergistic inhibition of breast cancer cell lines with a dual inhibitor of P00533 -HER-2/neu and a Bcl-2 inhibitor . The epidermal growth factor receptor ( P00533 ) ( ErbB1 ) and HER-2/neu ( ErbB2 ) are members of the ErbB family of receptor tyrosine kinases . These receptors are overexpressed in a variety of human tumors and overexpression generally correlates with poor prognosis and decreased survival . DB01259 , a reversible inhibitor of both P00533 and HER-2/neu , has shown some success in achieving clinical responses in heavily pretreated advanced cancer patients . GW2974 is a reversible dual inhibitor similar to lapatinib , but GW2974 was not progressed to clinical trials due to pharmacokinetic issues . Bcl-2 , an anti-apoptotic protein , is also overexpressed in a number of human tumors . Bcl-2 inhibitors induce apoptosis and sensitize cancer cells to other therapies . The purpose of this study was to assess the effects of combining ErbB and Bcl-2 inhibitors on the growth of human breast cancer cell lines . P00533 /HER-2/neu tyrosine kinase inhibitors ( lapatinib and GW2974 ) were combined with Bcl-2 inhibitors ( HA14-1 or GX15-070 ) and the anti-proliferative effects were determined by the MTT tetrazolium dye assay . Combinations were tested in MCF-7 human breast cancer cells , a HER-2/neu transfected MCF-7 cell line ( MCF/18 ) , and a tamoxifen-resistant MCF-7 cell line ( Q99707 -3 ) . A synergistic inhibitory effect was observed with the combination of inhibitors of P00533 -HER-2/neu ( lapatinib or GW2974 ) and Bcl-2 ( GX15-070 or HA14-1 ) on the growth of the MCF-7 , MCF/18 , and Q99707 -3 human breast cancer cell lines . This study suggests that simultaneously blocking the ErbB family of receptor tyrosine kinases and Bcl-2 family of proteins may be a benefit to breast cancer patients . Molecular determinants of trastuzumab efficacy : What is their clinical relevance ? DB00072 -containing therapy is a standard of care for human epidermal growth factor receptor-2 ( P04626 ) -positive breast cancer . In pre-clinical models , a wide range of molecular mechanisms have been associated with reduced sensitivity to trastuzumab in vitro . These include expression of the truncated P04626 receptor fragment p95HER2 , activating mutation of the gene encoding the class 1A catalytic subunit of phosphatidylinositol 3-kinase ( P42336 ) , loss of phosphatase and tensin homolog ( P60484 ) , activation of other downstream signal transducers , prevention of cell cycle arrest , increased signaling through alternative ( HER or non-HER ) tyrosine kinase receptors , and resistance to antibody-dependent cellular cytotoxicity . However , the clinical significance of these mechanisms as determinants of trastuzumab efficacy in vivo has been unclear . Here , we review clinical studies of potential predictive biomarkers of trastuzumab efficacy in P04626 -positive breast cancer and consider whether evaluation of such markers might inform patient selection for therapy . We find that clinical evidence relating to potential predictive biomarkers is mostly limited to small , retrospective studies , many of which have yielded conflicting findings . Some trends are evident in the retrospective data and in biomarker analyses from randomized clinical trials , particularly relating to activation of the phosphatidylinositol 3-kinase pathway , but none is sufficiently strong to form a basis for patient selection . This may be explained by the fact that multiple mechanisms of action determine the clinical efficacy of trastuzumab . In the absence of novel , validated biomarkers of efficacy , trastuzumab eligibility should continue to be based on evaluation of P04626 status according to standard methods . T lymphocytes expressing a CD16 signaling receptor exert antibody-dependent cancer cell killing . To expand applications for T-cell-based immunotherapy in cancer , we designed a receptor that binds the Fc portion of human immunoglobulins and delivers activation signals . The construct included the high-affinity CD16 ( P08637 ) V158 variant , CD8α hinge , and transmembrane domains , along with signaling domains from CD3ζ and 4-1BB ( Q07011 ) , forming a chimeric receptor termed CD16V-BB-ζ . After retrovirus-mediated expression in human T cells , CD16V-BB-ζ bound humanized antibodies with higher affinity than a control receptor containing the more common F158 variant . Engagement of CD16V-BB-ζ provoked T-cell activation , exocytosis of lytic granules , and sustained proliferation , with a mean cell recovery after 4-week coculture with Daudi lymphoma cells and rituximab of nearly 70-fold relative to input cells . In contrast , unbound antibody alone produced no effect . CD16V-BB-ζ T cells specifically killed lymphoma cells and primary chronic lymphocytic leukemia cells in combination with rituximab at a low effector:target ratio , even when assayed on mesenchymal cells . DB00072 triggered CD16V-BB-ζ-mediated killing of P04626 ( P04626 ) (+) breast and gastric cancer cells ; similar results were obtained with an anti-GD2 antibody in neuroblastoma and osteosarcoma cells . Furthermore , coadministration of CD16V-BB-ζ T cells with immunotherapeutic antibodies exerted considerable antitumor activity in vivo . Signaling mediated by 4-1BB-CD3ζ induced higher T-cell activation , proliferation , and cytotoxicity than CD3ζ or FcεRIγ , and the receptor was expressed effectively after mRNA electroporation without viral vectors , facilitating clinical translation . Our results offer preclinical proof of concept for CD16V-BB-ζ as a universal , next-generation chimeric receptor with the potential to augment the efficacy of antibody therapies for cancer . Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor/ P04626 -positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F. Hoffmann-La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 -positive metastatic breast cancer , trastuzumab/chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . DB00072 adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single-agent activity in breast cancer , including capecitabine ( DB01101 ; F. Hoffmann-La Roche ) , gemcitabine , and vinorelbine . DB00072 is also being investigated as part of triplet drug regimens . DB00072 has good single-agent activity in first-line therapy . This is of relevance to women with P04626 -positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab-containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible . DB05332 administration shows reduced megakaryocyte response-capacity and increased myelofibrosis in a mouse model of P35579 -RD . Macrothrombocytopenia in P35579 -related disease ( P35579 -RD ) results from defects in nonmuscular myosin-IIA function . P40238 agonists ( eltrombopag ; romiplostim ) seem to improve hemostasis , but little is known about their biologic effects in P35579 -RD . We administered romiplostim to Myh9(-/-) mice ( 100 μg/kg , every 3 days , during 1 month ) . MKs increased to similar numbers in Myh9(-/-) and wild-type ( WT ) mice ( with an increase in immature MKs ) , but Myh9(-/-) platelet count response was much less ( 2.5-fold vs 8-fold increase ) . A strong increase in MK nuclei emboli in the lung , in WT and Myh9(-/-) mice , indicates increased transmigration of MKs from the BM . Prolonged ( but not acute ) treatment with romiplostim decreased expression of GPIb-IX-V complex and Q9HCN6 , but not of GPIIbIIIa , and bleeding time increased in WT mice . Microcirculation was not altered by the increased number of large platelets in any of the assessed organs , but in Myh9(-/-) mice a much stronger increase in BM reticulin fibers was present after 4 weeks of romiplostim treatment vs WT mice . These data further encourage short-term use of thrombopoietic agents in patients with P35579 -RDs ; however , myelofibrosis has to be considered as a potential severe adverse effect during longer treatment . Reduction of GPIbIX/ Q9HCN6 expression by romiplostim requires further studies . DB00072 has preferential activity against breast cancers driven by P04626 homodimers . In breast cancer cells with P04626 gene amplification , P04626 receptors exist on the cell surface as monomers , homodimers , and heterodimers with P00533 / P21860 . The therapeutic antibody trastuzumab , an approved therapy for P04626 (+) breast cancer , can not block ligand-induced P04626 heterodimers , suggesting it can not effectively inhibit P04626 signaling . Hence , P04626 oligomeric states may predict the odds of a clinical response to trastuzumab in P04626 -driven tumors . To test this hypothesis , we generated nontransformed human MCF10A mammary epithelial cells stably expressing a chimeric P04626 -FKBP molecule that could be conditionally induced to homodimerize by adding the FKBP ligand AP1510 , or instead induced to heterodimerize with P00533 or P21860 by adding the heterodimer ligands P01133 /TGFα or heregulin . AP1510 , P01133 , and heregulin each induced growth of MCF10A cells expressing P04626 -FKBP . DB00072 inhibited homodimer-mediated but not heterodimer-mediated cell growth . In contrast , the P04626 antibody pertuzumab , which blocks P04626 heterodimerization , inhibited growth induced by heregulin but not AP1510 . Lastly , the P04626 / P00533 tyrosine kinase inhibitor lapatinib blocked both homodimer- and heterodimer-induced growth . AP1510 triggered phosphorylation of Erk1/2 but not AKT , whereas trastuzumab inhibited AP1510-induced Erk1/2 phosphorylation and Shc- P04626 homodimer binding , but not TGFα-induced AKT phosphorylation . Consistent with these observations , high levels of P04626 homodimers correlated with longer time to progression following trastuzumab therapy in a cohort of patients with P04626 -overexpressing breast cancer . Together , our findings confirm the notion that P04626 oligomeric states regulate P04626 signaling , also arguing that trastuzumab sensitivity of homodimers may reflect their inability to activate the PI3K ( phosphoinositide 3-kinase ) /AKT pathway . A clinical implication of our results is that high levels of P04626 homodimers may predict a positive response to trastuzumab . Targeted therapy in gastric cancer . Gastric cancer is often diagnosed at an advanced stage . Although chemotherapy prolongs survival and improves quality of life , the survival of gastric cancer patients with advanced disease is short . Thanks to recent insights into the molecular pathways involved in gastric carcinogenesis , new targeted treatment options have become available for gastric cancer patients . DB00072 , an antibody targeted to HER-2 , was shown to improve survival of advanced gastric cancer patients harboring HER-2 overexpression due to gene amplification in their tumor cells , and is currently also explored in adjuvant and neoadjuvant settings . Another agent with promising results in clinical trials is ramucirumab , an antibody targeting P35968 . No clear survival benefit , however , were experienced with agents targeting P00533 ( cetuximab , panitumumab ) , P15692 ( bevacizumab ) , or P42345 ( everolimus ) . Drugs targeting c-MET/ P14210 are currently under investigation in biomarker-selected cohorts , with promising results in early clinical trials . This review will summarize the current status of targeted treatment options in gastric cancer . Oral leucine supplementation is sensed by the brain but neither reduces food intake nor induces an anorectic pattern of gene expression in the hypothalamus . DB00149 activates the intracellular mammalian target of the rapamycin ( P42345 ) pathway , and hypothalamic P42345 signaling regulates food intake . Although central infusion of leucine reduces food intake , it is still uncertain whether oral leucine supplementation is able to affect the hypothalamic circuits that control energy balance . We observed increased phosphorylation of p70s6k in the mouse hypothalamus after an acute oral gavage of leucine . We then assessed whether acute oral gavage of leucine induces the activation of neurons in several hypothalamic nuclei and in the brainstem . DB00149 did not induce the expression of Fos in hypothalamic nuclei , but it increased the number of Fos-immunoreactive neurons in the area postrema . In addition , oral gavage of leucine acutely increased the 24 h food intake of mice . Nonetheless , chronic leucine supplementation in the drinking water did not change the food intake and the weight gain of ob/ob mice and of wild-type mice consuming a low- or a high-fat diet . We assessed the hypothalamic gene expression and observed that leucine supplementation increased the expression of enzymes ( P54687 , O15382 and O14874 ) that metabolize branched-chain amino acids . Despite these effects , leucine supplementation did not induce an anorectic pattern of gene expression in the hypothalamus . In conclusion , our data show that the brain is able to sense oral leucine intake . However , the food intake is not modified by chronic oral leucine supplementation . These results question the possible efficacy of leucine supplementation as an appetite suppressant to treat obesity . Identification of novel genetic alterations in samples of malignant glioma patients . Glioblastoma is the most frequent and malignant human brain tumor . High level of genomic instability detected in glioma cells implies that numerous genetic alterations accumulate during glioma pathogenesis . We investigated alterations in AP-PCR DNA profiles of 30 glioma patients , and detected specific changes in 11 genes not previously associated with this disease : Q86UP9 , Q13326 , Q13639 , P05556 , P31327 , P07225 , P55259 , Q9UJ96 , Q08499 , Q8N743 , and Q14642 . Further correlations revealed that 8 genes might play important role in pathogenesis of glial tumors , while changes in P55259 , Q9UJ96 and Q8N743 should be considered as passenger mutations , consequence of high level of genomic instability . Identified genes have a significant role in signal transduction or cell adhesion , which are important processes for cancer development and progression . According to our results , Q86UP9 might be characteristic of primary glioblastoma , Q13326 , Q13639 , P05556 , P31327 , P07225 and Q14642 were detected predominantly in anaplastic astrocytoma , suggesting their role in progression of secondary glioblastoma , while alterations of Q08499 seem to have important role in development of both glioblastoma subtypes . Some of the identified genes showed significant association with p53 , p16 , and P00533 , but there was no significant correlation between loss of P60484 and any of identified genes . In conclusion our study revealed genetic alterations that were not previously associated with glioma pathogenesis and could be potentially used as molecular markers of different glioblastoma subtypes . P19957 kinase/AKT pathway as a therapeutic target in multiple myeloma . The development of novel therapies for multiple myeloma depends on a comprehensive understanding of the events leading to cellular proliferation and survival . Controlling pathways that regulate growth signals is an emerging and complementary approach to myeloma treatment . The PI3K/Akt pathway is a central gatekeeper for crucial cellular functions including adhesion , angiogenesis , migration and development of drug resistance . Established proteins and genes such as P42345 , p53 , NF-kappaB and Q92934 are all regulated through PI3K and Akt activation , making them attractive targets for broad downstream effects . Direct PI3K inhibition has demonstrated impressive tumor inhibition and regression in cell-line and animal models , and multiple agents including DB05210 are currently in clinical trials . Drugs such as perifosine that are specific for Akt are also in development . Combinations of these agents with existing therapies are rational approaches on the path to improving myeloma treatment .