MH_dev_265

Q13639 REA receptors located on cholinergic nerves in human colon circular muscle . 5 - Hydroxytryptamine 4 ( Q13639 REA ) receptor agonists promote colonic propulsion . The alteration of circular muscle ( CM ) motility underlying this involves inhibition of contractility via smooth muscle Q13639 REA receptors and proximal colonic motility stimulation , the mechanism of the latter not having been characterized . Our aim was to identify and characterize a Q13639 REA receptor-mediated stimulation of human colon CM contractile activity . Q13639 REA 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 MENMAX DB06480 MEN ( 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 MEN 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 REA receptor antagonist GR113808 . The results obtained indicate the presence of excitatory Q13639 REA receptors on cholinergic nerves within the CM of human colon .

DB06699 MEN . DB06699 MEN is a gonadotropin-releasing hormone ( DB00644 ) receptor antagonist that , in common with P30968 REA 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 MEN 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 MEN 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 MEN 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 MEN decreased plasma soluble vascular endothelial growth factor receptor 2 ( s - P35968 REA ) , with significant correlation between change in s - P35968 REA 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 REA and axitinib exposure . DB06626 MEN 5 mg twice-daily is the recommended starting dose for Japanese patients . This trial is registered with ClinicalTrials.gov , identifier NCT 00447005 .

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 Cgamma 2 , 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 REA or - beta strongly and selectively suppressed Q9HCN6 - induced Ca ( 2 + ) mobilization and inositol 1,4 , 5 - triphosphate production , thus demonstrating enhancement of phospholipase Cgamma 2 by P42336 REA / beta . That P42336 REA 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 REA / beta was blocked or p8 5alpha was deficient . In contrast , Q9HCN6 - induced platelet activation was insensitive to inhibition or deficiency of O00329 REA or - gamma . Furthermore , P42336 REA / beta , but not P48736 REA , contributed to Q9HCN6 - induced Rap 1b activation and , surprisingly , also to Rap 1b - independent platelet activation via Q9HCN6 . Together , these findings demonstrate that both P42336 REA and - beta isoforms are required for full Q9HCN6 - dependent platelet Ca ( 2 + ) signaling and thrombus formation , partly independently of Rap 1b . This provides a new mechanistic explanation for the anti-thrombotic effect of PI3K inhibition and makes P42336 REA 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 REA Val 158Met , P21397 REA 3 ' VNTR , 5HTTLPR , 102T / C 5 - Q13049 REA , Q01959 REA 3 ' VNTR and P14416 REA 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 REA ) were lowest in the entire group . The effects of gender , age and the Q13049 REA gene for the T / T genotype and attachment ( Q7Z3Z2 ) were highest in women . The effects of gender , age and the Q01959 REA gene on the 9/9 Q01959 REA genotype , compassion ( C4 ) and cooperativeness ( C ) were lowest in women . The effects of gender , age and the P21964 REA gene on the DB00134 / DB00134 genotype and neuroticism ( P04626 REA ) NEO-FFI were also lowest in women . CONCLUSIONS : Our results suggest considerable influence of individual genes on the formation of personality traits .

P08637 REA - 158 polymorphism influences the biological response to infliximab in Crohn ' s disease through affecting the ADCC activity . An association between P08637 REA - 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 REA levels , respectively . The infliximab-binding affinity of natural killer ( NK ) cells from P08637 REA - 158 V / V , V / F and F / F donors was examined . DB00065 MEN - mediated antibody-dependent cell-mediated cytotoxicity ( ADCC ) activities were also determined using transmembrane P01375 REA - 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 REA - 158 polymorphism is a predicting factor of biological responses to infliximab in the early phases . P08637 REA - 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 REA ) on daily urinary excretion of dopamine and metabolites and on natriuresis and phosphaturia in 3/4 nephrectomized ( 3/4 nx ) and Sham rats . METHODS : The 3/4 nx and Sham rats were placed in metabolic cages and received the P21397 REA - selective inhibitor Ro - 411049 ( 7.5 mg x kg ( - 1 ) bid ) and / or the P21964 REA - selective inhibitor DB03336 MEN 3-202 ( 30 mg x kg ( - 1 ) bid ) orally for 3 days during high sodium diet . RESULTS : Selective P21964 REA 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 REA inhibition increased the urinary excretion of 3 - MT and reduced the urinary excretion of both DOPAC and HVA in either 3/4 nx or Sham rats . Combined inhibition of P21397 REA and P21964 REA 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 REA and P21964 REA did not alter the daily urinary excretion of dopamine , sodium or phosphate in either 3/4 nx or Sham rats . CONCLUSIONS : Chronic selective or combined inhibition of P21397 REA and P21964 REA is not of major importance in regulating the dopamine-dependent natriuresis and phosphaturia in either 3/4 nx 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 REA - 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 REA - 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 MEN 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 REA 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 REA - HER - 2 / neu and a Bcl - 2 inhibitor . The epidermal growth factor receptor ( P00533 REA ) ( ErbB 1 ) and HER - 2 / neu ( ErbB 2 ) 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 REA 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 REA / 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 REA - 3 ) . A synergistic inhibitory effect was observed with the combination of inhibitors of P00533 REA - 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 REA - 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 SUB - containing therapy is a standard of care for human epidermal growth factor receptor - 2 ( P04626 REA ) - 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 REA receptor fragment p95HER2 , activating mutation of the gene encoding the class 1A catalytic subunit of phosphatidylinositol 3 - kinase ( P42336 REA ) , loss of phosphatase and tensin homolog ( P60484 REA ) , 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 REA - 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 REA 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 REA ) V158 variant , CD8α hinge , and transmembrane domains , along with signaling domains from CD3ζ and 4-1 BB ( Q07011 REA ) , 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 SUB triggered CD16V - BB-ζ-mediated killing of P04626 REA ( P04626 REA ) ( + ) breast and gastric cancer cells ; similar results were obtained with an anti-GD 2 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 4-1 BB-CD 3ζ 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 REA status . A feasible approach for women with less aggressive , estrogen receptor / P04626 REA - 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 REA - 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 SUB 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 SUB is also being investigated as part of triplet drug regimens . DB00072 SUB has good single-agent activity in first-line therapy . This is of relevance to women with P04626 REA - 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 MEN administration shows reduced megakaryocyte response-capacity and increased myelofibrosis in a mouse model of P35579 REA - RD . Macrothrombocytopenia in P35579 REA - related disease ( P35579 REA - RD ) results from defects in nonmuscular myosin-IIA function . P40238 REA agonists ( eltrombopag ; romiplostim ) seem to improve hemostasis , but little is known about their biologic effects in P35579 REA - RD . We administered romiplostim to Myh 9 ( - / - ) mice ( 100 μg / kg , every 3 days , during 1 month ) . MKs increased to similar numbers in Myh 9 ( - / - ) and wild-type ( WT ) mice ( with an increase in immature MKs ) , but Myh 9 ( - / - ) 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 Myh 9 ( - / - ) 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 Myh 9 ( - / - ) 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 REA - 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 SUB has preferential activity against breast cancers driven by P04626 REA homodimers . In breast cancer cells with P04626 REA gene amplification , P04626 REA receptors exist on the cell surface as monomers , homodimers , and heterodimers with P00533 REA / P21860 REA . The therapeutic antibody trastuzumab , an approved therapy for P04626 REA ( + ) breast cancer , can not block ligand-induced P04626 REA heterodimers , suggesting it can not effectively inhibit P04626 REA signaling . Hence , P04626 REA oligomeric states may predict the odds of a clinical response to trastuzumab in P04626 REA - driven tumors . To test this hypothesis , we generated nontransformed human MCF 10A mammary epithelial cells stably expressing a chimeric P04626 REA - FKBP molecule that could be conditionally induced to homodimerize by adding the FKBP ligand AP1510 , or instead induced to heterodimerize with P00533 REA or P21860 REA by adding the heterodimer ligands P01133 REA / TGFα or heregulin . AP1510 , P01133 REA , and heregulin each induced growth of MCF 10A cells expressing P04626 REA - FKBP . DB00072 SUB inhibited homodimer-mediated but not heterodimer-mediated cell growth . In contrast , the P04626 REA antibody pertuzumab , which blocks P04626 REA heterodimerization , inhibited growth induced by heregulin but not AP1510 . Lastly , the P04626 REA / P00533 REA tyrosine kinase inhibitor lapatinib blocked both homodimer - and heterodimer-induced growth . AP1510 triggered phosphorylation of Erk 1/2 but not AKT , whereas trastuzumab inhibited AP1510 - induced Erk 1/2 phosphorylation and Shc - P04626 REA homodimer binding , but not TGFα-induced AKT phosphorylation . Consistent with these observations , high levels of P04626 REA homodimers correlated with longer time to progression following trastuzumab therapy in a cohort of patients with P04626 REA - overexpressing breast cancer . Together , our findings confirm the notion that P04626 REA oligomeric states regulate P04626 REA 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 REA 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 SUB , 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 REA . No clear survival benefit , however , were experienced with agents targeting P00533 REA ( cetuximab , panitumumab ) , P15692 REA ( bevacizumab ) , or P42345 REA ( everolimus ) . Drugs targeting c-MET / P14210 REA 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 MEN activates the intracellular mammalian target of the rapamycin ( P42345 REA ) pathway , and hypothalamic P42345 REA 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 MEN 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 REA , O15382 REA and O14874 REA ) 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 REA , P05556 REA , P31327 REA , P07225 REA , P55259 REA , Q9UJ96 , Q08499 REA , Q8N743 , and Q14642 REA . Further correlations revealed that 8 genes might play important role in pathogenesis of glial tumors , while changes in P55259 REA , 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 REA , P05556 REA , P31327 REA , P07225 REA and Q14642 REA were detected predominantly in anaplastic astrocytoma , suggesting their role in progression of secondary glioblastoma , while alterations of Q08499 REA seem to have important role in development of both glioblastoma subtypes . Some of the identified genes showed significant association with p53 , p16 , and P00533 REA , but there was no significant correlation between loss of P60484 REA 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 REA 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 REA , p53 , NF-kappaB and Q92934 REA 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 MEN 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 .