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Sample records for autism-associated met receptor

  1. Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase.

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    Qiu, Shenfeng; Anderson, Charles T; Levitt, Pat; Shepherd, Gordon M G

    2011-04-13

    Local hyperconnectivity in the neocortex is a hypothesized pathophysiological state in autism spectrum disorder (ASD). MET, a receptor tyrosine kinase that regulates dendrite and spine morphogenesis, has been established as a risk gene for ASD. Here, we analyzed the synaptic circuit organization of identified pyramidal neurons in the anterior frontal cortex of mice with a dorsal pallium-derived, conditional knock-out (cKO) of Met. Synaptic mapping by glutamate uncaging identified layer 2/3 as the main source of local excitatory input to layer 5 projection neurons in controls. In both cKO and heterozygotes, this pathway was stronger by a factor of approximately 2. This increase was both sublayer and projection-class specific, restricted to corticostriatal neurons in upper layer 5B and not neighboring corticopontine neurons. Paired recordings in cKO slices demonstrated increased unitary connectivity. We propose that excitatory hyperconnectivity in specific neocortical microcircuits constitutes a physiological basis for Met-mediated ASD risk.

  2. The autism-associated MET receptor tyrosine kinase engages early neuronal growth mechanism and controls glutamatergic circuits development in the forebrain.

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    Peng, Y; Lu, Z; Li, G; Piechowicz, M; Anderson, M; Uddin, Y; Wu, J; Qiu, S

    2016-07-01

    The human MET gene imparts a replicated risk for autism spectrum disorder (ASD), and is implicated in the structural and functional integrity of brain. MET encodes a receptor tyrosine kinase, MET, which has a pleiotropic role in embryogenesis and modifies a large number of neurodevelopmental events. Very little is known, however, on how MET signaling engages distinct cellular events to collectively affect brain development in ASD-relevant disease domains. Here, we show that MET protein expression is dynamically regulated and compartmentalized in developing neurons. MET is heavily expressed in neuronal growth cones at early developmental stages and its activation engages small GTPase Cdc42 to promote neuronal growth, dendritic arborization and spine formation. Genetic ablation of MET signaling in mouse dorsal pallium leads to altered neuronal morphology indicative of early functional maturation. In contrast, prolonged activation of MET represses the formation and functional maturation of glutamatergic synapses. Moreover, manipulating MET signaling levels in vivo in the developing prefrontal projection neurons disrupts the local circuit connectivity made onto these neurons. Therefore, normal time-delimited MET signaling is critical in regulating the timing of neuronal growth, glutamatergic synapse maturation and cortical circuit function. Dysregulated MET signaling may lead to pathological changes in forebrain maturation and connectivity, and thus contribute to the emergence of neurological symptoms associated with ASD.

  3. C-terminal truncated forms of Met, the hepatocyte growth factor receptor.

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    Prat, M; Crepaldi, T; Gandino, L; Giordano, S; Longati, P; Comoglio, P

    1991-12-01

    The MET proto-oncogene encodes a transmembrane tyrosine kinase of 190 kDa (p190MET), which has recently been identified as the receptor for hepatocyte growth factor/scatter factor. p190MET is a heterodimer composed of two disulfide-linked chains of 50 kDa (p50 alpha) and 145 kDa (p145 beta). We have produced four different monoclonal antibodies that are specific for the extracellular domain of the Met receptor. These antibodies immunoprecipitate with p190MET two additional Met proteins of 140 and 130 kDa. The first protein (p140MET) is membrane bound and is composed of an alpha chain (p50 alpha) and an 85-kDa C-terminal truncated beta chain (p85 beta). The second protein (p130MET) is released in the culture supernatant and consists of an alpha chain (p50 alpha) and a 75-kDa C-terminal truncated beta chain (p75 beta). Both truncated forms lack the tyrosine kinase domain. p140MET and p130MET are consistently detected in vivo, together with p190MET, in different cell lines or their culture supernatants. p140MET is preferentially localized at the cell surface, where it is present in roughly half the amount of p190MET. The two C-terminal truncated forms of the Met receptor are also found in stable transfectants expressing the full-length MET cDNA, thus showing that they originate from posttranslational proteolysis. This process is regulated by protein kinase C activation. Together, these data suggest that the production of the C-terminal truncated Met forms may have a physiological role in modulating the Met receptor function.

  4. [Role of the expression of c-Met receptor in the progression of gastric cancer].

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    Amemiya, Hideki; Menolascino, Francisco; Peña, Alix

    2010-09-01

    The product of the proto-oncogene C-MET (the c-Met receptor) and its ligand, hepatocyte growth factor (HGF), have been implicated in the progression of gastric cancer. The aim of this study was to analyze the expression of c-Met receptor, HGF and proliferating cell nuclear antigen (PCNA) by the immunohistochemistry method of labeled streptavidin-biotin, as well as survival, and they were correlated with anatomopathological factors in stomach specimens of 40 patients, who underwent gastrectomy for gastric cancer in the Department of General Surgery, Hospital Central Universitario "Antonio María Pineda" in Barquisimeto, Venezuela, in 2001-2004. High expression of c-Met receptor and PCNA was observed in patients with advanced stages of gastric cancer (III and IV) compared with early stages (I and II) (pmigration in Venezuelan patients with gastric cancer and could be used as a prognostic factor in this pathology.

  5. c-MET receptor tyrosine kinase as a molecular target in advanced hepatocellular carcinoma.

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    Granito, Alessandro; Guidetti, Elena; Gramantieri, Laura

    2015-01-01

    c-MET is the membrane receptor for hepatocyte growth factor (HGF), also known as scatter factor or tumor cytotoxic factor, a mitogenic growth factor for hepatocytes. HGF is mainly produced by cells of mesenchymal origin and it mainly acts on neighboring epidermal and endothelial cells, regulating epithelial growth and morphogenesis. HGF/MET signaling has been identified among the drivers of tumorigenesis in human cancers. As such, c-MET is a recognized druggable target, and against it, targeted agents are currently under clinical investigation. c-MET overexpression is a common event in a wide range of human malignancies, including gastric, lung, breast, ovary, colon, kidney, thyroid, and liver carcinomas. Despite c-MET overexpression being reported by a large majority of studies, no evidence for a c-MET oncogenic addiction exists in hepatocellular carcinoma (HCC). In particular, c-MET amplification is a rare event, accounting for 4%-5% of cases while no mutation has been identified in c-MET oncogene in HCC. Thus, the selection of patient subgroups more likely to benefit from c-MET inhibition is challenging. Notwithstanding, c-MET overexpression was reported to be associated with increased metastatic potential and poor prognosis in patients with HCC, providing a rationale for its therapeutic inhibition. Here we summarize the role of activated HGF/MET signaling in HCC, its prognostic relevance, and the implications for therapeutic approaches in HCC.

  6. c-MET receptor tyrosine kinase as a molecular target in advanced hepatocellular carcinoma

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    Granito A

    2015-04-01

    Full Text Available Alessandro Granito,1 Elena Guidetti,1 Laura Gramantieri2,3 1Dipartimento di Scienze Mediche e Chirurgiche Università di Bologna, Bologna, Italy; 2Dipartimento dell'Apparato Digerente, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; 3Centro di Ricerca Biomedica Applicata (CRBA, Azienda Ospedaliero-Universitaria Policlinico S Orsola-Malpighi e Università di Bologna, Bologna, Italy Abstract: c-MET is the membrane receptor for hepatocyte growth factor (HGF, also known as scatter factor or tumor cytotoxic factor, a mitogenic growth factor for hepatocytes. HGF is mainly produced by cells of mesenchymal origin and it mainly acts on neighboring epidermal and endothelial cells, regulating epithelial growth and morphogenesis. HGF/MET signaling has been identified among the drivers of tumorigenesis in human cancers. As such, c-MET is a recognized druggable target, and against it, targeted agents are currently under clinical investigation. c-MET overexpression is a common event in a wide range of human malignancies, including gastric, lung, breast, ovary, colon, kidney, thyroid, and liver carcinomas. Despite c-MET overexpression being reported by a large majority of studies, no evidence for a c-MET oncogenic addiction exists in hepatocellular carcinoma (HCC. In particular, c-MET amplification is a rare event, accounting for 4%–5% of cases while no mutation has been identified in c-MET oncogene in HCC. Thus, the selection of patient subgroups more likely to benefit from c-MET inhibition is challenging. Notwithstanding, c-MET overexpression was reported to be associated with increased metastatic potential and poor prognosis in patients with HCC, providing a rationale for its therapeutic inhibition. Here we summarize the role of activated HGF/MET signaling in HCC, its prognostic relevance, and the implications for therapeutic approaches in HCC. Keywords: hepatocellular carcinoma, c-MET, clinical trials

  7. The Pleiotropic MET Receptor Network: Circuit Development and the Neural-Medical Interface of Autism.

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    Eagleson, Kathie L; Xie, Zhihui; Levitt, Pat

    2017-03-01

    People with autism spectrum disorder and other neurodevelopmental disorders (NDDs) are behaviorally and medically heterogeneous. The combination of polygenicity and gene pleiotropy-the influence of one gene on distinct phenotypes-raises questions of how specific genes and their protein products interact to contribute to NDDs. A preponderance of evidence supports developmental and pathophysiological roles for the MET receptor tyrosine kinase, a multifunctional receptor that mediates distinct biological responses depending upon cell context. MET influences neuron architecture and synapse maturation in the forebrain and regulates homeostasis in gastrointestinal and immune systems, both commonly disrupted in NDDs. Peak expression of synapse-enriched MET is conserved across rodent and primate forebrain, yet regional differences in primate neocortex are pronounced, with enrichment in circuits that participate in social information processing. A functional risk allele in the MET promoter, enriched in subgroups of children with autism spectrum disorder, reduces transcription and disrupts socially relevant neural circuits structurally and functionally. In mice, circuit-specific deletion of Met causes distinct atypical behaviors. MET activation increases dendritic complexity and nascent synapse number, but synapse maturation requires reductions in MET. MET mediates its specific biological effects through different intracellular signaling pathways and has a complex protein interactome that is enriched in autism spectrum disorder and other NDD candidates. The interactome is coregulated in developing human neocortex. We suggest that a gene as pleiotropic and highly regulated as MET, together with its interactome, is biologically relevant in normal and pathophysiological contexts, affecting central and peripheral phenotypes that contribute to NDD risk and clinical symptoms. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  8. {sup 89}Zr-Onartuzumab PET imaging of c-MET receptor dynamics

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    Pool, Martin; Kol, Arjan; Giesen, Danique; Vries, Elisabeth G.E. de [University of Groningen, Department of Medical Oncology, University Medical Center Groningen, Groningen (Netherlands); Terwisscha van Scheltinga, Anton G.T. [University of Groningen, Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen (Netherlands); Lub-de Hooge, Marjolijn N. [University of Groningen, Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen (Netherlands); University of Groningen, Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen (Netherlands)

    2017-08-15

    c-MET and its ligand hepatocyte growth factor are often dysregulated in human cancers. Dynamic changes in c-MET expression occur and might predict drug efficacy or emergence of resistance. Noninvasive visualization of c-MET dynamics could therefore potentially guide c-MET-directed therapies. We investigated the feasibility of {sup 89}Zr-labelled one-armed c-MET antibody onartuzumab PET for detecting relevant changes in c-MET levels induced by c-MET-mediated epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib resistance or heat shock protein-90 (HSP90) inhibitor NVP-AUY-922 treatment in human non-small-cell lung cancer (NSCLC) xenografts. In vitro membrane c-MET levels were determined by flow cytometry. HCC827ErlRes, an erlotinib-resistant clone with c-MET upregulation, was generated from the exon-19 EGFR-mutant human NSCLC cell line HCC827. Mice bearing HCC827 and HCC827ErlRes tumours in opposite flanks underwent {sup 89}Zr-onartuzumab PET scans. The HCC827-xenografted mice underwent {sup 89}Zr-onartuzumab PET scans before treatment and while receiving biweekly intraperitoneal injections of 100 mg/kg NVP-AUY-922 or vehicle. Ex vivo, tumour c-MET immunohistochemistry was correlated with the imaging results. In vitro, membrane c-MET was upregulated in HCC827ErlRes tumours by 213 ± 44% in relation to the level in HCC827 tumours, while c-MET was downregulated by 69 ± 9% in HCC827 tumours following treatment with NVP-AUY-922. In vivo, {sup 89}Zr-onartuzumab uptake was 26% higher (P < 0.05) in erlotinib-resistant HCC827ErlRes than in HCC827 xenografts, while HCC827 tumour uptake was 33% lower (P < 0.001) following NVP-AUY-922 treatment. The results show that {sup 89}Zr-onartuzumab PET effectively discriminates relevant changes in c-MET levels and could potentially be used clinically to monitor c-MET status. (orig.)

  9. Insights into function of PSI domains from structure of the Met receptor PSI domain

    International Nuclear Information System (INIS)

    Kozlov, Guennadi; Perreault, Audrey; Schrag, Joseph D.; Park, Morag; Cygler, Miroslaw; Gehring, Kalle; Ekiel, Irena

    2004-01-01

    PSI domains are cysteine-rich modules found in extracellular fragments of hundreds of signaling proteins, including plexins, semaphorins, integrins, and attractins. Here, we report the solution structure of the PSI domain from the human Met receptor, a receptor tyrosine kinase critical for proliferation, motility, and differentiation. The structure represents a cysteine knot with short regions of secondary structure including a three-stranded antiparallel β-sheet and two α-helices. All eight cysteines are involved in disulfide bonds with the pattern consistent with that for the PSI domain from Sema4D. Comparison with the Sema4D structure identifies a structurally conserved core comprising the N-terminal half of the PSI domain. Interestingly, this part links adjacent SEMA and immunoglobulin domains in the Sema4D structure, suggesting that the PSI domain serves as a wedge between propeller and immunoglobulin domains and is responsible for the correct positioning of the ligand-binding site of the receptor

  10. Studies on Platelet-Derived Growth Factor Beta-Receptor and Hepatocyte Growth Factor Receptor c-met in Paracrine Interactions in Human Breast Cancer

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    1996-09-01

    specific expression, and transforming submandibular gland . Growth Factors 1994, 10:145- activity of the mouse met proto-oncogene. Cell Growth 151...Derived Growth Factor Beta-Receptor and Hepatocyte Growth Factor Receptor c-met in Paracrine Interactions in Human Breast Cancer PRINCIPAL INVESTIGATOR...Interactions in Human Breast DAMDI7-94-J-4407 Cancer 6. AUTHOR(S) Bruce E. Elliott, Ph.D. 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING

  11. Met receptor tyrosine kinase signaling induces secretion of the angiogenic chemokine interleukin-8/CXCL8 in pancreatic cancer.

    Directory of Open Access Journals (Sweden)

    Kristen S Hill

    Full Text Available At diagnosis, the majority of pancreatic cancer patients present with advanced disease when curative resection is no longer feasible and current therapeutic treatments are largely ineffective. An improved understanding of molecular targets for effective intervention of pancreatic cancer is thus urgent. The Met receptor tyrosine kinase is one candidate implicated in pancreatic cancer. Notably, Met is over expressed in up to 80% of invasive pancreatic cancers but not in normal ductal cells correlating with poor overall patient survival and increased recurrence rates following surgical resection. However the functional role of Met signaling in pancreatic cancer remains poorly understood. Here we used RNA interference to directly examine the pathobiological importance of increased Met signaling for pancreatic cancer. We show that Met knockdown in pancreatic tumor cells results in decreased cell survival, cell invasion, and migration on collagen I in vitro. Using an orthotopic model for pancreatic cancer, we provide in vivo evidence that Met knockdown reduced tumor burden correlating with decreased cell survival and tumor angiogenesis, with minimal effect on cell growth. Notably, we report that Met signaling regulates the secretion of the pro-angiogenic chemokine interleukin-8/CXCL8. Our data showing that the interleukin-8 receptors CXCR1 and CXCR2 are not expressed on pancreatic tumor cells, suggests a paracrine mechanism by which Met signaling regulates interleukin-8 secretion to remodel the tumor microenvironment, a novel finding that could have important clinical implications for improving the effectiveness of treatments for pancreatic cancer.

  12. ARQ 197, a novel and selective inhibitor of the human c-Met receptor tyrosine kinase with antitumor activity.

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    Munshi, Neru; Jeay, Sébastien; Li, Youzhi; Chen, Chang-Rung; France, Dennis S; Ashwell, Mark A; Hill, Jason; Moussa, Magdi M; Leggett, David S; Li, Chiang J

    2010-06-01

    The met proto-oncogene is functionally linked with tumorigenesis and metastatic progression. Validation of the receptor tyrosine kinase c-Met as a selective anticancer target has awaited the emergence of selective c-Met inhibitors. Herein, we report ARQ 197 as the first non-ATP-competitive small molecule that selectively targets the c-Met receptor tyrosine kinase. Exposure to ARQ 197 resulted in the inhibition of proliferation of c-Met-expressing cancer cell lines as well as the induction of caspase-dependent apoptosis in cell lines with constitutive c-Met activity. These cellular responses to ARQ 197 were phenocopied by RNAi-mediated c-Met depletion and further demonstrated by the growth inhibition of human tumors following oral administration of ARQ 197 in multiple mouse xenograft efficacy studies. Cumulatively, these data suggest that ARQ 197, currently in phase II clinical trials, is a promising agent for targeting cancers in which c-Met-driven signaling is important for their survival and proliferation.

  13. Activation of hepatocyte growth factor receptor, c-met, in renal tubules is required for renoprotection after acute kidney injury.

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    Zhou, Dong; Tan, Roderick J; Lin, Lin; Zhou, Lili; Liu, Youhua

    2013-09-01

    Hepatocyte growth factor is a pleiotrophic protein that promotes injury repair and regeneration in multiple organs. Here, we show that after acute kidney injury (AKI), the HGF receptor, c-met, was induced predominantly in renal tubular epithelium. To investigate the role of tubule-specific induction of c-met in AKI, we generated conditional knockout mice, in which the c-met gene was specifically disrupted in renal tubules. These Ksp-met-/- mice were phenotypically normal and had no appreciable defect in kidney morphology and function. However, in AKI induced by cisplatin or ischemia/reperfusion injury, the loss of tubular c-met substantially aggravated renal injury. Compared with controls, Ksp-met-/- mice displayed higher serum creatinine, more severe morphologic lesions, and increased apoptosis, which was accompanied by an increased expression of Bax and Fas ligand and decreased phosphorylation/activation of Akt. In addition, ablation of c-met in renal tubules promoted chemokine expression and renal inflammation after AKI. Consistently, ectopic expression of hepatocyte growth factor in vivo protected the kidneys against AKI in control mice, but not in Ksp-met-/- counterparts. Thus, our results suggest that tubule-specific c-met signaling is crucial in conferring renal protection after AKI, primarily by its anti-apoptotic and anti-inflammatory mechanisms.

  14. The MET Receptor Tyrosine Kinase Confers Repair of Murine Pancreatic Acinar Cells following Acute and Chronic Injury.

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    Gaziova, Ivana; Jackson, Daniel; Boor, Paul J; Carter, Dwayne; Cruz-Monserrate, Zobeida; Elferink, Cornelis J; Joshi, Aditya D; Kaphalia, Bhupendra; Logsdon, Craig D; Pereira de Castro, Karen; Soong, Lynn; Tao, Xinrong; Qiu, Suimin; Elferink, Lisa A

    2016-01-01

    Acinar cells represent the primary target in necroinflammatory diseases of the pancreas, including pancreatitis. The signaling pathways guiding acinar cell repair and regeneration following injury remain poorly understood. The purpose of this study was to determine the importance of Hepatocyte Growth Factor Receptor/MET signaling as an intrinsic repair mechanism for acinar cells following acute damage and chronic alcohol-associated injury. Here, we generated mice with targeted deletion of MET in adult acinar cells (MET-/-). Acute and repetitive pancreatic injury was induced in MET-/- and control mice with cerulein, and chronic injury by feeding mice Lieber-DeCarli diets containing alcohol with or without enhancement of repetitive pancreatic injury. We examined the exocrine pancreas of these mice histologically for acinar death, edema, inflammation and collagen deposition and changes in the transcriptional program. We show that MET expression is relatively low in normal adult pancreas. However, MET levels were elevated in ductal and acinar cells in human pancreatitis specimens, consistent with a role for MET in an adaptive repair mechanism. We report that genetic deletion of MET in adult murine acinar cells was linked to increased acinar cell death, chronic inflammation and delayed recovery (regeneration) of pancreatic exocrine tissue. Notably, increased pancreatic collagen deposition was detected in MET knockout mice following repetitive injury as well alcohol-associated injury. Finally, we identified specific alterations of the pancreatic transcriptome associated with MET signaling during injury, involved in tissue repair, inflammation and endoplasmic reticulum stress. Together, these data demonstrate the importance of MET signaling for acinar repair and regeneration, a novel finding that could attenuate the symptomology of pancreatic injury.

  15. CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Complexes to Regulate Innate Immune Signaling

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    Matous Hrdinka

    2016-03-01

    Full Text Available Innate immune signaling relies on the deposition of non-degradative polyubiquitin at receptor-signaling complexes, but how these ubiquitin modifications are regulated by deubiquitinases remains incompletely understood. Met1-linked ubiquitin (Met1-Ub is assembled by the linear ubiquitin assembly complex (LUBAC, and this is counteracted by the Met1-Ub-specific deubiquitinase OTULIN, which binds to the catalytic LUBAC subunit HOIP. In this study, we report that HOIP also interacts with the deubiquitinase CYLD but that CYLD does not regulate ubiquitination of LUBAC components. Instead, CYLD limits extension of Lys63-Ub and Met1-Ub conjugated to RIPK2 to restrict signaling and cytokine production. Accordingly, Met1-Ub and Lys63-Ub were individually required for productive NOD2 signaling. Our study thus suggests that LUBAC, through its associated deubiquitinases, coordinates the deposition of not only Met1-Ub but also Lys63-Ub to ensure an appropriate response to innate immune receptor activation.

  16. X-ray and neutron small-angle scattering analysis of the complex formed by the Met receptor and the Listeria monocytogenes invasion protein InlB.

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    Niemann, Hartmut H; Petoukhov, Maxim V; Härtlein, Michael; Moulin, Martine; Gherardi, Ermanno; Timmins, Peter; Heinz, Dirk W; Svergun, Dmitri I

    2008-03-21

    The Listeria monocytogenes surface protein InlB binds to the extracellular domain of the human receptor tyrosine kinase Met, the product of the c-met proto-oncogene. InlB binding activates the Met receptor, leading to uptake of Listeria into normally nonphagocytic host cells. The N-terminal half of InlB (InlB(321)) is sufficient for Met binding and activation. The complex between this Met-binding domain of InlB and various constructs of the Met ectodomain was characterized by size exclusion chromatography and dynamic light scattering, and structural models were built using small-angle X-ray scattering and small-angle neutron scattering. Although most receptor tyrosine kinase ligands induce receptor dimerization, InlB(321) consistently binds the Met ectodomain with a 1:1 stoichiometry. A construct comprising the Sema and PSI domains of Met, although sufficient to bind the physiological Met ligand hepatocyte growth factor/scatter factor, does not form a complex with InlB(321) in solution, highlighting the importance of Met Ig domains for InlB binding. Small-angle X-ray scattering and small-angle neutron scattering measurements of ligand and receptor, both free and in complex, reveal an elongated shape for the receptor. The four Ig domains form a bent, rather than a fully extended, conformation, and InlB(321) binds to Sema and the first Ig domain of Met, in agreement with the recent crystal structure of a smaller Met fragment in complex with InlB(321). These results call into question whether receptor dimerization is the basic underlying event in InlB(321)-mediated Met activation and demonstrate differences in the mechanisms by which the physiological ligand hepatocyte growth factor/scatter factor and InlB(321) bind and activate the Met receptor.

  17. Human epidermal growth factor receptor 2, epidermal growth factor receptor, and c-MET overexpression and survival in biliary tract cancer: A meta-analysis.

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    Zhou, Wei; Jiang, Congqing; Zhan, Nan; Lv, Xiaoguang; Fan, Lifang; Ninu, Maskey

    2018-01-01

    Tyrosine kinase growth factor receptors (TKGFRs) play an important role in the progression of cancer. A variety of studies have investigated the clinicopathologic correlation of these receptors and their influences on patient survival in different types of cancer. As the members of TKGFRs, the biomarkers c-MET, epidermal growth factor receptor (EGFR), and human epidermal growth factor receptor 2 (HER-2) have been extensively investigated in biliary tract cancer (BTC). However, their prognostic value is still controversial. Our study aimed to evaluate the prognostic significance of the three markers in BTC patients based on the published studies. The correlation between high expression of these markers and clinical parameters or overall survival (OS) has been assumed in this paper. Including PubMed, EMBASE, China National Knowledge Infrastructure, and Springer, a comprehensive search for the related literature published in Chinese and English has been done. Finally, 31 studies were selected in our research. Surprisingly, the meta-analysis indicated that HER-2 high expression was not correlated with age, gender, primary tumor, tumor node metastasis (TNM) stage, lymph node status, and differentiation. We also found that EGFR high expression was not associated with the parameters, such as age, gender, TNM stage, differentiation, or lymph node status. c-MET high-expression was not associated with age, differentiation, gender, TNM stage, or lymph node status. In addition, our study showed that HER-2, EGFR, and c-MET high expression had an adverse influence on OS in BTC, the pooled hazard ratio for HER-2, EGFR, and c-MET was statistically significant. The present meta-analysis indicated that EGFR and HER-2 high expression have little impact on OS in patients with BTC while c-MET high expression influenced OS in patients with BTC to a large extent. However, c-MET, EGFR, and HER-2 expression did not show any correlation with those clinical parameters. c-MET may be a

  18. Differential impact of Met receptor gene interaction with early-life stress on neuronal morphology and behavior in mice.

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    Heun-Johnson, Hanke; Levitt, Pat

    2018-02-01

    Early adversity in childhood increases the risk of anxiety, mood, and post-traumatic stress disorders in adulthood, and specific gene-by-environment interactions may increase risk further. A common functional variant in the promoter region of the gene encoding the human MET receptor tyrosine kinase (rs1858830 ' C' allele) reduces expression of MET and is associated with altered cortical circuit function and structural connectivity. Mice with reduced Met expression exhibit changes in anxiety-like and conditioned fear behavior, precocious synaptic maturation in the hippocampus, and reduced neuronal arbor complexity and synaptogenesis. These phenotypes also can be produced independently by early adversity in wild-type mice. The present study addresses the outcome of combining early-life stress and genetic influences that alter timing of maturation on enduring functional and structural phenotypes. Using a model of reduced Met expression ( Met +/- ) and early-life stress from postnatal day 2-9, social, anxiety-like, and contextual fear behaviors in later life were measured. Mice that experienced early-life stress exhibited impairments in social interaction, whereas alterations in anxiety-like behavior and fear learning were driven by Met haploinsufficiency, independent of rearing condition. Early-life stress or reduced Met expression decreased arbor complexity of ventral hippocampal CA1 pyramidal neurons projecting to basolateral amygdala. Paradoxically, arbor complexity in Met +/- mice was increased following early-life stress, and thus not different from arbors in wild-type mice raised in control conditions. The changes in dendritic morphology are consistent with the hypothesis that the physiological state of maturation of CA1 neurons in Met +/- mice influences their responsiveness to early-life stress. The dissociation of behavioral and structural changes suggests that there may be phenotype-specific sensitivities to early-life stress.

  19. Immunohistochemical expression of receptor tyrosine kinase PDGFR-α, c-Met, and EGFR in skull base chordoma.

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    Akhavan-Sigari, R; Abili, M; Gaab, M R; Rohde, V; Zafar, N; Emami, P; Ostertag, H

    2015-01-01

    Chordomas are rare, locally aggressive malignancies that often exhibit an insidious natural history and are difficult to eradicate. Surgery and radiotherapy are the treatment mainstays of chordoma, but the chance of local recurrence remains high. Reports of receptor tyrosine kinase (RTK) expression in chordoma suggest that these tumors may respond to kinase inhibitor therapy. Currently, there are no effective chemotherapeutic protocols for chordoma. A tissue microarray containing 74 tumor specimens from primary chordoma patients and 71 from their recurrent tumors for a total of 145 tumor specimens was immunohistochemically analyzed for expression of a number of proteins involved in signal transduction from RTKs. Platelet-derived growth factor receptor-α (PDGFR-α), epidermal growth factor receptor (EGFR), c-Met, and CD-34 were detected in 100, 92, 100, and 59% of cases, respectively. PDGFR-α and c-Met staining was of moderate to strong intensity in all cases. In contrast, total EGFR staining was variable; weak staining was detected in 10 cases. Our results contribute to the understanding of the expression of RTKs in skull base chordomas and support the development of targeted therapies that inhibit RTKs, which may have a synergistic effect for chemotherapy in patients. There were statistically significant correlations between the expression of PDGFR-α, c-Met, and EGFR and disease-free survival. The results nonetheless suggest that chordomas may respond to RTK inhibitors or modulators of other downstream signaling.

  20. The Pim-1 protein kinase is an important regulator of MET receptor tyrosine kinase levels and signaling.

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    Cen, Bo; Xiong, Ying; Song, Jin H; Mahajan, Sandeep; DuPont, Rachel; McEachern, Kristen; DeAngelo, Daniel J; Cortes, Jorge E; Minden, Mark D; Ebens, Allen; Mims, Alice; LaRue, Amanda C; Kraft, Andrew S

    2014-07-01

    MET, the receptor for hepatocyte growth factor (HGF), plays an important role in signaling normal and tumor cell migration and invasion. Here, we describe a previously unrecognized mechanism that promotes MET expression in multiple tumor cell types. The levels of the Pim-1 protein kinase show a positive correlation with the levels of MET protein in human tumor cell lines and patient-derived tumor materials. Using small interfering RNA (siRNA), Pim knockout mice, small-molecule inhibitors, and overexpression of Pim-1, we confirmed this correlation and found that Pim-1 kinase activity regulates HGF-induced tumor cell migration, invasion, and cell scattering. The novel biochemical mechanism for these effects involves the ability of Pim-1 to control the translation of MET by regulating the phosphorylation of eukaryotic initiation factor 4B (eIF4B) on S406. This targeted phosphorylation is required for the binding of eIF4B to the eIF3 translation initiation complex. Importantly, Pim-1 action was validated by the evaluation of patient blood and bone marrow from a phase I clinical trial of a Pim kinase inhibitor, AZD1208. These results suggest that Pim inhibitors may have an important role in the treatment of patients where MET is driving tumor biology. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  1. Deletion of Macrophage Mineralocorticoid Receptor Protects Hepatic Steatosis and Insulin Resistance Through ERα/HGF/Met Pathway.

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    Zhang, Yu-Yao; Li, Chao; Yao, Gao-Feng; Du, Lin-Juan; Liu, Yuan; Zheng, Xiao-Jun; Yan, Shuai; Sun, Jian-Yong; Liu, Yan; Liu, Ming-Zhu; Zhang, Xiaoran; Wei, Gang; Tong, Wenxin; Chen, Xiaobei; Wu, Yong; Sun, Shuyang; Liu, Suling; Ding, Qiurong; Yu, Ying; Yin, Huiyong; Duan, Sheng-Zhong

    2017-06-01

    Although the importance of macrophages in nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) has been recognized, how macrophages affect hepatocytes remains elusive. Mineralocorticoid receptor (MR) has been implicated to play important roles in NAFLD and T2DM. However, cellular and molecular mechanisms are largely unknown. We report that myeloid MR knockout (MRKO) improves glucose intolerance, insulin resistance, and hepatic steatosis in obese mice. Estrogen signaling is sufficient and necessary for such improvements. Hepatic gene and protein expression suggests that MRKO reduces hepatic lipogenesis and lipid storage. In the presence of estrogen, MRKO in macrophages decreases lipid accumulation and increases insulin sensitivity of hepatocytes through hepatocyte growth factor (HGF)/Met signaling. MR directly regulates estrogen receptor 1 ( Esr1 [encoding ERα]) in macrophages. Knockdown of hepatic Met eliminates the beneficial effects of MRKO in female obese mice. These findings identify a novel MR/ERα/HGF/Met pathway that conveys metabolic signaling from macrophages to hepatocytes in hepatic steatosis and insulin resistance and provide potential new therapeutic strategies for NAFLD and T2DM. © 2017 by the American Diabetes Association.

  2. Expression of hepatocyte growth factor/scatter factor and its receptor, MET, suggests roles in human embryonic organogenesis.

    Science.gov (United States)

    Kolatsi-Joannou, M; Moore, R; Winyard, P J; Woolf, A S

    1997-05-01

    Hepatocyte growth factor/scatter factor (HGF/SF) is secreted by mesenchymal cells and elicits proliferation, motility, differentiation, and morphogenesis of epithelia and other cells. These effects are mediated by binding to MET, a receptor tyrosine kinase. Genetically engineered mice lacking HGF/SF die in utero due to a failure of placental and hepatocyte differentiation, but little information exists regarding the expression of this signaling system in human development. Using reverse transcriptase-polymerase chain reaction, Western blots, and immunohistochemistry, we report that HGF/SF and MET are expressed during critical early periods of human organogenesis from 6 to 13 wk of gestation. Organs that expressed both genes included liver, metanephric kidney, intestine, and lung, each of which develop by inductive interactions between mesenchyme and epithelia. Of all organs studied, the placenta contained the highest levels of HGF/SF protein, and MET was detected in trophoblastic cells of chorionic villi as early as the 5th wk of gestation. Finally, examination of a human multicystic dysplastic kidney demonstrated that malformed, hyperproliferative tubules expressed MET, whereas HGF/SF protein was immunolocalized to the same epithelia and also to the surrounding undifferentiated cells. Hence HGF/SF might be an important growth factor in normal human embryogenesis and may additionally play a role in human organ malformations.

  3. Cerebral 5-HT2A receptor and serotonin transporter binding in humans are not affected by the val66met BDNF polymorphism status or blood BDNF levels

    DEFF Research Database (Denmark)

    Klein, Anders Bue; Trajkovska, Viktorija; Erritzoe, David

    2010-01-01

    Recent studies have proposed an interrelation between the brain-derived neurotrophic factor (BDNF) val66met polymorphism and the serotonin system. In this study, we investigated whether the BDNF val66met polymorphism or blood BDNF levels are associated with cerebral 5-hydroxytryptamine 2A (5-HT(2A......)) receptor or serotonin transporter (SERT) binding in healthy subjects. No statistically significant differences in 5-HT(2A) receptor or SERT binding were found between the val/val and met carriers, nor were blood BDNF values associated with SERT binding or 5-HT(2A) receptor binding. In conclusion, val66met...... BDNF polymorphism status is not associated with changes in the serotonergic system. Moreover, BDNF levels in blood do not correlate with either 5-HT(2A) or SERT binding....

  4. Detection of hepatocyte growth factor/scatter factor receptor (c-Met) in axillary drainage after operations for breast cancer using reverse transcriptase–polymerase chain reaction

    International Nuclear Information System (INIS)

    Greenberg, Ron; Schwartz, Ignat; Skornick, Yehuda; Kaplan, Ofer

    2003-01-01

    The diverse biological effects of hepatocyte growth factor/scatter factor (HGF/SF) are mediated by c-Met, which is preferentially expressed on epithelial cells. Met signaling has a role in normal cellular activities, and may be associated with the development and progression of malignant processes. In this study we examined whether Met can be detected in the axillary drainage from patients who underwent conservative operations for breast cancer, and its prognostic significance. Thirty-one consecutive patients with invasive ductal carcinoma of the breast suitable for breast-conserving treatment were studied. The output of the drain that had been placed in the axilla during the operation was collected, and the presence of Met and β-actin were assessed by reverse transcriptase–polymerase chain reaction (RT–PCR) assays. The data were compared with the pathological features of the tumor and the axillary lymph nodes, and with the estrogen receptor and progesterone receptor status. RT–PCR of the axillary lymphatic drainage was positive for Met in 23 (74.2%) of the patients. Positive assays were correlated with increasing tumor size and grade, with capillary and lymphatic invasion, and with lymph node metastasis (P < 0.02, for all comparisons). All 12 patients with axillary lymph node metastases had positive assays for Met, compared with 57.9% of patients without lymph node metastases. All five patients with tumor involvement in the margins of the resection had positive assays for Met in their lymphatic fluid, compared with 18 of 26 positive assays (69.2%) for patients without involved margins (P < 0.04). Finally, Met showed negative correlations with positivity for estrogen receptor and progesterone receptor (P < 0.02). Met can be detected in the axillary fluids of patients with breast cancer and its expression in the axillary drainage may have potential as a prognostic factor. This finding might be relevant to therapeutic considerations, because a positive assay

  5. Ginsenoside-Rg{sub 1} induces angiogenesis by the inverse regulation of MET tyrosine kinase receptor expression through miR-23a

    Energy Technology Data Exchange (ETDEWEB)

    Kwok, Hoi-Hin [Dr. Gilbert Hung Ginseng Laboratory, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR (China); Chan, Lai-Sheung [Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR (China); Poon, Po-Ying [Dr. Gilbert Hung Ginseng Laboratory, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR (China); Yue, Patrick Ying-Kit [Dr. Gilbert Hung Ginseng Laboratory, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR (China); Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR (China); Wong, Ricky Ngok-Shun, E-mail: rnswong@hkbu.edu.hk [Dr. Gilbert Hung Ginseng Laboratory, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR (China); Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR (China)

    2015-09-15

    Therapeutic angiogenesis has been implicated in ischemic diseases and wound healing. Ginsenoside-Rg{sub 1} (Rg{sub 1}), one of the most abundant active components of ginseng, has been demonstrated as an angiogenesis-stimulating compound in different models. There is increasing evidence implicating microRNAs (miRNAs), a group of non-coding RNAs, as important regulators of angiogenesis, but the role of microRNAs in Rg{sub 1}-induced angiogenesis has not been fully explored. In this report, we found that stimulating endothelial cells with Rg{sub 1} could reduce miR-23a expression. In silico experiments predicted hepatocyte growth factor receptor (MET), a well-established mediator of angiogenesis, as the target of miR-23a. Transfection of the miR-23a precursor or inhibitor oligonucleotides validated the inverse relationship of miR-23a and MET expression. Luciferase reporter assays further confirmed the interaction between miR-23a and the MET mRNA 3′-UTR. Intriguingly, ginsenoside-Rg{sub 1} was found to increase MET protein expression in a time-dependent manner. We further demonstrated that ginsenoside-Rg{sub 1}-induced angiogenic activities were indeed mediated through the down-regulation of miR-23a and subsequent up-regulation of MET protein expression, as confirmed by gain- and loss-of-function angiogenic experiments. In summary, our results demonstrated that ginsenoside-Rg{sub 1} could induce angiogenesis by the inverse regulation of MET tyrosine kinase receptor expression through miR-23a. This study has broadened our understanding of the non-genomic effects of ginsenoside-Rg{sub 1,} and provided molecular evidence that warrant further development of natural compound as novel angiogenesis-promoting therapy. - Highlights: • Therapeutic angiogenesis has been implicated in ischemic diseases and wound healing. • Ginsenoside-Rg{sub 1} (Rg{sub 1}) has been demonstrated as an angiogenesis-stimulating compound. • We found that Rg{sub 1} induces angiogenesis by

  6. Araguspongine C Induces Autophagic Death in Breast Cancer Cells through Suppression of c-Met and HER2 Receptor Tyrosine Kinase Signaling

    Directory of Open Access Journals (Sweden)

    Mohamed R. Akl

    2015-01-01

    Full Text Available Receptor tyrosine kinases are key regulators of cellular growth and proliferation. Dysregulations of receptor tyrosine kinases in cancer cells may promote tumorigenesis by multiple mechanisms including enhanced cell survival and inhibition of cell death. Araguspongines represent a group of macrocyclic oxaquinolizidine alkaloids isolated from the marine sponge Xestospongia species. This study evaluated the anticancer activity of the known oxaquinolizidine alkaloids araguspongines A, C, K and L, and xestospongin B against breast cancer cells. Araguspongine C inhibited the proliferation of multiple breast cancer cell lines in vitro in a dose-dependent manner. Interestingly, araguspongine C-induced autophagic cell death in HER2-overexpressing BT-474 breast cancer cells was characterized by vacuole formation and upregulation of autophagy markers including LC3A/B, Atg3, Atg7, and Atg16L. Araguspongine C-induced autophagy was associated with suppression of c-Met and HER2 receptor tyrosine kinase activation. Further in-silico docking studies and cell-free Z-LYTE assays indicated the potential of direct interaction between araguspongine C and the receptor tyrosine kinases c-Met and HER2 at their kinase domains. Remarkably, araguspongine C treatment resulted in the suppression of PI3K/Akt/mTOR signaling cascade in breast cancer cells undergoing autophagy. Induction of autophagic death in BT-474 cells was also associated with decreased levels of inositol 1,4,5-trisphosphate receptor upon treatment with effective concentration of araguspongine C. In conclusion, results of this study are the first to reveal the potential of araguspongine C as an inhibitor to receptor tyrosine kinases resulting in the induction of autophagic cell death in breast cancer cells.

  7. A Val85Met Mutation in Melanocortin-1 Receptor Is Associated with Reductions in Eumelanic Pigmentation and Cell Surface Expression in Domestic Rock Pigeons (Columba livia)

    Science.gov (United States)

    Guernsey, Michael W.; Ritscher, Lars; Miller, Matthew A.; Smith, Daniel A.; Schöneberg, Torsten; Shapiro, Michael D.

    2013-01-01

    Variation in the melanocortin-1 receptor (Mc1r) is associated with pigmentation diversity in wild and domesticated populations of vertebrates, including several species of birds. Among domestic bird species, pigmentation variation in the rock pigeon ( Columba livia ) is particularly diverse. To determine the potential contribution of Mc1r variants to pigment diversity in pigeons, we sequenced Mc1r in a wide range of pigeon breeds and identified several single nucleotide polymorphisms, including a variant that codes for an amino acid substitution (Val85Met). In contrast to the association between Val85Met and eumelanism in other avian species, this change was associated with pheomelanism in pigeons. In vitro cAMP accumulation and protein expression assays revealed that Val85Met leads to decreased receptor function and reduced cell surface expression of the mutant protein. The reduced in vitro function is consistent with the observed association with reduced eumelanic pigmentation. Comparative genetic and cellular studies provide important insights about the range of mechanisms underlying diversity among vertebrates, including different phenotypic associations with similar mutations in different species. PMID:23977400

  8. A Val85Met mutation in melanocortin-1 receptor is associated with reductions in eumelanic pigmentation and cell surface expression in domestic rock pigeons (Columba livia.

    Directory of Open Access Journals (Sweden)

    Michael W Guernsey

    Full Text Available Variation in the melanocortin-1 receptor (Mc1r is associated with pigmentation diversity in wild and domesticated populations of vertebrates, including several species of birds. Among domestic bird species, pigmentation variation in the rock pigeon (Columbalivia is particularly diverse. To determine the potential contribution of Mc1r variants to pigment diversity in pigeons, we sequenced Mc1r in a wide range of pigeon breeds and identified several single nucleotide polymorphisms, including a variant that codes for an amino acid substitution (Val85Met. In contrast to the association between Val85Met and eumelanism in other avian species, this change was associated with pheomelanism in pigeons. In vitro cAMP accumulation and protein expression assays revealed that Val85Met leads to decreased receptor function and reduced cell surface expression of the mutant protein. The reduced in vitro function is consistent with the observed association with reduced eumelanic pigmentation. Comparative genetic and cellular studies provide important insights about the range of mechanisms underlying diversity among vertebrates, including different phenotypic associations with similar mutations in different species.

  9. Phosphorylated hepatocyte growth factor receptor/c-Met is associated with tumor growth and prognosis in patients with bladder cancer: correlation with matrix metalloproteinase-2 and -7 and E-cadherin.

    Science.gov (United States)

    Miyata, Yasuyoshi; Sagara, Yuji; Kanda, Shigeru; Hayashi, Tomayoshi; Kanetake, Hiroshi

    2009-04-01

    Hepatocyte growth factor receptor/c-Met is associated with malignant aggressiveness and survival in various cancers including bladder cancer. Although phosphorylation of hepatocyte growth factor receptor/c-Met is essential for its function, the pathologic significance of phosphorylated hepatocyte growth factor receptor/c-Met in bladder cancer remains elusive. We investigated the clinical significance of its expression, and its correlation with cancer cell progression-related molecules. The expression levels of 2 tyrosine residues of hepatocyte growth factor receptor/c-Met (pY1234/1235 and pY1349) were examined immunohistochemically in 133 specimens with nonmetastatic bladder cancer. We also investigated their correlation with matrix metalloproteinase-1, -2, -7, and -14; urokinase-type plasminogen activator; E-cadherin; CD44 standard, variant 3, and variant 6; and vascular endothelial growth factor. Expression of phosphorylated hepatocyte growth factor receptor/c-Met was detected in cancer cells, but was rare in normal urothelial cells. Although hepatocyte growth factor receptor/c-Met, pY1234/1235 hepatocyte growth factor receptor/c-Met, and pY1349 hepatocyte growth factor receptor/c-Met were associated with pT stage, multivariate analysis identified pY1349 hepatocyte growth factor receptor/c-met expression only as a significant factor for high pT stage. Expression of pY1349 hepatocyte growth factor receptor/c-Met was a marker of metastasis and (P = .001) and cause-specific survival (P = .003). Expressions of matrix metalloproteinase-2, matrix metalloproteinase-7, and E-cadherin correlated with pY1349 hepatocyte growth factor receptor/c-Met expression. Our results demonstrated that pY1349 hepatocyte growth factor receptor/c-Met plays an important role in tumor development, and its expression is a significant predictor of metastasis and survival of patients with bladder cancer. The results suggest that these activities are mediated, at least in part, by matrix

  10. Conformation of cyclo-(Gln-Trp-Phe-{beta}Ala-Leu-Met), a NK-2 tachykinin receptor antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Ha, Jong Myung [Silla Univ., Pusan (Korea, Republic of)

    1999-10-01

    Solution conformation of cyclo-(Gln-Trp-Phe-{beta}Ala-Leu-Met), new NK-2 antagonist in dimethyl sulfoxide solution, has been determined by the use of two-dimensional nuclear magnetic resonance spectroscopy combined with simulated annealing calculations. The peptide exhibited converged structures with the atomic root-mean-square difference for the backbone atoms (N, C{sup a}, C') of all residues being 0.02A in the 25 annealed structures. The analysis of the structures indicated that the cyclic peptide has three intramolecular hydrogen bonds between Met NH and {beta}Ala CO, {beta}Ala NH and Met CO, Phe NH and Met CO, and contain a type-I {beta}-turn with Gln and Trp and a {gamma}-turn with Leu. The addition of an extra methylene group to Gly, i.e. {beta}-Ala residue, may relax some unfavorable restraints in the cyclic backbone structure, hence enabling an additional hydrogen bond, which results in stabilizing one conformation.

  11. Photoaffinity labeling of opiate (enkephalin) receptor of rat brain plasma membranes with 125I(D-Ala2, p-N3-Phe4-Met5)-enkephalin

    International Nuclear Information System (INIS)

    Yeung, C.W.T.

    1986-01-01

    A photoreactive (D-Ala 2 , p-N 3 -Phe 4 -Met 5 )enkephalin derivative was prepared, iodinated with carrier free 125 I and then purified by high performance liquid chromatography. The purified radioactive photoprobe was monoiodinated at the amino terminal tyrosine residue. This radioactive photoprobe was used to photoaffinity label plasma membranes prepared from rat brain, spinal cord and cerebellum. The photolabeled plasma membranes were analyzed by sodium dodecyl sulfate gel electrophoresis. A 46,000-daltons band was specifically photolabeled in the plasma membranes of brain and spinal cord but not in the plasma membranes from cerebellum. The photolabeling of this band was inhibited by peptides related to enkephalin by not but substance P or gastrin tetrapeptide. These data demonstrate that the labeled 46,000-daltons band is a protein of the opiate (enkephalin)receptor

  12. The DNA replication licensing factor miniature chromosome maintenance 7 is essential for RNA splicing of epidermal growth factor receptor, c-Met, and platelet-derived growth factor receptor.

    Science.gov (United States)

    Chen, Zhang-Hui; Yu, Yan P; Michalopoulos, George; Nelson, Joel; Luo, Jian-Hua

    2015-01-16

    Miniature chromosome maintenance 7 (MCM7) is an essential component of DNA replication licensing complex. Recent studies indicate that MCM7 is amplified and overexpressed in a variety of human malignancies. In this report, we show that MCM7 binds SF3B3. The binding motif is located in the N terminus (amino acids 221-248) of MCM7. Knockdown of MCM7 or SF3B3 significantly increased unspliced RNA of epidermal growth factor receptor, platelet-derived growth factor receptor, and c-Met. A dramatic drop of reporter gene expression of the oxytocin exon 1-intron-exon 2-EGFP construct was also identified in SF3B3 and MCM7 knockdown PC3 and DU145 cells. The MCM7 or SF3B3 depleted cell extract failed to splice reporter RNA in in vitro RNA splicing analyses. Knockdown of SF3B3 and MCM7 leads to an increase of cell death of both PC3 and DU145 cells. Such cell death induction is partially rescued by expressing spliced c-Met. To our knowledge, this is the first report suggesting that MCM7 is a critical RNA splicing factor, thus giving significant new insight into the oncogenic activity of this protein. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. The C. elegans Discoidin Domain Receptor DDR-2 Modulates the Met-like RTK-JNK Signaling Pathway in Axon Regeneration.

    Science.gov (United States)

    Hisamoto, Naoki; Nagamori, Yuki; Shimizu, Tatsuhiro; Pastuhov, Strahil I; Matsumoto, Kunihiro

    2016-12-01

    The ability of specific neurons to regenerate their axons after injury is governed by cell-intrinsic regeneration pathways. However, the signaling pathways that orchestrate axon regeneration are not well understood. In Caenorhabditis elegans, initiation of axon regeneration is positively regulated by SVH-2 Met-like growth factor receptor tyrosine kinase (RTK) signaling through the JNK MAPK pathway. Here we show that SVH-4/DDR-2, an RTK containing a discoidin domain that is activated by collagen, and EMB-9 collagen type IV regulate the regeneration of neurons following axon injury. The scaffold protein SHC-1 interacts with both DDR-2 and SVH-2. Furthermore, we demonstrate that overexpression of svh-2 and shc-1 suppresses the delay in axon regeneration observed in ddr-2 mutants, suggesting that DDR-2 functions upstream of SVH-2 and SHC-1. These results suggest that DDR-2 modulates the SVH-2-JNK pathway via SHC-1. We thus identify two different RTK signaling networks that play coordinated roles in the regulation of axonal regeneration.

  14. The C. elegans Discoidin Domain Receptor DDR-2 Modulates the Met-like RTK–JNK Signaling Pathway in Axon Regeneration

    Science.gov (United States)

    Shimizu, Tatsuhiro; Matsumoto, Kunihiro

    2016-01-01

    The ability of specific neurons to regenerate their axons after injury is governed by cell-intrinsic regeneration pathways. However, the signaling pathways that orchestrate axon regeneration are not well understood. In Caenorhabditis elegans, initiation of axon regeneration is positively regulated by SVH-2 Met-like growth factor receptor tyrosine kinase (RTK) signaling through the JNK MAPK pathway. Here we show that SVH-4/DDR-2, an RTK containing a discoidin domain that is activated by collagen, and EMB-9 collagen type IV regulate the regeneration of neurons following axon injury. The scaffold protein SHC-1 interacts with both DDR-2 and SVH-2. Furthermore, we demonstrate that overexpression of svh-2 and shc-1 suppresses the delay in axon regeneration observed in ddr-2 mutants, suggesting that DDR-2 functions upstream of SVH-2 and SHC-1. These results suggest that DDR-2 modulates the SVH-2–JNK pathway via SHC-1. We thus identify two different RTK signaling networks that play coordinated roles in the regulation of axonal regeneration. PMID:27984580

  15. Association of the insulin-receptor variant Met-985 with hyperglycemia and non-insulin-dependent diabetes mellitus in the Netherlands : A population-based study

    NARCIS (Netherlands)

    tHart, LM; Stolk, RP; Heine, RJ; Grobbee, DE; vanderDoes, FEE; Maassen, JA

    1996-01-01

    One of the characteristics of non-insulin-dependent diabetes mellitus (NIDDM) is the presence of insulin resistance. Most NIDDM patients have a normal sequence of the insulin receptor, indicating that, if insulin-receptor mutations contribute to the development of NIDDM, they will be present only in

  16. COMT Val(158) met genotype and striatal D(2/3) receptor binding in adults with 22q11 deletion syndrome.

    LENUS (Irish Health Repository)

    Boot, Erik

    2011-09-01

    Although catechol-O-methyltransferase (COMT) activity evidently affects dopamine function in prefrontal cortex, the contribution is assumed less significant in striatum. We studied whether a functional polymorphism in the COMT gene (Val(158) Met) influences striatal D(2\\/3) R binding ratios (D(2\\/3) R BP(ND) ) in 15 adults with 22q11 deletion syndrome and hemizygous for this gene, using single photon emission computed tomography and the selective D(2\\/3) radioligand [(123) I]IBZM. Met hemizygotes had significantly lower mean D(2\\/3) R BPND than Val hemizygotes. These preliminary data suggest that low COMT activity may affect dopamine levels in striatum in humans and this may have implications for understanding the contribution of COMT activity to psychiatric disorders.

  17. Precisielandbouw komt met golven

    NARCIS (Netherlands)

    Schans, van der D.A.

    2009-01-01

    Met deze laatste golf van vernieuwing zijn we dicht bij het op grote schaal toepassen van prescisielandbouw gekomen. We kunnen beelden digitaal uitwisselen met bedrijfsmanagementprogramma's en kunnen ze op het perceel projecteren

  18. No increase in autism-associated genetic events in children conceived by assisted reproduction.

    Science.gov (United States)

    Ackerman, Sean; Wenegrat, Julia; Rettew, David; Althoff, Robert; Bernier, Raphael

    2014-08-01

    To understand the rate of genetic events in patients with autism spectrum disorder (ASD) who were exposed to assisted reproduction. Case control study using genetics data. Twelve collaborating data collection sites across North America as part of the Simons Simplex Collection. 2,760 children with ASD, for whom 1,994 had published copy number variation data and 424 had published gene mutation status available. None. Rates of autism-associated genetic events in children with ASD conceived with assisted reproduction versus those conceived naturally. No statistically significant differences in copy number variations or autism-associated gene-disrupting events were found when comparing ASD patients exposed to assisted reproduction with those not exposed to assisted reproduction. This is the first large genetic association to concurrently examine the genotype of individuals with ASD in relation to their exposure to ART versus natural conception, and it adds reassuring evidence to the argument that ART does not increase the risk of ASD. Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  19. Met1-linked Ubiquitination in Immune Signalling

    DEFF Research Database (Denmark)

    Fiil, Berthe Katrine; Gyrd-Hansen, Mads

    2014-01-01

    identification of physiological substrates for Met1-Ub in response to activation of innate immune receptors. These discoveries have significantly advanced our understanding of how non-degradative ubiquitin modifications control pro-inflammatory responses mediated by nuclear factor κB and mitogen......Methionine 1-linked ubiquitin chains (Met1-Ub), or linear ubiquitin, has emerged as a central post-translational modification in innate immune signalling. Molecular machinery that assembles, senses and, more recently, disassembles Met1-Ub has been identified, and technical advances have enabled...

  20. When Historiography Met Epistemology

    Directory of Open Access Journals (Sweden)

    Jean-François Stoffel

    2017-06-01

    Full Text Available Review of Bordoni, Stefano. When historiography met epistemology: Sophisticated histories and philosophies of science in French-speaking countries in the second half of the nineteenth century. Reviewed by Jean-François Stoffel.

  1. Autorijden met ADHD

    NARCIS (Netherlands)

    Fuermaier, Anselm B.M.; Tucha, Lara; de Vries, Stefanie M.; Koerts, Janneke; de Waard, Dick; Brookhuis, Karel; Tucha, Oliver

    Volwassenen met attention deficit hyperactivity disorder (ADHD) hebben uiteenlopende cognitieve beperkingen, die een aanzienlijke invloed kunnen hebben op verschillende aspecten van het dagelijks leven. Een van deze aspecten is het besturen van een auto. Autorijden is een belangrijke activiteit in

  2. Lindebladwespen bestrijd met geel

    NARCIS (Netherlands)

    Linden, van der A.

    2005-01-01

    De lindebladwesp (Caliros annulipes) komt in verschillende boomsoorten voor en is een lastig te bestrijden plaaginsect. PPO Bomen ontdekte dat de bladwesp goed te bestrijden is met behulp van gele signaalplaten

  3. Onderhandelen met Hamas?

    NARCIS (Netherlands)

    Boekestijn, A.J.

    2006-01-01

    Volgens de Wetenschappelijke Raad voor het Regeringsbeleid is de terroristische organisatie Hamas geleidelijk aan het moderniseren. De WRR vindt dan ook dat het Westen zonder condities vooraf met deze organisatie moet gaan praten. Onze regering wil pas onderhandelen indien Hamas geweld afzweert en

  4. SPSS met syntax

    NARCIS (Netherlands)

    Grotenhuis, H.F. te; Visscher, C.A.M.

    2007-01-01

    Dit boekje wijkt af van de gebruikelijke statistiekboeken omdat het sec gaat over het bekende statistische computerprogramma SPSS, en dan alleen nog de oorspronkelijke variant waarin wordt gewerkt met syntax (intypen commando's -zoals bij DOS) i.p.v. de later ontwikkelde 'Windows-schil' (aanklikken

  5. Targeted inactivation of hepatocyte growth factor receptor c-met in beta-cells leads to defective insulin secretion and GLUT-2 downregulation without alteration of beta-cell mass.

    Science.gov (United States)

    Roccisana, Jennifer; Reddy, Vasumathi; Vasavada, Rupangi C; Gonzalez-Pertusa, Jose A; Magnuson, Mark A; Garcia-Ocaña, Adolfo

    2005-07-01

    Overexpression of hepatocyte growth factor (HGF) in the beta-cell of transgenic mice enhances beta-cell proliferation, survival, and function. In the current studies, we have used conditional ablation of the c-met gene to uncover the physiological role of HGF in beta-cell growth and function. Mice in which c-met is inactivated in the beta-cell (MetCKO mice) display normal body weight, blood glucose, and plasma insulin compared with control littermates. In contrast, MetCKO mice displayed significantly diminished glucose tolerance and reduced plasma insulin after a glucose challenge in vivo. This impaired glucose tolerance in MetCKO mice was not caused by insulin resistance because sensitivity to exogenous insulin was similar in both groups. Importantly, in vitro glucose-stimulated insulin secretion in MetCKO islets was decreased by approximately 50% at high glucose concentrations compared with control islets. Furthermore, whereas insulin and glucokinase expression in MetCKO islets were normal, GLUT-2 expression was decreased by approximately 50%. These changes in beta-cell function in MetCKO mice were not accompanied by changes in total beta-cell mass, islet morphology, islet cell composition, and beta-cell proliferation. Interestingly, however, MetCKO mice display an increased number of small islets, mainly single and doublet beta-cells. We conclude that HGF/c-met signaling in the beta-cell is not essential for beta-cell growth, but it is essential for normal glucose-dependent insulin secretion.

  6. Met kerse op met -konstruksies 1 : 'n Verwysingspuntperspektief ...

    African Journals Online (AJOL)

    Met kerse op met-konstruksies1: 'n Verwysingspuntperspektief. Johanna Messerschmidt, Luna Bergh. Abstract. This article analyses the usage of the Afrikaans preposition met ('with'). The analysis is done within the framework of Cognitive Linguistics and more specifically within the model proposed by Langacker (1993) ...

  7. Aptamers Binding to c-Met Inhibiting Tumor Cell Migration.

    Directory of Open Access Journals (Sweden)

    Birgit Piater

    Full Text Available The human receptor tyrosine kinase c-Met plays an important role in the control of critical cellular processes. Since c-Met is frequently over expressed or deregulated in human malignancies, blocking its activation is of special interest for therapy. In normal conditions, the c-Met receptor is activated by its bivalent ligand hepatocyte growth factor (HGF. Also bivalent antibodies can activate the receptor by cross linking, limiting therapeutic applications. We report the generation of the RNA aptamer CLN64 containing 2'-fluoro pyrimidine modifications by systematic evolution of ligands by exponential enrichment (SELEX. CLN64 and a previously described single-stranded DNA (ssDNA aptamer CLN3 exhibited high specificities and affinities to recombinant and cellular expressed c-Met. Both aptamers effectively inhibited HGF-dependent c-Met activation, signaling and cell migration. We showed that these aptamers did not induce c-Met activation, revealing an advantage over bivalent therapeutic molecules. Both aptamers were shown to bind overlapping epitopes but only CLN3 competed with HGF binding to cMet. In addition to their therapeutic and diagnostic potential, CLN3 and CLN64 aptamers exhibit valuable tools to further understand the structural and functional basis for c-Met activation or inhibition by synthetic ligands and their interplay with HGF binding.

  8. OTULIN Restricts Met1-Linked Ubiquitination to Control Innate Immune Signaling

    DEFF Research Database (Denmark)

    Fiil, Berthe Katrine; Damgaard, Rune Busk; Wagner, Sebastian Alexander

    2013-01-01

    Conjugation of Met1-linked polyubiquitin (Met1-Ub) by the linear ubiquitin chain assembly complex (LUBAC) is an important regulatory modification in innate immune signaling. So far, only few Met1-Ub substrates have been described, and the regulatory mechanisms have remained elusive. We recently...... spontaneously accumulated Met1-Ub on LUBAC components, and NOD2 or TNFR1 stimulation led to extensive Met1-Ub accumulation on receptor complex components. We propose that OTULIN restricts Met1-Ub formation after immune receptor stimulation to prevent unwarranted proinflammatory signaling....

  9. c-Met and Other Cell Surface Molecules: Interaction, Activation and Functional Consequences

    Directory of Open Access Journals (Sweden)

    Giuditta Viticchiè

    2015-01-01

    Full Text Available The c-Met receptor, also known as the HGF receptor, is one of the most studied tyrosine kinase receptors, yet its biological functions and activation mechanisms are still not fully understood. c-Met has been implicated in embryonic development and organogenesis, in tissue remodelling homeostasis and repair and in cancer metastasis. These functions are indicative of the many cellular processes in which the receptor plays a role, including cell motility, scattering, survival and proliferation. In the context of malignancy, sustained activation of c-Met leads to a signalling cascade involving a multitude of kinases that initiate an invasive and metastatic program. Many proteins can affect the activation of c-Met, including a variety of other cell surface and membrane-spanning molecules or receptors. Some cell surface molecules share structural homology with the c-Met extracellular domain and can activate c-Met via clustering through this domain (e.g., plexins, whereas other receptor tyrosine kinases can enhance c-Met activation and signalling through intracellular signalling cascades (e.g., EGFR. In this review, we provide an overview of c-Met interactions and crosstalk with partner molecules and the functional consequences of these interactions on c-Met activation and downstream signalling, c-Met intracellular localization/recycling and c-Met degradation.

  10. Evaluación del grado de conversión de los receptores HER2, RE y RPg entre el cáncer de mama primario y sus respectivas metástasis

    OpenAIRE

    Martínez de Dueñas, Eduardo

    2017-01-01

    Introducción: Tradicionalmente, las decisiones terapéuticas tanto del cáncer de mama precoz como de los estadios avanzados se han basado en los marcadores predictivos del tumor primario, tales como el receptor de estrógeno (RE), el receptor de progesterona (RPg) y el receptor 2 del factor de crecimiento epidérmico humano (HER2), asumiendo que éstos permanecían inmutables a nivel de la recaída metastásica. Objetivos: El objetivo general de esta tesis era investigar si el estado de los recep...

  11. Plaagrups te lijf met seksferomoon

    NARCIS (Netherlands)

    Bouter, H.; Griepink, F.C.

    2006-01-01

    Onderzoekers van Plant Research International kunnen het seksferomoon van het plaaginsect Duponchelia fovealis namaken. Telers van onder andere potplanten en paprika kunnen met deze lokstof veel gewasschade voorkomen

  12. Role of Met Axis in Head and Neck Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Yiru, E-mail: xuyiru@umich.edu; Fisher, Gary J., E-mail: xuyiru@umich.edu [Department of Dermatology, University of Michigan, Ann Arbor, MI 48109 (United States)

    2013-11-26

    Head and neck cancer is the sixth most common type of cancer worldwide. Despite advances in aggressive multidisciplinary treatments, the 5-year survival rate for this dreadful disease is only 50%, mostly due to high rate of recurrence and early involvement of regional lymph nodes and subsequent metastasis. Understanding the molecular mechanisms responsible for invasion and metastasis is one of the most pressing goals in the field of head and neck cancer. Met, also known as hepatocyte growth factor receptor (HGFR), is a member of the receptor protein tyrosine kinase (RPTK) family. There is compelling evidence that Met axis is dysregulated and plays important roles in tumorigenesis, progression, metastasis, angiogenesis, and drug resistance in head and neck cancer. We describe in this review current understanding of Met axis in head and neck cancer biology and development of therapeutic inhibitors targeting Met axis.

  13. Microbewerking met behulp van lasers

    NARCIS (Netherlands)

    Ezendam, M.M.M.

    1994-01-01

    Het bewerken van materialen met behulp van lasers staat momenteel enorm in de belangstelling, en terecht. De ontwikkeling van bestaande en nieuwe typen lasers staat alles behalve stil. Ontwikkelingen bevinden zich met name in het gebied van hogere vermogens, betere bundelkwaliteit en hogere

  14. Targeting MET Amplification as a New Oncogenic Driver.

    Science.gov (United States)

    Kawakami, Hisato; Okamoto, Isamu; Okamoto, Wataru; Tanizaki, Junko; Nakagawa, Kazuhiko; Nishio, Kazuto

    2014-07-22

    Certain genetically defined cancers are dependent on a single overactive oncogene for their proliferation and survival, a phenomenon known as "oncogene addiction". A new generation of drugs that selectively target such "driver oncogenes" manifests a clinical efficacy greater than that of conventional chemotherapy in appropriate genetically defined patients. MET is a proto-oncogene that encodes a receptor tyrosine kinase, and aberrant activation of MET signaling occurs in a subset of advanced cancers as result of various genetic alterations including gene amplification, polysomy, and gene mutation. Our preclinical studies have shown that inhibition of MET signaling either with the small-molecule MET inhibitor crizotinib or by RNA interference targeted to MET mRNA resulted in marked antitumor effects in cancer cell lines with MET amplification both in vitro and in vivo. Furthermore, patients with non-small cell lung cancer or gastric cancer positive for MET amplification have shown a pronounced clinical response to crizotinib. Accumulating preclinical and clinical evidence thus suggests that MET amplification is an "oncogenic driver" and therefore a valid target for treatment. However, the prevalence of MET amplification has not been fully determined, possibly in part because of the difficulty in evaluating gene amplification. In this review, we provide a rationale for targeting this genetic alteration in cancer therapy.

  15. Targeting MET Amplification as a New Oncogenic Driver

    Directory of Open Access Journals (Sweden)

    Hisato Kawakami

    2014-07-01

    Full Text Available Certain genetically defined cancers are dependent on a single overactive oncogene for their proliferation and survival, a phenomenon known as “oncogene addiction”. A new generation of drugs that selectively target such “driver oncogenes” manifests a clinical efficacy greater than that of conventional chemotherapy in appropriate genetically defined patients. MET is a proto-oncogene that encodes a receptor tyrosine kinase, and aberrant activation of MET signaling occurs in a subset of advanced cancers as result of various genetic alterations including gene amplification, polysomy, and gene mutation. Our preclinical studies have shown that inhibition of MET signaling either with the small-molecule MET inhibitor crizotinib or by RNA interference targeted to MET mRNA resulted in marked antitumor effects in cancer cell lines with MET amplification both in vitro and in vivo. Furthermore, patients with non-small cell lung cancer or gastric cancer positive for MET amplification have shown a pronounced clinical response to crizotinib. Accumulating preclinical and clinical evidence thus suggests that MET amplification is an “oncogenic driver” and therefore a valid target for treatment. However, the prevalence of MET amplification has not been fully determined, possibly in part because of the difficulty in evaluating gene amplification. In this review, we provide a rationale for targeting this genetic alteration in cancer therapy.

  16. Targeting MET Amplification as a New Oncogenic Driver

    International Nuclear Information System (INIS)

    Kawakami, Hisato; Okamoto, Isamu; Okamoto, Wataru; Tanizaki, Junko; Nakagawa, Kazuhiko; Nishio, Kazuto

    2014-01-01

    Certain genetically defined cancers are dependent on a single overactive oncogene for their proliferation and survival, a phenomenon known as “oncogene addiction”. A new generation of drugs that selectively target such “driver oncogenes” manifests a clinical efficacy greater than that of conventional chemotherapy in appropriate genetically defined patients. MET is a proto-oncogene that encodes a receptor tyrosine kinase, and aberrant activation of MET signaling occurs in a subset of advanced cancers as result of various genetic alterations including gene amplification, polysomy, and gene mutation. Our preclinical studies have shown that inhibition of MET signaling either with the small-molecule MET inhibitor crizotinib or by RNA interference targeted to MET mRNA resulted in marked antitumor effects in cancer cell lines with MET amplification both in vitro and in vivo. Furthermore, patients with non-small cell lung cancer or gastric cancer positive for MET amplification have shown a pronounced clinical response to crizotinib. Accumulating preclinical and clinical evidence thus suggests that MET amplification is an “oncogenic driver” and therefore a valid target for treatment. However, the prevalence of MET amplification has not been fully determined, possibly in part because of the difficulty in evaluating gene amplification. In this review, we provide a rationale for targeting this genetic alteration in cancer therapy

  17. Targeting MET Amplification as a New Oncogenic Driver

    Energy Technology Data Exchange (ETDEWEB)

    Kawakami, Hisato [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Okamoto, Isamu, E-mail: okamotoi@kokyu.med.kyushu-u.ac.jp [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Center for Clinical and Translational Research, Kyushu University Hospital, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582 (Japan); Okamoto, Wataru [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Division of Transrlational Research, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577 (Japan); Tanizaki, Junko [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, HIM223, 450 Brookline Avenue, Boston, MA 02215 (United States); Nakagawa, Kazuhiko [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Nishio, Kazuto [Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511 (Japan)

    2014-07-22

    Certain genetically defined cancers are dependent on a single overactive oncogene for their proliferation and survival, a phenomenon known as “oncogene addiction”. A new generation of drugs that selectively target such “driver oncogenes” manifests a clinical efficacy greater than that of conventional chemotherapy in appropriate genetically defined patients. MET is a proto-oncogene that encodes a receptor tyrosine kinase, and aberrant activation of MET signaling occurs in a subset of advanced cancers as result of various genetic alterations including gene amplification, polysomy, and gene mutation. Our preclinical studies have shown that inhibition of MET signaling either with the small-molecule MET inhibitor crizotinib or by RNA interference targeted to MET mRNA resulted in marked antitumor effects in cancer cell lines with MET amplification both in vitro and in vivo. Furthermore, patients with non-small cell lung cancer or gastric cancer positive for MET amplification have shown a pronounced clinical response to crizotinib. Accumulating preclinical and clinical evidence thus suggests that MET amplification is an “oncogenic driver” and therefore a valid target for treatment. However, the prevalence of MET amplification has not been fully determined, possibly in part because of the difficulty in evaluating gene amplification. In this review, we provide a rationale for targeting this genetic alteration in cancer therapy.

  18. Gezondheidsrisico's in verband met het werken met Polychloorbifenylen : een onderzoek

    NARCIS (Netherlands)

    Geuskens, R.B.M.; Nossent, S.M.; Koëter, H.B.W.M.; Dreef-van der Meulen, H.C.; Stijkel, A.; Zielhuis, R.L.

    1989-01-01

    Met behulp van gegevens verkregen uit een werkplekinventarisatie naar gegevens over produktie/gebruik, risicopopulatie en (mogelijke) blootstelling aan polychloorbifenylen (PCB's), en een literatuurstudie naar mogelijke schadelijke eigenschappen van PCB's op het reproductiesysteem en/of nageslacht

  19. A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

    Science.gov (United States)

    Lin, Yu-Chih; Frei, Jeannine A.; Kilander, Michaela B. C.; Shen, Wenjuan; Blatt, Gene J.

    2016-01-01

    Autism spectrum disorder (ASD) comprises a range of neurological conditions that affect individuals’ ability to communicate and interact with others. People with ASD often exhibit marked qualitative difficulties in social interaction, communication, and behavior. Alterations in neurite arborization and dendritic spine morphology, including size, shape, and number, are hallmarks of almost all neurological conditions, including ASD. As experimental evidence emerges in recent years, it becomes clear that although there is broad heterogeneity of identified autism risk genes, many of them converge into similar cellular pathways, including those regulating neurite outgrowth, synapse formation and spine stability, and synaptic plasticity. These mechanisms together regulate the structural stability of neurons and are vulnerable targets in ASD. In this review, we discuss the current understanding of those autism risk genes that affect the structural connectivity of neurons. We sub-categorize them into (1) cytoskeletal regulators, e.g., motors and small RhoGTPase regulators; (2) adhesion molecules, e.g., cadherins, NCAM, and neurexin superfamily; (3) cell surface receptors, e.g., glutamatergic receptors and receptor tyrosine kinases; (4) signaling molecules, e.g., protein kinases and phosphatases; and (5) synaptic proteins, e.g., vesicle and scaffolding proteins. Although the roles of some of these genes in maintaining neuronal structural stability are well studied, how mutations contribute to the autism phenotype is still largely unknown. Investigating whether and how the neuronal structure and function are affected when these genes are mutated will provide insights toward developing effective interventions aimed at improving the lives of people with autism and their families. PMID:27909399

  20. receptores

    Directory of Open Access Journals (Sweden)

    Salete Regina Daronco Benetti

    2006-01-01

    Full Text Available Se trata de un estudio etnográfico, que tuvo lo objetivo de interpretar el sistema de conocimiento y del significado atribuidos a la sangre referente a la transfusión sanguínea por los donadores y receptores de un banco de sangre. Para la colecta de las informaciones se observaron los participantes y la entrevista etnográfica se realizó el análisis de dominio, taxonómicos y temáticos. Los dominios culturales fueron: la sangre es vida: fuente de vida y alimento valioso; creencias religiosas: fuentes simbólicas de apoyos; donación sanguínea: un gesto colaborador que exige cuidarse, gratifica y trae felicidad; donación sanguínea: fuente simbólica de inseguridad; estar enfermo es una condición para realizar transfusión sanguínea; transfusión sanguínea: esperanza de vida; Creencias populares: transfusión sanguínea como riesgo para la salud; donadores de sangre: personas benditas; donar y recibir sangre: como significado de felicidad. Temática: “líquido precioso que origina, sostiene, modifica la vida, provoca miedo e inseguridad”.

  1. Compost voor biggen met diarree

    NARCIS (Netherlands)

    Gommers, T.

    1990-01-01

    Het geven van compost aan biggen met diarree zorgt op het Proefstation voor de Varkenshouderij voor minder medicijngebruik. De biggen krijgen de compost van groente-, fruit- en tuinafval vanaf de tweede dag na de geboorte, zodra de diarreeverschijnselen zichtbaar zijn.

  2. Bewaring aardappelen met koeling & ventileren

    NARCIS (Netherlands)

    Kamp, J.A.L.M.; Montsma, M.P.

    2013-01-01

    In de praktijk blijkt dat nogal wat telers de bewaring ondersteunen met koelapparatuur. Dit betreft vooral pootaardappelen (verlenging kiemrust), de lange bewaring van tafelaardappelen en fritesaardappelen. Dit resulteert in een hoger energieverbruik, maar wel in een betere kwaliteit bij aflevering.

  3. Een model met een smaakje (Interview met Caroline Labrie)

    NARCIS (Netherlands)

    Langen, E.; Labrie, C.W.

    2013-01-01

    Over smaak valt niet te twisten. En toch gebeurt dat maar al te vaak. "Er kan oeverloos over de smaak van paprika's worden gepraat en gediscussieerd. Daarom is het belangrijk dat de smaak van paprika's geobjectiveerd wordt", vertelt Caroline Labrie van Wageningen UR Glastuinbouw. Dat kan met een

  4. Sociability Deficits and Altered Amygdala Circuits in Mice Lacking Pcdh10, an Autism Associated Gene.

    Science.gov (United States)

    Schoch, Hannah; Kreibich, Arati S; Ferri, Sarah L; White, Rachel S; Bohorquez, Dominique; Banerjee, Anamika; Port, Russell G; Dow, Holly C; Cordero, Lucero; Pallathra, Ashley A; Kim, Hyong; Li, Hongzhe; Bilker, Warren B; Hirano, Shinji; Schultz, Robert T; Borgmann-Winter, Karin; Hahn, Chang-Gyu; Feldmeyer, Dirk; Carlson, Gregory C; Abel, Ted; Brodkin, Edward S

    2017-02-01

    Behavioral symptoms in individuals with autism spectrum disorder (ASD) have been attributed to abnormal neuronal connectivity, but the molecular bases of these behavioral and brain phenotypes are largely unknown. Human genetic studies have implicated PCDH10, a member of the δ2 subfamily of nonclustered protocadherin genes, in ASD. PCDH10 expression is enriched in the basolateral amygdala, a brain region implicated in the social deficits of ASD. Previous reports indicate that Pcdh10 plays a role in axon outgrowth and glutamatergic synapse elimination, but its roles in social behaviors and amygdala neuronal connectivity are unknown. We hypothesized that haploinsufficiency of Pcdh10 would reduce social approach behavior and alter the structure and function of amygdala circuits. Mice lacking one copy of Pcdh10 (Pcdh10 +/- ) and wild-type littermates were assessed for social approach and other behaviors. The lateral/basolateral amygdala was assessed for dendritic spine number and morphology, and amygdala circuit function was studied using voltage-sensitive dye imaging. Expression of Pcdh10 and N-methyl-D-aspartate receptor (NMDAR) subunits was assessed in postsynaptic density fractions of the amygdala. Male Pcdh10 +/- mice have reduced social approach behavior, as well as impaired gamma synchronization, abnormal spine morphology, and reduced levels of NMDAR subunits in the amygdala. Social approach deficits in Pcdh10 +/- male mice were rescued with acute treatment with the NMDAR partial agonist d-cycloserine. Our studies reveal that male Pcdh10 +/- mice have synaptic and behavioral deficits, and establish Pcdh10 +/- mice as a novel genetic model for investigating neural circuitry and behavioral changes relevant to ASD. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  5. Non-agonistic bivalent antibodies that promote c-MET degradation and inhibit tumor growth and others specific for tumor related c-MET.

    Directory of Open Access Journals (Sweden)

    Sameer A Greenall

    Full Text Available The c-MET receptor has a function in many human cancers and is a proven therapeutic target. Generating antagonistic or therapeutic monoclonal antibodies (mAbs targeting c-MET has been difficult because bivalent, intact anti-Met antibodies frequently display agonistic activity, necessitating the use of monovalent antibody fragments for therapy. By using a novel strategy that included immunizing with cells expressing c-MET, we obtained a range of mAbs. These c-MET mAbs were tested for binding specificity and anti-tumor activity using a range of cell-based techniques and in silico modeling. The LMH 80 antibody bound an epitope, contained in the small cysteine-rich domain of c-MET (amino acids 519-561, that was preferentially exposed on the c-MET precursor. Since the c-MET precursor is only expressed on the surface of cancer cells and not normal cells, this antibody is potentially tumor specific. An interesting subset of our antibodies displayed profound activities on c-MET internalization and degradation. LMH 87, an antibody binding the loop connecting strands 3d and 4a of the 7-bladed β-propeller domain of c-MET, displayed no intrinsic agonistic activity but promoted receptor internalization and degradation. LMH 87 inhibited HGF/SF-induced migration of SK-OV-3 ovarian carcinoma cells, the proliferation of A549 lung cancer cells and the growth of human U87MG glioma cells in a mouse xenograft model. These results indicate that c-MET antibodies targeting epitopes controlling receptor internalization and degradation provide new ways of controlling c-MET expression and activity and may enable the therapeutic targeting of c-MET by intact, bivalent antibodies.

  6. Mogelijkheden voor notenteelt met tussengewas

    NARCIS (Netherlands)

    Oosterbaan, A.; Schepers, H.

    2005-01-01

    Er zijn enkele presentaties gehouden over de ervaringen met de teelt van walnoten in Nederland tijdens het vijfde Internationale Walnotencongres in Sorrento, Italië, gehouden in november 2004. De productie van walnoten in Nederland stelt nog niet veel voor. Er is dus ruimte voor eigen productie

  7. Allemaal andersdenkenden: omgaan met cultuurverschillen

    NARCIS (Netherlands)

    Hofstede, G.; Hofstede, G.J.; Minkov, M.

    2011-01-01

    Mensen uit andere landen denken, voelen en handelen anders dan wij hier gewend zijn. Ook landgenoten uit een andere streek of een andere sociale klasse gedragen zich vaak anders dan wij. In een open samenleving komt iedereen vaker met zulke andersdenkenden in aanraking dan vroeger. Voor die anderen

  8. Water zuiveren met drijvende planten

    NARCIS (Netherlands)

    Keizer-Vlek, H.E.; Verdonschot, P.F.M.; Verdonschot, R.C.M.; Dekkers, T.B.M.

    2013-01-01

    Drijvende moerassystemen met helofyten, ook wel floating treatment wetlands of floatlands genoemd, worden in Nederland uitsluitend toegepast om natuurbeleving te stimuleren en de biodiversiteit van het oppervlaktewater te vergroten. Floatlands zijn echter mogelijk ook geschikt om nutriënten uit het

  9. Voedingsnavorsing met die weidende dier

    African Journals Online (AJOL)

    van veral beeste (Bisschop, 1964; Niemann, Lombard & Van. Schalkwyk, 1963). In teenstelling met die relatiewe groot hoeveelheid inligting oor die chemiese samestelling van natuurlike weidings, is daar betreklik min bekend oor die verteerbaarheid en vrywillige in- name daarvan deur herkouers. 'n Skerp daling in die ...

  10. Steeds preciezer met de sensor

    NARCIS (Netherlands)

    Houweling, van P.; PPO Akkerbouw, Groene Ruimte en Vollegrondsgroente

    2014-01-01

    Maurits Bax uit Luyksgestel werkt met de Yara N-sensor. Zo spuit hij minder dan een derde van de voorgeschreven dosering voor loofdodingsmiddel in aardappelen. Andere toepassingen zijn minder praktijkrijp, zoals aardappelen bijmesten. Daarvoor lijkt een app, ontwikkeld door het PPO, uitkomst te gaan

  11. The functional antagonist Met-RANTES: a modified agonist that induces differential CCR5 trafficking.

    Science.gov (United States)

    Kiss, Debra L; Longden, James; Fechner, Gregory A; Avery, Vicky M

    2009-01-01

    CC chemokine receptor 5 (CCR5) is a pro-inflammatory chemokine receptor that is expressed on cells of the immune system, and specializes in cell migration in response to inflammation and tissue damage. Due to its key role in cell communication and migration, this receptor is involved in various inflammatory and autoimmune diseases, in addition to HIV infection. Met-RANTES is a modified CCR5 ligand that has previously been shown to antagonize CCR5 activation and function in response to its natural ligands in vitro. In vivo, Met-RANTES is able to reduce inflammation in models of induced inflammatory and autoimmune diseases. However, due to the fact that Met-RANTES is also capable of partial agonist activity regarding receptor signaling and internalization, it is clear that Met-RANTES does not function as a conventional receptor antagonist. To further elucidate the effect of Met-RANTES on CCR5, receptor trafficking was investigated in a CHO-CCR5-GFP cell line using the Opera confocal plate reader. The internalization response of CCR5 was quantified, and showed that Met-RANTES internalized CCR5 in a slower, less potent manner than the agonists CCL3 and CCL5. Fluorescent organelle labeling and live cell imaging showed CCL3 and CCL5 caused CCR5 to traffic through sorting endosomes, recycling endosomes and the Golgi apparatus. In contrast, Met-RANTES caused CCR5 to traffic through sorting endosomes and the Golgi apparatus in a manner that was independent of recycling endosomes. As receptor trafficking impacts on cell surface expression and the ability of the receptor to respond to more ligand, this information may indicate an alternative regulation of CCR5 by Met-RANTES that allows the modified ligand to reduce inflammation through stimulation of a pro-inflammatory receptor.

  12. La metáfora

    DEFF Research Database (Denmark)

    Agustin, Oscar Garcia

    2007-01-01

    cuestionamiento de la lógica y de las leyes establecidas se corresponde con lo que denominamos autonomía. Así pues, el proceso de autonomía zapatista consiste, por un lado, en la declaración y aplicación de los derechos indígenas y, por otro, en la creación de un sentido alternativo, donde la metáfora juega un...

  13. ONDERHOUD MET EDWIN ARRISON1

    African Journals Online (AJOL)

    Toe gaan ek met 'n UDF t‑hemp kerk toe. En die UDF t‑hemp was baie geel so mense kon dit maklik en duidelik sien, en agterop het gestaan “UDF unites; apartheid divides.” En daar was mense wat gevoel het dat ons politiek in die kerk wou inbring. – veral die persone wat in die leierskap was. Nie die predikant soveel nie,.

  14. MET targeted therapy for lung cancer: clinical development and future directions

    Directory of Open Access Journals (Sweden)

    Feng Y

    2012-08-01

    Full Text Available Yan Feng,1,2 Patrick C Ma1–31Translational Hematology and Oncology Research, 2Solid Tumor Oncology, 3Aerodigestive Oncology Translational Research, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USAAbstract: MET, the receptor for hepatocyte growth factor, has been identified as a novel promising target in various human malignancies, including lung cancer. Research studies have demonstrated that MET signaling plays important physiologic roles in embryogenesis and early development, whereas its deregulation from an otherwise quiescent signaling state in mature adult tissues can lead to upregulated cell proliferation, survival, scattering, motility and migration, angiogenesis, invasion, and metastasis in tumorigenesis and tumor progression. The MET pathway can be activated through ligand (hepatocyte growth factor, HGF or MET receptor overexpression, genomic amplification, MET mutations, and alternative splicing. A number of novel therapeutic agents that target the MET/hepatocyte growth factor pathway have been tested in early-phase clinical studies with promising results. Phase III studies of MET targeting agents have recently been initiated. This paper will review the MET signaling pathway and biology in lung cancer, and the recent clinical development and advances of MET/hepatocyte growth factor targeting agents. Emphasis will be placed on discussing various unanswered issues and key strategies needed to optimize further clinical development of MET targeting personalized lung cancer therapy.Keywords: MET, HGF, lung cancer, targeted therapy

  15. Higher Levels of c-Met Expression and Phosphorylation Identify Cell Lines With Increased Sensitivity to AMG-458, a Novel Selective c-Met Inhibitor With Radiosensitizing Effects

    International Nuclear Information System (INIS)

    Li Bo; Torossian, Artour; Sun, Yunguang; Du, Ruihong; Dicker, Adam P.; Lu Bo

    2012-01-01

    Purpose: c-Met is overexpressed in some non-small cell lung cancer (NSCLC) cell lines and tissues. Cell lines with higher levels of c-Met expression and phosphorylation depend on this receptor for survival. We studied the effects of AMG-458 on 2 NSCLC cell lines. Methods and Materials: 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl) -2H-tetrazolium assays assessed the sensitivities of the cells to AMG-458. Clonogenic survival assays illustrated the radiosensitizing effects of AMG-458. Western blot for cleaved caspase 3 measured apoptosis. Immunoblotting for c-Met, phospho-Met (p-Met), Akt/p-Akt, and Erk/p-Erk was performed to observe downstream signaling. Results: AMG-458 enhanced radiosensitivity in H441 but not in A549. H441 showed constitutive phosphorylation of c-Met. A549 expressed low levels of c-Met, which were phosphorylated only in the presence of exogenous hepatocyte growth factor. The combination of radiation therapy and AMG-458 treatment was found to synergistically increase apoptosis in the H441 cell line but not in A549. Radiation therapy, AMG-458, and combination treatment were found to reduce p-Akt and p-Erk levels in H441 but not in A549. H441 became less sensitive to AMG-458 after small interfering RNA knockdown of c-Met; there was no change in A549. After overexpression of c-Met, A549 became more sensitive, while H441 became less sensitive to AMG-458. Conclusions: AMG-458 was more effective in cells that expressed higher levels of c-Met/p-Met, suggesting that higher levels of c-Met and p-Met in NSCLC tissue may classify a subset of tumors that are more sensitive to molecular therapies against this receptor.

  16. Recent advances in the discovery of small molecule c-Met Kinase inhibitors.

    Science.gov (United States)

    Parikh, Palak K; Ghate, Manjunath D

    2018-01-01

    c-Met is a prototype member of a subfamily of heterodimeric receptor tyrosine kinases (RTKs) and is the receptor for hepatocyte growth factor (HGF). Binding of HGF to its receptor c-Met, initiates a wide range of cellular signalling, including those involved in proliferation, motility, migration and invasion. Importantly, dysregulated HGF/c-Met signalling is a driving factor for numerous malignancies and promotes tumour growth, invasion, dissemination and/or angiogenesis. Dysregulated HGF/c-Met signalling has also been associated with poor clinical outcomes and resistance acquisition to some approved targeted therapies. Thus, c-Met kinase has emerged as a promising target for cancer drug development. Different therapeutic approaches targeting the HGF/c-Met signalling pathway are under development for targeted cancer therapy, among which small molecule inhibitors of c-Met kinase constitute the largest effort within the pharmaceutical industry. The review is an effort to summarize recent advancements in medicinal chemistry development of small molecule c-Met kinase inhibitors as potential anti-cancer agents which would certainly help future researchers to bring further developments in the discovery of small molecule c-Met kinase inhibitors. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  17. Inhibition of c-Met as a Therapeutic Strategy for Esophageal Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Gregory A. Watson

    2006-11-01

    Full Text Available The hepatocyte growth factor (HGF receptor c-Met is a tyrosine kinase receptor with established oncogenic properties. We have previously shown that c-Met is usually overexpressed in esophageal adenocarcinoma (EA, yet the implications of c-Met inhibition in EA remain unknown. Three c-Met-overexpressiog EA cell lines (Seg-1, Bic-1, Flo-1 were used to examine the effects of a c-Met-specific small molecule inhibitor (PHA665752 on cell viability, apoptosis, motility, invasion, downstream signaling pathways. PHA665752 demonstrated dose-dependent inhibition of constitutive and/or HGF-induced phosphorylation of c-Met, which correlated with reduced cell viability and inhibition of extracellular regulated kinase 1/2 phosphorylation in all three EA cell lines. In contrast, PHA665752 induced apoptosis and reduced motility and invasion in only one EA cell line, Flo-1. Interestingly, Flo-1 was the only cell line in which phosphatidylinositol 3-kinase (PI3K/Akt was induced following HGF stimulation. The PI3K inhibitor LY294002 produced effects equivalent to those of PHA665752 in these cells. We conclude that inhibition of c-Met may be a useful therapeutic strategy for EA. Factors other than receptor overexpression, such as c-Met-dependent PI3K/Akt signaling, may be predictive of an individual tumor's response to c-Met inhibition.

  18. Acuut nierfalen door vergiftiging met gordijnzwam

    NARCIS (Netherlands)

    Bouhbouh, S.; Haverkamp, L.; Kuyper, T.W.; Wolff, F.A.; Barendregt, J.N.M.

    2011-01-01

    Achtergrond Inname van bepaalde soorten gordijnzwammen kan leiden tot nierfalen. In Nederland is deze paddenstoelvergiftiging niet eerder beschreven. Casus Een 58-jarige vrouw presenteerde zich met hoofdpijn, braken en afnemende urineproductie, voorafgegaan door enkele dagen met pijnlijke,

  19. Roze appelluis bestrijden met plantenolie en feromoon

    NARCIS (Netherlands)

    Tol, van R.W.H.M.; Helsen, H.H.M.

    2004-01-01

    Gegevens figuren: 1) Reactie van gevleugelde roze appelluis op een onbespoten appelblad en op een met plantenoliën behandeld appelblad; 2) Reactie van gevleugelde roze appelluis op onbespoten appeltakken en op met Denka behandelde appeltakken

  20. Isolation and characterization of anti c-met single chain fragment variable (scFv) antibodies.

    Science.gov (United States)

    Qamsari, Elmira Safaie; Sharifzadeh, Zahra; Bagheri, Salman; Riazi-Rad, Farhad; Younesi, Vahid; Abolhassani, Mohsen; Ghaderi, Sepideh Safaei; Baradaran, Behzad; Somi, Mohammad Hossein; Yousefi, Mehdi

    2017-12-01

    The receptor tyrosine kinase (RTK) Met is the cell surface receptor for hepatocyte growth factor (HGF) involved in invasive growth programs during embryogenesis and tumorgenesis. There is compelling evidence suggesting important roles for c-Met in colorectal cancer proliferation, migration, invasion, angiogenesis, and survival. Hence, a molecular inhibitor of an extracellular domain of c-Met receptor that blocks c-Met-cell surface interactions could be of great thera-peutic importance. In an attempt to develop molecular inhibitors of c-Met, single chain variable fragment (scFv) phage display libraries Tomlinson I + J against a specific synthetic oligopeptide from the extracellular domain of c-Met receptor were screened; selected scFv were then characterized using various immune techniques. Three c-Met specific scFv (ES1, ES2, and ES3) were selected following five rounds of panning procedures. The scFv showed specific binding to c-Met receptor, and significantly inhibited proliferation responses of a human colorectal carcinoma cell line (HCT-116). Moreover, anti- apoptotic effects of selected scFv antibodies on the HCT-116 cell line were also evaluated using Annexin V/PI assays. The results demonstrated rates of apoptotic cell death of 46.0, 25.5, and 37.8% among these cells were induced by use of ES1, ES2, and ES3, respectively. The results demonstrated ability to successfully isolate/char-acterize specific c-Met scFv that could ultimately have a great therapeutic potential in immuno-therapies against (colorectal) cancers.

  1. Activated Met signalling in the developing mouse heart leads to cardiac disease.

    Directory of Open Access Journals (Sweden)

    Christian Leo

    Full Text Available BACKGROUND: The Hepatocyte Growth Factor (HGF is a pleiotropic cytokine involved in many physiological processes, including skeletal muscle, placenta and liver development. Little is known about its role and that of Met tyrosine kinase receptor in cardiac development. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we generated two transgenic mice with cardiac-specific, tetracycline-suppressible expression of either Hepatocyte Growth Factor (HGF or the constitutively activated Tpr-Met kinase to explore: i the effect of stimulation of the endogenous Met receptor by autocrine production of HGF and ii the consequence of sustained activation of Met signalling in the heart. We first showed that Met is present in the neonatal cardiomyocytes and is responsive to exogenous HGF. Exogenous HGF starting from prenatal stage enhanced cardiac proliferation and reduced sarcomeric proteins and Connexin43 (Cx43 in newborn mice. As adults, these transgenics developed systolic contractile dysfunction. Conversely, prenatal Tpr-Met expression was lethal after birth. Inducing Tpr-Met expression during postnatal life caused early-onset heart failure, characterized by decreased Cx43, upregulation of fetal genes and hypertrophy. CONCLUSIONS/SIGNIFICANCE: Taken together, our data show that excessive activation of the HGF/Met system in development may result in cardiac damage and suggest that Met signalling may be implicated in the pathogenesis of cardiac disease.

  2. Differences in MetS marker prevalence between black African and ...

    African Journals Online (AJOL)

    Multiple linear regression analysis, independent of covariates, showed that the albumin:creatinine ratio is explained only by glucose in Africans. Conclusion: African women, as a group, present with few MetS risk factors, and glucose is associated with renal function risk in Africans. Keywords: MetS, metabolic syndrome, ...

  3. Activated HGF-c-Met Axis in Head and Neck Cancer

    Directory of Open Access Journals (Sweden)

    Levi Arnold

    2017-12-01

    Full Text Available Head and neck squamous cell carcinoma (HNSCC is a highly morbid disease. Recent developments including Food and Drug Administration (FDA approved molecular targeted agent’s pembrolizumab and cetuximab show promise but did not improve the five-year survival which is currently less than 40%. The hepatocyte growth factor receptor; also known as mesenchymal–epithelial transition factor (c-Met and its ligand hepatocyte growth factor (HGF are overexpressed in head and neck squamous cell carcinoma (HNSCC; and regulates tumor progression and response to therapy. The c-Met pathway has been shown to regulate many cellular processes such as cell proliferation, invasion, and angiogenesis. The c-Met pathway is involved in cross-talk, activation, and perpetuation of other signaling pathways, curbing the cogency of a blockade molecule on a single pathway. The receptor and its ligand act on several downstream effectors including phospholipase C gamma (PLCγ, cellular Src kinase (c-Src, phosphotidylinsitol-3-OH kinase (PI3K alpha serine/threonine-protein kinase (Akt, mitogen activate protein kinase (MAPK, and wingless-related integration site (Wnt pathways. They are also known to cross-talk with other receptors; namely epidermal growth factor receptor (EGFR and vascular endothelial growth factor receptor (VEGFR and specifically contribute to treatment resistance. Clinical trials targeting the c-Met axis in HNSCC have been undertaken because of significant preclinical work demonstrating a relationship between HGF/c-Met signaling and cancer cell survival. Here we focus on HGF/c-Met impact on cellular signaling in HNSCC to potentiate tumor growth and disrupt therapeutic efficacy. Herein we summarize the current understanding of HGF/c-Met signaling and its effects on HNSCC. The intertwining of c-Met signaling with other signaling pathways provides opportunities for more robust and specific therapies, leading to better clinical outcomes.

  4. PHA665752, a small-molecule inhibitor of c-Met, inhibits hepatocyte growth factor-stimulated migration and proliferation of c-Met-positive neuroblastoma cells

    International Nuclear Information System (INIS)

    Crosswell, Hal E; Dasgupta, Anindya; Alvarado, Carlos S; Watt, Tanya; Christensen, James G; De, Pradip; Durden, Donald L; Findley, Harry W

    2009-01-01

    c-Met is a tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF), and both c-Met and its ligand are expressed in a variety of tissues. C-Met/HGF/SF signaling is essential for normal embryogenesis, organogenesis, and tissue regeneration. Abnormal c-Met/HGF/SF signaling has been demonstrated in different tumors and linked to aggressive and metastatic tumor phenotypes. In vitro and in vivo studies have demonstrated inhibition of c-Met/HGF/SF signaling by the small-molecule inhibitor PHA665752. This study investigated c-Met and HGF expression in two neuroblastoma (NBL) cell lines and tumor tissue from patients with NBL, as well as the effects of PHA665752 on growth and motility of NBL cell lines. The effect of the tumor suppressor protein PTEN on migration and proliferation of tumor cells treated with PHA665752 was also evaluated. Expression of c-Met and HGF in NBL cell lines SH-EP and SH-SY5Y and primary tumor tissue was assessed by immunohistochemistry and quantitative RT-PCR. The effect of PHA665752 on c-Met/HGF signaling involved in NBL cell proliferation and migration was evaluated in c-Met-positive cells and c-Met-transfected cells. The transwell chemotaxis assay and the MTT assay were used to measure migration and proliferation/cell-survival of tumor cells, respectively. The PPAR-γ agonist rosiglitazone was used to assess the effect of PTEN on PHA665752-induced inhibition of NBL cell proliferation/cell-survival and migration High c-Met expression was detected in SH-EP cells and primary tumors from patients with advanced-stage disease. C-Met/HGF signaling induced both migration and proliferation of SH-EP cells. Migration and proliferation/cell-survival were inhibited by PHA665752 in a dose-dependent manner. We also found that induced overexpression of PTEN following treatment with rosiglitazone significantly enhanced the inhibitory effect of PHA665752 on NBL-cell migration and proliferation. c-Met is highly expressed in most tumors from

  5. Is neurofeedback effectief bij kinderen met ADHD?

    NARCIS (Netherlands)

    de Hen, M.H.; Geurts, H.M.

    2008-01-01

    Kan neurofeedback verantwoord ingezet worden bij de behandeling van kinderen met ADHD? Omdeze vraag te beantwoorden worden zeven recente onderzoeken naar de effectiviteit van neurofeedback bij kinderen met ADHD geanalyseerd. Ondanks dat de resultaten in eerste instantie lijken te suggereren dat

  6. Resensies: Vakansiehuis met swembad | Maas | Tydskrif vir ...

    African Journals Online (AJOL)

    Resensies: Vakansiehuis met swembad. Tycho Maas. Abstract. Book Title: Vakansiehuis met swembad. Book Author: Herman Koch. Vertaal deur Daniel Hugo. Pretoria: Protea Boekhuis, 2015. 288 pp. ISBN: 978-1-4853-0545-3. Full Text: EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT · DOWNLOAD FULL TEXT ...

  7. Reciprocal activating crosstalk between c-Met and caveolin 1 promotes invasive phenotype in hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Peyda Korhan

    Full Text Available c-Met, the receptor for Hepatocyte Growth Factor (HGF, overexpressed and deregulated in Hepatocellular Carcinoma (HCC. Caveolin 1 (CAV1, a plasma membrane protein that modulates signal transduction molecules, is also overexpressed in HCC. The aim of this study was to investigate biological and clinical significance of co-expression and activation of c-Met and CAV1 in HCC. We showed that c-Met and CAV1 were co-localized in HCC cells and HGF treatment increased this association. HGF-triggered c-Met activation caused a concurrent rise in both phosphorylation and expression of CAV1. Ectopic expression of CAV1 accelerated c-Met signaling, resulted in enhanced migration, invasion, and branching-morphogenesis. Silencing of CAV1 downregulated c-Met signaling, and decreased migratory/invasive capability of cells and attenuated branching morphogenesis. In addition, activation and co-localization of c-Met and CAV1 were elevated during hepatocarcinogenesis. In conclusion reciprocal activating crosstalk between c-Met and CAV1 promoted oncogenic signaling of c-Met contributed to the initiation and progression of HCC.

  8. Reciprocal activating crosstalk between c-Met and caveolin 1 promotes invasive phenotype in hepatocellular carcinoma.

    Science.gov (United States)

    Korhan, Peyda; Erdal, Esra; Kandemiş, Emine; Cokaklı, Murat; Nart, Deniz; Yılmaz, Funda; Can, Alp; Atabey, Neşe

    2014-01-01

    c-Met, the receptor for Hepatocyte Growth Factor (HGF), overexpressed and deregulated in Hepatocellular Carcinoma (HCC). Caveolin 1 (CAV1), a plasma membrane protein that modulates signal transduction molecules, is also overexpressed in HCC. The aim of this study was to investigate biological and clinical significance of co-expression and activation of c-Met and CAV1 in HCC. We showed that c-Met and CAV1 were co-localized in HCC cells and HGF treatment increased this association. HGF-triggered c-Met activation caused a concurrent rise in both phosphorylation and expression of CAV1. Ectopic expression of CAV1 accelerated c-Met signaling, resulted in enhanced migration, invasion, and branching-morphogenesis. Silencing of CAV1 downregulated c-Met signaling, and decreased migratory/invasive capability of cells and attenuated branching morphogenesis. In addition, activation and co-localization of c-Met and CAV1 were elevated during hepatocarcinogenesis. In conclusion reciprocal activating crosstalk between c-Met and CAV1 promoted oncogenic signaling of c-Met contributed to the initiation and progression of HCC.

  9. HGF/MET-directed therapeutics in gastroesophageal cancer: a review of clinical and biomarker development.

    Science.gov (United States)

    Hack, Stephen P; Bruey, Jean-Marie; Koeppen, Hartmut

    2014-05-30

    Aberrant activation of the HGF/MET signaling axis has been strongly implicated in the malignant transformation and progression of gastroesophageal cancer (GEC). MET receptor overexpression in tumor samples from GEC patients has been consistently correlated with an aggressive metastatic phenotype and poor prognosis. In preclinical GEC models, abrogation of HGF/MET signaling has been shown to induce tumor regression as well as inhibition of metastatic dissemination. Promising clinical results in patient subsets in which MET is overexpressed have spurned several randomized studies of HGF/MET-directed agents, including two pivotal global Phase III trials. Available data highlight the need for predictive biomarkers in order to select patients most likely to benefit from HGF/MET inhibition. In this review, we discuss the current knowledge of mechanisms of MET activation in GEC, the current status of the clinical evaluation of MET-targeted therapies in GEC, characteristics of ongoing randomized GEC trials and the associated efforts to identify and validate biomarkers. We also discuss the considerations and challenges for HGF/MET inhibitor drug development in the GEC setting.

  10. Targeting Oncogenic ALK and MET: A Promising Therapeutic Strategy for Glioblastoma

    Science.gov (United States)

    Wallace, Gerald C; Dixon-Mah, Yaenette N; Vandergrift, W Alex; Ray, Swapan K; Haar, Catherine P; Mittendorf, Amber M; Patel, Sunil J; Banik, Naren L; Giglio, Pierre; Das, Arabinda

    2015-01-01

    Glioblastoma is the most common aggressive, highly glycolytic, and lethal brain tumor. In fact, it is among the most commonly diagnosed lethal malignancies, with thousands of new cases reported in the United States each year. Glioblastoma's lethality is derived from a number of factors including highly active pro-mitotic and pro-metastatic pathways. Two factors increasingly associated with the intracellular signaling and transcriptional machinery required for such changes are anaplastic lymphoma kinase (ALK) and the hepatocyte growth factor receptor (HGFR or, more commonly MET). Both receptors are members of the receptor tyrosine kinase (RTK) family, which has itself gained much attention for its role in modulating mitosis, migration, and survival in cancer cells. ALK was first described as a vital oncogene in lymphoma studies, but it has since been connected to many carcinomas, including non-small cell lung cancer and glioblastoma. As the receptor for HGF, MET has also been highly characterized and regulates numerous developmental and wound healing events which, when upregulated in cancer, can promote tumor progression. The wealth of information gathered over the last 30 years regarding these RTKs suggests three downstream cascades that depend upon activation of STAT3, Ras, and AKT. This review outlines the significance of ALK and MET as they relate to glioblastoma, explores the significance of STAT3, Ras, and AKT downstream of ALK/MET, and touches on the potential for new chemotherapeutics targeting ALK and MET to improve glioblastoma patient prognosis. PMID:23543207

  11. c-Met Confers Protection Against Chronic Liver Tissue Damage and Fibrosis Progression After Bile Duct Ligation in Mice.

    NARCIS (Netherlands)

    Giebeler, A.; Boekschoten, M.V.; Klein, C.; Borowiak, M.; Birchmeier, C.; Gassler, N.; Wasmuth, H.E.; Müller, M.R.; Trautwein, C.; Streetz, K.L.

    2009-01-01

    Background & Aims The hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-Met) system is an essential inducer of hepatocyte growth and proliferation. Although a fundamental role for the HGF receptor c-Met has been shown in acute liver regeneration, its cell-specific role

  12. c-Met must translocate to the nucleus to initiate calcium signals.

    Science.gov (United States)

    Gomes, Dawidson A; Rodrigues, Michele A; Leite, M Fatima; Gomez, Marcus V; Varnai, Peter; Balla, Tamas; Bennett, Anton M; Nathanson, Michael H

    2008-02-15

    Hepatocyte growth factor (HGF) is important for cell proliferation, differentiation, and related activities. HGF acts through its receptor c-Met, which activates downstream signaling pathways. HGF binds to c-Met at the plasma membrane, where it is generally believed that c-Met signaling is initiated. Here we report that c-Met rapidly translocates to the nucleus upon stimulation with HGF. Ca(2+) signals that are induced by HGF result from phosphatidylinositol 4,5-bisphosphate hydrolysis and inositol 1,4,5-trisphosphate formation within the nucleus rather than within the cytoplasm. Translocation of c-Met to the nucleus depends upon the adaptor protein Gab1 and importin beta1, and formation of Ca(2+) signals in turn depends upon this translocation. HGF may exert its particular effects on cells because it bypasses signaling pathways in the cytoplasm to directly activate signaling pathways in the nucleus.

  13. HGF/Met Signaling Is a Key Player in Malignant Mesothelioma Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Giovanni Gaudino

    2014-11-01

    Full Text Available Malignant mesothelioma (MM is a highly aggressive cancer related to asbestos or erionite exposure and resistant to current therapies. Hepatocyte Growth Factor (HGF and its tyrosine kinase receptor Met regulate cell growth, survival, motility/migration, and invasion. HGF and Met are expressed in MM cells, suggesting that the HGF/Met signaling plays a role in development and progression of this tumor, by autocrine and/or paracrine mechanisms. Upregulation and ligand-independent activation of Met, which is under suppressive control of miR-34 family members, correlate with enhanced invasion, migration and metastatic potential in several cancers, including MM. Moreover, Simian Virus 40 (SV40 Tag expression also induces a HGF autocrine circuit in an Rb-dependent manner in human mesothelial cells (HM and possibly other cell types, enhancing cell adhesion, invasion and angiogenesis. The resulting activation of Met causes HM transformation and cell cycle progression, and contributes to virus particle assembling and infection of adjacent cells. The constitutive activation of Met, frequently occurring in MM, has been successfully targeted in preclinical models of MM. In conclusion, Met expression, activation state, subcellular localization and also HGF co-receptors expression, such as CD44, have clinical relevance for novel targeted therapies in a cancer for which no effective treatment is currently available.

  14. Anti-c-MET Nanobody - a new potential drug in multiple myeloma treatment.

    Science.gov (United States)

    Slørdahl, Tobias Schmidt; Denayer, Tinneke; Moen, Siv Helen; Standal, Therese; Børset, Magne; Ververken, Cedric; Rø, Torstein Baade

    2013-11-01

    c-MET is the tyrosine kinase receptor of the hepatocyte growth factor (HGF). HGF-c-MET signaling is involved in many human malignancies, including multiple myeloma (MM). Recently, multiple agents have been developed directed to interfere at different levels in HGF-c-MET signaling pathway. Nanobodies are therapeutic proteins based on the smallest functional fragments of heavy-chain-only antibodies. In this study, we wanted to determine the anticancer effect of a novel anti-c-MET Nanobody in MM. We examined the effects of an anti-c-MET Nanobody on thymidine incorporation, migration, adhesion of MM cells, and osteoblastogenesis in vitro. Furthermore, we investigated the effects of the Nanobody on HGF-dependent c-MET signaling by Western blotting. We show that the anti-c-MET Nanobody effectively inhibited thymidine incorporation of ANBL-6 MM cells via inhibition of an HGF autocrine growth loop and thymidine incorporation in INA-6 MM cells induced by exogenous HGF. HGF-induced migration and adhesion of INA-6 were completely and specifically blocked by the Nanobody. Furthermore, the Nanobody abolished the inhibiting effect of HGF on bone morphogenetic protein-2-induced alkaline phosphatase activity and the mineralization of human mesenchymal stem cells. Finally, we show that the Nanobody reduced phosphorylation of tyrosine residues in c-MET, MAPK, and Akt. We also compared the Nanobody with anti-c-MET monoclonal antibodies and revealed the similar or better effect. The anti-c-MET Nanobody inhibited MM cell migration, thymidine incorporation, and adhesion, and blocked the HGF-mediated inhibition of osteoblastogenesis. The anti-c-MET Nanobody might represent a novel therapeutic agent in the treatment of MM and other cancers driven by HGF-c-MET signaling. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Mars MetNet Mission Payload Overview

    Science.gov (United States)

    Harri, A.-M.; Haukka, H.; Alexashkin, S.; Guerrero, H.; Schmidt, W.; Genzer, M.; Vazquez, L.

    2012-09-01

    A new kind of planetary exploration mission for Mars is being developed in collaboration between the Finnish Meteorological Institute (FMI), Lavochkin Association (LA), Space Research Institute (IKI) and Institutio Nacional de Tecnica Aerospacial (INTA). The Mars MetNet mission [1] is based on a new semi-hard landing vehicle called MetNet Lander (MNL). The scientific payload of the Mars MetNet Precursor mission is divided into three categories: Atmospheric instruments, Optical devices and Composition and structure devices. Each of the payload instruments will provide crucial scientific data about the Martian atmospheric phenomena.

  16. Pluimvee met smaak: behoeften-inventarisaties

    NARCIS (Netherlands)

    Bos, A.P.; Janssen, A.P.H.M.; Leenstra, F.R.; Groot Koerkamp, P.W.G.

    2010-01-01

    Een integraal duurzaam productiesysteem voor vleespluimvee moet voldoen aan functies en eisen, die voortkomen uit behoeften. Deze behoeften van belanghebbenden worden op hoofdlijnen geïnventariseerd. Belanghebbenden zijn: het vleeskuiken, de pluimveehouder, het milieu, de burger als burger met

  17. Extraboard performance : TriMet case study.

    Science.gov (United States)

    2012-02-01

    This paper examines extraboard operations and management at TriMet, the transit provider for the Portland Oregon metropolitan area. The : extraboard consists of a pool of operators who fill open work resulting from absences and other causes. The pape...

  18. Overzicht van zuiveringsmethoden voor reststromen met bestrijdingsmiddelen

    NARCIS (Netherlands)

    Vulto, V.C.; Beltman, W.H.J.

    2007-01-01

    In verschillende landbouwsectoren ontstaan reststromen water met bestrijdingsmiddelen die kunnen leiden tot puntbelasting van het oppervlaktewater. Er is behoefte aan een overzicht van methoden die er zijn om bestrijdingsmiddelen te verwijderen uit reststromen. Dit rapport geeft een korte

  19. Mars MetNet Precursor Mission Status

    Science.gov (United States)

    Harri, A.-M.; Aleksashkin, S.; Guerrero, H.; Schmidt, W.; Genzer, M.; Vazquez, L.; Haukka, H.

    2013-09-01

    We are developing a new kind of planetary exploration mission for Mars in collaboration between the Finnish Meteorological Institute (FMI), Lavochkin Association (LA), Space Research Institute (IKI) and Institutio Nacional de Tecnica Aerospacial (INTA). The Mars MetNet mission is based on a new semi-hard landing vehicle called MetNet Lander (MNL). The scientific payload of the Mars MetNet Precursor [1] mission is divided into three categories: Atmospheric instruments, Optical devices and Composition and structure devices. Each of the payload instruments will provide significant insights in to the Martian atmospheric behavior. The key technologies of the MetNet Lander have been qualified and the electrical qualification model (EQM) of the payload bay has been built and successfully tested.

  20. Mars MetNet Mission Status

    Science.gov (United States)

    Harri, A.-M.; Aleksashkin, S.; Arruego, I.; Schmidt, W.; Genzer, M.; Vazquez, L.; Haukka, H.; Palin, M.; Nikkanen, T.

    2015-10-01

    New kind of planetary exploration mission for Mars is under development in collaboration between the Finnish Meteorological Institute (FMI), Lavochkin Association (LA), Space Research Institute (IKI) and Institutio Nacional de Tecnica Aerospacial (INTA). The Mars MetNet mission is based on a new semihard landing vehicle called MetNet Lander (MNL). The scientific payload of the Mars MetNet Precursor [1] mission is divided into three categories: Atmospheric instruments, Optical devices and Composition and structure devices. Each of the payload instruments will provide significant insights in to the Martian atmospheric behavior. The key technologies of the MetNet Lander have been qualified and the electrical qualification model (EQM) of the payload bay has been built and successfully tested.

  1. MMPM - Mars MetNet Precursor Mission

    Science.gov (United States)

    Harri, A.-M.; Schmidt, W.; Pichkhadze, K.; Linkin, V.; Vazquez, L.; Uspensky, M.; Polkko, J.; Genzer, M.; Lipatov, A.; Guerrero, H.; Alexashkin, S.; Haukka, H.; Savijarvi, H.; Kauhanen, J.

    2008-09-01

    We are developing a new kind of planetary exploration mission for Mars - MetNet in situ observation network based on a new semi-hard landing vehicle called the Met-Net Lander (MNL). The eventual scope of the MetNet Mission is to deploy some 20 MNLs on the Martian surface using inflatable descent system structures, which will be supported by observations from the orbit around Mars. Currently we are working on the MetNet Mars Precursor Mission (MMPM) to deploy one MetNet Lander to Mars in the 2009/2011 launch window as a technology and science demonstration mission. The MNL will have a versatile science payload focused on the atmospheric science of Mars. Detailed characterization of the Martian atmospheric circulation patterns, boundary layer phenomena, and climatology cycles, require simultaneous in-situ measurements by a network of observation posts on the Martian surface. The scientific payload of the MetNet Mission encompasses separate instrument packages for the atmospheric entry and descent phase and for the surface operation phase. The MetNet mission concept and key probe technologies have been developed and the critical subsystems have been qualified to meet the Martian environmental and functional conditions. Prototyping of the payload instrumentation with final dimensions was carried out in 2003-2006.This huge development effort has been fulfilled in collaboration between the Finnish Meteorological Institute (FMI), the Russian Lavoschkin Association (LA) and the Russian Space Research Institute (IKI) since August 2001. Currently the INTA (Instituto Nacional de Técnica Aeroespacial) from Spain is also participating in the MetNet payload development. To understand the behavior and dynamics of the Martian atmosphere, a wealth of simultaneous in situ observations are needed on varying types of Martian orography, terrain and altitude spanning all latitudes and longitudes. This will be performed by the Mars MetNet Mission. In addition to the science aspects the

  2. MetNet - Martian Network Mission

    Science.gov (United States)

    Harri, A.-M.

    2009-04-01

    We are developing a new kind of planetary exploration mission for Mars - MetNet in situ observation network based on a new semi-hard landing vehicle called the Met-Net Lander (MNL). The actual practical mission development work started in January 2009 with participation from various countries and space agencies. The scientific rationale and goals as well as key mission solutions will be discussed. The eventual scope of the MetNet Mission is to deploy some 20 MNLs on the Martian surface using inflatable descent system structures, which will be supported by observations from the orbit around Mars. Currently we are working on the MetNet Mars Precursor Mission (MMPM) to deploy one MetNet Lander to Mars in the 2009/2011 launch window as a technology and science demonstration mission. The MNL will have a versatile science payload focused on the atmospheric science of Mars. Detailed characterization of the Martian atmospheric circulation patterns, boundary layer phenomena, and climatology cycles, require simultaneous in-situ measurements by a network of observation posts on the Martian surface. The scientific payload of the MetNet Mission encompasses separate instrument packages for the atmospheric entry and descent phase and for the surface operation phase. The MetNet mission concept and key probe technologies have been developed and the critical subsystems have been qualified to meet the Martian environmental and functional conditions. This development effort has been fulfilled in collaboration between the Finnish Meteorological Institute (FMI), the Russian Lavoschkin Association (LA) and the Russian Space Research Institute (IKI) since August 2001. Currently the INTA (Instituto Nacional de Técnica Aeroespacial) from Spain is also participating in the MetNet payload development.

  3. Mars MetNet Mission Status

    Science.gov (United States)

    Harri, Ari-Matti; Aleksashkin, Sergei; Arruego, Ignacio; Schmidt, Walter; Genzer, Maria; Vazquez, Luis; Haukka, Harri

    2015-04-01

    New kind of planetary exploration mission for Mars is under development in collaboration between the Finnish Meteorological Institute (FMI), Lavochkin Association (LA), Space Research Institute (IKI) and Institutio Nacional de Tecnica Aerospacial (INTA). The Mars MetNet mission is based on a new semi-hard landing vehicle called MetNet Lander (MNL). The scientific payload of the Mars MetNet Precursor [1] mission is divided into three categories: Atmospheric instruments, Optical devices and Composition and structure devices. Each of the payload instruments will provide significant insights in to the Martian atmospheric behavior. The key technologies of the MetNet Lander have been qualified and the electrical qualification model (EQM) of the payload bay has been built and successfully tested. 1. MetNet Lander The MetNet landing vehicles are using an inflatable entry and descent system instead of rigid heat shields and parachutes as earlier semi-hard landing devices have used. This way the ratio of the payload mass to the overall mass is optimized. The landing impact will burrow the payload container into the Martian soil providing a more favorable thermal environment for the electronics and a suitable orientation of the telescopic boom with external sensors and the radio link antenna. It is planned to deploy several tens of MNLs on the Martian surface operating at least partly at the same time to allow meteorological network science. 2. Scientific Payload The payload of the two MNL precursor models includes the following instruments: Atmospheric instruments: 1. MetBaro Pressure device 2. MetHumi Humidity device 3. MetTemp Temperature sensors Optical devices: 1. PanCam Panoramic 2. MetSIS Solar irradiance sensor with OWLS optical wireless system for data transfer 3. DS Dust sensor The descent processes dynamic properties are monitored by a special 3-axis accelerometer combined with a 3-axis gyrometer. The data will be sent via auxiliary beacon antenna throughout the

  4. The expression of hepatocyte growth factor (HGF) and c-Met in uterine serous carcinoma.

    Science.gov (United States)

    Bishop, Erin A; Lengyel, Ernst R; Yamada, S Diane; Montag, Anthony; Temkin, Sarah M

    2011-04-01

    The hepatocyte growth factor (HGF) receptor c-Met plays an important role in tumor dissemination by activating mitogenic signaling pathways. The goal of this study was to investigate immunohistochemical (IHC) staining patterns of HGF and c-Met in endometrioid endometrial cancer (EC) and uterine serous cancer (USC) and to correlate staining with patient outcomes. A tissue microarray was created using tissue from patients with atrophic endometrium (AE), grade 1 EC, grade 3 EC, and USC. Immunohistochemistry was used to detect c-Met, phosphorylated c-Met (p-c-Met), and HGF expression. Differences between IHC staining intensity were calculated using t-tests. Correlations between staining and clinicopathologic variables were determined by Chi-square testing for categorical variables and t-tests for continuous variables. Kaplan-Meier curves were constructed to analyze survival in USC. Patients with cancer had more total c-Met and HGF expression than those with AE (p=0.037, p<0.001 respectively), but no difference in p-c-Met staining. Total c-Met and HGF staining was significantly different between groups (p=0.042, p<0.001 respectively). This difference was accounted for by greater c-MET expression in USC compared to AE (p=0.027). Depth of invasion, stage, and lymph node status were not significantly related to staining intensity. Patients with strong c-Met and HGF staining had decreased overall survival compared to patients with weaker staining. HGF and c-Met may play a role in the progression of endometrial cancer and should be studied further as prognostic and therapeutic tools. Copyright © 2010 Elsevier Inc. All rights reserved.

  5. Targeting Met and VEGFR Axis in Metastatic Castration-Resistant Prostate Cancer: 'Game Over'?

    Science.gov (United States)

    Modena, Alessandra; Massari, Francesco; Ciccarese, Chiara; Brunelli, Matteo; Santoni, Matteo; Montironi, Rodolfo; Martignoni, Guido; Tortora, Giampaolo

    2016-08-01

    Despite recent advances that have been made in the therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC), effective management of bone metastases remains a key goal not yet reached. The receptor tyrosine kinase MET and the vascular endothelial growth factor receptor (VEGFR) seem to play an important role in prostate cancer progression and pathological bone turnover, representing potential targets for improving clinical outcomes in mCRPC. Studies evaluating agents that target one or both these pathways have demonstrated modest activity but no improvement in overall survival. Nevertheless, this therapeutic strategy seems to still be a promising and engaging area of prostate cancer research and the interest in better understanding the MET/VEGFR axis and the mechanism of action of these inhibitors is growing. This review describes the rationale for targeting MET and VEGFR pathway in mCRPC and provides the clinical data available to date and an update on ongoing trials.

  6. MetBaro - Pressure Device for Mars MetNet Lander

    Science.gov (United States)

    Haukka, Harri; Polkko, Jouni; Harri, Ari-Matti; Schmidt, Walter; Leinonen, Jussi; Genzer, Maria; Mäkinen, Teemu

    2010-05-01

    MetNet Mars Mission focused for Martian atmospheric science is based on a new semihard landing vehicle called the MetNet Lander (MNL). The MNL will have a versatile science payload focused on the atmospheric science of Mars. The scientific payload of the MetNet Mission encompasses separate instrument packages for the atmospheric entry and descent phase and for the surface operation phase. MetBaro is the pressure sensor of MetNet Lander designed to work on Martian surface. It is based on Barocap® technology developed by Vaisala, Inc. MetBaro is a capacitive type of sensing device where capasitor plates are moved by ambient pressure. MetBaro device consists of two pressure transducers including a total of 4 Barocap® sensor heads of high-stability and high-resolution types. The long-term stability of MetBaro is in order of 20…50 µBar and resolution a few µBar. MetBaro is small, lightweighed and has low power consumption. It weighs about 50g without wires and controlling FPGA, and consumes 15 mW of power. A similar device has successfully flown in Phoenix mission, where it performed months of measurements on Martian ground. Another device is also part of the Mars Science Laboratory REMS instrument (to be launched in 2011).

  7. MetHumi - Humidity Device for Mars MetNet Lander

    Science.gov (United States)

    Genzer, Maria; Polkko, Jouni; Harri, Ari-Matti; Schmidt, Walter; Leinonen, Jussi; Mäkinen, Teemu; Haukka, Harri

    2010-05-01

    MetNet Mars Mission focused for Martian atmospheric science is based on a new semihard landing vehicle called the MetNet Lander (MNL). The MNL will have a versatile science payload focused on the atmospheric science of Mars. The scientific payload of the MetNet Mission encompasses separate instrument packages for the atmospheric entry and descent phase and for the surface operation phase. MetHumi is the humidity sensor of MetNet Lander designed to work on Martian surface. It is based on Humicap® technology developed by Vaisala, Inc. MetHumi is a capacitive type of sensing device where an active polymer film changes capacitance as function of relative humidity. One MetHumi device package consists of one humidity transducer including three Humicap® sensor heads, an accurate temperature sensor head (Thermocap® by Vaisala, Inc.) and constant reference channels. MetHumi is very small, lightweighed and has low power consumption. It weighs only about 15 g without wires, and consumes 15 mW of power. MetHumi can make meaningful relative humidity measurements in range of 0 - 100%RH down to -70°C ambient temperature, but it survives even -135°C ambient temperature.

  8. Gender-specific differences in the incidence of microalbuminuria in metabolic syndrome patients after treatment with fimasartan: The K-MetS study.

    Science.gov (United States)

    Park, Jeong Bae; Kim, Su-A; Sung, Ki-Chul; Kim, Jang Young

    2017-01-01

    The effect of resolving metabolic syndrome on target organ damage in hypertensive patients is not well described. We evaluated whether treating metabolic syndrome (MetS) with an angiotensin receptor blocker subsequently reduced microalbuminuria in the K-MetS cohort. Among 10,601 total metabolic syndrome patients, 3,250 (52.2% male, 56.2±10.0 years) with sufficient data on five specific metabolic components were included in this study. Patients were divided into four groups based on MetS status at baseline and 3 months. All patients received an angiotensin receptor blocker, fimasartan, for these 3 months; thereafter, treatment was modified at the discretion of each patient's physician. Microalbuminuria and the albumin/creatine ratio were evaluated as a proxy of organ damage. Blood pressure and waist circumference decreased from baseline to 3 months and 1 year. The average albumin/creatinine ratio significantly improved during the first three months of the study from 36.0±147.4 to 21.0±74.9 mg/g (pTreatment of hypertensive patients for one year with the angiotensin receptor blocker fimasartan significantly reduced the albumin/creatine ratio, irrespective of whether the patient had MetS; however, the albumin/creatinine ratio was significantly higher in patents with persistent or newly developed MetS compared to patients without MetS. Additionally, these findings were more prominent in women than in men.

  9. MEK inhibitors against MET-amplified non-small cell lung cancer.

    Science.gov (United States)

    Chiba, Masato; Togashi, Yosuke; Tomida, Shuta; Mizuuchi, Hiroshi; Nakamura, Yu; Banno, Eri; Hayashi, Hidetoshi; Terashima, Masato; De Velasco, Marco A; Sakai, Kazuko; Fujita, Yoshihiko; Mitsudomi, Tetsuya; Nishio, Kazuto

    2016-12-01

    Several receptor tyrosine kinases (RTKs) including EGFR, ALK, and MET have been identified as therapeutic targets in non-small cell lung cancer (NSCLC). Among the downstream pathways of RTKs, the MAPK pathway is particularly important for cancer cell proliferation, differentiation, and survival. In this study, the effects of MEK inhibitors (trametinib and PD0325901) in several NSCLC cell lines with driver gene alterations, especially RTK genes, were tested in vitro using an MTT assay, and a wide range of sensitivities was found. In particular, all the EGFR-mutated cell lines were resistant to MEK inhibitors, whereas all the MET-amplified cell lines were sensitive. A bioinformatics technique and western blot analyses showed that the PI3K/AKT pathway is more activated in EGFR-mutated NSCLC than in MET-amplified NSCLC, and a PI3K inhibitor enhanced the sensitivity to trametinib in the EGFR-mutated cell lines, suggesting that this pathway is associated with resistance to MEK inhibitors. Although the HCC827 cell line (EGFR mutation) was resistant to MEK inhibitors, the HCC827CNXR cell line, whose driver gene shifts from EGFR to MET, exhibited enhanced sensitivity to MEK inhibitors, indicating the biological importance of the MAPK pathway for MET-amplified NCSLC. Furthermore, a synergistic effect of crizotinib (a MET inhibitor) and trametinib was observed in MET-amplified NCLC cell lines. Our findings indicate that the MAPK pathway is biologically important for MET-amplified NSCLC and strongly encourage the development of combination therapy with a MET inhibitor and a MEK inhibitor against MET-amplified NSCLC.

  10. C-MET overexpression and amplification in gliomas.

    Science.gov (United States)

    Kwak, Yoonjin; Kim, Seong-Ik; Park, Chul-Kee; Paek, Sun Ha; Lee, Soon-Tae; Park, Sung-Hye

    2015-01-01

    We investigated c-Met overexpression and MET gene amplification in gliomas to determine their incidence and prognostic significance. c-Met immunohistochemistry and MET gene fluorescence in situ hybridization were carried out on tissue microarrays from 250 patients with gliomas (137 grade IV GBMs and 113 grade II and III diffuse gliomas). Clinicopathological features of these cases were reviewed. c-Met overexpression and MET gene amplification were detected in 13.1% and 5.1% of the GBMs, respectively. All the MET-amplified cases showed c-Met overexpression, but MET amplification was not always concordant with c-Met overexpression. None of grade II and III gliomas demonstrated c-Met overexpression or MET gene amplification. Mean survival of the GBM patients with MET amplification was not significantly different from patients without MET amplification (P=0.155). However, GBM patients with c-Met overexpression survived longer than patients without c-Met overexpression (P=0.035). Although MET amplification was not related to poor GBM prognosis, it is partially associated with the aggressiveness of gliomas, as MET amplification was found only in grade IV, not in grade II and III gliomas. We suggest that MET inhibitor therapy may be beneficial in about 5% GBMs, which was the incidence of MET gene amplification found in the patients included in this study.

  11. Structural Basis for Selective Small Molecule Kinase Inhibition of Activated c-Met

    Energy Technology Data Exchange (ETDEWEB)

    Rickert, Keith W.; Patel, Sangita B.; Allison, Timothy J.; Byrne, Noel J.; Darke, Paul L.; Ford, Rachael E.; Guerin, David J.; Hall, Dawn L.; Kornienko, Maria; Lu, Jun; Munshi, Sanjeev K.; Reid, John C.; Shipman, Jennifer M.; Stanton, Elizabeth F.; Wilson, Kevin J.; Young, Jonathon R.; Soisson, Stephen M.; Lumb, Kevin J. (Merck)

    2012-03-15

    The receptor tyrosine kinase c-Met is implicated in oncogenesis and is the target for several small molecule and biologic agents in clinical trials for the treatment of cancer. Binding of the hepatocyte growth factor to the cell surface receptor of c-Met induces activation via autophosphorylation of the kinase domain. Here we describe the structural basis of c-Met activation upon autophosphorylation and the selective small molecule inhibiton of autophosphorylated c-Met. MK-2461 is a potent c-Met inhibitor that is selective for the phosphorylated state of the enzyme. Compound 1 is an MK-2461 analog with a 20-fold enthalpy-driven preference for the autophosphorylated over unphosphorylated c-Met kinase domain. The crystal structure of the unbound kinase domain phosphorylated at Tyr-1234 and Tyr-1235 shows that activation loop phosphorylation leads to the ejection and disorder of the activation loop and rearrangement of helix {alpha}C and the G loop to generate a viable active site. Helix {alpha}C adopts a orientation different from that seen in activation loop mutants. The crystal structure of the complex formed by the autophosphorylated c-Met kinase domain and compound 1 reveals a significant induced fit conformational change of the G loop and ordering of the activation loop, explaining the selectivity of compound 1 for the autophosphorylated state. The results highlight the role of structural plasticity within the kinase domain in imparting the specificity of ligand binding and provide the framework for structure-guided design of activated c-Met inhibitors.

  12. MetBaro - Pressure Instrument for Mars MetNet Lander

    Science.gov (United States)

    Polkko, J.; Haukka, H.; Harri, A.-M.; Schmidt, W.; Leinonen, J.; Mäkinen, T.

    2009-04-01

    THE METNET MISSION FOCUSED ON THE Martian atmospheric science is based on a new semihard landing vehicle called the MetNet Lander (MNL). The MNL will have a versatile science payload focused on the atmospheric science of Mars. The scientific payload of the MetNet Mission encompasses separate instrument packages for the atmospheric entry and descent phase and for the surface operation phase. MetBaro is the pressure instrument of MetNet Lander designed to work on Martian surface. It is based on Barocap® technology developed by Vaisala, Inc. MetBaro is a capacitic type of sensing device where capasitor plates are moved by ambient pressure. MetBaro device consists of two pressure transducers including a total of 6 Barocap® sensor heads of high-stability and high-resolution types. The long-term stability of MetBaro is in order of 20…50 µBar and resolution a few µBar. MetBaro is small, lightweighed and has low power consumption. It weighs about 50g without wires and controlling FPGA, and consumes 15 mW of power. A similar device has successfully flown in Phoenix mission, where it performed months of measurements on Martian ground. Another device is also part of the Mars Science Laboratory REMS instrument (to be launched in 2011).

  13. Groen proceswater: zuivering brouwerijprocesafvalwater met microalgen

    NARCIS (Netherlands)

    Dijk, van W.; Weide, van der R.Y.; Kroon, A.

    2016-01-01

    In 2012 is het project Groen Proceswater gestart. Hierin worden de mogelijkheden van zuivering van brouwerijprocesafvalwater met behulp van microalgen onderzocht. Dit is gedaan in een samenwerkingsverband van Heineken Nederland BV, Algae Food & Fuel en WUR-ACRRES. De resultaten behaald in 2012

  14. Allergische consument is tevreden met Santana

    NARCIS (Netherlands)

    Maas, van der M.P.; Schenk, M.F.

    2008-01-01

    Nederland had twee jaar geleden de primeur: Santana, een hyperallergeen appelras voor mensen met appelallergie. Wageningen UR heeft de ervaringen van de consumenten over 2006 en 2007 onderzocht. De vermindering van de allergische reactie is ongeveer volgens verwachting en de tevredenheid blijkt hoog

  15. Evangelisch Commando, onze omgamg met de buitenkerkelijke ...

    African Journals Online (AJOL)

    Test

    Of J. en E. dus interkerklik is, bly 'n vraag! Die gedeelte oor die „Oorzaken van buitenkerklijkheid is prikkelend en interessant. Die vraag is net of dit nie nog dieper gesoek moet word, nl. in die herontwaking van die Heidendom wat sig sins die Renaissance hardnekkig deur sit met die outonomie van die mens in die sentrum.

  16. Hindernisse met betrekking tot jeugsportdeelname | Coetzee | South ...

    African Journals Online (AJOL)

    Hindernisse met betrekking tot jeugsportdeelname. Zonja Coetzee, Mercia Coetzee, Karel Botha. Abstract. The purpose of this study was to assess barriers or constraints that can preclude or limit the sport participation of high school pupils in the Potchefstroom district. Four hundred and seventy eight pupils (211 boys and ...

  17. Met gezonde bijen naar de heide

    NARCIS (Netherlands)

    Cornelissen, B.; Calis, J.

    2010-01-01

    Op 22 maart 2010 kwam een bont gezelschap van bijenhouders van ABTB, ANI en NBV bijeen in Hoenderloo. Het onderwerp die avond was de vraag: “Hoe combineer ik varroabestrijding met de heidedracht?” Hieronder het antwoord en wel in de vorm van de basisprincipes van varroa bestrijding plus een concrete

  18. Varroabestrijding met bijenbroed als mijtenval (2)

    NARCIS (Netherlands)

    Calis, J.; Beetsma, J.; Boot, W.J.; Eijnde, van den J.; Ruijter, de A.

    1994-01-01

    Bij deze bestrijdingsmethode worden belegde darreraten uit een moergoede veger overgehangen naar het moerloze en later broedloze hoofdvolk. Hier worden de mijten die zich op de bijen bevinden gevangen. Nadat de laatste darreraat uit een hoofdvolk is verwijderd, wordt het bijenvolk met Perizine

  19. Beeldreconstructie in MRI met compressed sensing

    NARCIS (Netherlands)

    van Leeuwen, T.

    Philips Healthcare is een van de grootste fabrikanten van MRI-scanners ter wereld en is geïnteresseerd in het gebruik van compressed sensing-technieken om MRI-scans te versnellen. Tijdens de Studieweek Wiskunde met de Industrie 2015 in Utrecht vroeg Philips of en hoe patiënt-specifieke informatie

  20. Nieuwe ontwikkelingen met roofmijten tegen spint

    NARCIS (Netherlands)

    Dorresteijn, W.; Blok, de J.J.

    2008-01-01

    Bonenspintmijt is een lastig te bestrijden plaag. Een aantal boomkwekers heeft goede ervaringen met het inzetten van roofmijten tegen deze plaag. Nieuwe ontwikkelingen, zoals een lagere prijs en andere methoden van inzetten, kunnen ervoor zorgen dat deze vorm van geïntegreerde bestrijding steeds

  1. The cleverest man I never met

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics; Volume 96; Issue 5. The cleverest man I never met. PATRICK BATESON. HALDANE AT 125 Volume 96 Issue 5 November 2017 pp 801-804. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/jgen/096/05/0801-0804. Keywords. J. B. S. Haldane ...

  2. A brief report on mets system

    Digital Repository Service at National Institute of Oceanography (India)

    Fernandes, W.A.

    Mets system is basically a gas monitoring system, used for the detection of underwater gas. The system consists of a sensor, datalogger and energy module. The sensor works on the diffusion techniques. The system can be deployed to a water depth...

  3. Onkruidbestrijding met Basta 200 in zomerbloemen

    NARCIS (Netherlands)

    Bulle, A.A.E.

    2010-01-01

    Onkruidbestrijding in zomerbloemen is een stuk lastiger geworden sinds het middel Gramoxone, met als werkzame stof paraquat-dichloride, niet meer is toegelaten. In een eerder onderzoek is onderzocht welke middelen als alternatief voor paraquat-dichloride kunnen worden gebruikt in de winter en het

  4. Behandeling non-vitale pulpa met formocresol

    NARCIS (Netherlands)

    Wijk, Pieter Harm

    1971-01-01

    Het principe van de endodontische behandeling volgens de richtlijnen van De Boer is gebaseerd op de gedachte dat het niet nodig is het gehele wortelkanaal te reinigen, mits men er voor zorgt dat de achtergelaten noxen met behulp van een chemischestof - in dit geval formaldehyde - onschadelijk worden

  5. Overexpression of c-met in oral SCC promotes hepatocyte growth factor-induced disruption of cadherin junctions and invasion.

    Science.gov (United States)

    Murai, M; Shen, X; Huang, L; Carpenter, W M; Lin, C S; Silverman, S; Regezi, J; Kramer, R H

    2004-10-01

    Hepatocyte growth factor (HGF), the ligand for the c-met proto-oncogene product, is a multifunctional protein that enhances tumor cell motility, extracellular matrix invasion, and mitogenic or morphogenic activities of various cell types. In this study we examined the expression of the c-Met receptor in human oral squamous cell carcinoma (SCC) in vivo and in vitro to explore its relationship to tumor progression and invasiveness. Biopsy specimens of human oral SCC were immunohistochemically stained for c-Met. Nearly all primary oral SCC lesions and lymph node metastases consistently showed intense staining for c-Met, whereas normal oral mucosa showed faint to negative staining only on basal cells. In a panel of human oral SCC cell lines, we found a strong correlation between the levels of c-Met expression and the cells' response to HGF in motility and invasion assays. Sensitivity to HGF also correlated with the expression of the c-Met 9-kb mRNA. When the non-invasive HOC-605 cell line, which expresses a low level of c-Met receptor, was transfected with an expression plasmid containing human c-met cDNA, the transfectant cells showed motile and invasive responses to HGF. Immunostaining and immunoprecipitation studies demonstrated that E-cadherin and c-Met were physically associated at SCC cell-cell junctions, suggesting a direct role for c-Met in induction of junctional integrity. Importantly, HGF caused a rapid elevation of unbound beta-catenin, suggesting its availability for nuclear signal transduction and triggering of cell motility and invasiveness. Thus, overexpression of c-Met may facilitate disruption of E-cadherin junctions. Collectively, these results suggest that HGF/c-Met signaling is a common event in oral SCC that may trigger phenotype modulation and enhanced invasion and metastasis.

  6. Discovery of Fully Human Anti-MET Monoclonal Antibodies with Antitumor Activity against Colon Cancer Tumor Models In Vivo

    Directory of Open Access Journals (Sweden)

    Edward Htun van der Horst

    2009-04-01

    Full Text Available The receptor tyrosine kinase MET is a major component controlling the invasive growth program in embryonic development and in invasive malignancies. The discovery of therapeutic antibodies against MET has been difficult, and antibodies that compete with hepatocyte growth factor (HGF act as agonists. By applying phage technology and cell-based panning strategies, we discovered two fully human antibodies against MET (R13 and R28, which synergistically inhibit HGF binding to MET and elicit antibody-dependent cellular cytotoxicity. Cell-based phosphorylation assays demonstrate that R13 and R28 abrogate HGF-induced activation of MET, AKT1, ERK1/2, and HGF-induced migration and proliferation. FACS experiments suggest that the inhibitory effect is mediated by “locking” MET receptor in a state with R13, which then increases avidity of R28 for the extracellular domain of MET, thus blocking HGF binding without activating the receptor. In vivo studies demonstrate that the combination of R13/28 significantly inhibited tumor growth in various colon tumor xenograft models. Inhibition of tumor growth was associated with induction of hypoxia. Global gene expression analysis shows that inhibition of HGF/MET pathway significantly upregulated the tumor suppressors KLF6, CEACAM1, and BMP2, the negative regulator of phosphatidylinositol-3-OH-kinase PIK3IP1, and significantly suppressed SCF and SERPINE2, both enhancers of proliferation and invasiveness. Moreover, in an experimental metastasis model, R13/28 increased survival by preventing the recurrence of otherwise lethal lung metastases. Taken together, these results underscore the utility of a dual-antibody approach for targeting MET and possibly other receptor tyrosine kinases. Our approach could be expanded to drug discovery efforts against other cell surface proteins.

  7. Kwantitatieve massaspectrometrie van Clenbuterol met behulp van isotoopverdunning

    NARCIS (Netherlands)

    Traag, W.A.; Bennekom, van E.O.; Weseman, J.M.; Kienhuis, P.G.M.; Tuinstra, L.G.M.Th.

    1989-01-01

    Om de toepassing van massaspectrometrie met behulp van isotoopverdunning in urine, vlees en lever te onderzoeken is een aantal experimenten uitgevoerd met de 'Hewlett-Packard Hass Selective Detector' (Electron Impact). Ook zijn met Finnigan 4500 aanvullende experimenten (Chemical Ionisation)

  8. Gender-specific differences in the incidence of microalbuminuria in metabolic syndrome patients after treatment with fimasartan: The K-MetS study.

    Directory of Open Access Journals (Sweden)

    Jeong Bae Park

    Full Text Available The effect of resolving metabolic syndrome on target organ damage in hypertensive patients is not well described. We evaluated whether treating metabolic syndrome (MetS with an angiotensin receptor blocker subsequently reduced microalbuminuria in the K-MetS cohort.Among 10,601 total metabolic syndrome patients, 3,250 (52.2% male, 56.2±10.0 years with sufficient data on five specific metabolic components were included in this study. Patients were divided into four groups based on MetS status at baseline and 3 months. All patients received an angiotensin receptor blocker, fimasartan, for these 3 months; thereafter, treatment was modified at the discretion of each patient's physician. Microalbuminuria and the albumin/creatine ratio were evaluated as a proxy of organ damage.Blood pressure and waist circumference decreased from baseline to 3 months and 1 year. The average albumin/creatinine ratio significantly improved during the first three months of the study from 36.0±147.4 to 21.0±74.9 mg/g (p<0.05 and was persistently high in patients with MetS at baseline and 3 months versus other groups. Women in comparison with men showed significantly lower ACR among patients with newly developed MetS at 3-month.Treatment of hypertensive patients for one year with the angiotensin receptor blocker fimasartan significantly reduced the albumin/creatine ratio, irrespective of whether the patient had MetS; however, the albumin/creatinine ratio was significantly higher in patents with persistent or newly developed MetS compared to patients without MetS. Additionally, these findings were more prominent in women than in men.

  9. c-Met modulates RPE migratory response to laser-induced retinal injury.

    Directory of Open Access Journals (Sweden)

    Masataka Kasaoka

    Full Text Available Retinal laser injuries are often associated with aberrant migration of the retinal pigment epithelium (RPE, which can cause expansion of the scar beyond the confines of the original laser burn. In this study, we devised a novel method of laser-induced injury to the RPE layer in mouse models and began to dissect the mechanisms associated with pathogenesis and progression of laser-induced RPE injury. We have hypothesized that the proto-oncogene receptor, c-Met, is intimately involved with migration of RPE cells, and may be an early responder to injury. Using transgenic mouse models, we show that constitutive activation of c-Met induces more robust RPE migration into the outer retina of laser-injured eyes, while abrogation of the receptor using a cre-lox method reduces these responses. We also demonstrate that retinal laser injury increases expression of both HGF and c-Met, and activation of c-Met after injury is correlated with RPE cell migration. RPE migration may be responsible for clinically significant anatomic changes observed after laser injury. Abrogation of c-Met activity may be a therapeutic target to minimize retinal damage from aberrant RPE cell migration.

  10. ARQ-197, an oral small-molecule inhibitor of c-Met for the treatment of solid tumors.

    Science.gov (United States)

    Bagai, Rakesh; Fan, Weiwen; Ma, Patrick C

    2010-06-01

    ARQ-197 is an oral, selective c-Met inhibitor under development by ArQule Inc, in partnership with Daiichi Sankyo Co Ltd and Asian licensee Kyowa Hakko Kirin Co Ltd, for the potential treatment of solid tumors, including NSCLC, hepatocellular carcinoma and pancreatic cancer, as well as microphthalmia transcription factor-driven tumors. c-Met, a key cell surface receptor tyrosine kinase involved in diverse regulatory functions, is often aberrantly activated in human cancers. While the precise mechanism of action of ARQ-197 remains undefined, data from preclinical studies have demonstrated that ARQ-197 inhibits c-Met activation in numerous human tumor cell lines and specifically targets c-Met in various cancer types; uniquely, ARQ-197 inhibits c-Met in a non-ATP-competitive manner. Phase I/II clinical trials demonstrated promise in terms of both tolerability and tumor response. Intriguingly, dose-limiting adverse effects were hematological in nature. Combinational trials are also ongoing to take advantage of the signaling crosstalk between c-Met and other oncogenic signaling systems. Prioritization of the clinical development of c-Met inhibitors, such as ARQ-197, among different tumor disease types is a key challenge at present; an improved understanding of the prediction of molecular determinants in tumors with respect to c-Met kinase as the driver oncogenic receptor, and of the prediction of tumor response, is still urgently needed.

  11. MET and Small-Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Francesco Gelsomino

    2014-10-01

    Full Text Available Small-cell lung cancer (SCLC is one of the most aggressive lung tumors. The majority of patients with SCLC are diagnosed at an advanced stage. This tumor type is highly sensitive to chemo-radiation treatment, with very high response rates, but invariably relapses. At this time, treatment options are still limited and the prognosis of these patients is poor. A better knowledge of the molecular biology of SCLC allowed us to identify potential druggable targets. Among these, the MET/HGF axis seems to be one of the most aberrant signaling pathways involved in SCLC invasiveness and progression. In this review, we describe briefly all recent literature on the different molecular profiling in SCLC; in particular, we discuss the specific alterations involving c-MET gene and their implications as a potential target in SCLC.

  12. MET and Small-Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Gelsomino, Francesco, E-mail: francesco.gelsomino@istitutotumori.mi.it [Medical Oncology Unit 1, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Via G. Venezian 1, 20133 Milano (Italy); Rossi, Giulio [Operative Unit of Pathology, Azienda Ospedaliero-Universitaria Policlinico, Via del Pozzo 71, 41124 Modena (Italy); Tiseo, Marcello [Medical Oncology Unit, Azienda Ospedaliero-Universitaria, Viale A. Gramsci 14, 43126 Parma (Italy)

    2014-10-13

    Small-cell lung cancer (SCLC) is one of the most aggressive lung tumors. The majority of patients with SCLC are diagnosed at an advanced stage. This tumor type is highly sensitive to chemo-radiation treatment, with very high response rates, but invariably relapses. At this time, treatment options are still limited and the prognosis of these patients is poor. A better knowledge of the molecular biology of SCLC allowed us to identify potential druggable targets. Among these, the MET/HGF axis seems to be one of the most aberrant signaling pathways involved in SCLC invasiveness and progression. In this review, we describe briefly all recent literature on the different molecular profiling in SCLC; in particular, we discuss the specific alterations involving c-MET gene and their implications as a potential target in SCLC.

  13. Die Calvinistiese Sondagbeskouing met spesiale verwysing na ...

    African Journals Online (AJOL)

    omver te werp. Aan die ander kant het die orde en vrede in die kerk dit wel ook nodig gemaak om 'n dag vir gebruik van die diens van die Here af te sonder. Calvyn se insigte in verband met die oorgang van die Sabbat na die Sondag, is die insigte wat as die eg reformatoriese behoue gebly het. Haitjema (1961:249) sê in.

  14. cMET in NSCLC: Can We Cut off the Head of the Hydra? From the Pathway to the Resistance

    Directory of Open Access Journals (Sweden)

    Nele Van Der Steen

    2015-03-01

    Full Text Available In the last decade, the tyrosine kinase receptor cMET, together with its ligand hepatocyte growth factor (HGF, has become a target in non-small cell lung cancer (NSCLC. Signalization via cMET stimulates several oncological processes amongst which are cell motility, invasion and metastasis. It also confers resistance against several currently used targeted therapies, e.g., epidermal growth factor receptor (EGFR inhibitors. In this review, we will discuss the basic structure of cMET and the most important signaling pathways. We will also look into aberrations in the signaling and the effects thereof in cancer growth, with the focus on NSCLC. Finally, we will discuss the role of cMET as resistance mechanism.

  15. Metáfora y estructura conceptual

    Directory of Open Access Journals (Sweden)

    Emilia Castaño

    2012-01-01

    Full Text Available La lingüística cognitiva siempre ha argumentado que la metáfora no pertenece exclusivamente al lenguaje, sino que es una competencia que se basa en la habilidad humana de concebir un dominio de experiencia en términos de otro. Entendida así, la metáfora no puede ser otra cosa que un fenómeno conceptual. No obstante, pocos adeptos de la lingüística cognitiva han concentrados sus esfuerzos en catalogar manifestaciones metafóricas en ámbitos no lingüísticos. En este trabajo, sugerimos que es factible encontrar pruebas de que la metáfora es un proceso conceptual y, como tal, se manifiesta en esferas que no son estrictamente lingüísticas. Para ello, aportamos un seguido de evidencias muy diversas, como por ejemplo su papel en el razonamiento lógico-matemático de los niños en la fase preoperacional del desarrollo cognitivo, la programación de interfaces para aplicaciones informáticas y los resultados de tres estudios empíricos realizados recientemente en el campo  de la psicología cognitiva que analizan los efectos whorfianos en la conceptualización del tiempo y los efectos del espacio en la memoria emocional.

  16. Could the organ shortage ever be met?

    Science.gov (United States)

    Levitt, Mairi

    2015-01-01

    The organ shortage is commonly presented as having a clear solution, increase the number of organs donated and the problem will be solved. In the light of the Northern Ireland Assembly's consultation on moving to an opt-out organ donor register this article focuses on the social factors and complexities which impact strongly on both the supply of, and demand for, transplantable organs. Judging by the experience of other countries presumed consent systems may or may not increase donations but have not met demand. Donation rates have risen considerably in all parts of the UK recently but there is also an increasing demand for organs. Looking at international donation rates and attitudes, future demand for organs and education on donation, the question is whether the organ shortage could ever be met. The increase in longevity, in rates of diabetes and obesity and in alcohol related liver disease all contribute both to increased demand for transplants, and re-transplants, and a reduction in the number of usable organs. It is unlikely that demand could ever be met, since, if supply was unlimited, the focus would move to financial resources and competing demands on the health care budget in a publicly funded health system. These factors point to the need to focus on ways of reducing, or at least stabilizing, demand where lifestyle factors contribute to the underlying disease.

  17. The regulatory role of heparin on c-Met signaling in hepatocellular carcinoma cells.

    Science.gov (United States)

    İşcan, Evin; Güneş, Aysim; Korhan, Peyda; Yılmaz, Yeliz; Erdal, Esra; Atabey, Neşe

    2017-06-01

    The role of heparin as an anticoagulant is well defined; however, its role in tumorigenesis and tumor progression is not clear yet. Some studies have shown that anticoagulant treatment in cancer patients improve overall survival, however, recent clinical trials have not shown a survival benefit in cancer patients receiving heparin treatment. In our previous studies we have shown the inhibitory effects of heparin on Hepatocyte Growth Factor (HGF)-induced invasion and migration in hepatocellular carcinoma (HCC) cells. In this study, we showed the differential effects of heparin on the behaviors of HCC cells based on the presence or absence of HGF. In the absence of HGF, heparin activated HGF/c-Met signaling and promoted motility and invasion in HCC cells. Heparin treatment led to c-Met receptor dimerization and activated c-Met signaling in an HGF independent manner. Heparin-induced c-Met activation increased migration and invasion through ERK1/2, early growth response factor 1 (EGR1) and Matrix Metalloproteinases (MMP) axis. Interestingly, heparin modestly decreased the proliferation of HCC cells by inhibiting activatory phosphorylation of Akt. The inhibition of c-Met signaling reversed heparin-induced increase in motility and invasion and, proliferation inhibition. Our study provides a new perspective into the role of heparin on c-Met signaling in HCC.

  18. c-MET regulates myoblast motility and myocyte fusion during adult skeletal muscle regeneration.

    Science.gov (United States)

    Webster, Micah T; Fan, Chen-Ming

    2013-01-01

    Adult muscle stem cells, satellite cells (SCs), endow skeletal muscle with tremendous regenerative capacity. Upon injury, SCs activate, proliferate, and migrate as myoblasts to the injury site where they become myocytes that fuse to form new muscle. How migration is regulated, though, remains largely unknown. Additionally, how migration and fusion, which both require dynamic rearrangement of the cytoskeleton, might be related is not well understood. c-MET, a receptor tyrosine kinase, is required for myogenic precursor cell migration into the limb for muscle development during embryogenesis. Using a genetic system to eliminate c-MET function specifically in adult mouse SCs, we found that c-MET was required for muscle regeneration in response to acute muscle injury. c-MET mutant myoblasts were defective in lamellipodia formation, had shorter ranges of migration, and migrated slower compared to control myoblasts. Surprisingly, c-MET was also required for efficient myocyte fusion, implicating c-MET in dual functions of regulating myoblast migration and myocyte fusion.

  19. MET Signaling Mediates Intestinal Crypt-Villus Development, Regeneration, and Adenoma Formation and Is Promoted by Stem Cell CD44 Isoforms.

    Science.gov (United States)

    Joosten, Sander P J; Zeilstra, Jurrit; van Andel, Harmen; Mijnals, R Clinton; Zaunbrecher, Joost; Duivenvoorden, Annet A M; van de Wetering, Marc; Clevers, Hans; Spaargaren, Marcel; Pals, Steven T

    2017-10-01

    Resistance of metastatic human colorectal cancer cells to drugs that block epidermal growth factor (EGF) receptor signaling could be caused by aberrant activity of other receptor tyrosine kinases, activating overlapping signaling pathways. One of these receptor tyrosine kinases could be MET, the receptor for hepatocyte growth factor (HGF). We investigated how MET signaling, and its interaction with CD44 (a putative MET coreceptor regulated by Wnt signaling and highly expressed by intestinal stem cells [ISCs] and adenomas) affects intestinal homeostasis, regeneration, and adenoma formation in mini-gut organoids and mice. We established organoid cultures from ISCs stimulated with HGF or EGF and assessed intestinal differentiation by immunohistochemistry. Mice with total epithelial disruption of MET (Ah Cre /Met fl/fl /LacZ) or ISC-specific disruption of MET (Lgr5 Creert2 /Met fl/fl /LacZ) and control mice (Ah Cre /Met +/+ /LacZ, Lgr5 Creert2 /Met +/+ /LacZ) were exposed to 10 Gy total body irradiation; intestinal tissues were collected, and homeostasis and regeneration were assessed by immunohistochemistry. We investigated adenoma organoid expansion stimulated by HGF or EGF using adenomas derived from Lgr5 Creert2 /Met fl/fl /Apc fl/fl and Lgr5 Creert2 /Met +/+ /Apc fl/fl mice. The same mice were evaluated for adenoma prevalence and size. We also quantified adenomas in Ah Cre /Met fl/fl /Apc fl/+ mice compared with Ah Cre /Met +/+ /Apc fl/+ control mice. We studied expansion of organoids generated from crypts and adenomas, stimulated by HGF or EGF, that were derived from mice expressing different CD44 splice variants (Cd44 +/+ , Cd44 -/- , Cd44 s/s , or Cd44 v4-10/v4-10 mice). Crypts incubated with EGF or HGF expanded into self-organizing mini-guts with similar levels of efficacy and contained all differentiated cell lineages. MET-deficient mice did not have defects in intestinal homeostasis. Total body irradiation reduced numbers of proliferating crypts in Ah Cre

  20. PET of c-Met in Cancer with ⁶⁴Cu-Labeled Hepatocyte Growth Factor.

    Science.gov (United States)

    Luo, Haiming; Hong, Hao; Slater, Michael R; Graves, Stephen A; Shi, Sixiang; Yang, Yunan; Nickles, Robert J; Fan, Frank; Cai, Weibo

    2015-05-01

    The hepatocyte growth factor (HGF) and its receptor, c-Met, are actively involved in tumor progression and metastasis and are closely associated with a poor prognostic outcome for cancer patients. Thus, the development of PET agents that can assess c-Met expression would be extremely useful for diagnosing cancer and subsequently monitoring response to c-Met-targeted therapies. Here, we report the characterization of recombinant human HGF (rh-HGF) as a PET tracer for detection of c-Met expression in vivo. rh-HGF was expressed in human embryonic kidney 293 cells and purified by nickel-nitrilotriacetic acid affinity chromatography. The concentrated rh-HGF was conjugated to 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid and labeled with (64)Cu. c-Met binding evaluation by flow cytometry was performed on both U87MG and MDA-MB-231 cell lines, which have a high level and a low level, respectively, of c-Met. PET imaging and biodistribution studies were performed on nude mice bearing U87MG and MDA-MB-231 xenografted tumors. The rh-HGF expression yield was 150-200 μg of protein per 5 × 10(6) cells after a 48-h transfection, with purity of approximately 85%-90%. Flow cytometry examination confirmed that rh-HGF had a strong and specific capacity to bind to c-Met. After (64)Cu labeling, PET imaging revealed specific and prominent uptake of (64)Cu-NOTA-rh-HGF in c-Met-positive U87MG tumors (percentage injected dose per gram, 6.8 ± 1.8 at 9 h after injection) and significantly lower uptake in c-Met-negative MDA-MB-231 tumors (percentage injected dose per gram, 1.8 ± 0.6 at 9 h after injection). The fact that sonication-denatured rh-HGF had significantly lower uptake in U87MG tumors, along with histology analysis, confirmed the c-Met specificity of (64)Cu-NOTA-rh-HGF. This study provided initial evidence that (64)Cu-NOTA-rh-HGF visualizes c-Met expression in vivo, an application that may prove useful for c-Met-targeted cancer therapy. © 2015 by the

  1. The Antitumor Effect of C-terminus of Hsp70-Interacting Protein via Degradation of c-Met in Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Sung Ho Cho

    2017-06-01

    Full Text Available Background: The mesenchymal-epithelial transition factor (MET receptor can be overexpressed in solid tumors, including small cell lung cancer (SCLC. However, the molecular mechanism regulating MET stability and turnover in SCLC remains undefined. One potential mechanism of MET regulation involves the C-terminus of Hsp70-interacting protein (CHIP, which targets heat shock protein 90-interacting proteins for ubiquitination and proteasomal degradation. In the present study, we investigated the functional effects of CHIP expression on MET regulation and the control of SCLC cell apoptosis and invasion. Methods: To evaluate the expression of CHIP and c-Met, which is a protein that in humans is encoded by the MET gene (the MET proto-oncogene, we examined the expression pattern of c-Met and CHIP in SCLC cell lines by western blotting. To investigate whether CHIP overexpression reduced cell proliferation and invasive activity in SCLC cell lines, we transfected cells with CHIP and performed a cell viability assay and cellular apoptosis assays. Results: We found an inverse relationship between the expression of CHIP and MET in SCLC cell lines (n=5. CHIP destabilized the endogenous MET receptor in SCLC cell lines, indicating an essential role for CHIP in the regulation of MET degradation. In addition, CHIP inhibited MET-dependent pathways, and invasion, cell growth, and apoptosis were reduced by CHIP overexpression in SCLC cell lines. Conclusion: C HIP is c apable of regulating SCLC cell apoptosis and invasion by inhibiting MET-mediated cytoskeletal and cell survival pathways in NCI-H69 cells. CHIP suppresses MET-dependent signaling, and regulates MET-mediated SCLC motility.

  2. Gain of chromosome 7 by chromogenic in situ hybridization (CISH) in chordomas is correlated to c-MET expression.

    Science.gov (United States)

    Walter, Beatriz A; Begnami, Maria; Valera, Vladimir A; Santi, Mariarita; Rushing, Elisabeth J; Quezado, Martha

    2011-01-01

    Chordomas are low to intermediate grade malignancies that arise from remnants of embryonic notochord. They often recur after surgery and are highly resistant to conventional adjuvant therapies. Recently, the development of effective targeted molecular therapy has been investigated in chordomas that show receptors for tyrosine kinase (RTKs) activation. Expression of specific RTKs such as Epidermal Growth Factor Receptor (EGFR) and Mesenchymal-epithelial transition factor (c-MET) in chordomas may offer valuable therapeutic options. We investigated changes in copy number of chromosome 7 and correlated it with EGFR gene status and EGFR and c-MET protein expression in 22 chordoma samples. Chromosome 7 copy number was evaluated by chromogenic in situ hybridization (CISH) and protein expression of EGFR and c-MET by immunohistochemistry. Tumors mostly showed conventional histopathologic features and were found mainly in sacral (41%) and cranial sites (54.5%). Aneusomy of chromosome 7 was seen in 73% of the samples, 62% of primary tumors and in all recurrent chordomas. EGFR and c-MET were both expressed, but only c-MET protein expression was significantly correlated with chromosome 7 aneusomy (P ≤ 0.001). c-MET overexpression may represent an early chromosome 7 alteration that could play an important role during chordoma pathogenesis. c-MET overexpression shows promise as a molecular marker of response to targeted molecular therapy in the treatment of chordomas.

  3. Release of biologically active kinin peptides, Met-Lys-bradykinin and Leu-Met-Lys-bradykinin from human kininogens by two major secreted aspartic proteases of Candida parapsilosis.

    Science.gov (United States)

    Bras, Grazyna; Bochenska, Oliwia; Rapala-Kozik, Maria; Guevara-Lora, Ibeth; Faussner, Alexander; Kamysz, Wojciech; Kozik, Andrzej

    2013-10-01

    In terms of infection incidence, the yeast Candida parapsilosis is the second after Candida albicans as causative agent of candidiases in humans. The major virulence factors of C. parapsilosis are secreted aspartic proteases (SAPPs) which help the pathogen to disseminate, acquire nutrients and dysregulate the mechanisms of innate immunity of the host. In the current work we characterized the action of two major extracellular proteases of C. parapsilosis, SAPP1 and SAPP2, on human kininogens, proteinaceous precursors of vasoactive and proinflammatory bradykinin-related peptides, collectively called the kinins. The kininogens, preferably the form with lower molecular mass, were effectively cleaved by SAPPs, with the release of two uncommon kinins, Met-Lys-bradykinin and Leu-Met-Lys-bradykinin. While optimal at acidic pH (4-5), the kinin release yield was only 2-3-fold lower at neutral pH. These peptides were able to interact with cellular kinin receptors of B2 subtype and to stimulate the human endothelial cells HMEC-1 to increased secretion of proinflammatory interleukins (ILs), IL-1β and IL-6. The analysis of the stability of SAPP-generated kinins in plasma suggested that they are biologically equivalent to bradykinin, the best agonist of B2 receptor subtype and can be quickly converted to des-Arg(9)-bradykinin, the agonist of inflammation-inducible B1 receptors. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. MET Standards for Electro-Technical Officers

    Directory of Open Access Journals (Sweden)

    Janusz Mindykowski

    2014-12-01

    Full Text Available The paper deals with one of the most important changes in the STCW 1978 as amended in 2010 Convention, from the point of view of the watchkeeping officers responsible for control, maintenance, diagnostic and repair of electrical and electronic installations on board of ships. Some reasons, why the MET Standards for Electro-Technical had to be developed and implemented are shortly analyzed and described. A legislative way towards and a short description of the minimum standards competence for ETO are presented. Next, new tools supporting ETO’s standards implementation are appointed. Finally, the future works as well as the concluding remarks concerning discussed issue are formulated and commented on.

  5. Tidal analysis of Met rocket wind data

    Science.gov (United States)

    Bedinger, J. F.; Constantinides, E.

    1976-01-01

    A method of analyzing Met Rocket wind data is described. Modern tidal theory and specialized analytical techniques were used to resolve specific tidal modes and prevailing components in observed wind data. A representation of the wind which is continuous in both space and time was formulated. Such a representation allows direct comparison with theory, allows the derivation of other quantities such as temperature and pressure which in turn may be compared with observed values, and allows the formation of a wind model which extends over a broader range of space and time. Significant diurnal tidal modes with wavelengths of 10 and 7 km were present in the data and were resolved by the analytical technique.

  6. Development of antibody-based c-Met inhibitors for targeted cancer therapy

    Directory of Open Access Journals (Sweden)

    Lee D

    2015-02-01

    Full Text Available Dongheon Lee, Eun-Sil Sung, Jin-Hyung Ahn, Sungwon An, Jiwon Huh, Weon-Kyoo You Hanwha Chemical R&D Center, Biologics Business Unit, Daejeon, Republic of Korea Abstract: Signaling pathways mediated by receptor tyrosine kinases (RTKs and their ligands play important roles in the development and progression of human cancers, which makes RTK-mediated signaling pathways promising therapeutic targets in the treatment of cancer. Compared with small-molecule compounds, antibody-based therapeutics can more specifically recognize and bind to ligands and RTKs. Several antibody inhibitors of RTK-mediated signaling pathways, such as human epidermal growth factor receptor 2, vascular endothelial growth factor, epidermal growth factor receptor or vascular endothelial growth factor receptor 2, have been developed and are widely used to treat cancer patients. However, since the therapeutic options are still limited in terms of therapeutic efficacy and types of cancers that can be treated, efforts are being made to identify and evaluate novel RTK-mediated signaling pathways as targets for more efficacious cancer treatment. The hepatocyte growth factor/c-Met signaling pathway has come into the spotlight as a promising target for development of potent cancer therapeutic agents. Multiple antibody-based therapeutics targeting hepatocyte growth factor or c-Met are currently in preclinical or clinical development. This review focuses on the development of inhibitors of the hepatocyte growth factor/c-Met signaling pathway for cancer treatment, including critical issues in clinical development and future perspectives for antibody-based therapeutics. Keywords: hepatocyte growth factor, ligands, receptor tyrosine kinase, signaling pathway, therapeutic agent

  7. Metástasis hipofisaria Hypophyseal metastasis

    Directory of Open Access Journals (Sweden)

    Miguel Ángel Yanes Quesada

    2009-04-01

    Full Text Available mayoría son lesiones silentes descubiertas accidentalmente en las autopsia. La aparición de metástasis sintomáticas es, en cambio, excepcional. DESARROLLO: se describen aquí los hallazgos clínicos y radiológicos de una paciente femenina de 69 años, con un carcinoma indiferenciado del pulmón, diagnosticado hace 2 años y medio, que comenzó con cefalea y trastornos visuales sin hipopituitarismo ni diabetes insípida. Se le realizó resonancia magnética nuclear y se le diagnosticó una lesión hipofisaria, que fue operada por vía tranesfenoidal, y se informó por anatomía patológica una metástasis del carcinoma del pulmón. CONCLUSIONES: la paciente se encuentra en estos momentos recibiendo quimioterapia, radioterapia y anticuerpo monoclonal con evolución favorable.INTRODUCTION: metastatic tumors of hypophyseal gland are infrequent. Most are silent lesions discovered accidentally in necropsy. Appearance of symptomatic metastasis is however, exceptional. DEVELOPMENT: we describe here clinical and radiological findings in a female patient aged 69, presenting with a non-differential carcinoma of lung, diagnosed two years a half ago, starting with headache and visual disorders without hypopituitarism and insipidus diabetes. We made a nuclear magnetic resonance and diagnosis was a hypophyseal lesion operated on by trans-esphenoidal route, and Pathological Anatomy Service reports a metastasis of lung carcinoma. CONCLUSIONS: patient receives chemotherapy, radiotherapy, and monoclonal antibody with a favorable evolution.

  8. The Hepatocyte Growth Factor (HGF)/Met Axis: A Neglected Target in the Treatment of Chronic Myeloproliferative Neoplasms?

    Energy Technology Data Exchange (ETDEWEB)

    Boissinot, Marjorie [Translational Neuro-Oncology Group, Leeds Institute of Cancer and Pathology, University of Leeds, Level 5 Wellcome Trust Brenner Building, St James’s Hospital, Leeds LS9 7TF (United Kingdom); Vilaine, Mathias [Institute of Research on Cancer and Aging (IRCAN), CNRS-Inserm-UNS UMR 7284, U 1081, Centre A. Lacassagne, 33 Avenue Valombrose, Nice 06189 (France); Hermouet, Sylvie, E-mail: sylvie.hermouet@univ-nantes.fr [Centre Hospitalier Universitaire (CHU), Place Alexis Ricordeau, Nantes 44093 (France); Inserm UMR892, Centre de Recherche en Cancérologie Nantes-Angers, Institut de Recherche en Santé, Université de Nantes, 8 quai Moncousu, Nantes cedex 44007 (France)

    2014-08-12

    Met is the receptor of hepatocyte growth factor (HGF), a cytoprotective cytokine. Disturbing the equilibrium between Met and its ligand may lead to inappropriate cell survival, accumulation of genetic abnormalities and eventually, malignancy. Abnormal activation of the HGF/Met axis is established in solid tumours and in chronic haematological malignancies, including myeloma, acute myeloid leukaemia, chronic myelogenous leukaemia (CML), and myeloproliferative neoplasms (MPNs). The molecular mechanisms potentially responsible for the abnormal activation of HGF/Met pathways are described and discussed. Importantly, inCML and in MPNs, the production of HGF is independent of Bcr-Abl and JAK2V617F, the main molecular markers of these diseases. In vitro studies showed that blocking HGF/Met function with neutralizing antibodies or Met inhibitors significantly impairs the growth of JAK2V617F-mutated cells. With personalised medicine and curative treatment in view, blocking activation of HGF/Met could be a useful addition in the treatment of CML and MPNs for those patients with high HGF/MET expression not controlled by current treatments (Bcr-Abl inhibitors in CML; phlebotomy, hydroxurea, JAK inhibitors in MPNs)

  9. The Hepatocyte Growth Factor (HGF/Met Axis: A Neglected Target in the Treatment of Chronic Myeloproliferative Neoplasms?

    Directory of Open Access Journals (Sweden)

    Marjorie Boissinot

    2014-08-01

    Full Text Available Met is the receptor of hepatocyte growth factor (HGF, a cytoprotective cytokine. Disturbing the equilibrium between Met and its ligand may lead to inappropriate cell survival, accumulation of genetic abnormalities and eventually, malignancy. Abnormal activation of the HGF/Met axis is established in solid tumours and in chronic haematological malignancies, including myeloma, acute myeloid leukaemia, chronic myelogenous leukaemia (CML, and myeloproliferative neoplasms (MPNs. The molecular mechanisms potentially responsible for the abnormal activation of HGF/Met pathways are described and discussed. Importantly, inCML and in MPNs, the production of HGF is independent of Bcr-Abl and JAK2V617F, the main molecular markers of these diseases. In vitro studies showed that blocking HGF/Met function with neutralizing antibodies or Met inhibitors significantly impairs the growth of JAK2V617F-mutated cells. With personalised medicine and curative treatment in view, blocking activation of HGF/Met could be a useful addition in the treatment of CML and MPNs for those patients with high HGF/MET expression not controlled by current treatments (Bcr-Abl inhibitors in CML; phlebotomy, hydroxurea, JAK inhibitors in MPNs.

  10. Whole exome sequencing identifies a germline MET mutation in two siblings with hereditary wild-type RET medullary thyroid cancer.

    Science.gov (United States)

    Sponziello, Marialuisa; Benvenuti, Silvia; Gentile, Alessandra; Pecce, Valeria; Rosignolo, Francesca; Virzì, Anna Rita; Milan, Melissa; Comoglio, Paolo M; Londin, Eric; Fortina, Paolo; Barnabei, Agnese; Appetecchia, Marialuisa; Marandino, Ferdinando; Russo, Diego; Filetti, Sebastiano; Durante, Cosimo; Verrienti, Antonella

    2018-03-01

    Whole exome sequencing (WES) was used to investigate two Italian siblings with wild-type RET genotype, who developed medullary thyroid cancers (MTCs) and, later, primary prostate and breast cancers, respectively. The proband's MTC harbored a p.Met918Thr RET mutation; his sister's MTC was RET/RAS wild-type. Both siblings had a germline mutation (p.Arg417Gln) in the extracellular Sema domain of the proto-oncogene MET. Experiments involving ectopic expression of MET p.Arg417Gln in MET-negative T47D breast cancer cells documented the mutant receptor's functionality and its ability to enhance cell migration and invasion. Our findings highlight a possible link between MET germline mutations and MTCs and suggest that MET p. Arg417Gln may promote an invasive malignant phenotype. The possibility that MTC can be driven/co-driven by a MET mutation has potential management implications, since the tyrosine-kinase inhibitor cabozantinib-approved for treating advanced MTCs-is a specific MET inhibitor. © 2017 Wiley Periodicals, Inc.

  11. Resultaten boomkorsurvey 2013: BTS met onderzoeksvaartuigen Isis en Tridens (interview met Ingeborg de Boois)

    NARCIS (Netherlands)

    Boois, de I.J.

    2013-01-01

    Van begin augustus tot half september heeft IMARES de boomkorsurvey (BTS) uitgevoerd met de onderzoeksschepen Isis en Tridens. Op 29 maart 2014 wordt een bijeenkomst georganiseerd voor geinteresseerden, waar de resultaten van zowel de BTS als de bedrijfssurvey gepresenteerd worden. De BTS wordt

  12. Ziek en Zeer : Geelziek in Eucomis overdraagbaar met zaad

    NARCIS (Netherlands)

    Vink, P.

    2011-01-01

    In dit artikel een verslag van het onderzoek naar de risico's van overdracht van de geelziekbacterie Xanthomonas hyacinthi met Eucomiszaad. Uit het onderzoek is gebleken dat deze bacterie met het zaad kan overgaan naar een volgende teelt.

  13. MetNet Network Mission for Martian Atmospheric Investigations

    Science.gov (United States)

    Harri, A.-M.; Alexashkin, S.; Arrugeo, I.; Schmidt, W.; Vazquez, L.; Genzer, M.; Haukka, H.

    2014-07-01

    A new kind of planetary exploration mission for Mars called MetNet is being developed for martian atmospheric investigations. The eventual scope of the MetNet Mission is to deploy tens of small landers on the martian surface.

  14. Klimaatverandering en de stadsboom (interview met Jitze Kopinga)

    NARCIS (Netherlands)

    Bennink, P.; Kopinga, J.

    2010-01-01

    Bomen in de stad staan vaak op warme plaatsen met een gebrekkige waterhuishouding. Volgens het KNMI zal Nederland in de toekomst steeds vaker met hitte en droogte te maken hebben. Wat betekent dat voor onze stadsbomen?

  15. Effect of MET on formation and vigor of wheat roots

    International Nuclear Information System (INIS)

    Wang Bingkui; Jin Ziyu; Zhao Miaozhen; Zhao Yanshen

    1993-01-01

    Effect of MET on the formation and vigor of roots of wheat seedlings were studied. The results showed that 50 ∼ 200 ppm MET inhibited vertical elongation of roots, increased root, shoot ratio and enhanced the formation and vigor of roots. But MET had no effect on the dry weight of roots. The activity of peroxidase was decreased and the proportion of assimilates in roots was increased by MET treatment compared with the control

  16. Insulin receptors

    International Nuclear Information System (INIS)

    Kahn, C.R.; Harrison, L.C.

    1988-01-01

    This book contains the proceedings on insulin receptors. Part A: Methods for the study of structure and function. Topics covered include: Method for purification and labeling of insulin receptors, the insulin receptor kinase, and insulin receptors on special tissues

  17. Activation of c-MET induces a stem-like phenotype in human prostate cancer.

    Directory of Open Access Journals (Sweden)

    Geert J L H van Leenders

    Full Text Available Prostate cancer consists of secretory cells and a population of immature cells. The function of immature cells and their mutual relation with secretory cells are still poorly understood. Immature cells either have a hierarchical relation to secretory cells (stem cell model or represent an inducible population emerging upon appropriate stimulation of differentiated cells. Hepatocyte Growth Factor (HGF receptor c-MET is specifically expressed in immature prostate cells. Our objective is to determine the role of immature cells in prostate cancer by analysis of the HGF/c-MET pathway.Gene-expression profiling of DU145 prostate cancer cells stimulated with HGF revealed induction of a molecular signature associated with stem cells, characterized by up-regulation of CD49b, CD49f, CD44 and SOX9, and down-regulation of CD24 ('stem-like signature'. We confirmed the acquisition of a stem-like phenotype by quantitative PCR, FACS analysis and Western blotting. Further, HGF led to activation of the stem cell related Notch pathway by up-regulation of its ligands Jagged-1 and Delta-like 4. Small molecules SU11274 and PHA665752 targeting c-MET activity were both able to block the molecular and biologic effects of HGF. Knock-down of c-MET by shRNA infection resulted in significant reduction and delay of orthotopic tumour-formation in male NMRI mice. Immunohistochemical analysis in prostatectomies revealed significant enrichment of c-MET positive cells at the invasive front, and demonstrated co-expression of c-MET with stem-like markers CD49b and CD49f.In conclusion, activation of c-MET in prostate cancer cells induced a stem-like phenotype, indicating a dynamic relation between differentiated and stem-like cells in this malignancy. Its mediation of efficient tumour-formation in vivo and predominant receptor expression at the invasive front implicate that c-MET regulates tumour infiltration in surrounding tissues putatively by acquisition of a stem-like phenotype.

  18. The functional Thr130Ile and Val255Met polymorphisms of the hepatocyte nuclear factor-4alpha (HNF4A)

    DEFF Research Database (Denmark)

    Ek, Jakob; Rose, Christian Schack; Jensen, Dorit Packert

    2005-01-01

    HNF4A encodes an orphan nuclear receptor that plays crucial roles in regulating hepatic gluconeogenesis and insulin secretion. The aim of the present study was to examine two rare missense polymorphisms of HNF4A, Thr130Ile and Val255Met, for altered function and for association with type 2 diabetes...

  19. Groen proceswater: zuivering brouwerijprocesafvalwater met microalgen : Resultaten onderzoek 2013

    NARCIS (Netherlands)

    Dijk, van W.; Diem, van A.; Doornbusch, P.; Grobben-Gaastra, S.A.; Kleinhout, G.; Kroon, A.; Weide, van der R.Y.

    2014-01-01

    Afgelopen jaar is de pilot met het kweken van algen met afvalwater van de brouwerijlocatie Zoeterwoude geslaagd. Dit is gedaan in een samenwerkingsverband van Heineken Nederland BV, Algae Food & Fuel en WUR-Acrres. Dit is de eerste inline pilot in de wereld waarbij met LED verlichting op 1000 L

  20. Innoveren met serious games : Wat is serious gaming?

    NARCIS (Netherlands)

    Werkhoven, P.J.

    2008-01-01

    Het begrip serious gaming is inmiddels gekaapt door vele aanbieders van wat vroeger simulatie en virtual reality technologie genoemd werd. Met die technologie kunnen we mensen laten rondlopen in virtuele gebouwen en landschappen, al dan niet met grote projectieschermen of met brillen op. Maar dat is

  1. Bepaling van cadmium in levers en nieren van humane herkomst met behulp van atomaire-absorptiespectrofotometrie met vlamatomisatie

    NARCIS (Netherlands)

    Wubs KL; Mulder W; de Groot G

    1988-01-01

    In dit rapport wordt een methode beschreven voor de bepaling van cadmium in levers en nieren van humane herkomst met behulp van atomaire absorptiespectrofotometrie en vlamatomisatie. De weefselmonsters worden ontleed met een enzymatische methode onder fysiologische condities, gevolgd door

  2. Phase I Trial of Anti-MET Monoclonal Antibody in MET-Overexpressed Refractory Cancer.

    Science.gov (United States)

    Lee, Jeeyun; Kim, Seung Tae; Park, Sungju; Lee, Sujin; Park, Se Hoon; Park, Joon Oh; Lim, Ho Yeong; Ahn, Hongmo; Bok, Haesook; Kim, Kyoung-Mee; Ahn, Myung Ju; Kang, Won Ki; Park, Young Suk

    2018-01-31

    Samsung Advance Institute of Technology-301 (SAIT301) is a human immunoglobulin G2 antibody that can specifically target mesenchymal epithelial transition factor (c-MET). This novel antibody has higher priority over hepatocyte growth factors when binding to the Sema domain of c-MET and accelerates the internalization and degradation of c-MET, proving its powerful antitumor activities in intra- as well as extracellular areas. SAIT301 was administered intravenously once every 3 weeks in c-MET overexpressed solid tumor patients, focusing on metastatic colorectal cancer (CRC) according to common clinical phase I criteria. Dose escalation was performed according to a modified Fibonacci design, following the conventional 3+3 design. The purpose of this phase I study was to assess the safety profile, to establish the recommended dose for clinical phase II studies and to assess potential anticancer activity of the compound. Sixteen patients with a median age of 56 (range, 39-69) years were enrolled in the study. The most common adverse events were decreased appetite (50.0%), hypophosphatemia, fatigue and dizziness (25.0%, respectively), and diarrhea, blood alkaline phosphatase increased and dyspnea (18.8%, respectively). For tumor response, no patients achieved complete response. One (9.1%) CRC patient had a partial response in the 1.23 mg/kg group, 4 (36.4%) patients achieved stable disease (2 in the 0.41 mg/kg group, 2 in the 1.23 mg/kg group, 0 in the 3.69 mg/kg group, and 1 in the 8.61 mg/kg group). Because of the increase in dose-limiting toxicities (DLTs) at 8.61 mg/kg, the 3.69 mg/kg dose was considered the maximum tolerated dose and selected for further assessment in phase II. We successfully completed a phase I trial with MET antibody in a MET-overexpressed patient population focusing on CRC, and found that the DLTs were alkaline phosphatase elevation or hypophosphatemia. The recommended dose of SAIT301 for phase II is the dose of 3.69 mg/kg. Copyright © 2018

  3. 3D RoboMET Characterization

    Energy Technology Data Exchange (ETDEWEB)

    Madison, Jonathan D. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Susan, Donald F. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Kilgo, Alice C. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2015-10-01

    The goal of this project is to generate 3D microstructural data by destructive and non-destructive means and provide accompanying characterization and quantitative analysis of such data. This work is a continuing part of a larger effort to relate material performance variability to microstructural variability. That larger effort is called “Predicting Performance Margins” or PPM. In conjunction with that overarching initiative, the RoboMET.3D™ is a specific asset of Center 1800 and is an automated serialsectioning system for destructive analysis of microstructure, which is called upon to provide direct customer support to 1800 and non-1800 customers. To that end, data collection, 3d reconstruction and analysis of typical and atypical microstructures have been pursued for the purposes of qualitative and quantitative characterization with a goal toward linking microstructural defects and/or microstructural features with mechanical response. Material systems examined in FY15 include precipitation hardened 17-4 steel, laser-welds of 304L stainless steel, thermal spray coatings of 304L and geological samples of sandstone.

  4. Responses to the multitargeted MET/ALK/ROS1 inhibitor crizotinib and co-occurring mutations in lung adenocarcinomas with MET amplification or MET exon 14 skipping mutation.

    Science.gov (United States)

    Jorge, Susan E; Schulman, Sol; Freed, Jason A; VanderLaan, Paul A; Rangachari, Deepa; Kobayashi, Susumu S; Huberman, Mark S; Costa, Daniel B

    2015-12-01

    Genomic aberrations involving ALK, ROS1 and MET can be driver oncogenes in lung adenocarcinomas. Identification of tyrosine kinase inhibitors (TKIs) with activity against these tumors and of preclinical systems to model response are warranted. We analyzed cases with lung adenocarcinomas for representative genomic aberrations, evaluated the response to the multitargeted MET/ALK/ROS1 crizotinib TKI in cases with MET aberrations and profiled lung cancer cell lines with the aforementioned genomic changes. Lung cancer cell lines with ALK rearrangement, ROS1 rearrangement or MET amplification had expected in vitro responses to crizotinib and the ALK/ROS1 TKI ceritinib. However, a commercially-available cell line with MET exon 14 skipping mutation and co-occurring PIK3CA-p.Glu545Lys mutation did not respond to crizotinib; suggesting the latter abrogated response. 10% of MET exon 14 skipping mutation co-occurred with PIK3CA mutation in the TCGA cohort. Putative crizotinib-responsive somatic mutations (ALK rearrangements, ROS1 rearrangements, high level MET amplification or MET exon 14 skipping mutations) were present in 10% of lung adenocarcinomas analyzed at our service and in 9.5% of the TCGA lung adenocarcinoma database. One patient each whose advanced tumors harbored high level MET amplification with wild-type PIK3CA or MET exon 14 skipping mutation with PIK3CA-p.Glu542Lys had significant responses to crizotinib; suggesting that PIK3CA co-mutation did not affect clinical response. Approximately 10% of lung adenocarcinomas harbor aberrations that are targetable using the approved multitargeted TKI crizotinib. MET exon 14 skipping mutation predicts for response to MET TKIs in human lung adenocarcinomas but co-occurrence of PIK3CA mutation needs to be better evaluated as a modifier of response to TKI therapy. MET TKIs should not be omitted from MET exon 14 skipping mutated tumors until further preclinical and clinical data can confirm or refute mechanisms of primary or

  5. An under-met and over-met expectations model of employee reactions to merit raises.

    Science.gov (United States)

    Schaubroeck, John; Shaw, Jason D; Duffy, Michelle K; Mitra, Atul

    2008-03-01

    The authors developed a model of how raise expectations influence the relationship between merit pay raises and employee reactions and tested it using a sample of hospital employees. Pay-for-performance (PFP) perceptions were consistently related to personal reactions (e.g., pay raise happiness, pay-level satisfaction, and turnover intentions). Merit pay raises were strongly related to reactions only among employees with high raise expectations and high PFP perceptions. The interactive effects of under-met/over-met expectations and PFP perceptions were mediated by the extent to which participants saw the raise as generous and they were happy with the raises they received. The authors discuss the implications of these findings for expectation-fulfillment theories, merit pay research, and the administration of incentives. Copyright 2008 APA

  6. EVIDENCE OF CELL-NONAUTONOMOUS CHANGES IN DENDRITE AND DENDRITIC SPINE MORPHOLOGY IN THE MET-SIGNALING DEFICIENT MOUSE FOREBRAIN

    Science.gov (United States)

    Judson, Matthew C.; Eagleson, Kathie L.; Wang, Lily; Levitt, Pat

    2010-01-01

    Human genetic findings and murine neuroanatomical expression mapping have intersected to implicate Met receptor tyrosine kinase signaling in the development of forebrain circuits controlling social and emotional behaviors that are atypical in autism spectrum disorders (ASD). To clarify roles for Met signaling during forebrain circuit development in vivo, we generated mutant mice (Emx1Cre/Metfx/fx) with an Emx1-Cre-driven deletion of signaling-competent Met in dorsal pallially-derived forebrain neurons. Morphometric analyses of Lucifer Yellow-injected pyramidal neurons in postnatal day 40 anterior cingulate cortex (ACC) revealed no statistically significant changes in total dendritic length, but a selective reduction in apical arbor length distal to the soma in Emx1Cre/Metfx/fx neurons relative to wild type, consistent with a decrease in the total tissue volume sampled by individual arbors in the cortex. The effects on dendritic structure appear to be circuit-selective, as basal arbor length was increased in Emx1Cre/Metfx/fx layer 2/3 neurons. Spine number was not altered on Emx1Cre/Metfx/fx pyramidal cell populations studied, but spine head volume was significantly increased (~20%). Cell-nonautonomous, circuit-level influences of Met signaling on dendritic development were confirmed by studies of medium spiny neurons (MSN), which do not express Met, but receive Met-expressing corticostriatal afferents during development. Emx1Cre/Metfx/fx MSN exhibited robust increases in total arbor length (~20%). Like in the neocortex, average spine head volume was also increased (~12%). These data demonstrate that a developmental loss of presynaptic Met receptor signaling can affect postsynaptic morphogenesis and suggest a mechanism whereby attenuated Met signaling could disrupt both local and long-range connectivity within circuits relevant to ASD. PMID:20853516

  7. Progress in switching technology for METS systems

    International Nuclear Information System (INIS)

    Honig, E.M.; Swannack, C.E.; Warren, R.W.; Whitaker, D.H.

    1977-01-01

    Three distinct sets of switching requirements have emerged from design optimization studies of large superconducting magnetic energy storage systems, such as the METS system to power the adiabatic plasma compression field in the proposed theta-pinch SFTR. Extremely low joule loss cryogenic disconnects are required between storage coils in the liquid helium environment to allow charging the coils in series over a prolonged time, then to isolate the coils for parallel fast discharging into the load. Another switch must break the current in the series charging loop and absorb the energy from the stray inductance. This action will allow the subsequent opening of the cryogenic disconnects under near zero current condition. The current now has been transferred to the many paralleled circuits, each containing a high current, high voltage interrupter. The opening and arc commutation of the interrupter starts the energy transfer into the load. The primary activities associated with cryogenic disconnect have been testing and development of contact materials, configurations, and closing forces for carrying 26 kA with a resistance less than 40 nΩ, and development of an actuating system that is both reliable and fast acting in a liquid helium environment. The charging loop switch will include a continuous duty switch and a vacuum interrupter. The continuous duty switch resistance can be an order of magnitude larger than that of the cryogenic disconnect because it does not present a refrigeration load. The HVDC interrupter must break 26 kA and withstand 60 kV during the energy transfer time of 700 μs. Testing in progress already has shown successful interruption using single vacuum interrupters up to 31 kA and 66 kV

  8. Measurements of HONO during BAQS-Met

    Directory of Open Access Journals (Sweden)

    J. J. B. Wentzell

    2010-12-01

    Full Text Available Measurements of nitrous acid (HONO were performed as part of the 2007 Border Air Quality and Meteorology Study (BAQS-Met at the Harrow, Ontario, Canada supersite between 20 June and 10 July 2007. Nitrous acid is an important precursor of the hydroxyl radical and understanding its chemistry is important to understanding daytime oxidation chemistry. The HONO measurements were made using a custom built Long Path Absorption Photometer (LOPAP. The goal of this work was to shed light on sources of daytime HONO in the border region. During the course of the campaign HONO mixing ratios consistently exceeded expected daytime values by more than a factor of 6. Mean daytime mixing ratios of 61 pptv were observed. While HONO decay began at sunrise, minimum HONO values were measured during the late afternoon. There was little difference between the daytime (mean = 1.5% and night-time (mean = 1.7% ratios of HONO/NO2, thus there was a very strong daytime source of HONO which is consistent with other recent studies. Correlations of daytime HONO production with a variety of chemical and meteorological parameters indicate that production is dependent on UV radiation, NO2 and water vapour but is not consistent with a simple gas phase process. Apparent rate constants for the production of HONO from photolyticaly excited NO2 and water vapour vary from 2.8–7.8×10−13 cm3 molec−1 s−1, during the campaign. These results appear to be consistent with the heterogeneous conversion of NO2 enhanced by photo-excitation.

  9. MiR-181a-5p is downregulated in hepatocellular carcinoma and suppresses motility, invasion and branching-morphogenesis by directly targeting c-Met.

    Science.gov (United States)

    Korhan, Peyda; Erdal, Esra; Atabey, Neşe

    2014-08-08

    c-Met receptor tyrosine kinase has been regarded as a promising therapeutic target for hepatocellular carcinoma (HCC). Recently, microRNAs (miRNAs) have been shown as a novel mechanism to control c-Met expression in cancer. In this study, we investigate the potential contribution of miR-181a-5p dysregulation to the biology of c-Met overexpression in HCC. Herein, we found an inverse expression pattern between miR-181a-5p and c-Met expression in normal, cirrhotic and HCC liver tissues. Luciferase assay confirmed that miR-181a-5p binding to the 3'-UTR of c-Met downregulated the expression of c-Met in HCC cells. Overexpression of miR-181a-5p suppressed both HGF-independent and -dependent activation of c-Met and consequently diminished branching-morphogenesis and invasion. Combined treatment with miR-181a-5p and c-Met inhibitor led to a further inhibition of c-Met-driven cellular activities. Knockdown of miR-181a-5p promoted HGF-independent/-dependent signaling of c-Met and accelerated migration, invasion and branching-morphogenesis. In conclusion, our results demonstrated for the first time that c-Met is a functional target gene of miR-181a-5p and the loss of miR-181a-5p expression led to the activation of c-Met-mediated oncogenic signaling in hepatocarcinogenesis. These findings display a novel molecular mechanism of c-Met regulation in HCC and strategies to increase miR-181a5p level might be an alternative approach for the enhancement of the inhibitory effects of c-Met inhibitors. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Research progress in c-Met and hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    WANG Changqing

    2015-06-01

    Full Text Available c-Met plays a pivotal role in the development and progression of hepatocellular carcinoma (HCC, which can lead to proliferation, survival, cytoskeleton reorganization, separation and diffusion, and angiogenesis of tumor cells. Moreover, c-Met is an important prognostic factor for HCC. In HCC, c-Met acts as an activator of a series of signaling pathways, including PI3K/AKT/mTOR, ERK/MAPK, and Rac-Pak. In recent years, it has been reported that small-molecule kinase inhibitors can abolish phosphorylation at the intracellular carboxyl terminal of c-Met, and then inhibit the recruitment of signal convertors and downstream signaling pathways, which finally achieve anti-tumor activities. Based on the carcinogenic activity of c-Met in HCC, this paper points out that selective inhibitors of c-Met hold promise for targeted therapies for HCC.

  11. Effective implementation of novel MET pharmacodynamic assays in translational studies.

    Science.gov (United States)

    Srivastava, Apurva K; Navas, Tony; Herrick, William G; Hollingshead, Melinda G; Bottaro, Donald P; Doroshow, James H; Parchment, Ralph E

    2017-01-01

    MET tyrosine kinase (TK) dysregulation is significantly implicated in many types of cancer. Despite over 20 years of drug development to target MET in cancers, a pure anti-MET therapeutic has not yet received market approval. The failure of two recently concluded phase III trials point to a major weakness in biomarker strategies to identify patients who will benefit most from MET therapies. The capability to interrogate oncogenic mutations in MET via circulating tumor DNA (ctDNA) provides an important advancement in identification and stratification of patients for MET therapy. However, a wide range in type and frequency of these mutations suggest there is a need to carefully link these mutations to MET dysregulation, at least in proof-of-concept studies. In this review, we elaborate how we can utilize recently developed and validated pharmacodynamic biomarkers of MET not only to show target engagement, but more importantly to quantitatively measure MET dysregulation in tumor tissues. The MET assay endpoints provide evidence of both canonical and non-canonical MET signaling, can be used as "effect markers" to define biologically effective doses (BEDs) for molecularly targeted drugs, confirm mechanism-of-action in testing combination of drugs, and establish whether a diagnostic test is reporting MET dysregulation. We have established standard operating procedures for tumor biopsy collections to control pre-analytical variables that have produced valid results in proof-of-concept studies. The reagents and procedures are made available to the research community for potential implementation on multiple platforms such as ELISA, quantitative immunofluorescence assay (qIFA), and immuno-MRM assays.

  12. De kracht van sport: Sporten voor kinderen met gedragsproblemen

    OpenAIRE

    Pruim, Arjan; Mombarg, Remo

    2016-01-01

    In deze presentatie staat centraal hoe het bewegingsonderwijs kan worden aangepast op kinderen met een beperking. We weten dat kinderen met een beperking duidelijk minder vaak sporten en/of lid zijn van een vereniging. Desondanks heeft sport ook voor deze kinderen een betekenis. Zo kan sport een middel zijn om hyperactiviteit, emotionele problemen en externaliserende gedragsproblemen te verminderen. Een voorbeeld van een nationaal sportstimuleringsproject gericht op kinderen met een beperking...

  13. Loss of c-Met signaling sensitizes hepatocytes to lipotoxicity and induces cholestatic liver damage by aggravating oxidative stress

    International Nuclear Information System (INIS)

    Gomez-Quiroz, Luis E.; Seo, Daekwan; Lee, Yun-Han; Kitade, Mitsuteru; Gaiser, Timo; Gillen, Matthew; Lee, Seung-Bum; Gutierrez-Ruiz, Ma Concepcion; Conner, Elizabeth A.; Factor, Valentina M; Thorgeirsson, Snorri S.; Marquardt, Jens U.

    2016-01-01

    Recent studies confirmed a critical importance of c-Met signaling for liver regeneration by modulating redox balance. Here we used liver-specific conditional knockout mice (MetKO) and a nutritional model of hepatic steatosis to address the role of c-Met in cholesterol-mediated liver toxicity. Liver injury was assessed by histopathology and plasma enzymes levels. Global transcriptomic changes were examined by gene expression microarray, and key molecules involved in liver damage and lipid homeostasis were evaluated by Western blotting. Loss of c-Met signaling amplified the extent of liver injury in MetKO mice fed with high-cholesterol diet for 30 days as evidenced by upregulation of liver enzymes and increased synthesis of total bile acids, aggravated inflammatory response and enhanced intrahepatic lipid deposition. Global transcriptomic changes confirmed the enrichment of networks involved in steatosis and cholestasis. In addition, signaling pathways related to glutathione and lipid metabolism, oxidative stress and mitochondria dysfunction were significantly affected by the loss of c-Met function. Mechanistically, exacerbation of oxidative stress in MetKO livers was corroborated by increased lipid and protein oxidation. Western blot analysis further revealed suppression of Erk, NF-kB and Nrf2 survival pathways and downstream target genes (e.g. cyclin D1, SOD1, gamma-GCS), as well as up-regulation of proapoptotic signaling (e.g. p53, caspase 3). Consistent with the observed steatotic and cholestatic phenotype, nuclear receptors RAR, RXR showed increased activation while expression levels of CAR, FXR and PPAR-alpha were decreased in MetKO. Collectively, our data provide evidence for the critical involvement of c-Met signaling in cholesterol and bile acids toxicity.

  14. Mars MetNet Mission Pressure and Humidity Devices

    Science.gov (United States)

    Haukka, H.; Harri, A.-M.; Schmidt, W.; Genzer, M.; Polkko, J.; Kemppinen, O.; Leinonen, J.

    2012-09-01

    A new kind of planetary exploration mission for Mars is being developed in collaboration between the Finnish Meteorological Institute (FMI), Lavochkin Association (LA), Space Research Institute (IKI) and Institutio Nacional de Tecnica Aerospacial (INTA). The Mars MetNet mission [1] is based on a new semi-hard landing vehicle called MetNet Lander (MNL). MetBaro and MetHumi are part of the scientific payload of the MNL. Main scientific goal of both devices is to measure the meteorological phenomena (pressure and humidity) of the Martian atmosphere and complement the previous Mars mission atmospheric measurements (Viking and Phoenix) for better understanding of the Martian atmospheric conditions.

  15. Pleiotropic activities of HGF/c-Met system in testicular physiology: paracrine and endocrine implications

    Directory of Open Access Journals (Sweden)

    Giulia eRicci

    2014-04-01

    Full Text Available In the last decades a growing body of evidences has been reported concerning the expression and functional role of Hepathocyte Growth Factor (HGF on different aspects of testicular physiology. This review has the aim to summarize what is currently known regarding this topic. From early embryonic development to adult age, HGF and its receptor c-Met appeared to be clearly detectable in the testis. These molecules acquire different distribution patterns and roles depending on the developmental stage or the post-natal age considered. HGF acts as a paracrine modulator of testicular functions promoting the ephitelium-mesenchyme cross-talk as described even in other organs. Interestingly, it has been reported that testicular HGF acts even as an autocrine factor and that its receptor might be modulated by endocrine signals that change at puberty: HGF receptor expressed by Sertoli cells, in fact, is up-regulated by FSH administration. HGF is in turn able to modify endocrine state of the organism being able to increase testosterone secretion of both fetal and adult Leydig cells. Moreover c-Met is expressed in mitotic and meiotic male germ cells as well as in spermatozoa. The distribution pattern of c-Met on sperm cell membrane changes in the caput and cauda epididymal sperms and HGF is able to maintain epididymal sperm motility in vitro suggesting a physiological role of this growth factor in the acquisition of sperm motility. Noteworthy changes in HGF concentration in seminal plasma have been reported in different andrological diseases. All together these data indicate that HGF has a role in the control of spermatogenesis and sperm quality either directly, acting on male germ cells, or indirectly acting on tubular and interstitial somatic cells of the testis.

  16. Effects of the BDNF Val66Met polymorphism and met allele load on declarative memory related neural networks

    DEFF Research Database (Denmark)

    Dodds, Chris M; Henson, Richard N; Suckling, John

    2013-01-01

    It has been suggested that the BDNF Val66Met polymorphism modulates episodic memory performance via effects on hippocampal neural circuitry. However, fMRI studies have yielded inconsistent results in this respect. Moreover, very few studies have examined the effect of met allele load on activation...... of memory circuitry. In the present study, we carried out a comprehensive analysis of the effects of the BDNF polymorphism on brain responses during episodic memory encoding and retrieval, including an investigation of the effect of met allele load on memory related activation in the medial temporal lobe....... In contrast to previous studies, we found no evidence for an effect of BDNF genotype or met load during episodic memory encoding. Met allele carriers showed increased activation during successful retrieval in right hippocampus but this was contrast-specific and unaffected by met allele load. These results...

  17. Effects of prenatal ethanol exposure on central dopamine and Met-enkephalin system ontogeny

    Energy Technology Data Exchange (ETDEWEB)

    Hand, D.E.

    1987-01-01

    The effect of utero ethanol exposure on the development of central neurotransmitter systems was examined in rat offspring of dams that consumed liquid diets containing 35% ethanol derived calories either before and during pregnancy (E-P and P), or exclusively during gestation (E-Preg). Autoradiography of tritiated ligand receptor binding was used to rapidly screen neurotransmitter receptors in cholinergic, dopaminergic, serotonergic, noradrenergic, GABAergic, and opiatergic systems. The results led to a more comprehensive study of (1) the dopaminergic D-2 receptor binding using (/sup 3/H)spiroperidol, and (2) the opiatergic mu and delta receptor binding defined by (/sup 3/H)Met-enkephalin. Significant reductions in (/sup 3/H)spiroperidol binding were found in the 15 day old E-Preg caudate-putamen, which may be related to reductions in neurotransmission and increased locomotor activity. This provides a link between the hyperactivity reported in animal models and children with fetal alcohol syndrome (FAS) and its attenuation by drugs that facilitate dopaminergic transmission. Significant reductions were also seen in D-2 receptor binding in the inferior colliculus, which may be related to the functional deficits in the auditory processing of information by hyperactive children and the changes in the auditory evoked potentials of FAS children found at the level of that structure. The hyperactivity and auditory dysfunction improve with age, consistent with the trend in binding of (/sup 3/H)spiroperidol to D-2 receptors. The D-2 receptor binding in the E-P and P group was normal in nearly all brain regions which suggests that ethanol exposure begun during pregnancy may be more harmful than when initiated before pregnancy.

  18. MET Expression in Primary and Metastatic Clear Cell Renal Cell Carcinoma: Implications of Correlative Biomarker Assessment to MET Pathway Inhibitors

    Directory of Open Access Journals (Sweden)

    Brian Shuch

    2015-01-01

    Full Text Available Aims. Inhibitors of the MET pathway hold promise in the treatment for metastatic kidney cancer. Assessment of predictive biomarkers may be necessary for appropriate patient selection. Understanding MET expression in metastases and the correlation to the primary site is important, as distant tissue is not always available. Methods and Results. MET immunofluorescence was performed using automated quantitative analysis and a tissue microarray containing matched nephrectomy and distant metastatic sites from 34 patients with clear cell renal cell carcinoma. Correlations between MET expressions in matched primary and metastatic sites and the extent of heterogeneity were calculated. The mean expression of MET was not significantly different between primary tumors when compared to metastases (P=0.1. MET expression weakly correlated between primary and matched metastatic sites (R=0.5 and a number of cases exhibited very high levels of discordance between these tumors. Heterogeneity within nephrectomy specimens compared to the paired metastatic tissues was not significantly different (P=0.39. Conclusions. We found that MET expression is not significantly different in primary tumors than metastatic sites and only weakly correlates between matched sites. Moderate concordance of MET expression and significant expression heterogeneity may be a barrier to the development of predictive biomarkers using MET targeting agents.

  19. Co-Expression of Plexin-B1 and Met in Human Breast and Ovary Tumours Enhances the Risk of Progression

    Directory of Open Access Journals (Sweden)

    Guido Valente

    2009-01-01

    Full Text Available Background: Plex-B1, the receptor of Sema4D, has been implicated in tumour growth, angiogenesis and metastasis. The binding of Sema4D to Plex-B1 can trigger the activation of Met tyrosine kinase, thereby promoting cell dissociation and invasive growth. We tested the hypothesis that the expression of Plex-B1, either alone or in association with Met, can be of predictive value for tumour progression.

  20. Combined Wnt/β-Catenin, Met, and CXCL12/CXCR4 Signals Characterize Basal Breast Cancer and Predict Disease Outcome

    Directory of Open Access Journals (Sweden)

    Jane D. Holland

    2013-12-01

    Full Text Available Prognosis for patients with estrogen-receptor (ER-negative basal breast cancer is poor, and chemotherapy is currently the best therapeutic option. We have generated a compound-mutant mouse model combining the activation of β-catenin and HGF (Wnt-Met signaling, which produced rapidly growing basal mammary gland tumors. We identified the chemokine system CXCL12/CXCR4 as a crucial driver of Wnt-Met tumors, given that compound-mutant mice also deficient in the CXCR4 gene were tumor resistant. Wnt-Met activation rapidly expanded a population of cancer-propagating cells, in which the two signaling systems control different functions, self-renewal and differentiation. Molecular therapy targeting Wnt, Met, and CXCR4 in mice significantly delayed tumor development. The expression of a Wnt-Met 322 gene signature was found to be predictive of poor survival of human patients with ER-negative breast cancers. Thus, targeting CXCR4 and its upstream activators, Wnt and Met, might provide an efficient strategy for breast cancer treatment.

  1. Massage bij verpleeghuisbewoners met ernstige dementie: een waardevolle interventie.

    NARCIS (Netherlands)

    Inhulsen, M.B.; Verkaik, R.; Busch, M.; Francke, A.

    2016-01-01

    Zorgverleners vinden dat massage een waardevolle bijdrage levert aan de zorg voor verpleeghuisbewoners met ernstige dementie. Met name in het maken van contact en het verminderen van onrust. Dit blijkt uit een pilot uitgevoerd door zorgorganisatie Laurens, het Van Praag Instituut en

  2. Ringonderzoek : bepaling van coccidiostaticagehalte in diervoeders, met behulp van turbidimetrie

    NARCIS (Netherlands)

    Broex, N.J.G.; Huf, F.

    1988-01-01

    Voor de gehalte bepaling van monensin, salinomycine en narasin in diervoeders is de zg. turbidimetrische methode geringtest door 12 laboratoria. Ieder laboratorium heeft 9 monsters ontvangen, resp. 3 voormengsels en 6 diervoeders met monensin, salinomycine of narasin. De monsters zijn onderzocht met

  3. De kracht van sport : Sporten voor kinderen met gedragsproblemen

    NARCIS (Netherlands)

    dr. Remo Mombarg; Arjan Pruim

    2016-01-01

    In deze presentatie staat centraal hoe het bewegingsonderwijs kan worden aangepast op kinderen met een beperking. We weten dat kinderen met een beperking duidelijk minder vaak sporten en/of lid zijn van een vereniging. Desondanks heeft sport ook voor deze kinderen een betekenis. Zo kan sport een

  4. Wat doet sport met kinderen? : 'Inspiratiedag Aangepast Sporten’

    NARCIS (Netherlands)

    dr. Remo Mombarg

    2016-01-01

    Leren sporten is niet voor iedereen vanzelfsprekend. Zo heeft sport voor kinderen met een beperking vaak een andere betekenis dan voor kinderen zonder een beperking en zijn er voor kinderen met een beperking meer drempels om lid te worden van een sportvereniging. Drie belangrijke aspecten; de

  5. Invloed krachtvoerniveau op vleesproduktiekenmerken van Piemontese met zwartbont kruislingstieren

    NARCIS (Netherlands)

    Hanekamp, W.J.A.

    1989-01-01

    Met 3 ronden van elk 36 Piemontese X zwartbonte kruislingstieren is het effect van extra krachtvoer vergeleken met de normaal gangbare gift naast onbeperkt snijmaoskuil. De stieren waren gehuisvest in een natuurlijk geventileerde stal (space-boarding)en op een volledige roostervloer.

  6. Success, but Slowly, as Met School Redefines Learning

    Science.gov (United States)

    Pearson, George

    2012-01-01

    Seven Oaks Met School, the only high school in Canada that is part of the U.S.-based Big Picture Learning network of innovative schools, graduated its first class this spring. Internships with businesses and institutions in the community are a core element of the Met School experience. Students report on their internship experience, as well as on…

  7. Ontwerpen met biobased plastics : unieke eigenschappen en inspirerende toepassingsmogelijkheden

    NARCIS (Netherlands)

    Oskam, Inge; de Jong, Matthijs; Lepelaar, Mark; ten Kate, Rogier

    ‘Ontwerpen met biobased plastics’ is de eindpublicatie van het project “Design Challenges with Biobased Plastics”. In dit onderzoeksproject deed de HvA, samen met diverse mkb-bedrijven onderzoek naar de kennis een tools die ontwerpers nodig hebben om biobased plastics, kunststoffen van hernieuwbare

  8. BioMet Toolbox: genome-wide analysis of metabolism

    DEFF Research Database (Denmark)

    Cvijovic, M.; Olivares Hernandez, Roberto; Agren, R.

    2010-01-01

    standardized simulations. Model files for various model organisms (fungi and bacteria) are included. Overall, the BioMet Toolbox serves as a valuable resource for exploring the capabilities of these metabolic networks. BioMet Toolbox is freely available at www.sysbio.se/BioMet/....... models. Systematic analysis of biological processes by means of modelling and simulations has made the identification of metabolic networks and prediction of metabolic capabilities under different conditions possible. For facilitating such systemic analysis, we have developed the BioMet Toolbox, a web......-based resource for stoichiometric analysis and for integration of transcriptome and interactome data, thereby exploiting the capabilities of genome-scale metabolic models. The BioMet Toolbox provides an effective user-friendly way to perform linear programming simulations towards maximized or minimized growth...

  9. C. elegans as a model organism for in vivo screening in cancer: effects of human c-Met in lung cancer affect C. elegans vulva phenotypes.

    Science.gov (United States)

    Siddiqui, Shahid S; Loganathan, Sivakumar; Krishnaswamy, Soundararajan; Faoro, Leonardo; Jagadeeswaran, Ramasamy; Salgia, Ravi

    2008-06-01

    Cancers typically harbour several mutant forms of key cellular genes that contribute to its complex phenotype. Our lab has previously identified gain-of-function mutations in some of the receptor tyrosine kinases such as c-Met in lung cancer. In order to investigate the mutant gene in the context of a whole organism, the current choice of in vivo model is limited to the mouse. To rapidly screen the functional aspects of mutant forms of c-Met detected in lung cancer, we used the nematode C. elegans as the model organism. Transgenic worms were generated that harbour wild type or the frequently seen mutant forms of c-Met in lung cancer (c-MetR988C and c-MetT1010I). Expression of the mutant human c-Met forms in C. elegans consistently resulted in significantly low fecundity and abnormal vulval development characterized by hyperplasia. Interestingly, exposure of c-Met mutant transgenic worms to nicotine resulted in enhanced abnormal vulval development, fecundity and locomotion. Our studies provide first evidence that human c-Met mutations can be studied in C. elegans, and that carcinogens can enhance mutant c-Met function expressed in C. elegans transgenic animals. We therefore propose the use of C. elegans as a model to rapidly assess the role of cancer specific gene mutations in the context of a whole organism.

  10. Aberrations of MET are associated with copy number gain of EGFR and loss of PTEN and predict poor outcome in patients with salivary gland cancer.

    Science.gov (United States)

    Ach, Tobias; Zeitler, Katharina; Schwarz-Furlan, Stephan; Baader, Katharina; Agaimy, Abbas; Rohrmeier, Christian; Zenk, Johannes; Gosau, Martin; Reichert, Torsten E; Brockhoff, Gero; Ettl, Tobias

    2013-01-01

    Hepatocyte growth factor receptor (MET) is a key driver of oncogenic transformation. Copy number gain and amplification of MET positively enhance tumour growth, invasiveness and metastasis in different cancer types. In the present study, 266 carcinomas of the major and minor salivary glands were investigated for genomic MET status by fluorescence in situ hybridization and for protein expression by immunohistochemistry. Results were matched with clinicopathological parameters, long-term survival and the status of epidermal growth factor receptor (EGFR) and phosphatase and tensin homologue (PTEN). Low polysomy (n = 42), high polysomy (n = 27), amplification (n = 2) and deletion (n = 18) were found as aberrations of genomic MET in certain subtypes. MET aberrations were associated with increased patient age (>70 years, p = 0.003), male gender (p = 0.01), increased tumour size (p = 0.002), lymph node metastases (p < 0.001), high-grade malignancy (p < 0.001) and unfavourable overall survival (p < 0.001). Both copy number gain (p < 0.001) and deletion (p = 0.031) of MET correlated with copy number gain of EGFR. Tumours with genomic loss of PTEN (n = 48) concurrently presented aberration of genomic MET (p < 0.001). MET gene status significantly correlated with protein status (p = 0.038). In conclusion, gain but also loss of genomic MET activity correlates with aggressive tumour growth, nodal metastasis and worse overall survival in salivary gland cancer. Moreover, aberrations of MET are associated with EGFR and PTEN signalling and might possess relevance for targeted therapies of salivary gland carcinomas in the future.

  11. Transcriptional activation of the Axl and PDGFR-α by c-Met through a ras- and Src-independent mechanism in human bladder cancer

    International Nuclear Information System (INIS)

    Yeh, Chen-Yun; Tseng, Vincent S; Lee, Yuan-Chii G; Shen, Cheng-Huang; Chow, Nan-Haw; Liu, Hsiao-Sheng; Shin, Shin-Mei; Yeh, Hsuan-Heng; Wu, Tsung-Jung; Shin, Jyh-Wei; Chang, Tsuey-Yu; Raghavaraju, Giri; Lee, Chung-Ta; Chiang, Jung-Hsien

    2011-01-01

    A cross-talk between different receptor tyrosine kinases (RTKs) plays an important role in the pathogenesis of human cancers. Both NIH-Met5 and T24-Met3 cell lines harboring an inducible human c-Met gene were established. C-Met-related RTKs were screened by RTK microarray analysis. The cross-talk of RTKs was demonstrated by Western blotting and confirmed by small interfering RNA (siRNA) silencing, followed by elucidation of the underlying mechanism. The impact of this cross-talk on biological function was demonstrated by Trans-well migration assay. Finally, the potential clinical importance was examined in a cohort of 65 cases of locally advanced and metastatic bladder cancer patients. A positive association of Axl or platelet-derived growth factor receptor-alpha (PDGFR-α) with c-Met expression was demonstrated at translational level, and confirmed by specific siRNA knock-down. The transactivation of c-Met on Axl or PDGFR-α in vitro was through a ras- and Src-independent activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) pathway. In human bladder cancer, co-expression of these RTKs was associated with poor patient survival (p < 0.05), and overexpression of c-Met/Axl/PDGFR-α or c-Met alone showed the most significant correlation with poor survival (p < 0.01). In addition to c-Met, the cross-talk with Axl and/or PDGFR-α also contributes to the progression of human bladder cancer. Evaluation of Axl and PDGFR-α expression status may identify a subset of c-Met-positive bladder cancer patients who may require co-targeting therapy

  12. MET gene copy number predicts worse overall survival in patients with non-small cell lung cancer (NSCLC); a systematic review and meta-analysis.

    Science.gov (United States)

    Dimou, Anastasios; Non, Lemuel; Chae, Young Kwang; Tester, William J; Syrigos, Konstantinos N

    2014-01-01

    MET is a receptor present in the membrane of NSCLC cells and is known to promote cell proliferation, survival and migration. MET gene copy number is a common genetic alteration and inhibition o MET emerges as a promising targeted therapy in NSCLC. Here we aim to combine in a meta-analysis, data on the effect of high MET gene copy number on the overall survival of patients with resected NSCLC. Two independent investigators applied parallel search strategies with the terms "MET AND lung cancer", "MET AND NSCLC", "MET gene copy number AND prognosis" in PubMed through January 2014. We selected the studies that investigated the association of MET gene copy number with survival, in patients who received surgery. Among 1096 titles that were identified in the initial search, we retrieved 9 studies on retrospective cohorts with adequate retrievable data regarding the prognostic impact of MET gene copy number on the survival of patients with NSCLC. Out of those, 6 used FISH and the remaining 3 used RT PCR to assess the MET gene copy number in the primary tumor. We calculated the I2 statistic to assess heterogeneity (I2 = 72%). MET gene copy number predicted worse overall survival when all studies were combined in a random effects model (HR = 1.78, 95% CI 1.22-2.60). When only the studies that had at least 50% of adenocarcinoma patients in their populations were included, the effect was significant (five studies, HR 1.55, 95% CI 1.23-1.94). This was not true when we included only the studies with no more than 50% of the patients having adenocarcinoma histology (four studies HR 2.18, 95% CI 0.97-4.90). Higher MET gene copy number in the primary tumor at the time of diagnosis predicts worse outcome in patients with NSCLC. This prognostic impact may be adenocarcinoma histology specific.

  13. MET and AKT genetic influence on facial emotion perception.

    Directory of Open Access Journals (Sweden)

    Ming-Teng Lin

    Full Text Available BACKGROUND: Facial emotion perception is a major social skill, but its molecular signal pathway remains unclear. The MET/AKT cascade affects neurodevelopment in general populations and face recognition in patients with autism. This study explores the possible role of MET/AKT cascade in facial emotion perception. METHODS: One hundred and eighty two unrelated healthy volunteers (82 men and 100 women were recruited. Four single nucleotide polymorphisms (SNP of MET (rs2237717, rs41735, rs42336, and rs1858830 and AKT rs1130233 were genotyped and tested for their effects on facial emotion perception. Facial emotion perception was assessed by the face task of Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT. Thorough neurocognitive functions were also assessed. RESULTS: Regarding MET rs2237717, individuals with the CT genotype performed better in facial emotion perception than those with TT (p = 0.016 by ANOVA, 0.018 by general linear regression model [GLM] to control for age, gender, and education duration, and showed no difference with those with CC. Carriers with the most common MET CGA haplotype (frequency = 50.5% performed better than non-carriers of CGA in facial emotion perception (p = 0.018, df = 1, F = 5.69, p = 0.009 by GLM. In MET rs2237717/AKT rs1130233 interaction, the C carrier/G carrier group showed better facial emotion perception than those with the TT/AA genotype (p = 0.035 by ANOVA, 0.015 by GLM, even when neurocognitive functions were controlled (p = 0.046 by GLM. CONCLUSIONS: To our knowledge, this is the first study to suggest that genetic factors can affect performance of facial emotion perception. The findings indicate that MET variances and MET/AKT interaction may affect facial emotion perception, implicating that the MET/AKT cascade plays a significant role in facial emotion perception. Further replication studies are needed.

  14. MET and AKT genetic influence on facial emotion perception.

    Science.gov (United States)

    Lin, Ming-Teng; Huang, Kuo-Hao; Huang, Chieh-Liang; Huang, Yu-Jhen; Tsai, Guochuan E; Lane, Hsien-Yuan

    2012-01-01

    Facial emotion perception is a major social skill, but its molecular signal pathway remains unclear. The MET/AKT cascade affects neurodevelopment in general populations and face recognition in patients with autism. This study explores the possible role of MET/AKT cascade in facial emotion perception. One hundred and eighty two unrelated healthy volunteers (82 men and 100 women) were recruited. Four single nucleotide polymorphisms (SNP) of MET (rs2237717, rs41735, rs42336, and rs1858830) and AKT rs1130233 were genotyped and tested for their effects on facial emotion perception. Facial emotion perception was assessed by the face task of Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). Thorough neurocognitive functions were also assessed. Regarding MET rs2237717, individuals with the CT genotype performed better in facial emotion perception than those with TT (p = 0.016 by ANOVA, 0.018 by general linear regression model [GLM] to control for age, gender, and education duration), and showed no difference with those with CC. Carriers with the most common MET CGA haplotype (frequency = 50.5%) performed better than non-carriers of CGA in facial emotion perception (p = 0.018, df = 1, F = 5.69, p = 0.009 by GLM). In MET rs2237717/AKT rs1130233 interaction, the C carrier/G carrier group showed better facial emotion perception than those with the TT/AA genotype (p = 0.035 by ANOVA, 0.015 by GLM), even when neurocognitive functions were controlled (p = 0.046 by GLM). To our knowledge, this is the first study to suggest that genetic factors can affect performance of facial emotion perception. The findings indicate that MET variances and MET/AKT interaction may affect facial emotion perception, implicating that the MET/AKT cascade plays a significant role in facial emotion perception. Further replication studies are needed.

  15. HGF/c-MET Axis in Tumor Microenvironment and Metastasis Formation

    Directory of Open Access Journals (Sweden)

    Anna Spina

    2015-01-01

    Full Text Available Tumor metastases are responsible for approximately 90% of all cancer-related deaths. Metastasis formation is a multistep process that requires acquisition by tumor cells of a malignant phenotype that allows them to escape from the primary tumor site and invade other organs. Each step of this mechanism involves a deep crosstalk between tumor cells and their microenvironment where the host cells play a key role in influencing metastatic behavior through the release of many secreted factors. Among these signaling molecules, Hepatocyte Growth Factor (HGF is released by many cell types of the tumor microenvironment to target its receptor c-MET within the cells of the primary tumor. Many studies reveal that HGF/c-MET axis is implicated in various human cancers, and genetic and epigenetic gain of functions of this signaling contributes to cancer development through a variety of mechanisms. In this review, we describe the specific types of cells in the tumor microenvironment that release HGF in order to promote the metastatic outgrowth through the activation of extracellular matrix remodeling, inflammation, migration, angiogenesis, and invasion. We dissect the potential use of new molecules that interfere with the HGF/c-MET axis as therapeutic targets for future clinical trials in cancer disease.

  16. MetNet Precursor - Network Mission to Mars

    Science.gov (United States)

    Harri, Arri-Matti

    2010-05-01

    We are developing a new kind of planetary exploration mission for Mars - MetNet in situ observation network based on a new semi-hard landing vehicle called the Met-Net Lander (MNL). The first MetNet vehicle, MetNet Precursor, slated for launch in 2011. The MetNet development work started already in 2001. The actual practical Precursor Mission development work started in January 2009 with participation from various space research institutes and agencies. The scientific rationale and goals as well as key mission solutions will be discussed. The eventual scope of the MetNet Mission is to deploy some 20 MNLs on the Martian surface using inflatable descent system structures, which will be supported by observations from the orbit around Mars. Currently we are working on the MetNet Mars Precursor Mission (MMPM) to deploy one MetNet Lander to Mars in the 2011 launch window as a technology and science demonstration mission. The MNL will have a versatile science payload focused on the atmospheric science of Mars. Time-resolved in situ Martian meteorological measurements acquired by the Viking, Mars Pathfinder and Phoenix landers and remote sensing observations by the Mariner 9, Viking, Mars Global Surveyor, Mars Odyssey and the Mars Express orbiters have provided the basis for our current understanding of the behavior of weather and climate on Mars. However, the available amount of data is still scarce and a wealth of additional in situ observations are needed on varying types of Martian orography, terrain and altitude spanning all latitudes and longitudes to address microscale and mesoscale atmospheric phenomena. Detailed characterization of the Martian atmospheric circulation patterns and climatological cycles requires simultaneous in situ atmospheric observations. The scientific payload of the MetNet Mission encompasses separate instrument packages for the atmospheric entry and descent phase and for the surface operation phase. The MetNet mission concept and key probe

  17. EGFR is dispensable for c-Met-mediated proliferation and survival activities in mouse adult liver oval cells.

    Science.gov (United States)

    Martínez-Palacián, A; del Castillo, G; Herrera, B; Fernández, M; Roncero, C; Fabregat, I; Sánchez, A

    2012-02-01

    Liver progenitor cells rise as potential critical players in hepatic regeneration but also carcinogenesis. It is therefore mandatory to define the signals controlling their activation and expansion. Recently, by using a novel in vitro model of oval cell lines expressing a mutant tyrosine kinase-inactive form of c-Met we demonstrated that autocrine c-Met signalling plays an essential role in promoting oval cell survival. Here, we investigated the significance of the epidermal growth factor receptor (EGFR) signalling in oval cell proliferation and survival, as well as a potential functional crosstalk between the c-Met and the EGFR pathways. We found an autocrine activation of the EGFR-triggered pathway in Met(flx/flx) and Met(-/-) oval cells as judged by constitutive expression of the EGFR ligands, transforming growth factor-alpha (TGF-α) and heparin-binding EGF like growth factor (HB-EGF), and activation of EGFR. On the other hand, treatment with AG1478, a specific inhibitor of EGFR, effectively blocked endogenous and EGF-induced proliferation, while increased serum withdrawal and transforming growth factor-beta (TGF-β)-induced apoptosis. These results suggest that constitutively activated EGFR might promote oval cell proliferation and survival. We found that hepatocyte growth factor (HGF) does not transactivate EGFR nor EGF transactivates c-Met. Furthermore, treatment with AG1478 or EGFR gene silencing did not interfere with HGF-mediated activation of target signals, such as protein kinase B (AKT/PKB), and extracellular signal-regulated kinases 1/2 (ERK 1/2), nor did it have any effect on HGF-induced proliferative and antiapoptotic activities in Met(flx/flx) cells, showing that HGF does not require EGFR activation to mediate such responses. EGF induced proliferation and survival equally in Met(flx/flx) and Met(-/-) oval cells, proving that EGFR signalling does not depend on c-Met tyrosine kinase activity. Together, our results provide strong evidence that in

  18. Functional expression of single-chain variable fragment antibody against c-Met in the cytoplasm of Escherichia coli.

    Science.gov (United States)

    Heo, Mi-Ae; Kim, Su-Hyun; Kim, So-Yeon; Kim, Yu-Jin; Chung, Junho; Oh, Min-Kyu; Lee, Sun-Gu

    2006-05-01

    c-Met, a high affinity receptor for hepatocyte growth factor/scatter factor, shown to be overexpressed in a variety of malignant cells, is a potential biomarker as well as a therapeutic target. Thus, single-chain antibody fragment (scFv) specific for c-Met is expected to be efficiently employed in the clinical treatment or imaging of many cancer cells. Here, we constructed the expression system for anti-c-Met scFv fused with T7 tag at its N-terminus using pET vector and investigated the expression conditions to achieve a functional and soluble expression of the scFv in the cytoplasm of recombinant Escherichia coli. The redox potential of E. coli cytoplasm was the most critical factor for the functional expression of anti-c-Met scFv. The employment of a host with oxidizing cytoplasm, E. coli trxB/gor double mutant, improved the productivity of functional anti-c-Met scFv by approximately 10-fold compared to the production of anti-c-Met scFv in the reducing cytoplasm of wild type E. coli. Productivity of functional anti-c-Met scFv could be further enhanced by co-expressing molecular chaperones such as GroELS, trigger factor, and DsbC with the scFv. Coexpression of DsbC increased the yield of functional anti-c-Met scFv about 2.5-fold in the cytoplasm of E. coli trxB/gor mutant compared to the production of scFv without DsbC coexpression. Lowering the IPTG concentration from 1 to 0.05 mM led to the slight enhancement, approximately 1.6-fold, of productivity of functional scFv. Although the use of low temperature for anti-c-Met scFv expression increased the ratio of soluble scFv fraction to insoluble fraction, productivity of soluble scFv decreased owing to the significant reduction of expression rate. The addition of 0.5 M sucrose in the medium inhibited the formation of intracellular insoluble anti-c-Met scFv. To purify the anti-c-Met scFv simply, we fused hexahistidine at the C-terminus of scFv and purified the scFv showing 98% of purity through the interaction

  19. Combinatie van walnoten met grasproductie en reactie : verslag van resultaten en ervaringen van de eerste jaren met 'Multifunctionele beplantingen', als bouwsteen voor meervoudig duurzaam landgebruik

    NARCIS (Netherlands)

    Oosterbaan, A.; Berg, van den C.A.; Valk, H.

    2003-01-01

    In de omgeving van Winterswijk is vanaf 1999 10 ha multifunctionele beplantingen aangelegd, hoofdzakelijk van walnoot met gras. Overhoeken zijn ingeplant met vruchtstruiken. De eerste ervaringen met aanplant, grasbeheer, bijdrage aan recreatie en dergelijke zijn in dit rapport weergegeven.

  20. Intensieve veehouderij: met nieuwe producten samen naar gangbaar plus

    NARCIS (Netherlands)

    Kortstee, H.J.M.

    2007-01-01

    Samenwerkingverbanden van varkens- en pluimveehouders kunnen een geschikt instrument zijn om een nieuw product in de markt te zetten. Een succesvolle vermarkting vereist, naast een sterke initiatiefnemer met een overtuigend idee, ook krachtige partners in de keten en ondersteuning bij

  1. Leven met de varroamijt in de 21ste eeuw

    NARCIS (Netherlands)

    Blacquiere, T.; Cornelissen, B.; Smeekens, C.C.; Steen, van der J.J.M.

    2002-01-01

    Overzicht van voorhanden bestrijdingsmethoden tegen Varroa destructor op de korte termijn en vooruitzichten voor de bestrijding op langere termijn. In de nabije toekomst gaat het om bestrijding met diergeneesmiddelen van natuurlijke oorsprong (mierenzuur, oxaalzuur, thymol) in het kader van een

  2. Mars MetNet Mission - Martian Atmospheric Observational Post Network

    Science.gov (United States)

    Hari, Ari-Matti; Haukka, Harri; Aleksashkin, Sergey; Arruego, Ignacio; Schmidt, Walter; Genzer, Maria; Vazquez, Luis; Siikonen, Timo; Palin, Matti

    2017-04-01

    A new kind of planetary exploration mission for Mars is under development in collaboration between the Finnish Meteorological Institute (FMI), Lavochkin Association (LA), Space Research Institute (IKI) and Institutio Nacional de Tecnica Aerospacial (INTA). The Mars MetNet mission is based on a new semi-hard landing vehicle called MetNet Lander (MNL). The scientific payload of the Mars MetNet Precursor [1] mission is divided into three categories: Atmospheric instruments, Optical devices and Composition and structure devices. Each of the payload instruments will provide significant insights in to the Martian atmospheric behavior. The key technologies of the MetNet Lander have been qualified and the electrical qualification model (EQM) of the payload bay has been built and successfully tested. 1. MetNet Lander The MetNet landing vehicles are using an inflatable entry and descent system instead of rigid heat shields and parachutes as earlier semi-hard landing devices have used. This way the ratio of the payload mass to the overall mass is optimized. The landing impact will burrow the payload container into the Martian soil providing a more favorable thermal environment for the electronics and a suitable orientation of the telescopic boom with external sensors and the radio link antenna. It is planned to deploy several tens of MNLs on the Martian surface operating at least partly at the same time to allow meteorological network science. 2. Strawman Scientific Payload The strawman payload of the two MNL precursor models includes the following instruments: Atmospheric instruments: - MetBaro Pressure device - MetHumi Humidity device - MetTemp Temperature sensors Optical devices: - PanCam Panoramic - MetSIS Solar irradiance sensor with OWLS optical wireless system for data transfer - DS Dust sensor Composition and Structure Devices: Tri-axial magnetometer MOURA Tri-axial System Accelerometer The descent processes dynamic properties are monitored by a special 3-axis

  3. Mars MetNet Mission - Martian Atmospheric Observational Post Network

    Science.gov (United States)

    Harri, A.-M.; Haukka, H.; Aleksashkin, S.; Arruego, I.; Schmidt, W.; Genzer, M.; Vazquez, L.; Siikonen, T.; Palin, M.

    2017-09-01

    A new kind of planetary exploration mission for Mars is under development in collaboration between the Finnish Meteorological Institute (FMI), Lavochkin Association (LA), Space Research Institute (IKI) and Institutio Nacional de Tecnica Aerospacial (INTA). The Mars MetNet mission is based on a new semi-hard landing vehicle called MetNet Lander (MNL). The scientific payload of the Mars MetNet Precursor [1] mission is divided into three categories: Atmospheric instruments, Optical devices and Composition and structure devices. Each of the payload instruments will provide significant insights in to the Martian atmospheric behavior. The key technologies of the MetNet Lander have been qualified and the electrical qualification model (EQM) of the payload bay has been built and successfully tested.

  4. MMPM - Mission implementation of Mars MetNet Precursor

    Science.gov (United States)

    Harri, A.-M.

    2009-04-01

    We are developing a new kind of planetary exploration mission for Mars - MetNet in situ observation network based on a new semi-hard landing vehicle called the Met-Net Lander (MNL). The key technical aspects and solutions of the mission will be discussed. The eventual scope of the MetNet Mission is to deploy some 20 MNLs on the Martian surface using inflatable descent system structures, which will be supported by observations from the orbit around Mars. Currently we are working on the MetNet Mars Precursor Mission (MMPM) to deploy one MetNet Lander to Mars in the 2009/2011 launch window as a technology and science demonstration mission. The MNL will have a versatile science payload focused on the atmospheric science of Mars. Detailed characterization of the Martian atmospheric circulation patterns, boundary layer phenomena, and climatology cycles, require simultaneous in-situ measurements by a network of observation posts on the Martian surface. The scientific payload of the MetNet Mission encompasses separate instrument packages for the atmospheric entry and descent phase and for the surface operation phase. The MetNet mission concept and key probe technologies have been developed and the critical subsystems have been qualified to meet the Martian environmental and functional conditions. This development effort has been fulfilled in collaboration between the Finnish Meteorological Institute (FMI), the Russian Lavoschkin Association (LA) and the Russian Space Research Institute (IKI) since August 2001. Currently the INTA (Instituto Nacional de Técnica Aeroespacial) from Spain is also participating in the MetNet payload development.

  5. Somatostatin receptors

    DEFF Research Database (Denmark)

    Møller, Lars Neisig; Stidsen, Carsten Enggaard; Hartmann, Bolette

    2003-01-01

    therefore been acknowledged to be a third endogenous ligand at SRIF receptors. This review goes through mechanisms of signal transduction, pharmacology, and anatomical distribution of SRIF receptors. Structurally, SRIF receptors belong to the superfamily of G protein-coupled (GPC) receptors, sharing....... The generation of knock-out (KO) mice, intended as a means to define the contributions made by individual receptor subtypes, necessarily marks but an approximation. Furthermore, we must now take into account the stunning complexity of receptor co-operation indicated by the observation of receptor homo......-peptides, receptor agonists and antagonists. Relatively long half lives, as compared to those of the endogenous ligands, have been paramount from the outset. Motivated by theoretical puzzles or the shortcomings of present-day diagnostics and therapy, investigators have also aimed to produce subtype...

  6. COMT (Val158Met and BDNF (Val66Met Genes Polymorphism in Schizophrenia: A Case-Control Report

    Directory of Open Access Journals (Sweden)

    ramin saravani

    2017-10-01

    Full Text Available Objective: The effects of human brain-derived neurotropic factor (BDNF Val66Met (G>A and the human Catechol-O-methylTransferase (COMT Val158Met (G>A polymorphisms on Schizophrenia (SCZ risk were evaluated.Methods: This case control study included 92 SCZ patients and 92 healthy controls (HCs. Genotyping of both variants were conducted using Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR.Results: The findings showed that BDNF Val66Met (G>A variant increased the risk of SCZ (OR=2.008 95%CI=1.008-4.00, P=0.047, GA vs. GG, OR=3.876 95%CI=1.001-14.925, P=0.049. AA vs. GG, OR=2.272. 95%CI=1.204-4.347, P=0.011, GA+AA vs. GG, OR=2.22 95%CI=1.29-3.82. P=0.005, A vs. G. COMT Val158Met (G>A polymorphism was not associated with the risk/protective of SCZ.Conclusion: The results proposed that BDNF Val66Met (G>A polymorphism may increase the risk of SCZ development and did not support an association between COMT Val158Met (G>A variant and risk/protective of SCZ. Further studies and different ethnicities are recommended to confirm the findings.

  7. Hydrogen storage capacity of titanium met-cars

    Energy Technology Data Exchange (ETDEWEB)

    Akman, N [Department of Physics, Mersin University, 33342 Mersin (Turkey); Durgun, E [Department of Physics, Bilkent University, 06800 Ankara (Turkey); Yildirim, T [NIST Center for Neutron Research, National Institute of Standards and Technology, Gaithersburg, MD 20899 (United States); Ciraci, S [Department of Physics, Bilkent University, 06800 Ankara (Turkey)

    2006-10-18

    The adsorption of hydrogen molecules on the titanium metallocarbohedryne (met-car) cluster has been investigated by using the first-principles plane wave method. We have found that, while a single Ti atom at the corner can bind up to three hydrogen molecules, a single Ti atom on the surface of the cluster can bind only one hydrogen molecule. Accordingly, a Ti{sub 8}C{sub 12} met-car can bind up to 16 H{sub 2} molecules and hence can be considered as a high-capacity hydrogen storage medium. Strong interaction between two met-car clusters leading to the dimer formation can affect H{sub 2} storage capacity slightly. Increasing the storage capacity by directly inserting H{sub 2} into the met-car or by functionalizing it with an Na atom have been explored. It is found that the insertion of neither an H{sub 2} molecule nor an Na atom could further promote the H{sub 2} storage capacity of a Ti{sub 8}C{sub 12} cluster. We have also tested the stability of the H{sub 2}-adsorbed Ti{sub 8}C{sub 12} met-car with ab initio molecular dynamics calculations which have been carried out at room temperature.

  8. MetAmyl: a METa-predictor for AMYLoid proteins.

    Directory of Open Access Journals (Sweden)

    Mathieu Emily

    Full Text Available The aggregation of proteins or peptides in amyloid fibrils is associated with a number of clinical disorders, including Alzheimer's, Huntington's and prion diseases, medullary thyroid cancer, renal and cardiac amyloidosis. Despite extensive studies, the molecular mechanisms underlying the initiation of fibril formation remain largely unknown. Several lines of evidence revealed that short amino-acid segments (hot spots, located in amyloid precursor proteins act as seeds for fibril elongation. Therefore, hot spots are potential targets for diagnostic/therapeutic applications, and a current challenge in bioinformatics is the development of methods to accurately predict hot spots from protein sequences. In this paper, we combined existing methods into a meta-predictor for hot spots prediction, called MetAmyl for METapredictor for AMYLoid proteins. MetAmyl is based on a logistic regression model that aims at weighting predictions from a set of popular algorithms, statistically selected as being the most informative and complementary predictors. We evaluated the performances of MetAmyl through a large scale comparative study based on three independent datasets and thus demonstrated its ability to differentiate between amyloidogenic and non-amyloidogenic polypeptides. Compared to 9 other methods, MetAmyl provides significant improvement in prediction on studied datasets. We further show that MetAmyl is efficient to highlight the effect of point mutations involved in human amyloidosis, so we suggest this program should be a useful complementary tool for the diagnosis of these diseases.

  9. Requirements to be met by the operation manual

    International Nuclear Information System (INIS)

    1981-03-01

    The rule applies to the contents and the lay-out of the operating manual for stationary nuclear power plants. The draft contains: 1. General requirement to be met by the contents of the operating manual. The operating manual to be arranged in 4 parts (part 1: internal rules and regulations; part 2: operation overall plant; part 3: incidents; part 4: operation systems). Safety specifications to be included in the manual, the exemption being the system of technical documentation. 2. General requirements to be met by the lay-out of the operating manual. Comprehensibility; legibility; structure and subdivisions; arrangement of the instructions and design of the manuals cover. 3. Requirements to be met by part 1. Defining the various internal rules and regulations (personnel management); rules and regulations concerning inspections and shift work; maintenance and repair; radiation protection; guard duty and admission; alarm; fire protection; first aid. 4. Requirements to be met by part 2. Provisions and operational limitations; limit values important from the point of view of safety; normal operation; anomalous operation; in-service inspections. 6. Requirements to be met by part 3. 7. Annex: Rules, regulations and stipulations mentioned in the rule draft. (orig.)

  10. MetReS, an Efficient Database for Genomic Applications.

    Science.gov (United States)

    Vilaplana, Jordi; Alves, Rui; Solsona, Francesc; Mateo, Jordi; Teixidó, Ivan; Pifarré, Marc

    2018-02-01

    MetReS (Metabolic Reconstruction Server) is a genomic database that is shared between two software applications that address important biological problems. Biblio-MetReS is a data-mining tool that enables the reconstruction of molecular networks based on automated text-mining analysis of published scientific literature. Homol-MetReS allows functional (re)annotation of proteomes, to properly identify both the individual proteins involved in the processes of interest and their function. The main goal of this work was to identify the areas where the performance of the MetReS database performance could be improved and to test whether this improvement would scale to larger datasets and more complex types of analysis. The study was started with a relational database, MySQL, which is the current database server used by the applications. We also tested the performance of an alternative data-handling framework, Apache Hadoop. Hadoop is currently used for large-scale data processing. We found that this data handling framework is likely to greatly improve the efficiency of the MetReS applications as the dataset and the processing needs increase by several orders of magnitude, as expected to happen in the near future.

  11. Hydrogen storage capacity of titanium met-cars

    International Nuclear Information System (INIS)

    Akman, N; Durgun, E; Yildirim, T; Ciraci, S

    2006-01-01

    The adsorption of hydrogen molecules on the titanium metallocarbohedryne (met-car) cluster has been investigated by using the first-principles plane wave method. We have found that, while a single Ti atom at the corner can bind up to three hydrogen molecules, a single Ti atom on the surface of the cluster can bind only one hydrogen molecule. Accordingly, a Ti 8 C 12 met-car can bind up to 16 H 2 molecules and hence can be considered as a high-capacity hydrogen storage medium. Strong interaction between two met-car clusters leading to the dimer formation can affect H 2 storage capacity slightly. Increasing the storage capacity by directly inserting H 2 into the met-car or by functionalizing it with an Na atom have been explored. It is found that the insertion of neither an H 2 molecule nor an Na atom could further promote the H 2 storage capacity of a Ti 8 C 12 cluster. We have also tested the stability of the H 2 -adsorbed Ti 8 C 12 met-car with ab initio molecular dynamics calculations which have been carried out at room temperature

  12. Discovery of a novel mode of protein kinase inhibition characterized by the mechanism of inhibition of human mesenchymal-epithelial transition factor (c-Met) protein autophosphorylation by ARQ 197.

    Science.gov (United States)

    Eathiraj, Sudharshan; Palma, Rocio; Volckova, Erika; Hirschi, Marscha; France, Dennis S; Ashwell, Mark A; Chan, Thomas C K

    2011-06-10

    A number of human malignancies exhibit sustained stimulation, mutation, or gene amplification of the receptor tyrosine kinase human mesenchymal-epithelial transition factor (c-Met). ARQ 197 is a clinically advanced, selective, orally bioavailable, and well tolerated c-Met inhibitor, currently in Phase 3 clinical testing in non-small cell lung cancer patients. Herein, we describe the molecular and structural basis by which ARQ 197 selectively targets c-Met. Through our analysis we reveal a previously undisclosed, novel inhibitory mechanism that utilizes distinct regulatory elements of the c-Met kinase. The structure of ARQ 197 in complex with the c-Met kinase domain shows that the inhibitor binds a conformation that is distinct from published kinase structures. ARQ 197 inhibits c-Met autophosphorylation and is highly selective for the inactive or unphosphorylated form of c-Met. Through our analysis of the interplay between the regulatory and catalytic residues of c-Met, and by comparison between the autoinhibited canonical conformation of c-Met bound by ARQ 197 to previously described kinase domains of type III receptor tyrosine kinases, we believe this to be the basis of a powerful new in silico approach for the design of similar inhibitors for other protein kinases of therapeutic interest.

  13. Somatostatin receptors

    DEFF Research Database (Denmark)

    Møller, Lars Neisig; Stidsen, Carsten Enggaard; Hartmann, Bolette

    2003-01-01

    therefore been acknowledged to be a third endogenous ligand at SRIF receptors. This review goes through mechanisms of signal transduction, pharmacology, and anatomical distribution of SRIF receptors. Structurally, SRIF receptors belong to the superfamily of G protein-coupled (GPC) receptors, sharing......- and heterodimerisation, let alone oligomerisation. Theoretically, this phenomenon adds a novel series of functional megareceptors/super-receptors, with varied pharmacological profiles, to the catalogue of monomeric receptor subtypes isolated and cloned in the past. SRIF analogues include both peptides and non......-peptides, receptor agonists and antagonists. Relatively long half lives, as compared to those of the endogenous ligands, have been paramount from the outset. Motivated by theoretical puzzles or the shortcomings of present-day diagnostics and therapy, investigators have also aimed to produce subtype...

  14. c-Met Expression Is a Marker of Poor Prognosis in Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma Treated With Chemoradiation

    Energy Technology Data Exchange (ETDEWEB)

    Baschnagel, Andrew M. [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, Michigan (United States); Williams, Lindsay [Department of Pathology, William Beaumont Hospital, Royal Oak, Michigan (United States); Hanna, Alaa; Chen, Peter Y.; Krauss, Daniel J. [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, Michigan (United States); Pruetz, Barbara L. [Beaumont BioBank, William Beaumont Hospital, Royal Oak, Michigan (United States); Akervall, Jan [Beaumont BioBank, William Beaumont Hospital, Royal Oak, Michigan (United States); Department of Otolaryngology, William Beaumont Hospital, Royal Oak, Michigan (United States); Wilson, George D., E-mail: George.Wilson@Beaumont.edu [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, Michigan (United States); Beaumont BioBank, William Beaumont Hospital, Royal Oak, Michigan (United States)

    2014-03-01

    Purpose: To examine the prognostic significance of c-Met expression in relation to p16 and epidermal growth factor receptor (EGFR) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with definitive concurrent chemoradiation. Methods and Materials: Archival tissue from 107 HNSCC patients treated with chemoradiation was retrieved, and a tissue microarray was assembled. Immunohistochemical staining of c-Met, p16, and EGFR was performed. c-Met expression was correlated with p16, EGFR, clinical characteristics, and clinical endpoints including locoregional control (LRC), distant metastasis (DM), disease-free survival (DFS), and overall survival (OS). Results: Fifty-one percent of patients were positive for p16, and 53% were positive for EGFR. Both p16-negative (P≤.001) and EGFR-positive (P=.019) status predicted for worse DFS. Ninety-three percent of patients stained positive for c-Met. Patients were divided into low (0, 1, or 2+ intensity) or high (3+ intensity) c-Met expression. On univariate analysis, high c-Met expression predicted for worse LRC (hazard ratio [HR] 2.27; 95% CI, 1.08-4.77; P=.031), DM (HR 4.41; 95% CI, 1.56-12.45; P=.005), DFS (HR 3.00; 95% CI, 1.68-5.38; P<.001), and OS (HR 4.35; 95% CI, 2.13-8.88; P<.001). On multivariate analysis, after adjustment for site, T stage, smoking history, and EGFR status, only high c-Met expression (P=.011) and negative p16 status (P=.003) predicted for worse DFS. High c-Met expression was predictive of worse DFS in both EGFR-positive (P=.032) and -negative (P=.008) patients. In the p16-negative patients, those with high c-Met expression had worse DFS (P=.036) than did those with low c-Met expression. c-Met expression was not associated with any outcome in the p16-positive patients. Conclusions: c-Met is expressed in the majority of locally advanced HNSCC cases, and high c-Met expression predicts for worse clinical outcomes. High c-Met expression predicted for worse DFS in p16

  15. El acertijo de la metáfora visual

    OpenAIRE

    De la Rosa Alzate, Adriana; Universidad Autónoma de Occidente

    2016-01-01

    En este artículo se presentan los resultados de la investigación sobre el proceso de interpretación de la metáfora visual, en niños entre tres y cuatro años de edad. El propósito de la investigación fue dar cuenta del proceso de interpretación de la metáfora visual y del razonamiento involucrado. La metáfora visual se entiende como un fenómeno en el que los objetos representados presentan transformaciones que traen como consecuencia la emergencia de nuevas categorías e incluso la ambigüedad, ...

  16. Metáforas rígidas

    Directory of Open Access Journals (Sweden)

    González-Marín, Carmen

    1997-04-01

    Full Text Available No disponible.Las metáforas del tipo «Julieta es el sol» se interpretan normalmente como enunciados predicativos, y en consecuencia, como usos defectivos del lenguaje. Como tratamiento alternativo, analizamos el citado tipo de metáforas como enunciados que instauran una identidad entre dos objetos y no como enunciados que predican una semejanza o una defectiva pertenencia de un objeto a una clase dada. Las metáforas que responden a un esquema «a es (un b» son consideradas como parte de un enunciado que da cuenta de un estado intencional, o en otras palabras, como el alcance de un operador epistémico M, con la fuerza ilocucionaria de una declaración. Un trasfondo platónico justifica nuestra propuesta.

  17. Remembering the early days of the Met Lab

    International Nuclear Information System (INIS)

    Katz, J.J.

    1990-01-01

    The Met Lab was set up by the war-time Manhattan District, US Corp of Engineers to (i) find a system using normal uranium in which a chain reaction would occur; (ii) to show that if such a chain reaction did occur, it would be possible to separate plutonium chemically from the uranium matrix and the fission products formed in the chain reactions; and (iii) to prepare plans for the large-scale production of plutonium. Chemistry Section C-1 of the Met Lab was assigned the responsibility for developing separation methods for plutonium production on the industrial scale. This report describes some aspects of daily life in Section C-1

  18. Esiselkeytysaltaan lietepatjan hallinta Metsä-Board Kyrolla

    OpenAIRE

    Isokivijärvi, Jyri

    2016-01-01

    Metsä-Board Kyron kartonkitehtaan jätevesilaitoksella oli tarve saada tietoa esiselkeytysaltaan pohjalla olevasta lietepatjasta. Tiedon avulla haluttiin optimoida lietteenkäsittelyn toimintaa, säästää raaka-ainekustannuksissa ja estää esiselkeytysaltaan kaavintasillan liiallisesta kuormituksesta aiheutuva pysähtyminen. Aikaisemmin Metsä-Board Kyrolla pyrittiin pitämään lietepatja mahdollisimman vähissä, joka on johtanut siihen, että käyttökelpoista kuitupitoista paperi/kartonkimassaa on joudu...

  19. Stabilized (111)in-labeled sCCK8 analogues for targeting CCK2-receptor positive tumors: synthesis and evaluation.

    NARCIS (Netherlands)

    Roosenburg, S.; Laverman, P.; Joosten, L.; Eek, A.; Oyen, W.J.G.; Jong, M. de; Rutjes, F.P.J.T.; Delft, F.L. van; Boerman, O.C.

    2010-01-01

    Radiolabeled cholecystokinin-8 (CCK8) peptide analogues can be used for peptide receptor radionuclide imaging and therapy for tumors expressing CCK2/gastrin receptors. Earlier findings indicated that sulfated CCK8 (sCCK8, Asp-Tyr(OSO(3)H)-Met-Gly-Trp-Met-Asp-Phe-NH(2)) may have better

  20. Magic-factor 1, a partial agonist of Met, induces muscle hypertrophy by protecting myogenic progenitors from apoptosis.

    Directory of Open Access Journals (Sweden)

    Marco Cassano

    2008-09-01

    Full Text Available Hepatocyte Growth Factor (HGF is a pleiotropic cytokine of mesenchymal origin that mediates a characteristic array of biological activities including cell proliferation, survival, motility and morphogenesis. Its high affinity receptor, the tyrosine kinase Met, is expressed by a wide range of tissues and can be activated by either paracrine or autocrine stimulation. Adult myogenic precursor cells, the so called satellite cells, express both HGF and Met. Following muscle injury, autocrine HGF-Met stimulation plays a key role in promoting activation and early division of satellite cells, but is shut off in a second phase to allow myogenic differentiation. In culture, HGF stimulation promotes proliferation of muscle precursors thereby inhibiting their differentiation.Magic-Factor 1 (Met-Activating Genetically Improved Chimeric Factor-1 or Magic-F1 is an HGF-derived, engineered protein that contains two Met-binding domains repeated in tandem. It has a reduced affinity for Met and, in contrast to HGF it elicits activation of the AKT but not the ERK signaling pathway. As a result, Magic-F1 is not mitogenic but conserves the ability to promote cell survival. Here we show that Magic-F1 protects myogenic precursors against apoptosis, thus increasing their fusion ability and enhancing muscular differentiation. Electrotransfer of Magic-F1 gene into adult mice promoted muscular hypertrophy and decreased myocyte apoptosis. Magic-F1 transgenic mice displayed constitutive muscular hypertrophy, improved running performance and accelerated muscle regeneration following injury. Crossing of Magic-F1 transgenic mice with alpha-sarcoglycan knock-out mice -a mouse model of muscular dystrophy- or adenovirus-mediated Magic-F1 gene delivery resulted in amelioration of the dystrophic phenotype as measured by both anatomical/histological analysis and functional tests.Because of these features Magic-F1 represents a novel molecular tool to counteract muscle wasting in major

  1. Affect-modulated startle: interactive influence of catechol-O-methyltransferase Val158Met genotype and childhood trauma.

    Directory of Open Access Journals (Sweden)

    Benedikt Klauke

    Full Text Available The etiology of emotion-related disorders such as anxiety or affective disorders is considered to be complex with an interaction of biological and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic and noradrenergic system--partly conferred by catechol-O-methyltransferase (COMT gene variation--for the adenosinergic system as well as for early life trauma to constitute risk factors for those conditions. Applying a multi-level approach, in a sample of 95 healthy adults, we investigated effects of the functional COMT Val158Met polymorphism, caffeine as an adenosine A2A receptor antagonist (300 mg in a placebo-controlled intervention design and childhood maltreatment (CTQ as well as their interaction on the affect-modulated startle response as a neurobiologically founded defensive reflex potentially related to fear- and distress-related disorders. COMT val/val genotype significantly increased startle magnitude in response to unpleasant stimuli, while met/met homozygotes showed a blunted startle response to aversive pictures. Furthermore, significant gene-environment interaction of COMT Val158Met genotype with CTQ was discerned with more maltreatment being associated with higher startle potentiation in val/val subjects but not in met carriers. No main effect of or interaction effects with caffeine were observed. Results indicate a main as well as a GxE effect of the COMT Val158Met variant and childhood maltreatment on the affect-modulated startle reflex, supporting a complex pathogenetic model of the affect-modulated startle reflex as a basic neurobiological defensive reflex potentially related to anxiety and affective disorders.

  2. Las metáforas de comunicación como metáforas que cobran realidad

    OpenAIRE

    Meunier, Jean Pierrer; Université catholique de Louvain

    1997-01-01

    En el paisaje teórico relativo a la comunicación, la noción de metáfora parece manifestarse y producir efectos en todas las dimensiones de la comunicación que sucesivamente se dan en el campo de la investigación: la significación, la relación, la cognición. La metáfora se presenta a la vez como un concepto iluminador y un concepto apra iluminar, como un concepto capaz de esclarecer toda clase de relaciones concretas de comunicación.

  3. Vakansiehuis met swembad. Herman Koch. Vertaal deur Daniel ...

    African Journals Online (AJOL)

    - tig minuten (“my verkoopspunt”), maar. “[p]asiënte verwar tyd met aandag”. Marc luistert niet echt, want een huisarts. “hoef mense nie gesond te maak nie” (12). En als ze zich niet laten afschepen, doet hij maar een rectaal touché, want “hulle.

  4. Permanent dysphagia in familial amyloid polyneuropathy (ATTRVal30Met).

    Science.gov (United States)

    Monteiro, Cecília; Magalhães, Marina; Correia, Carlos; Taipa, Ricardo

    2012-06-01

    Gastrointestinal symptoms are frequent in familial amyloid polyneuropathy, mainly resulting from autonomic nervous system involvement. Dysphagia is one of the possible symptoms, although rarely severe or sudden. We describe a case of a sudden onset and severe dysphagia, a rare form of presentation, in a patient whose polyneuropathy was still beeing investigated and turned out to be ATTRVal30Met-polyneuropathy.

  5. De overeenkomst van internet service providers met consumenten

    NARCIS (Netherlands)

    Siemerink, Leonie Anna Rika

    2007-01-01

    Dit boek schetst het juridisch kader voor overeenkomsten van Internet Service Providers (ISP’s) met consumenten. Daartoe is ondermeer een analyse gemaakt van de inhoud van algemene voorwaarden die verschillende ISP’s hanteren.Wat regelen de ISP’s in hun algemene voorwaarden en wat zijn de

  6. Beoordeling gezondheidsrisico's door sporten op kunstgrasvelden met rubbergranulaat

    NARCIS (Netherlands)

    Oomen AG; de Groot GM; CPV; M&V

    2016-01-01

    Uit nieuw onderzoek van het RIVM blijkt dat het risico voor de gezondheid van sporten op kunstgrasvelden die zijn ingestrooid met rubbergranulaat, praktisch verwaarloosbaar is. Dat betekent dat het verantwoord is om op deze velden te sporten. Aanleiding voor het onderzoek is de maatschappelijke

  7. Ontsmetten met Easy Ice Clean ("Coldblast") "Proof of principle"

    NARCIS (Netherlands)

    Ludeking, D.J.W.; Hamelink, R.; Gulik, van M.W.; Diepenhorst, T.

    2012-01-01

    In dit onderzoek is er gekeken naar de potentie en het proof of principle van de Cold Jet techniek van Easy Ice Clean in de tuinbouw. Met dit onderzoek is getracht te beantwoorden of de Cold Jet techniek potentie heeft als alternatieve ontsmettingstechniek voor chemische middelen. De techniek die in

  8. Aanvullend radiumonderzoek op twee met woningen bebouwde havenspeciepolders

    NARCIS (Netherlands)

    Stoop P; Hiemstra YS; Lembrechts JFMM; LSO

    1995-01-01

    Dit rapport beschrijft een onderzoek naar radiumgehalten dat uitgevoerd is voor de locaties Steendijkpolder-zuid, Maassluis (STPZ) en Woudhoek-noord, Schiedam (WH). Het doel van het onderzoek is, voor een met havenspecie opgespoten polder zonder afdeklaag (STPZ), te bepalen of de variatie in het

  9. Een adolescente jongen met fibreuze dysplasie van het kaakbot

    NARCIS (Netherlands)

    Nieuwland, A.C.; Vierhout, I.; Eekhoff, E.M.W.; van der Waal, I.

    2012-01-01

    Een 16-jarige jongen bleek na diagnostisch onderzoek met computertomografie en een skeletscan de monostotische verschijningsvorm van fibreuze dysplasie in de maxilla te hebben. De diagnose is bevestigd aan de hand van een botbiopt. Tijdens een periode van 8 jaar afwachtend beleid hebben zich geen

  10. Klaverbank Survey met de ARCA 17‐21 Nov 2014

    NARCIS (Netherlands)

    Lavaleye, M.

    2014-01-01

    Op Maandag 17 Nov 2014 vertrok de ARCA om 9:00 van uit de haven van Scheveningen richting Klaverbank. Het weer was bijzonder mooi en rustig, uitzonderlijk voor deze tijd van het jaar. Om 19:00 werd de Klaverbank bereikt, en werd gelijk begonnen met de Multibeam en side scan sonar raaien (Fig. 1).

  11. Liturgiese klere met besondere verwysing na die Nederduitsch ...

    African Journals Online (AJOL)

    koorrok 'n mantel en 'n bef gedra het. In Suid-Afrika was daar aanvanklik nie sprake van ampsdrag nie (SKLAS 1987: 9). Uit sketse en foto's is dit egter duidelik dat predikante en reg.sgeleerdes oral in die alledaagse deftige drag met toga of mantel en bef gekleed gegaan het. Sommige foto's toon predikante uit die agtiende ...

  12. Christus' offer bij Paulus vergeleken met de offeropvattingen van Philo

    NARCIS (Netherlands)

    Stelma, Juurd Hari

    1938-01-01

    Een vergelijking der offeropvattingen van Paulus en Philo brengt ons in aanraking met twee principieel verschillende voorstellingen aangaande het offer. Het offer van Christus is voor Paulus de gave Gods, waardoor de macht van de zonde en dood vernietigd en de schuld verzoend is. Door de

  13. 'Epistemology models ontology'− In gesprek met John Polkinghorne

    African Journals Online (AJOL)

    Test

    7 Jun 2011 ... en wel aan die hand van John Polkinghorne2, 'n ander laureatus en wat verlede jaar 80 jaar oud geword het en spesifiek met die onderhawige kwessie dekades lank reeds ... Triniteitsleer word dus 'n heuristiese instrument om die natuur te verstaan: 'we know the economic quark but not the immanent ...

  14. Die hervertolking van die paradigma in verband met die ...

    African Journals Online (AJOL)

    Die hervertolking van die paradigma in verband met die Kollegialisme om die. Afrikaanse kerke kerkregtelik te verstaan. E Brown. Universiteit van Stellenbosch. Abstract. Reinterpreting the paradigm concerning 'Kollegialisme' in order to understand the Afrikaans churches accoring to church law. The Afrikaans term ...

  15. Voedingsnavorsing met die weidende dier | Engels | South African ...

    African Journals Online (AJOL)

    South African Journal of Animal Science. Journal Home · ABOUT THIS JOURNAL · Advanced Search · Current Issue · Archives · Journal Home > Vol 13, No 4 (1983) >. Log in or Register to get access to full text downloads. Username, Password, Remember me, or Register. Voedingsnavorsing met die weidende dier.

  16. Tweetalig onderwijs met vervroegd Engels in het basisonderwijs

    NARCIS (Netherlands)

    Aarts, R.; Ronde, S.

    2006-01-01

    In dit artikel wordt verslag gedaan van een explortief onderzoek naar het functioneren van een tweetalig onderwijsprogramma waarin (naast het Nederlands) Engels aangeboden wordt in de onderbouw van het basisonderwijs. De resultaten laten zien dat de betrokkenen positieve ervaringen met en hoge

  17. DYNAMIND: Naar dynamisch en gestructureerd vraaggestuurd leren met digitaal mindmappen

    NARCIS (Netherlands)

    Harry Stokhof; Haske van Vlokhoven; Martijn Peters; Dominique Sluijsmans

    2011-01-01

    Werken met papieren mindmaps lijkt echter nog onvoldoende uit te nodigen tot het herzien en herschikken van conceptuele verbanden (Stokhof, De Vries 2009). Mindmapping via meer dynamische tools lijkt dit meer mogelijk te maken. In dit quasi-experimentele exploratieve onderzoek worden twee vragen

  18. Evidence-based doceren in het hoger onderwijs met ICT

    NARCIS (Netherlands)

    Van den Berg, Ellen; Kirschner, Paul A.

    2013-01-01

    Van den Berg, E., & Kirschner, P. A. (2012). Evidence-based doceren in het hoger onderwijs met ICT [Evidence based teaching in higher education with ICT]. In L. A. Plugge (Ed.), WTR Trendrapport 2012 De Bakens verzetten (pp. 1-10). Utrecht, Nederland: Stichting SURF.

  19. Zuivering brouwerijprocesafvalwater met behulp van microalgen: Resultaten onderzoek 2012

    NARCIS (Netherlands)

    Dijk, van W.; Schipperus, R.; Grobben, S.A.; Weide, van der R.Y.

    2013-01-01

    In een samenwerkingsverband van Heineken Nederland BV, Algae Food & Fuel en WUR (Acrres) is in 2012 een onderzoeksproject gestart om de mogelijkheden van zuivering van procesafvalwater van de brouwerijen met behulp van algen te onderzoeken. In het kader van dit project is in 2012 een

  20. Een bepalingsmethode voor thallium in regenwater met behulp van voltammetrie

    NARCIS (Netherlands)

    Struijs; J.; Wolfs; P.M.; Esseveld; F.G.van

    1985-01-01

    In dit rapport wordt een bepalingmethode beschreven voor thallium in het nanogram/liter-gebied, waarbij gebruik wordt gemaakt van differentiele pulse-anodic stripping voltammetry (DPASV) aan de dunne kwikfilm. Met deze techniek blijkt het mogelijk om de concentratie van dit element rechtstreeks

  1. Consumentenpanel Gezondheidszorg: basisrapport met informatie over het panel .

    NARCIS (Netherlands)

    Brabers, A.E.M.; Reitsma-van Rooijen, M.; Jong, J.D. de

    2012-01-01

    Het NIVEL is onlangs gestart met de werving van 1.000 migranten voor het Consumentenpanel Gezondheidszorg. In het panel worden landelijk meningen en ervaringen verzameld van gebruikers van de gezondheidszorg. De panelleden moeten daarom een goede afspiegeling vormen van de bevolking. Het panel

  2. Consumentenpanel Gezondheidszorg: basisrapport met informatie over het panel, 2009.

    NARCIS (Netherlands)

    Reitsma-van Rooijen, M.; Jong, J.D. de

    2009-01-01

    Wat vinden we van de gezondheidszorg? Wat weten we ervan en wat zijn onze verwachtingen en ervaringen? Het NIVEL vindt een antwoord op dit soort vragen met het Consumentenpanel Gezondheidszorg, waarover nu een basisrapport is verschenen. De gezondheidszorg gaat iedereen aan. Het Consumentenpanel

  3. Testen van stoffen met een mogelijk afwerende werking op trips

    NARCIS (Netherlands)

    Pijnakker, J.; Leman, A.

    2014-01-01

    Secundaire plantenstoffen, zoals essentiële oliën, hebben het vermogen om te interfereren met het selectieproces van een geschikte waardplant door een plaaginsect. In het eerste gedeelte van dit verslag worden de resultaten beschreven van laboratorium- en kasproeven waarin een aantal mogelijk

  4. Effect of c-Met Inhibitor on HGF-induced Ovarian Carcinoma Cell Migration

    Science.gov (United States)

    Lo, Chun-Min; Lo, Jun-Chih; Yip, Kay-Pong

    2010-03-01

    The dysregulation of hepatocyte growth factor (HGF) and its receptor, c-Met, in cell migration contributes to tumor invasion and metastasis in numerous cancers including ovarian cancer. Specific inhibitors against HGF/c-Met signaling like SU11274, therefore, may have important therapeutic potential for the treatment of cancers. Here, we applied electric cell-substrate impedance sensing (ECIS) and traction force microscopy to evaluate the effect of SU11274 on HGF-treated SKOV-3 ovarian cancer cells. Our results showed that, compared with control cells, HGF-treated cell monolayer displayed lower junctional resistance between cells, larger cell-substrate separation, and higher cell micromotion. In addition, individual HGF-treated SKOV-3 cells demonstrated weaker traction forces on the collagen-coated polyacrylamide substrate than did control cells. These changes lead to faster directional movement of HGF-treated cells, as demonstrated with wound healing assay. Treatment of SKOV-3 cells with SU11274 indicated significant inhibition of HGF stimulation on all assays tested.

  5. MetAssimulo:Simulation of Realistic NMR Metabolic Profiles

    Directory of Open Access Journals (Sweden)

    De Iorio Maria

    2010-10-01

    Full Text Available Abstract Background Probing the complex fusion of genetic and environmental interactions, metabolic profiling (or metabolomics/metabonomics, the study of small molecules involved in metabolic reactions, is a rapidly expanding 'omics' field. A major technique for capturing metabolite data is 1H-NMR spectroscopy and this yields highly complex profiles that require sophisticated statistical analysis methods. However, experimental data is difficult to control and expensive to obtain. Thus data simulation is a productive route to aid algorithm development. Results MetAssimulo is a MATLAB-based package that has been developed to simulate 1H-NMR spectra of complex mixtures such as metabolic profiles. Drawing data from a metabolite standard spectral database in conjunction with concentration information input by the user or constructed automatically from the Human Metabolome Database, MetAssimulo is able to create realistic metabolic profiles containing large numbers of metabolites with a range of user-defined properties. Current features include the simulation of two groups ('case' and 'control' specified by means and standard deviations of concentrations for each metabolite. The software enables addition of spectral noise with a realistic autocorrelation structure at user controllable levels. A crucial feature of the algorithm is its ability to simulate both intra- and inter-metabolite correlations, the analysis of which is fundamental to many techniques in the field. Further, MetAssimulo is able to simulate shifts in NMR peak positions that result from matrix effects such as pH differences which are often observed in metabolic NMR spectra and pose serious challenges for statistical algorithms. Conclusions No other software is currently able to simulate NMR metabolic profiles with such complexity and flexibility. This paper describes the algorithm behind MetAssimulo and demonstrates how it can be used to simulate realistic NMR metabolic profiles with

  6. Sociale economie en de lokale overheid : samenwerken met sociale ondernemers als strategie bij werkgelegenheidsbeleid

    NARCIS (Netherlands)

    Smit, A.; Fermin, B.; Penninga, M.; Andriessen, S.

    2007-01-01

    Deze uitgave, vooral bestemd voor gemeenten, gaat over sociale economie en samenwerken met sociale ondernemingen. Sociale ondernemingen zijn bedrijven met een dubbele doelstelling, economisch én sociaal. Gemeenten kunnen met deze bedrijven samenwerken vanuit publieke doelstellingen, zoals activering

  7. The Met-genotype of the BDNF Val66Met polymorphism is associated with reduced Stroop interference in elderly.

    Science.gov (United States)

    Gajewski, Patrick D; Hengstler, Jan G; Golka, Klaus; Falkenstein, Michael; Beste, Christian

    2012-12-01

    Aging is accompanied by impairments of executive functions that rely on the functional integrity of fronto-striatal networks. This integrity is modulated by the release of neurotrophins like the brain-derived-neurotrophic factor (BDNF). Here, we investigate effects of the functional BDNF Val66Met polymorphism on interference processing in 131 healthy elderly subjects using event-related potentials (ERPs). In a Stroop task, participants had to indicate the name or the colour of colour-words while colour was either compatible or incompatible with the name. We show that susceptibility to Stroop-interference is affected by the BDNF Val66Met polymorphism: the Met-allele carriers showed better performance and enhanced N450 in interference trials. Other processes necessary to prepare and allocate cognitive resources to a particular task were not affected by BDNF Val66Met polymorphism, underlining the specificity of the observed effects. The observed performance and ERP difference is possibly due to dopamine related effects of BDNF in fronto-striatal networks, where it putatively mediates a shift in the balance of the direct and indirect pathway involved in inhibitory functions. Copyright © 2012 Elsevier Ltd. All rights reserved.

  8. A New Transgenic Mouse Model of Heart Failure and Cardiac Cachexia Raised by Sustained Activation of Met Tyrosine Kinase in the Heart

    Directory of Open Access Journals (Sweden)

    Valentina Sala

    2016-01-01

    Full Text Available Among other diseases characterized by the onset of cachexia, congestive heart failure takes a place of relevance, considering the high prevalence of this pathology in most European countries and in the United States, and is undergoing a rapid increase in developing countries. Actually, only few models of cardiac cachexia exist. Difficulties in the recruitment and follow-up of clinical trials implicate that new reproducible and well-characterized animal models are pivotal in developing therapeutic strategies for cachexia. We generated a new model of cardiac cachexia: a transgenic mouse expressing Tpr-Met receptor, the activated form of c-Met receptor of hepatocyte growth factor, specifically in the heart. We showed that the cardiac-specific induction of Tpr-Met raises a cardiac hypertrophic remodelling, which progresses into concentric hypertrophy with concomitant increase in Gdf15 mRNA levels. Hypertrophy progresses to congestive heart failure with preserved ejection fraction, characterized by reduced body weight gain and food intake and skeletal muscle wasting. Prevention trial by suppressing Tpr-Met showed that loss of body weight could be prevented. Skeletal muscle wasting was also associated with altered gene expression profiling. We propose transgenic Tpr-Met mice as a new model of cardiac cachexia, which will constitute a powerful tool to understand such complex pathology and test new drugs/approaches at the preclinical level.

  9. Activating mutation in MET oncogene in familial colorectal cancer

    Directory of Open Access Journals (Sweden)

    Schildkraut Joellen M

    2011-10-01

    Full Text Available Abstract Background In developed countries, the lifetime risk of developing colorectal cancer (CRC is 5%, and it is the second leading cause of death from cancer. The presence of family history is a well established risk factor with 25-35% of CRCs attributable to inherited and/or familial factors. The highly penetrant inherited colon cancer syndromes account for approximately 5%, leaving greater than 20% without clear genetic definition. Familial colorectal cancer has been linked to chromosome 7q31 by multiple affected relative pair studies. The MET proto-oncogene which resides in this chromosomal region is considered a candidate for genetic susceptibility. Methods MET exons were amplified by PCR from germline DNA of 148 affected sibling pairs with colorectal cancer. Amplicons with altered sequence were detected with high-resolution melt-curve analysis using a LightScanner (Idaho Technologies. Samples demonstrating alternative melt curves were sequenced. A TaqMan assay for the specific c.2975C >T change was used to confirm this mutation in a cohort of 299 colorectal cancer cases and to look for allelic amplification in tumors. Results Here we report a germline non-synonymous change in the MET proto-oncogene at amino acid position T992I (also reported as MET p.T1010I in 5.2% of a cohort of sibling pairs affected with CRC. This genetic variant was then confirmed in a second cohort of individuals diagnosed with CRC and having a first degree relative with CRC at prevalence of 4.1%. This mutation has been reported in cancer cells of multiple origins, including 2.5% of colon cancers, and in Conclusions Although the MET p.T992I genetic mutation is commonly found in somatic colorectal cancer tissues, this is the first report also implicating this MET genetic mutation as a germline inherited risk factor for familial colorectal cancer. Future studies on the cancer risks associated with this mutation and the prevalence in different at-risk populations will

  10. Met-Independent Hepatocyte Growth Factor-mediated regulation of cell adhesion in human prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Davis Rodney

    2006-07-01

    Full Text Available Abstract Background Prostate cancer cells communicate reciprocally with the stromal cells surrounding them, inside the prostate, and after metastasis, within the bone. Each tissue secretes factors for interpretation by the other. One stromally-derived factor, Hepatocyte Growth Factor (HGF, was found twenty years ago to regulate invasion and growth of carcinoma cells. Working with the LNCaP prostate cancer progression model, we found that these cells could respond to HGF stimulation, even in the absence of Met, the only known HGF receptor. The new HGF binding partner we find on the cell surface may help to clarify conflicts in the past literature about Met expression and HGF response in cancer cells. Methods We searched for Met or any HGF binding partner on the cells of the PC3 and LNCaP prostate cancer cell models, using HGF immobilized on agarose beads. By using mass spectrometry analyses and sequencing we have identified nucleolin protein as a novel HGF binding partner. Antibodies against nucleolin (or HGF were able to ameliorate the stimulatory effects of HGF on met-negative prostate cancer cells. Western blots, RT-PCR, and immunohistochemistry were used to assess nucleolin levels during prostate cancer progression in both LNCaP and PC3 models. Results We have identified HGF as a major signaling component of prostate stromal-conditioned media (SCM and have implicated the protein nucleolin in HGF signal reception by the LNCaP model prostate cancer cells. Antibodies that silence either HGF (in SCM or nucleolin (on the cell surfaces eliminate the adhesion-stimulatory effects of the SCM. Likewise, addition of purified HGF to control media mimics the action of SCM. C4-2, an LNCaP lineage-derived, androgen-independent human prostate cancer cell line, responds to HGF in a concentration-dependent manner by increasing its adhesion and reducing its migration on laminin substratum. These HGF effects are not due to shifts in the expression levels of

  11. Met-Independent Hepatocyte Growth Factor-mediated regulation of cell adhesion in human prostate cancer cells

    International Nuclear Information System (INIS)

    Tate, Amanda; Isotani, Shuji; Bradley, Michael J; Sikes, Robert A; Davis, Rodney; Chung, Leland WK; Edlund, Magnus

    2006-01-01

    Prostate cancer cells communicate reciprocally with the stromal cells surrounding them, inside the prostate, and after metastasis, within the bone. Each tissue secretes factors for interpretation by the other. One stromally-derived factor, Hepatocyte Growth Factor (HGF), was found twenty years ago to regulate invasion and growth of carcinoma cells. Working with the LNCaP prostate cancer progression model, we found that these cells could respond to HGF stimulation, even in the absence of Met, the only known HGF receptor. The new HGF binding partner we find on the cell surface may help to clarify conflicts in the past literature about Met expression and HGF response in cancer cells. We searched for Met or any HGF binding partner on the cells of the PC3 and LNCaP prostate cancer cell models, using HGF immobilized on agarose beads. By using mass spectrometry analyses and sequencing we have identified nucleolin protein as a novel HGF binding partner. Antibodies against nucleolin (or HGF) were able to ameliorate the stimulatory effects of HGF on met-negative prostate cancer cells. Western blots, RT-PCR, and immunohistochemistry were used to assess nucleolin levels during prostate cancer progression in both LNCaP and PC3 models. We have identified HGF as a major signaling component of prostate stromal-conditioned media (SCM) and have implicated the protein nucleolin in HGF signal reception by the LNCaP model prostate cancer cells. Antibodies that silence either HGF (in SCM) or nucleolin (on the cell surfaces) eliminate the adhesion-stimulatory effects of the SCM. Likewise, addition of purified HGF to control media mimics the action of SCM. C4-2, an LNCaP lineage-derived, androgen-independent human prostate cancer cell line, responds to HGF in a concentration-dependent manner by increasing its adhesion and reducing its migration on laminin substratum. These HGF effects are not due to shifts in the expression levels of laminin-binding integrins, nor can they be linked to

  12. MET-RODOS: A comprehensive atmospheric dispersion module

    DEFF Research Database (Denmark)

    Mikkelsen, T.; Thykier-Nielsen, S.; Astrup, P.

    1997-01-01

    air concentrations, and ground level gamma dose rates from up to 15 simultaneous released nuclides are calculated using a nested system of local and long range atmospheric dispersion models, driven by real-time available on-line meteorological information. The MET-PODOS module uses concurrently...... the available source term and weather information in the RODOS data base system, and returns, up to +36 h forecasts of nuclei-specific air and deposited concentrations including gamma dose rate estimations for display and subsequent processing within the RODOS framework. Weather and meteorology is available...... for operational use in 1999, the: MET-RODOS meteorological module is intended to service the PODOS system with actual and forecast (+36 h) nuclei-specific air concentrations, deposition values, and gamma radiation estimates on the local, national, and European scale. Provisions are furthermore being made...

  13. Operational Use of OGC Web Services at the Met Office

    Science.gov (United States)

    Wright, Bruce

    2010-05-01

    The Met Office has adopted the Service-Orientated Architecture paradigm to deliver services to a range of customers through Rich Internet Applications (RIAs). The approach uses standard Open Geospatial Consortium (OGC) web services to provide information to web-based applications through a range of generic data services. "Invent", the Met Office beta site, is used to showcase Met Office future plans for presenting web-based weather forecasts, product and information to the public. This currently hosts a freely accessible Weather Map Viewer, written in JavaScript, which accesses a Web Map Service (WMS), to deliver innovative web-based visualizations of weather and its potential impacts to the public. The intention is to engage the public in the development of new web-based services that more accurately meet their needs. As the service is intended for public use within the UK, it has been designed to support a user base of 5 million, the analysed level of UK web traffic reaching the Met Office's public weather information site. The required scalability has been realised through the use of multi-tier tile caching: - WMS requests are made for 256x256 tiles for fixed areas and zoom levels; - a Tile Cache, developed in house, efficiently serves tiles on demand, managing WMS request for the new tiles; - Edge Servers, externally hosted by Akamai, provide a highly scalable (UK-centric) service for pre-cached tiles, passing new requests to the Tile Cache; - the Invent Weather Map Viewer uses the Google Maps API to request tiles from Edge Servers. (We would expect to make use of the Web Map Tiling Service, when it becomes an OGC standard.) The Met Office delivers specialist commercial products to market sectors such as transport, utilities and defence, which exploit a Web Feature Service (WFS) for data relating forecasts and observations to specific geographic features, and a Web Coverage Service (WCS) for sub-selections of gridded data. These are locally rendered as maps or

  14. Testing ATLAS Z+MET excess with LHC run 2

    International Nuclear Information System (INIS)

    Lu, Xiaochuan; Terada, Takahiro

    2016-05-01

    The ATLAS collaboration reported a 3σ excess in the search of events containing on-Z dilepton, jets, and large missing momentum (MET) in the 8 TeV LHC run. Motivated by this excess, many models of new physics have been proposed. Recently, the ATLAS and CMS collaborations reported new results for similar Z+MET channels in the 13 TeV run. In this paper, we comprehensively discuss the consistency between the proposed models and the LHC results of Run 1 and Run 2. We find that in models with heavy gluino production, there is generically some tension between the 8 TeV and 13 TeV results. On the other hand, models with light squark production provide relatively better fitting to both results.

  15. Estimation of METs by Accelerometers while Walking and Running

    Science.gov (United States)

    Kurihara, Yosuke; Watanabe, Kajiro; Yoneyama, Mitsuru

    It is quite important for Japan to maintain or promote the health condition of elderly citizens. Given the circumstances, the Ministry of Health, Labour and Welfare has established the standards for the activities and exercises for promoting the health, and quantitatively determined the exercise intensity on 107 items of activities. This exercise intensity, however, requires recording the type and the duration of the activity to be calculated. In this paper, the exercise intensities are surmised using 3D accelerometer while the subjects are walking and running. As the result, the exercise intensities were surmised to be within the root mean square error of 1.2[METs] for walking and 3.2[METs] for running respectively.

  16. MetWAMer: eukaryotic translation initiation site prediction

    Directory of Open Access Journals (Sweden)

    Brendel Volker

    2008-09-01

    Full Text Available Abstract Background Translation initiation site (TIS identification is an important aspect of the gene annotation process, requisite for the accurate delineation of protein sequences from transcript data. We have developed the MetWAMer package for TIS prediction in eukaryotic open reading frames of non-viral origin. MetWAMer can be used as a stand-alone, third-party tool for post-processing gene structure annotations generated by external computational programs and/or pipelines, or directly integrated into gene structure prediction software implementations. Results MetWAMer currently implements five distinct methods for TIS prediction, the most accurate of which is a routine that combines weighted, signal-based translation initiation site scores and the contrast in coding potential of sequences flanking TISs using a perceptron. Also, our program implements clustering capabilities through use of the k-medoids algorithm, thereby enabling cluster-specific TIS parameter utilization. In practice, our static weight array matrix-based indexing method for parameter set lookup can be used with good results in data sets exhibiting moderate levels of 5'-complete coverage. Conclusion We demonstrate that improvements in statistically-based models for TIS prediction can be achieved by taking the class of each potential start-methionine into account pending certain testing conditions, and that our perceptron-based model is suitable for the TIS identification task. MetWAMer represents a well-documented, extensible, and freely available software system that can be readily re-trained for differing target applications and/or extended with existing and novel TIS prediction methods, to support further research efforts in this area.

  17. El sexo de las metáforas

    Directory of Open Access Journals (Sweden)

    Pérez Sedeño, Eulalia

    2011-02-01

    Full Text Available The hypothesis that states metaphors are structurally determinant in our social relations, routines, and experience has been accepted broadly in the last decades. Moreover, metaphors are to be found in many different levels of scientific practices, and have a diverse set of functions in science. Therefore, they impregnate all scientific enterprise. In this work we examine selected gender metaphors used in biology. We show metaphors are effective precisely because its effectiveness depends on shared social conventions, kinship relations and, authority that, by convention, is given to those that use them.

    La tesis de que las metáforas estructuran gran parte de nuestras relaciones sociales y nuestra experiencia cotidiana ha sido ampliamente aceptada en las últimas décadas. En la ciencia, además, aparecen en muchos niveles y desempeñan diversas funciones, impregnando todo el quehacer científico. En este trabajo se examinan algunas metáforas de género usadas en biología. Se muestra que las metáforas eficaces lo son porque su efectividad depende de las convenciones sociales compartidas, los parecidos de familia ya vigentes y de la autoridad que, por convención, se otorga a quienes las usan.

  18. Impact of COMT Val 108/158 Met and DRD2 Taq1B gene polymorphisms on vulnerability to cigarette smoking of Thai males.

    Science.gov (United States)

    Suriyaprom, Kanjana; Tungtrongchitr, Rungsunn; Harnroongroj, Talabporn

    2013-03-01

    The nicotine in cigarette smoke can stimulate the dopaminergic reward pathways. The catechol O-methyltransferase gene (COMT) and dopamine receptor 2 gene (DRD2) are dopamine-related genes. Genetic polymorphisms in these two genes are potential candidates in determining an individual's predisposition to cigarette smoking. The purposes of this study were to examine the association between two polymorphisms in COMT Val (108/158) Met and DRD2 Taq1B and anthropometric-biochemical parameters and to ascertain the association between these polymorphisms and cigarette smoking. The levels of anthropometric-biochemical parameters were determined. COMT Val (108/158) Met and DRD2 Taq1B polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism technique. With regard to COMT Val (108/158) Met and DRD2 Taq1B polymorphisms, no differences were found in anthropometric-biochemical variables, except for thiocyanate concentration. Smoking status was significantly associated with COMT Val (108/158) Met polymorphism, but not associated with DRD2 Taq1B polymorphism. Logistic regression analysis showed that COMT Val (108/158) Met gene polymorphism, educational status, parental smoking, and alcohol consumption had statistically significant impacts on cigarette smoking. The results suggest that COMT Val (108/158) Met genetic polymorphisms, but not DRD2 Taq1B, may influence susceptibility to cigarette smoking among Thai males.

  19. MET tyrosine kinase inhibitor crizotinib (PF-02341066) shows differential antitumor effects in non-small cell lung cancer according to MET alterations.

    Science.gov (United States)

    Tanizaki, Junko; Okamoto, Isamu; Okamoto, Kunio; Takezawa, Ken; Kuwata, Kiyoko; Yamaguchi, Haruka; Nakagawa, Kazuhiko

    2011-10-01

    Tyrosine kinase inhibitors (TKIs) targeted to MET are undergoing clinical trials in patients with solid tumors, but the precise mechanism of the antitumor activity of these drugs remains unclear. We examined the antitumor action of the MET-TKI crizotinib (PF-02341066) in lung cancer cells that are positive or negative for MET amplification or mutation. The antitumor action of crizotinib was evaluated on the basis of signal transduction, cell proliferation, apoptosis, and progression of tumor xenografts. Inhibition of MET signaling by crizotinib or by RNA interference-mediated MET depletion resulted in the induction of apoptosis accompanied by inhibition of AKT and extracellular signal-regulated kinase phosphorylation in lung cancer cells with MET amplification but not in cells with a MET mutation or in those without amplification or mutation of MET. These results suggest that MET signaling is essential for the survival of cells with MET amplification but not for that of cells without this genetic change, including those with a MET mutation. Crizotinib up-regulated the expression of BIM, a proapoptotic member of the Bcl-2 family, and down-regulated that of survivin, a member of the inhibitor of apoptosis protein family, in cells with MET amplification. Forced depletion of BIM and expression of survivin each inhibited crizotinib-induced apoptosis, suggesting that both up-regulation of BIM and down-regulation of survivin contribute to the proapoptotic effect of crizotinib. Crizotinib shows a marked antitumor action in MET amplification-positive lung cancer cells but not in cells without MET amplification, including those with a MET mutation.

  20. MET gene exon 14 deletion created using the CRISPR/Cas9 system enhances cellular growth and sensitivity to a MET inhibitor.

    Science.gov (United States)

    Togashi, Yosuke; Mizuuchi, Hiroshi; Tomida, Shuta; Terashima, Masato; Hayashi, Hidetoshi; Nishio, Kazuto; Mitsudomi, Tetsuya

    2015-12-01

    MET splice site mutations resulting in an exon 14 deletion have been reported to be present in about 3% of all lung adenocarcinomas. Patients with lung adenocarcinoma and a MET splice site mutation who have responded to MET inhibitors have been reported. The CRISPR/Cas9 system is a recently developed genome-engineering tool that can easily and rapidly cause small insertions or deletions. We created an in vitro model for MET exon 14 deletion using the CRISPR/Cas9 system and the HEK293 cell line. The phenotype, which included MET inhibitor sensitivity, was then investigated in vitro. Additionally, MET splice site mutations were analyzed in several cancers included in The Cancer Genome Atlas (TCGA) dataset. An HEK293 cell line with a MET exon 14 deletion was easily and rapidly created; this cell line had a higher MET protein expression level, enhanced MET phosphorylation, and prolonged MET activation. In addition, a direct comparison of phenotypes using this system demonstrated enhanced cellular growth, colony formation, and MET inhibitor sensitivity. In the TCGA dataset, lung adenocarcinomas had the highest incidence of MET exon 14 deletions, while other cancers rarely carried such mutations. Approximately 10% of the lung adenocarcinoma samples without any of driver gene alterations carried the MET exon 14 deletion. These findings suggested that this system may be useful for experiments requiring the creation of specific mutations, and the present experimental findings encourage the development of MET-targeted therapy against lung cancer carrying the MET exon 14 deletion. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  1. MET17 and Hydrogen Sulfide Formation in Saccharomyces cerevisiae

    Science.gov (United States)

    Spiropoulos, Apostolos; Bisson, Linda F.

    2000-01-01

    Commercial isolates of Saccharomyces cerevisiae differ in the production of hydrogen sulfide (H2S) during fermentation, which has been attributed to variation in the ability to incorporate reduced sulfur into organic compounds. We transformed two commercial strains (UCD522 and UCD713) with a plasmid overexpressing the MET17 gene, which encodes the bifunctional O-acetylserine/O-acetylhomoserine sulfhydrylase (OAS/OAH SHLase), to test the hypothesis that the level of activity of this enzyme limits reduced sulfur incorporation, leading to H2S release. Overexpression of MET17 resulted in a 10- to 70-fold increase in OAS/OAH SHLase activity in UCD522 but had no impact on the level of H2S produced. In contrast, OAS/OAH SHLase activity was not as highly expressed in transformants of UCD713 (0.5- to 10-fold) but resulted in greatly reduced H2S formation. Overexpression of OAS/OAH SHLase activity was greater in UCD713 when grown under low-nitrogen conditions, but the impact on reduction of H2S was greater under high-nitrogen conditions. Thus, there was not a good correlation between the level of enzyme activity and H2S production. We measured cellular levels of cysteine to determine the impact of overexpression of OAS/OAH SHLase activity on sulfur incorporation. While Met17p activity was not correlated with increased cysteine production, conditions that led to elevated cytoplasmic levels of cysteine also reduced H2S formation. Our data do not support the simple hypothesis that variation in OAS/OAH SHLase activity is correlated with H2S production and release. PMID:11010893

  2. Sandscape - engaging people in Met Office science through sand sculpture

    Science.gov (United States)

    Liggins, Felicity; Dowell, Ellen; Wardley, Jamie; Jamieson, Claire

    2017-04-01

    In 2015, the Met Office's award-winning outreach programme, designed to inspire the next generation of scientists and engineers, delivered one of its most ambitious and creative activities to date. It explored how scientists and artists can come together to create an engaging experience for young people and families. This activity was called Sandscape. Sandscape is an interactive sand sculpture workshop exploring how weather and climate affect our health. Budding sand sculptors are shown how to fashion elaborate structures from sand and water - creating a landscape with bridges, skyscrapers, forests and factories. As they work, participants are encouraged by the scientists delivering the activity to reflect on what makes a healthy city, considering how the natural and built environments influence air quality and circulation and how this impacts our health. Topics discussed include urban heat islands, air pollution and dispersion modelling, pollen forecasting and predicting the wind-borne spread of animal diseases. Each hour long workshop culminates in a dramatic demonstration that uses dry ice to represent clean air circulating from mountains, along rivers and into cities. Here we present an overview of Sandscape, identify the strengths and challenges of such a collaborative, innovative and playful approach to public engagement and share the results of our evaluation. Sandscape was originally supported by the Met Office and the Wellcome Trust, and produced by Einstein's Garden in collaboration with the Met Office, scientists from the University of Exeter and sand sculptors from Sand in Your Eye. It was first presented in Einstein's Garden at Green Man festival 2015, an independent music and arts festival held annually in Wales, and has since been invited to run at the 2015 Bournemouth Arts By the Sea Festival and Teignmouth's TRAIL Sculpture Festival in the summer of 2016.

  3. A Comparative Study of virtual and operational met mast data

    International Nuclear Information System (INIS)

    Orhan, Dr Ö Emre; Ahmet, Gökhan

    2014-01-01

    Performance of wind assessment studies depend on the adequacy and duration of the wind data. For a reasonable wind assessment, at least one full year wind data is needed so that, all the variations throughout the year are represented. On the other hand, it is always a question of time and cost how to get the wind data. On-site measurements are the most common way of obtaining wind data but it is the most expensive and time consuming as well. Apart from onsite data, there are also reanalysis long term data sources like MERRA, NCAR, etc. Time and spatial resolution of these long term data are lower compared to on-site measurements but in cases where on-site measurements are not available, they are also utilized. On top of on-site and reanalysis wind data, weather forecasting models like WRF, MM5 are available. Although, these models mainly are used for forecasting services, flexibility of the models makes them suitable for preliminary resource assessment purposes. In this study, comparisons of annual energy production estimations are computed using virtual and on-site met mast data separately for a specific time range. The widely used weather research and forecasting model (WRF) is used to provide virtual met mast data. Once WRF simulations are completed, interpolation routines are employed in order to extract data for a specific location. The on-site met mast is located inside a wind farm project area which is under development. Project site is located in the south of Turkey. There are four different met masts, three of them recording wind data presently. On-site measurements together with WRF results are used to obtain energy yields for the project area. The performance of both methodologies is compared. It has been observed that WRF can as well serve as a preliminary model in cases where no other data source is available but the model has to be implemented with great care depending on the project site conditions

  4. Flare forecasting at the Met Office Space Weather Operations Centre

    OpenAIRE

    Murray, Sophie A.; Bingham, Suzy; Sharpe, Michael; Jackson, David R.

    2017-01-01

    The Met Office Space Weather Operations Centre produces 24/7/365 space weather guidance, alerts, and forecasts to a wide range of government and commercial end users across the United Kingdom. Solar flare forecasts are one of its products, which are issued multiple times a day in two forms; forecasts for each active region on the solar disk over the next 24 hours, and full-disk forecasts for the next four days. Here the forecasting process is described in detail, as well as first verification...

  5. Mechanism of the modulating action of met-enkephalin on glutamatergic synaptic transmission

    Energy Technology Data Exchange (ETDEWEB)

    Kuznetsov, V.I.; Godukhin, O.V.

    1985-11-01

    The authors show that the inhibiting effect of met-enkephalin on the glutamate-induced responses of the neurons of the neostriatum may be due to the inhibiting influence of the opioid peptide on the binding of glutamate to its postsynaptic receptors. The authors extracted the striatum from the brains of Wistar rats (100-150 g) and homogenized in 20 volumes of 0.32 sucrose. The homogenate was centrifuged at 900g for 10 min. The supernatant was removed and centrifuged at 20,000g for 40 min. The precipitate obtained (P2-fraction) was subjected to hypoosmotic shock in de-ionized water and recentrifuged at 20,000g for 30 min. The precipitate, containing the fraction of plasma membranes, was suspended in 50 ml of Tris-HCl, pH 7.4, to a protein concentration of 1-2 mg/ml, and used in experiments on the binding of (/sup 3/H)glutamate on the same day. To determine the binding of (/sup 3/H)glutamate, 20 microliters of (/sup 3/H)glutamate (specific activity 29 Ci/mmole), 20 microliters of the membrane suspension, 40 microliters of (0.5 x 10/sup -8/-10/sup -7/ M) met-enkephalin, and 100 microliters of Tris-buffer were introduced into 1.5 ml polyethylene test tubes. The final concentration of (/sup 3/H)glutamate in solution was 10/sup -8/-4 x 10/sup -7/ M. Non-specific binding was determined in the presence of 10/sup -3/ M glutamate. The membranes were incubated with a solution of (/sup 3/H)glutamate at 20/sup 0/C for 30 min.

  6. HGF-independent regulation of MET and GAB1 by nonreceptor tyrosine kinase FER potentiates metastasis in ovarian cancer.

    Science.gov (United States)

    Fan, Gaofeng; Zhang, Siwei; Gao, Yan; Greer, Peter A; Tonks, Nicholas K

    2016-07-01

    Ovarian cancer cells disseminate readily within the peritoneal cavity, which promotes metastasis, and are often resistant to chemotherapy. Ovarian cancer patients tend to present with advanced disease, which also limits treatment options; consequently, new therapies are required. The oncoprotein tyrosine kinase MET, which is the receptor for hepatocyte growth factor (HGF), has been implicated in ovarian tumorigenesis and has been the subject of extensive drug development efforts. Here, we report a novel ligand- and autophosphorylation-independent activation of MET through the nonreceptor tyrosine kinase feline sarcoma-related (FER). We demonstrated that the levels of FER were elevated in ovarian cancer cell lines relative to those in immortalized normal surface epithelial cells and that suppression of FER attenuated the motility and invasive properties of these cancer cells. Furthermore, loss of FER impaired the metastasis of ovarian cancer cells in vivo. Mechanistically, we demonstrated that FER phosphorylated a signaling site in MET: Tyr1349. This enhanced activation of RAC1/PAK1 and promoted a kinase-independent scaffolding function that led to recruitment and phosphorylation of GAB1 and the specific activation of the SHP2-ERK signaling pathway. Overall, this analysis provides new insights into signaling events that underlie metastasis in ovarian cancer cells, consistent with a prometastatic role of FER and highlighting its potential as a novel therapeutic target for metastatic ovarian cancer. © 2016 Fan et al.; Published by Cold Spring Harbor Laboratory Press.

  7. Verification of space weather forecasts at the UK Met Office

    Science.gov (United States)

    Bingham, S.; Sharpe, M.; Jackson, D.; Murray, S.

    2017-12-01

    The UK Met Office Space Weather Operations Centre (MOSWOC) has produced space weather guidance twice a day since its official opening in 2014. Guidance includes 4-day probabilistic forecasts of X-ray flares, geomagnetic storms, high-energy electron events and high-energy proton events. Evaluation of such forecasts is important to forecasters, stakeholders, model developers and users to understand the performance of these forecasts and also strengths and weaknesses to enable further development. Met Office terrestrial near real-time verification systems have been adapted to provide verification of X-ray flare and geomagnetic storm forecasts. Verification is updated daily to produce Relative Operating Characteristic (ROC) curves and Reliability diagrams, and rolling Ranked Probability Skill Scores (RPSSs) thus providing understanding of forecast performance and skill. Results suggest that the MOSWOC issued X-ray flare forecasts are usually not statistically significantly better than a benchmark climatological forecast (where the climatology is based on observations from the previous few months). By contrast, the issued geomagnetic storm activity forecast typically performs better against this climatological benchmark.

  8. Analysis of PGC-1α variants Gly482Ser and Thr612Met concerning their PPARγ2-coactivation function

    International Nuclear Information System (INIS)

    Nitz, Inke; Ewert, Agnes; Klapper, Maja; Doering, Frank

    2007-01-01

    Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a cofactor involved in adaptive thermogenesis, fatty acid oxidation, and gluconeogenesis. Dysfunctions of this protein are likely to contribute to the development of obesity and the metabolic syndrome. This is in part but not definitely confirmed by results of population studies. The aim of this study was to investigate if common genetic variants rs8192678 (Gly482Ser) and rs3736265 (Thr612Met) in the PGC-1α gene lead to a functional consequence in cofactor activity using peroxisome proliferator-activated receptor-γ 2 (PPARγ2) as interacting transcription factor. Reporter gene assays in HepG2 cells with wildtype and mutant proteins of both PGC1α and PPARγ2 (Pro12Ala, rs1801282) using the acyl-CoA-binding protein (ACBP) promoter showed no difference in coactivator activity. This is First study implicating that the Gly482Ser and Thr612Met polymorphisms in PGC-1α and Pro12Ala polymorphism in PPARγ2 do not affect the functional integrity of these proteins

  9. Early Clinical Development of ARQ 197, a Selective, Non–ATP-Competitive Inhibitor Targeting MET Tyrosine Kinase for the Treatment of Advanced Cancers

    Science.gov (United States)

    Schwartz, Brian; Garmey, Edward

    2011-01-01

    Expression of the receptor tyrosine kinase c-MET (MET, mesenchymal-epithelial transition factor) in many cancers, and its participation in multiple signal transduction pathways involved in malignant tumor growth, suggest a wide therapeutic potential for MET inhibition in human cancer. Here we describe the discovery and early clinical development of ARQ 197, a novel, selective, non–ATP-competitive inhibitor of MET. Phase I studies demonstrate that ARQ 197 has a predictable pharmacokinetics and favorable safety profile, making it a potentially ideal partner for combination with cytotoxic chemotherapies and targeted anticancer agents. Results from phase I and phase II trials demonstrate preliminary evidence of anticancer activity. New data from a global phase II randomized trial comparing a combination of ARQ 197 plus erlotinib with erlotinib/placebo, in endothelial growth factor receptor inhibitor-naïve patients with locally advanced/metastatic non–small cell lung cancer, demonstrate improvement in progression-free and overall survival with combined therapy. Results were especially pronounced for patients with non–squamous lung cancer histologies, and in particular molecularly defined subgroups including KRAS mutations. These and other data from ARQ 197 clinical trials in hepatocellular, germ-cell, pancreatic (in combination with gemcitabine), and colorectal (in combination with cetuximab and irinotecan) cancers further highlight the potential role of ARQ 197 in existing and emerging anticancer therapeutic regimens. PMID:21632449

  10. Early clinical development of ARQ 197, a selective, non-ATP-competitive inhibitor targeting MET tyrosine kinase for the treatment of advanced cancers.

    Science.gov (United States)

    Adjei, Alex A; Schwartz, Brian; Garmey, Edward

    2011-01-01

    Expression of the receptor tyrosine kinase c-MET (MET, mesenchymal-epithelial transition factor) in many cancers, and its participation in multiple signal transduction pathways involved in malignant tumor growth, suggest a wide therapeutic potential for MET inhibition in human cancer. Here we describe the discovery and early clinical development of ARQ 197, a novel, selective, non-ATP-competitive inhibitor of MET. Phase I studies demonstrate that ARQ 197 has a predictable pharmacokinetics and favorable safety profile, making it a potentially ideal partner for combination with cytotoxic chemotherapies and targeted anticancer agents. Results from phase I and phase II trials demonstrate preliminary evidence of anticancer activity. New data from a global phase II randomized trial comparing a combination of ARQ 197 plus erlotinib with erlotinib/placebo, in endothelial growth factor receptor inhibitor-naïve patients with locally advanced/metastatic non-small cell lung cancer, demonstrate improvement in progression-free and overall survival with combined therapy. Results were especially pronounced for patients with non-squamous lung cancer histologies, and in particular molecularly defined subgroups including KRAS mutations. These and other data from ARQ 197 clinical trials in hepatocellular, germ-cell, pancreatic (in combination with gemcitabine), and colorectal (in combination with cetuximab and irinotecan) cancers further highlight the potential role of ARQ 197 in existing and emerging anticancer therapeutic regimens.

  11. Peritoneal administration of Met-RANTES attenuates inflammatory and nociceptive responses in a murine neuropathic pain model.

    Science.gov (United States)

    Liou, Jiin-Tarng; Mao, Chih-Chieh; Ching-Wah Sum, Daniel; Liu, Fu-Chao; Lai, Ying-Shu; Li, Jui-Chin; Day, Yuan-Ji

    2013-01-01

    The C-C motif chemokine ligand 5 (CCL5; also known as regulated on activation, normal T expressed and secreted, or RANTES) is a member of the CC family of chemokines that specifically attract and activate leukocytes to sites of inflammation. Although CCL5 has been implicated in the processing of pain, its detailed mechanisms of action are still unknown. In this study, we investigated the potential of the Met-RANTES, a selective CCL5 receptor antagonist, via peritoneal administration to modulate the recruitment of inflammatory cells in injured sites and attenuate nociceptive responses in a neuropathic pain model in mice. Nociceptive sensitization, immune cell infiltration, multiple cytokine secretion, and opioid peptide expression in damaged nerves were studied. Our results indicated that Met-RANTES-treated mice had less behavioral hypersensitivity after partial sciatic nerve ligation. Macrophage infiltration, pro-inflammatory cytokine (TNFα, IL-1β, IL-6, and IFNγ) protein secretion, and enkephalin, β-endorphin, and dynorphin mRNA expression in damaged nerves following partial sciatic nerve ligation were significantly decreased, and anti-inflammatory cytokine (IL-10) protein was significantly increased in Met-RANTES-treated mice. These results suggest that CCL5 is capable of regulating the microenvironment that controls behavioral hypersensitivity at the level of the peripheral injured site in a murine chronic neuropathic pain model. The present study identifies the potent pro-inflammatory potential of CCL5 and verifies the possible role of selective CCL5 receptor inhibitor in a murine neuropathic pain model. Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.

  12. Frequency of mesenchymal-epithelial transition factor gene (MET) and the catalytic subunit of phosphoinositide-3-kinase (PIK3CA) copy number elevation and correlation with outcome in patients with early stage breast cancer.

    Science.gov (United States)

    Gonzalez-Angulo, Ana M; Chen, Huiqin; Karuturi, Meghan S; Chavez-MacGregor, Mariana; Tsavachidis, Spyrus; Meric-Bernstam, Funda; Do, Kim-Anh; Hortobagyi, Gabriel N; Thompson, Patricia A; Mills, Gordon B; Bondy, Melissa L; Blumenschein, George R

    2013-01-01

    The current study was conducted to determine the frequency and association between recurrence-free survival (RFS) and MET and catalytic subunit of phosphoinositide-3-kinase (PIK3CA) copy number elevations in patients with early stage breast cancer. Tumor DNA was extracted from 971 formalin-fixed, paraffin-embedded early breast cancers for molecular inversion probes arrays. Data were segmented using the single-nucleotide polymorphism (SNP)-FASST2 segmentation algorithm. Copy number gains were called when the copy number of each segment was greater than 2.3 or 1.7, respectively. RFS was estimated by the Kaplan-Meier method. Cox proportional hazards models were fit to determine independent associations between copy number and RFS. Of the 971 tumors studied, 82 (8.44%) and 134 (13.8%) had an elevation of the MET or PIK3CA copy number, respectively, and 25.6% of tumors with a MET copy number elevation had a PIK3CA copy number elevation. Patients with either a MET or PI3KCA high copy number tended to have poorer prognostic features (larger tumor size, higher tumor grade, and hormone receptor negativity). Both MET and PIK3CA high copy numbers were more likely to occur in patients with triple receptor-negative disease (P = .019 and P number and MET normal/low copy number, respectively (P = .06) and 73.1%, and 82.3% for PIK3CA high copy number and PIK3CA normal/low copy number, respectively (P = .15). A high copy number for either gene was not found to be an independent predictor of RFS. A high copy number of MET or PIK3CA was found to be associated with poorer prognostic features and triple receptor-negative disease. Coamplification was frequent. Patients with tumors with high MET copy numbers tended to have a worse RFS. Copyright © 2012 American Cancer Society.

  13. Olive phenolics as c-Met inhibitors: (--Oleocanthal attenuates cell proliferation, invasiveness, and tumor growth in breast cancer models.

    Directory of Open Access Journals (Sweden)

    Mohamed R Akl

    Full Text Available Dysregulation of the Hepatocyte growth factor (HGF/c-Met signaling axis upregulates diverse tumor cell functions, including cell proliferation, survival, scattering and motility, epithelial-to-mesenchymal transition (EMT, angiogenesis, invasion, and metastasis. (--Oleocanthal is a naturally occurring secoiridoid from extra-virgin olive oil, which showed antiproliferative and antimigratory activity against different cancer cell lines. The aim of this study was to characterize the intracellular mechanisms involved in mediating the anticancer effects of (--oleocanthal treatment and the potential involvement of c-Met receptor signaling components in breast cancer. Results showed that (--oleocanthal inhibits the growth of human breast cancer cell lines MDA-MB-231, MCF-7 and BT-474 while similar treatment doses were found to have no effect on normal human MCF10A cell growth. In addition, (--oleocanthal treatment caused a dose-dependent inhibition of HGF-induced cell migration, invasion and G1/S cell cycle progression in breast cancer cell lines. Moreover, (--oleocanthal treatment effects were found to be mediated via inhibition of HGF-induced c-Met activation and its downstream mitogenic signaling pathways. This growth inhibitory effect is associated with blockade of EMT and reduction in cellular motility. Further results from in vivo studies showed that (--oleocanthal treatment suppressed tumor cell growth in an orthotopic model of breast cancer in athymic nude mice. Collectively, the findings of this study suggest that (--oleocanthal is a promising dietary supplement lead with potential for therapeutic use to control malignancies with aberrant c-Met activity.

  14. Deguelin action involves c-Met and EGFR signaling pathways in triple negative breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Rajeshwari Mehta

    Full Text Available Treatment of breast cancer patients with antiestrogens and aromatase inhibitor(s or Herceptin have shown significant success in steroid receptor positive or Her-2+ breast cancers respectively. However, choice of treatments for breast cancer patients with negative status for estrogen, progesterone receptors and HER2/neu is limited. As a result, search for appropriate therapy regimen for these triple negative breast cancers (TNBC has become a major focus of investigations for many laboratories. Recently, Deguelin, a natural product isolated from African plant Mundulea sericea (Leguminossae has shown both antiproliferative actions in various cancers including breast as well as chemoprenventive activity against carcinogen induced experimental cancers. In this report we evaluated efficacy and mechanism of action of Deguelin in triple negative breast cancer cell lines.In vitro, Deguelin in a dose and time dependent manner inhibited the growth of MDA-MB-231, MDA-MB-468, BT-549 and BT-20 cells. Deguelin (2 or 4 mg/kg body weight, when injected intraperitoneally, reduced the in vivo tumor growth of MDA-MB-231 cells transplanted subcutaneously in athymic mice. Moreover it was nontoxic as evident from daily observations on mobility, food and water consumption and comparison of bodyweight and other visceral organ weights with those in control animals at the termination of the study. The western blot analyses and immunostaining studies indicated that the deguelin effects may be mediated through EGFR-PAKT/c-Met p-ERK and NF-κB by down regulating their downstream targets such as p-STAT3, c-Myc, Survivin.These results suggest that Deguelin may have a significant therapeutic value for the treatment of TNBC patients.

  15. Metallography at the Met Lab -- The first fifty years

    International Nuclear Information System (INIS)

    Lee, R.H.

    1995-01-01

    The Met Lab at the University of Chicago was established to build the world's first nuclear reactor. The object was to see if a pile (CP-1) could be built to create a sustained chain reaction, i.e., controlled nuclear fission. New materials of the very best quality were needed and people of many skills worked together to achieve the goal as quickly as possible. This is the story of a select group of people who were scientific and engineering pioneers in this new field. Research continued at new sites on more advanced reactors and cooling systems. Many problems were encountered in the fabrication of reactor components, and metallography was a crucial method of analyzing the reactions and quality of consolidation. 1996 will be the 50th anniversary of the beginning of the National Laboratories, so it is appropriate to commemorate and recall some pioneering achievements

  16. Flare forecasting at the Met Office Space Weather Operations Centre

    Science.gov (United States)

    Murray, S. A.; Bingham, S.; Sharpe, M.; Jackson, D. R.

    2017-04-01

    The Met Office Space Weather Operations Centre produces 24/7/365 space weather guidance, alerts, and forecasts to a wide range of government and commercial end-users across the United Kingdom. Solar flare forecasts are one of its products, which are issued multiple times a day in two forms: forecasts for each active region on the solar disk over the next 24 h and full-disk forecasts for the next 4 days. Here the forecasting process is described in detail, as well as first verification of archived forecasts using methods commonly used in operational weather prediction. Real-time verification available for operational flare forecasting use is also described. The influence of human forecasters is highlighted, with human-edited forecasts outperforming original model results and forecasting skill decreasing over longer forecast lead times.

  17. The MeteoMet2 project—highlights and results

    Science.gov (United States)

    Merlone, A.; Sanna, F.; Beges, G.; Bell, S.; Beltramino, G.; Bojkovski, J.; Brunet, M.; del Campo, D.; Castrillo, A.; Chiodo, N.; Colli, M.; Coppa, G.; Cuccaro, R.; Dobre, M.; Drnovsek, J.; Ebert, V.; Fernicola, V.; Garcia-Benadí, A.; Garcia-Izquierdo, C.; Gardiner, T.; Georgin, E.; Gonzalez, A.; Groselj, D.; Heinonen, M.; Hernandez, S.; Högström, R.; Hudoklin, D.; Kalemci, M.; Kowal, A.; Lanza, L.; Miao, P.; Musacchio, C.; Nielsen, J.; Nogueras-Cervera, M.; Oguz Aytekin, S.; Pavlasek, P.; de Podesta, M.; Rasmussen, M. K.; del-Río-Fernández, J.; Rosso, L.; Sairanen, H.; Salminen, J.; Sestan, D.; Šindelářová, L.; Smorgon, D.; Sparasci, F.; Strnad, R.; Underwood, R.; Uytun, A.; Voldan, M.

    2018-02-01

    Launched in 2011 within the European Metrology Research Programme (EMRP) of EURAMET, the joint research project ‘MeteoMet’—Metrology for Meteorology—is the largest EMRP consortium; national metrology institutes, universities, meteorological and climate agencies, research institutes, collaborators and manufacturers are working together, developing new metrological techniques, as well as improving existing ones, for use in meteorological observations and climate records. The project focuses on humidity in the upper and surface atmosphere, air temperature, surface and deep-sea temperatures, soil moisture, salinity, permafrost temperature, precipitation, and the snow albedo effect on air temperature. All tasks are performed using a rigorous metrological approach and include the design and study of new sensors, new calibration facilities, the investigation of sensor characteristics, improved techniques for measurements of essential climate variables with uncertainty evaluation, traceability, laboratory proficiency and the inclusion of field influencing parameters, long-lasting measurements, and campaigns in remote and extreme areas. The vision for MeteoMet is to take a step further towards establishing full data comparability, coherency, consistency, and long-term continuity, through a comprehensive evaluation of the measurement uncertainties for the quantities involved in the global climate observing systems and the derived observations. The improvement in quality of essential climate variables records, through the inclusion of measurement uncertainty budgets, will also highlight possible strategies for the reduction of the uncertainty. This contribution presents selected highlights of the MeteoMet project and reviews the main ongoing activities, tasks and deliverables, with a view to its possible future evolution and extended impact.

  18. Recursos minerais não-metálicos

    Directory of Open Access Journals (Sweden)

    Arlei Benedito Macedo

    1998-08-01

    Full Text Available OS RECURSOS minerais não-metálicos, embora muito importantes para o atendimento das necessidades da população e para o comércio exterior, são pouco contemplados pelas ações governamentais e ignorados pelo público. Geralmente não-incluída no planejamento territorial, a mineração de não-metálicos no Brasil causa extensos impactos ambientais mal controlados. Propõe-se uma ação coordenada de fomento e controle patrimonial e ambiental da mineração, que só será conseguida por ação política, a qual depende da formação abrangente dos profissionais da mineração e de sua maior comunicação com a totalidade da população.NONMETALLIC mineral resources, albeit very important for the needs of the population and for exportation, are ill-favored by governmental actions and ignored by the public. Generally not included in territorial planning, the mining of nonmetallic minerals in Brazil produces extensive, ill-controlled environmental impacts. A coordinated action of promotion and control, both patrimonial and environmental of mining, is proposed. This will only be achieved by political action, which depends on a more comprehensive education of mining professionals and on a greater communication by them with the population as a whole.

  19. c-Met in esophageal squamous cell carcinoma: an independent prognostic factor and potential therapeutic target

    International Nuclear Information System (INIS)

    Ozawa, Yohei; Nakamura, Yasuhiro; Fujishima, Fumiyoshi; Felizola, Saulo JA; Takeda, Kenichiro; Okamoto, Hiroshi; Ito, Ken; Ishida, Hirotaka; Konno, Takuro; Kamei, Takashi; Miyata, Go; Ohuchi, Noriaki; Sasano, Hironobu

    2015-01-01

    c-Met is widely known as a poor prognostic factor in various human malignancies. Previous studies have suggested the involvement of c-Met and/or its ligand, hepatocyte growth factor (HGF), in esophageal squamous cell carcinoma (ESCC), but the correlation between c-Met status and clinical outcome remains unclear. Furthermore, the identification of a novel molecular therapeutic target might potentially help improve the clinical outcome of ESCC patients. The expression of c-Met and HGF was immunohistochemically assessed in 104 surgically obtained tissue specimens. The correlation between c-Met/HGF expression and patients’ clinicopathological features, including survival, was evaluated. We also investigated changes in cell functions and protein expression of c-Met and its downstream signaling pathway components under treatments with HGF and/or c-Met inhibitor in ESCC cell lines. Elevated expression of c-Met was significantly correlated with tumor depth and pathological stage. Patients with high c-Met expression had significantly worse survival. In addition, multivariate analysis identified the high expression of c-Met as an independent prognostic factor. Treatment with c-Met inhibitor under HGF stimulation significantly inhibited the invasive capacity of an ESCC cell line with elevated c-Met mRNA expression. Moreover, c-Met and its downstream signaling inactivation was also detected after treatment with c-Met inhibitor. The results of our study identified c-Met expression as an independent prognostic factor in ESCC patients and demonstrated that c-Met could be a potential molecular therapeutic target for the treatment of ESCC with elevated c-Met expression. The online version of this article (doi:10.1186/s12885-015-1450-3) contains supplementary material, which is available to authorized users

  20. Treatment rationale and study design for a randomized, double-blind, placebo-controlled phase II study evaluating onartuzumab (MetMAb) in combination with bevacizumab plus mFOLFOX-6 in patients with previously untreated metastatic colorectal cancer.

    Science.gov (United States)

    Bendell, Johanna C; Ervin, Thomas J; Gallinson, David; Singh, Jaswinder; Wallace, James A; Saleh, Mansoor N; Vallone, Marcy; Phan, See-Chun; Hack, Stephen P

    2013-09-01

    Dysregulation of the hepatocyte growth factor (HGF)/MET pathway is associated with poor prognosis, more aggressive biological characteristics of the tumor, and shortened survival in patients with metastatic colorectal cancer (mCRC). Onartuzumab (MetMAb) is a recombinant humanized monovalent monoclonal antibody directed against MET. We present the treatment rationale and protocol for an ongoing randomized multicenter placebo-controlled phase II study designed to evaluate the efficacy and safety of MetMAb combined with bevacizumab and mFOLFOX-6 (5-fluoruracil, leucovorin, and oxaliplatin). Eligible patients with previously untreated mCRC are randomized 1:1 to either mFOLFOX-6 combined with bevacizumab and placebo followed by 5-fluorouracil/leucovorin plus bevacizumab and placebo or mFOLFOX6, bevacizumab plus MetMAb followed by 5 FU/LV, bevacizumab, and MetMAb. The primary end point of this study is progression-free survival (PFS) in the intent-to-treat (ITT) population. Secondary end points include overall survival (OS), objective response rate, and safety. Subanalyses will be performed to evaluate the effect of MET receptor expression on study primary and secondary end points. Correlative studies will be performed on tissue- and blood-derived biomarkers related to both HGF/MET signaling and other associated pathway markers. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Glutamate receptors

    DEFF Research Database (Denmark)

    Kristensen, Anders S; Geballe, Matthew T; Snyder, James P

    2006-01-01

    Fast excitatory synaptic transmission in the CNS relies almost entirely on the neurotransmitter glutamate and its family of ion channel receptors. An appreciation of the coupling between agonist binding and channel opening has advanced rapidly during the past five years, largely as a result of ne...

  2. MetNetAPI: A flexible method to access and manipulate biological network data from MetNet

    Directory of Open Access Journals (Sweden)

    Sucaet Yves

    2010-11-01

    Full Text Available Abstract Background Convenient programmatic access to different biological databases allows automated integration of scientific knowledge. Many databases support a function to download files or data snapshots, or a webservice that offers "live" data. However, the functionality that a database offers cannot be represented in a static data download file, and webservices may consume considerable computational resources from the host server. Results MetNetAPI is a versatile Application Programming Interface (API to the MetNetDB database. It abstracts, captures and retains operations away from a biological network repository and website. A range of database functions, previously only available online, can be immediately (and independently from the website applied to a dataset of interest. Data is available in four layers: molecular entities, localized entities (linked to a specific organelle, interactions, and pathways. Navigation between these layers is intuitive (e.g. one can request the molecular entities in a pathway, as well as request in what pathways a specific entity participates. Data retrieval can be customized: Network objects allow the construction of new and integration of existing pathways and interactions, which can be uploaded back to our server. In contrast to webservices, the computational demand on the host server is limited to processing data-related queries only. Conclusions An API provides several advantages to a systems biology software platform. MetNetAPI illustrates an interface with a central repository of data that represents the complex interrelationships of a metabolic and regulatory network. As an alternative to data-dumps and webservices, it allows access to a current and "live" database and exposes analytical functions to application developers. Yet it only requires limited resources on the server-side (thin server/fat client setup. The API is available for Java, Microsoft.NET and R programming environments and offers

  3. Die era van Suid-Afrika se militere hoogbloei met die ...

    African Journals Online (AJOL)

    -. Afrikaanse inmenging in .... Yaaldriehoekers is oak met die begrip die 'totale aanslag' teen Suid-Afrika bekend gemaak.26 Met die ..... Anon, "White flee violent Vaal Triangle", in Vaal Ster, 21-25 Feb 1994. Dagboek, J. Bergh ...

  4. Featured Article: Serum [Met5]-enkephalin levels are reduced in multiple sclerosis and restored by low-dose naltrexone.

    Science.gov (United States)

    Ludwig, Michael D; Zagon, Ian S; McLaughlin, Patricia J

    2017-09-01

    Low-dose naltrexone is a widely used off-label therapeutic prescribed for a variety of immune-related disorders. The mechanism underlying low-dose naltrexone's efficacy for fatigue, Crohn's disease, fibromyalgia, and multiple sclerosis is, in part, intermittent blockade of opioid receptors followed by upregulation of endogenous opioids. Short, intermittent blockade by naltrexone specifically blocks the opioid growth factor receptor resulting in biofeedback events that increase production of the endogenous opioid growth factor (OGF) (chemically termed [Met 5 ]-enkephalin) facilitating interactions between opioid growth factor and opioid growth factor receptor that ultimately, result in inhibited cell proliferation. Preclinical studies have reported that enkephalin levels are deficient in animal models of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Our hypothesis is that serum enkephalin levels are diminished in humans with multiple sclerosis and experimental autoimmune encephalomyelitis mice, and that change in serum opioid growth factor levels may serve as a reasonable candidate biomarker for the onset of experimental autoimmune encephalomyelitis and response to therapy. To address this, we designed a two-part study to measure endogenous opioids in multiple sclerosis patients, and to investigate the temporal pattern of decline in serum enkephalin concentrations in mice with chronic progressive experimental autoimmune encephalomyelitis and treated with low-dose naltrexone. For comparison, we investigated whether low-dose naltrexone exposure in normal mice also resulted in altered enkephalin levels. In both animal models, we monitored tactile and heat sensitivity, as well as differential white blood cell counts as indicators of inflammation. Serum [Met 5 ]-enkephalin levels were lower in humans with multiple sclerosis relative to non-multiple sclerosis patients, and low-dose naltrexone restored their levels. In experimental

  5. Kids are not little adults: what MET threshold captures sedentary behavior in children?

    Science.gov (United States)

    Saint-Maurice, Pedro F; Kim, Youngwon; Welk, Gregory J; Gaesser, Glenn A

    2016-01-01

    The study compares MET-defined cutpoints used to classify sedentary behaviors in children using a simulated free-living design. A sample of 102 children (54 boys and 48 girls; 7-13 years) completed a set of 12 activities (randomly selected from a pool of 24 activities) in a random order. Activities were predetermined and ranged from sedentary to vigorous intensities. Participant's energy expenditure was measured using a portable indirect calorimetry system, Oxycon mobile. Measured minute-by-minute VO2 values (i.e., ml/kg/min) were converted to an adult- or child-MET value using the standard 3.5 ml/kg/min or the estimated child resting metabolic rate, respectively. Classification agreement was examined for both the "standard" (1.5 adult-METs) and an "adjusted" (2.0 adult-METs) MET-derived threshold for classifying sedentary behavior. Alternatively, we also tested the classification accuracy of a 1.5 child-MET threshold. Classification accuracy of sedentary activities was evaluated relative to the predetermined intensity categorization using receiver operator characteristic curves. There were clear improvements in the classification accuracy for sedentary activities when a threshold of 2.0 adult-METs was used instead of 1.5 METs (Se1.5 METs = 4.7%, Sp1.5 METs = 100.0%; Se2.0 METs = 36.9%, Sp2.0 METs = 100.0 %). The use of child-METs while maintaining the 1.5 threshold also resulted in improvements in classification (Se = 45.1%, Sp = 100.0%). Adult-MET thresholds are not appropriate for children when classifying sedentary activities. Classification accuracy for identifying sedentary activities was improved when either an adult-MET of 2.0 or a child-MET of 1.5 was used.

  6. Dual inhibition of MET and SRC kinase activity as a combined targeting strategy for colon cancer.

    Science.gov (United States)

    Song, Na; Qu, Xiujuan; Liu, Shizhou; Zhang, Simeng; Liu, Jing; Qu, Jinglei; Zheng, Huachuan; Liu, Yunpeng; Che, Xiaofang

    2017-08-01

    Hepatocyte growth factor (HGF)/MET signaling is implicated in the development of colorectal cancer (CRC) and possesses therapeutic value for various types of cancer. However, inhibition of MET alone has been demonstrated to have limited efficacy. The present study examined the combined inhibition of MET and SRC kinase activity in colon cancer cells. Furthermore, the role of the HGF/MET pathway in ligand-dependent and -independent activation was demonstrated. The single inhibition of MET by knockdown small interfering RNA or inhibitor indicated a limited anti-viability effects without inhibiting the basal phosphorylation levels of SRC, protein kinase B (AKT) or extracellular signal-regulated kinase (ERK). In view of the strong association between MET and SRC identified by direct regulation, growth factor-induced MET activation was suppressed by pretreatment with the SRC inhibitor, dasatinib, and downstream phosphorylation of AKT and ERK partially decreased, which suggested that SRC activation was essential for ligand-dependent and -independent activation of MET. Considering that both the activation of MET and SRC was required in ligand-dependent and -independent MET activation, the antitumor effect of concurrent inhibition of MET and SRC was examined, and it was demonstrated that combination treatment exerted increased viability inhibition and apoptosis enhancement in mutant and wild type RAS colon cancer cells. Therefore, combinational inhibition of MET and SRC may be a promising strategy for the treatment of CRC.

  7. 76 FR 401 - MetLife Insurance Company of Connecticut, et al.

    Science.gov (United States)

    2011-01-04

    ... Funds' adviser, profit distributions from the adviser. These profits from investment advisory fees may...''). ACTION: Notice of application for an order pursuant to Section 26(c) of the Investment Company Act of... CPPVUL 1''), MetLife Investors Insurance Company (``MetLife Investors''), MetLife Investors Variable...

  8. Samen opgespoord? : Eindrapport "Pilot samenwerking particuliere onderzoeksbureaus met politie en OM"

    NARCIS (Netherlands)

    Friperson, R.; Bouman, S.; Wilms, P.

    2013-01-01

    In samenwerking met de Nederlandse Veiligheidsbranche (NV) is een pilot ingericht met als doel na te gaan welke rol particuliere onderzoeksbureau's (POB’s) kunnen spelen bij de opsporing in strafzaken. De pilot heeft plaatsgevonden tussen 1 mei 2012 tot en met 3o april 2013. Aan de pilot namen negen

  9. Hepatic Radiofrequency Ablation–induced Stimulation of Distant Tumor Growth Is Suppressed by c-Met Inhibition

    Science.gov (United States)

    Kumar, Gaurav; Moussa, Marwan; Wang, Yuanguo; Rozenblum, Nir; Galun, Eithan; Goldberg, S. Nahum

    2016-01-01

    Purpose To elucidate how hepatic radiofrequency (RF) ablation affects distant extrahepatic tumor growth by means of two key molecular pathways. Materials and Methods Rats were used in this institutional animal care and use committee–approved study. First, the effect of hepatic RF ablation on distant subcutaneous in situ R3230 and MATBIII breast tumors was evaluated. Animals were randomly assigned to standardized RF ablation, sham procedure, or no treatment. Tumor growth rate was measured for 3½ to 7 days. Then, tissue was harvested for Ki-67 proliferative indexes and CD34 microvascular density. Second, hepatic RF ablation was performed for hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and c-Met receptor expression measurement in periablational rim, serum, and distant tumor 24 hours to 7 days after ablation. Third, hepatic RF ablation was combined with either a c-Met inhibitor (PHA-665752) or VEGF receptor inhibitor (semaxanib) and compared with sham or drug alone arms to assess distant tumor growth and growth factor levels. Finally, hepatic RF ablation was performed in rats with c-Met–negative R3230 tumors for comparison with the native c-Met–positive line. Tumor size and immunohistochemical quantification at day 0 and at sacrifice were compared with analysis of variance and the two-tailed Student t test. Tumor growth curves before and after treatment were analyzed with linear regression analysis to determine mean slopes of pre- and posttreatment growth curves on a per-tumor basis and were compared with analysis of variance and paired two-tailed t tests. Results After RF ablation of normal liver, distant R3230 tumors were substantially larger at 7 days compared with tumors treated with the sham procedure and untreated tumors, with higher growth rates and tumor cell proliferation. Similar findings were observed in MATBIII tumors. Hepatic RF ablation predominantly increased periablational and serum HGF and downstream distant tumor

  10. Collarín para soportes metálicos

    Directory of Open Access Journals (Sweden)

    de Miguel, J. L.

    1998-10-01

    Full Text Available In architectural works, structural calculations are usually few and simple, they mostly corroborate what is already known. Calculations are made for the most part with the purpose of exploring solutions. When working in a specific case operations ought to be framed in the practical understanding, with predictable values and tabulated solutions, with no surprises. To write numbers and trust them blindly, is like a reckless appointment, something that should not be done in structures. This article shows how to use the structural knowledge in order to explore a specific solution: a collar for metal supports.

    En las obras de arquitectura los cálculos estructurales suelen ser pocos y sencillos, más bien para corroborar algo que se sabía de antemano. Los números se hacen, en su mayor parte, para explorar soluciones; cuando se trabaja en un caso particular debe operarse en un marco conocido, con valores predictables y soluciones tabuladas, sin sorpresas. Hacer números para fiarse a pies juntillas de ellos, es como una cita a ciegas, algo no recomendable en estructuras. Este artículo muestra cómo usar los conocimientos estructurales para explorar una solución: la de un collarín para soportes metálicos.

  11. Mecanismo cognitivos en la memoria; la Metáfora

    Directory of Open Access Journals (Sweden)

    Francisco José Ruiz de Mendoza Ibañez

    2010-12-01

    Full Text Available La Lingüística Cognitiva (LC es una disciplina que, pese a su juventud, ha experimentado un desarrollo vertiginoso en los últimos treinta años1. Uno de los mayores logros de la LC (que la distingue de enfoques anteriores sobre el lenguaje como el estructuralismo y el generativismo chomskyano radica en no considerar el lenguaje como un sistema autosuficiente, sino más bien como una facultad cognitiva que interactúa con otras capacidades como son la percepción, la atención, la memoria, la emoción y el razonamiento. Por tanto, en LC los significados son parte de nuestro mundo conceptual. En la versión más temprana de la TMC Lakoff y Johnson defienden que tanto el lenguaje como el pensamiento están ligados y se estructuran de acuerdo con la experiencia corpórea (embodied experience. Así, la experiencia perceptual y espacial es la base para la categorización del mundo de manera que estas categorías (que pertenecen a dominios concretos se hacen corresponder con dominios más abstractos como los de la emoción, el tiempo o la estructura. Por tanto, la metáfora queda definida como un conjunto de correspondencias (conceptual mapping entre un dominio fuente (más concreto y un dominio meta (más abstracto.

  12. Recurrent MET fusion genes represent a drug target in pediatric glioblastoma

    DEFF Research Database (Denmark)

    Sehested, Astrid Marie

    2016-01-01

    fusions activated mitogen-activated protein kinase (MAPK) signaling and, in cooperation with lesions compromising cell cycle regulation, induced aggressive glial tumors in vivo. MET inhibitors suppressed MET tumor growth in xenograft models. Finally, we treated a pediatric patient bearing a MET-fusion......Pediatric glioblastoma is one of the most common and most deadly brain tumors in childhood. Using an integrative genetic analysis of 53 pediatric glioblastomas and five in vitro model systems, we identified previously unidentified gene fusions involving the MET oncogene in ∼10% of cases. These MET...

  13. Pattern recognition receptors, sensing re(n)al danger

    NARCIS (Netherlands)

    Pulskens, W.P.C.

    2012-01-01

    Wilco Pulskens bestudeerde de rol van verschillende receptoren van het aangeboren immuunsysteem (waaronder Toll-like receptor-4 (TLR4) en het NLRP3-inflammasome) en liganden (bindingsmoleculen) die deze receptoren kunnen activeren tijdens acute en chronische nierschade. Met behulp van diermodellen

  14. Metáfora y terrorismo étnico

    Directory of Open Access Journals (Sweden)

    de Bustos, Eduardo

    2012-06-01

    Full Text Available The terrorist discourse has been critically analysed with the traditional tools provided by the discourse analysis, the argumentation theory and, broadly speaking, by rhetoric. This paper proposes rather a critical analysis of the ethnic terrorist or nationalist discourse that makes use of the contemporary theory of metaphor to reveal the cognitive frames that ascribes sense to the terrorist language, particularly the discourse used the ETA organization as the Basque nationalist and independentist discourse in general. This approach allows overcoming the shortcomings of the classical rhetorical tools, with its focus in the lexical or argumentative analysis, and gives an explanation of the mental settings characteristic of this kind of terrorist discourse.

    El discurso terrorista ha sido analizado críticamente con los instrumentos tradicionales proporcionados por el análisis del discurso, la teoría de la argumentación y, en general, la retórica. Este ensayo propone en cambio un análisis crítico del discurso terrorista étnico o nacionalista que hace uso de la teoría contemporánea de la metáfora para desvelar los marcos cognitivos que confieren sentido tanto al lenguaje terrorista de la organización ETA como al discurso nacionalista e independentista vasco en general. Este enfoque permite trascender las limitaciones de los instrumentos retóricos clásicos, centrados en el análisis léxico o argumentativo, para proporcionar una explicación de las configuraciones mentales propias de esta clase de discurso terrorista.

  15. Mercuralismo metálico crônico ocupacional

    Directory of Open Access Journals (Sweden)

    Faria Marcília de Araújo Medrado

    2003-01-01

    Full Text Available Revisão que analisa os conhecimento atuais das manifestações do mercuralismo crônico ocupacional. Avaliaram-se os principais estudos e revisões científicas concernentes às formas clínicas e fisiopatogenia desta intoxicação. Foram pesquisadas, entre outras fontes, as bases de dados Medline e Lilacs. O eretismo ou a síndrome neuropsíquica caracterizada por sintomas de irritabilidade, ansiedade, mudanças de comportamento, apatia, perda da auto-estima e de memória, depressão, insônia, delírio, cefaléia, dores musculares e tremores é observada após a exposição ao mercúrio metálico. Manifestações de hipertensão arterial, renais, imunológicas e alérgicas são freqüentes. A falta de medidas preventivas aumenta o risco da doença em indústrias, no garimpo e consultórios odontológicos. A legislação brasileira assinala 16 manifestações clínicas determinadas pela intoxicação, todavia ocorre subdiagnóstico. O diagnóstico clínico é importante e as novas tecnologias médicas podem detectar alterações do sistema nervoso central, renal e imunológico, proporcionando avanços no conhecimento neuro-imuno-toxicológico e nas medidas de prevenção do mercuralismo.

  16. Mercuralismo metálico crônico ocupacional

    Directory of Open Access Journals (Sweden)

    Marcília de Araújo Medrado Faria

    2003-02-01

    Full Text Available Revisão que analisa os conhecimento atuais das manifestações do mercuralismo crônico ocupacional. Avaliaram-se os principais estudos e revisões científicas concernentes às formas clínicas e fisiopatogenia desta intoxicação. Foram pesquisadas, entre outras fontes, as bases de dados Medline e Lilacs. O eretismo ou a síndrome neuropsíquica caracterizada por sintomas de irritabilidade, ansiedade, mudanças de comportamento, apatia, perda da auto-estima e de memória, depressão, insônia, delírio, cefaléia, dores musculares e tremores é observada após a exposição ao mercúrio metálico. Manifestações de hipertensão arterial, renais, imunológicas e alérgicas são freqüentes. A falta de medidas preventivas aumenta o risco da doença em indústrias, no garimpo e consultórios odontológicos. A legislação brasileira assinala 16 manifestações clínicas determinadas pela intoxicação, todavia ocorre subdiagnóstico. O diagnóstico clínico é importante e as novas tecnologias médicas podem detectar alterações do sistema nervoso central, renal e imunológico, proporcionando avanços no conhecimento neuro-imuno-toxicológico e nas medidas de prevenção do mercuralismo.

  17. Fusion Welding of AerMet 100 Alloy

    Energy Technology Data Exchange (ETDEWEB)

    ENGLEHART, DAVID A.; MICHAEL, JOSEPH R.; NOVOTNY, PAUL M.; ROBINO, CHARLES V.

    1999-08-01

    A database of mechanical properties for weldment fusion and heat-affected zones was established for AerMet{reg_sign}100 alloy, and a study of the welding metallurgy of the alloy was conducted. The properties database was developed for a matrix of weld processes (electron beam and gas-tungsten arc) welding parameters (heat inputs) and post-weld heat treatment (PWHT) conditions. In order to insure commercial utility and acceptance, the matrix was commensurate with commercial welding technology and practice. Second, the mechanical properties were correlated with fundamental understanding of microstructure and microstructural evolution in this alloy. Finally, assessments of optimal weld process/PWHT combinations for cotildent application of the alloy in probable service conditions were made. The database of weldment mechanical properties demonstrated that a wide range of properties can be obtained in welds in this alloy. In addition, it was demonstrated that acceptable welds, some with near base metal properties, could be produced from several different initial heat treatments. This capability provides a means for defining process parameters and PWHT's to achieve appropriate properties for different applications, and provides useful flexibility in design and manufacturing. The database also indicated that an important region in welds is the softened region which develops in the heat-affected zone (HAZ) and analysis within the welding metallurgy studies indicated that the development of this region is governed by a complex interaction of precipitate overaging and austenite formation. Models and experimental data were therefore developed to describe overaging and austenite formation during thermal cycling. These models and experimental data can be applied to essentially any thermal cycle, and provide a basis for predicting the evolution of microstructure and properties during thermal processing.

  18. Founder effect in the Horn of Africa for an insulin receptor mutation that may impair receptor recycling

    DEFF Research Database (Denmark)

    Raffan, E; Soos, M A; Rocha, N

    2011-01-01

    Genetic insulin receptoropathies are a rare cause of severe insulin resistance. We identified the Ile119Met missense mutation in the insulin receptor INSR gene, previously reported in a Yemeni kindred, in four unrelated patients with Somali ancestry. We aimed to investigate a possible genetic...

  19. CBL is frequently altered in lung cancers: its relationship to mutations in MET and EGFR tyrosine kinases.

    Directory of Open Access Journals (Sweden)

    Yi-Hung Carol Tan

    2010-01-01

    Full Text Available Non-small cell lung cancer (NSCLC is a heterogeneous group of disorders with a number of genetic and proteomic alterations. c-CBL is an E3 ubiquitin ligase and adaptor molecule important in normal homeostasis and cancer. We determined the genetic variations of c-CBL, relationship to receptor tyrosine kinases (EGFR and MET, and functionality in NSCLC.Using archival formalin-fixed paraffin embedded (FFPE extracted genomic DNA, we show that c-CBL mutations occur in somatic fashion for lung cancers. c-CBL mutations were not mutually exclusive of MET or EGFR mutations; however they were independent of p53 and KRAS mutations. In normal/tumor pairwise analysis, there was significant loss of heterozygosity (LOH for the c-CBL locus (22%, n = 8/37 and none of these samples revealed any mutation in the remaining copy of c-CBL. The c-CBL LOH also positively correlated with EGFR and MET mutations observed in the same samples. Using select c-CBL somatic mutations such as S80N/H94Y, Q249E and W802* (obtained from Caucasian, Taiwanese and African-American samples, respectively transfected in NSCLC cell lines, there was increased cell viability and cell motility.Taking the overall mutation rate of c-CBL to be a combination as somatic missense mutation and LOH, it is clear that c-CBL is highly mutated in lung cancers and may play an essential role in lung tumorigenesis and metastasis.

  20. MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy

    Science.gov (United States)

    Pilotto, Sara; Gkountakos, Anastasios; Carbognin, Luisa; Scarpa, Aldo; Tortora, Giampaolo

    2017-01-01

    The MET proto-oncogene plays crucial roles in cell growth and proliferation, survival and apoptosis, epithelial-mesenchymal transition (EMT) and invasion, potentially conditioning the development and progression of the carcinogenesis process. The MET-associated aberrant signaling could be triggered by a variety of mechanisms, such as mutations, gene amplification, increased gene copy number and Met/HGF protein expression. Among the various MET alterations, MET exon 14 splicing abnormalities, causing the loss of the Met juxtamembrane (JM) domain, recently emerged as a new potential oncogenic driver and have been identified and validated across different cancer and histology subtypes. Moreover, this aberration was found to be mutually exclusive with other recognized drivers, thus strongly nominating its potential oncogenic role. Recently, the clinical activity of anti-Met-targeted therapy was demonstrated particularly in patients harboring MET exon 14 skipping lung cancer, resulting in a renewed enthusiasm to further test MET precision therapy in prospective trials. In this review, the key preclinical and clinical data regarding MET exon 14 skipping splicing variants as an actionable genomic aberration in cancer are described, and the perspectives deriving from the validation of such alteration as a potential target, which may further allow driving the therapeutic approach in this molecularly selected patients’ subgroup, are explored. PMID:28164087

  1. Serotonin Transporter-Independent Actions of the Antidepressant Vortioxetine As Revealed Using the SERT Met172 Mouse.

    Science.gov (United States)

    Nackenoff, Alex G; Simmler, Linda D; Baganz, Nicole L; Pehrson, Alan L; Sánchez, Connie; Blakely, Randy D

    2017-05-17

    Selective serotonin (5-HT, SERT) reuptake inhibitors (SSRIs) are the most commonly prescribed treatments for depression. However, they have delayed efficacy and can induce side-effects that can encourage discontinuation. Recently, agents have been developed, including vortioxetine (Trintellix), that augment SERT blockade with interactions at other targets. At therapeutic doses, vortioxetine interacts with SERT as well as 5-HT 1A , 5-HT 1B , 5-HT 3 , and 5-HT 7 receptors. We assessed the SERT-dependency of vortioxetine action using the SERT Met172 mouse model, which disrupts high-affinity interactions of many antidepressants with the transporter. We demonstrate that the SERT Met172 substitution induces an ∼19-fold loss in vortioxetine potency for SERT inhibition in midbrain synaptosomes. Moreover, in these mice, we observed reduced SERT occupancy, a diminished ability to prolong 5-HT clearance, and a reduced capacity to elevate extracellular 5-HT. Despite reduced interactions with SERT, vortioxetine maintained its ability to enhance mobility in tail suspension and forced swim tests, reduce consumption latency in the novelty induced hypophagia test, and promoted proliferation and survival of subgranular zone hippocampal stem cells. Our findings suggest that the antidepressant actions of vortioxetine may be SERT-independent, and encourage consideration of agents that mimic one or more actions of the drug in the development of improved depression treatments.

  2. Future Plans for MetNet Lander Mars Missions

    Science.gov (United States)

    Harri, A.-M.; Schmidt, W.; Guerrero, H.; Vázquez, L.

    2012-04-01

    For the next decade several Mars landing missions and the construction of major installations on the Martian surface are planned. To be able to bring separate large landing units safely to the surface in sufficiently close vicinity to one another, the knowledge of the Martian weather patterns, especially dust and wind, is important. The Finnish - Russian - Spanish low-mass meteorological stations are designed to provide the necessary observation data network which can provide the in-situ observations for model verification and weather forecasts. As the requirements for a transfer vehicle are not very extensive, the MetNet Landers (MNLs) [1] could be launched with any mission going to Mars. This could be a piggy-bag solution to a Martian orbiter from ESA, NASA, Russia or China or an add-on to a planned larger Martian Lander like ExoMars. Also a dedicated launch with several units from LEO is under discussion. The data link implementation uses the UHF-band with Proximity-1 protocol as other current and future Mars lander missions which makes any Mars-orbiting satellite a potential candidate for a data relay to Earth. Currently negotiations for possible opportunities with the European and the Chinese space agencies are ongoing aiming at a launch window in the 2015/16 time frame. In case of favorable results the details will be presented at the EGU. During 2011 the Mars MetNet Precursor Mission (MMPM) has completed all flight qualifications for Lander system and payload. At least two units will be ready for launch in the 2013/14 launch window or beyond. With an entry mass of 22.2kg per unit and 4kg payload allocation the MNL(s) can be easily deployed from a wide range of transfer vehicles. The simple structure allows the manufacturing of further units on short notice and to reasonable prices. The autonomous operations concept makes the implementation of complex commanding options unnecessary while offering a flexible adaptation to different operational scenarios. This

  3. Cooperative interaction of MUC1 with the HGF/c-Met pathway during hepatocarcinogenesis

    Directory of Open Access Journals (Sweden)

    Bozkaya Giray

    2012-09-01

    Full Text Available Abstract Background Hepatocyte growth factor (HGF induced c-Met activation is known as the main stimulus for hepatocyte proliferation and is essential for liver development and regeneration. Activation of HGF/c-Met signaling has been correlated with aggressive phenotype and poor prognosis in hepatocellular carcinoma (HCC. MUC1 is a transmembrane mucin, whose over-expression is reported in most cancers. Many of the oncogenic effects of MUC1 are believed to occur through the interaction of MUC1 with signaling molecules. To clarify the role of MUC1 in HGF/c-Met signaling, we determined whether MUC1 and c-Met interact cooperatively and what their role(s is in hepatocarcinogenesis. Results MUC1 and c-Met over-expression levels were determined in highly motile and invasive, mesenchymal-like HCC cell lines, and in serial sections of cirrhotic and HCC tissues, and these levels were compared to those in normal liver tissues. Co-expression of both c-Met and MUC1 was found to be associated with the differentiation status of HCC. We further demonstrated an interaction between c-Met and MUC1 in HCC cells. HGF-induced c-Met phosphorylation decreased this interaction, and down-regulated MUC1 expression. Inhibition of c-Met activation restored HGF-mediated MUC1 down-regulation, and decreased the migratory and invasive abilities of HCC cells via inhibition of β-catenin activation and c-Myc expression. In contrast, siRNA silencing of MUC1 increased HGF-induced c-Met activation and HGF-induced cell motility and invasion. Conclusions These findings indicate that the crosstalk between MUC1 and c-Met in HCC could provide an advantage for invasion to HCC cells through the β-catenin/c-Myc pathway. Thus, MUC1 and c-Met could serve as potential therapeutic targets in HCC.

  4. Cooperative interaction of MUC1 with the HGF/c-Met pathway during hepatocarcinogenesis.

    Science.gov (United States)

    Bozkaya, Giray; Korhan, Peyda; Cokaklı, Murat; Erdal, Esra; Sağol, Ozgül; Karademir, Sedat; Korch, Christopher; Atabey, Neşe

    2012-09-11

    Hepatocyte growth factor (HGF) induced c-Met activation is known as the main stimulus for hepatocyte proliferation and is essential for liver development and regeneration. Activation of HGF/c-Met signaling has been correlated with aggressive phenotype and poor prognosis in hepatocellular carcinoma (HCC). MUC1 is a transmembrane mucin, whose over-expression is reported in most cancers. Many of the oncogenic effects of MUC1 are believed to occur through the interaction of MUC1 with signaling molecules. To clarify the role of MUC1 in HGF/c-Met signaling, we determined whether MUC1 and c-Met interact cooperatively and what their role(s) is in hepatocarcinogenesis. MUC1 and c-Met over-expression levels were determined in highly motile and invasive, mesenchymal-like HCC cell lines, and in serial sections of cirrhotic and HCC tissues, and these levels were compared to those in normal liver tissues. Co-expression of both c-Met and MUC1 was found to be associated with the differentiation status of HCC. We further demonstrated an interaction between c-Met and MUC1 in HCC cells. HGF-induced c-Met phosphorylation decreased this interaction, and down-regulated MUC1 expression. Inhibition of c-Met activation restored HGF-mediated MUC1 down-regulation, and decreased the migratory and invasive abilities of HCC cells via inhibition of β-catenin activation and c-Myc expression. In contrast, siRNA silencing of MUC1 increased HGF-induced c-Met activation and HGF-induced cell motility and invasion. These findings indicate that the crosstalk between MUC1 and c-Met in HCC could provide an advantage for invasion to HCC cells through the β-catenin/c-Myc pathway. Thus, MUC1 and c-Met could serve as potential therapeutic targets in HCC.

  5. Characterization of HGF/Met Signaling in Cell Lines Derived From Urothelial Carcinoma of the Bladder

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Young H. [Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Apolo, Andrea B. [Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Agarwal, Piyush K.; Bottaro, Donald P., E-mail: dbottaro@helix.nih.gov [Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States)

    2014-11-25

    There is mounting evidence of oncogenic hepatocyte growth factor (HGF)/Met signaling in urothelial carcinoma (UC) of the bladder. The effects of three kinase inhibitors, cabozantinib, crizotinib and EMD1214063, on HGF-driven signaling and cell growth, invasion and tumorigenicity were analyzed in cultured UC cell lines. SW780 xenograft growth in SCID and human HGF knock-in SCID (hHGF/SCID) mice treated with cabozantinib or vehicle, as well as tumor levels of Met and pMet, were also determined. Met content was robust in most UC-derived cell lines. Basal pMet content and effector activation state in quiescent cells were low, but significantly enhanced by added HGF, as were cell invasion, proliferation and anchorage independent growth. These HGF-driven effects were reversed by Met inhibitor treatment. Tumor xenograft growth was significantly higher in hHGF/SCID mice vs. SCID mice and significantly inhibited by cabozantinib, as was tumor phospho-Met content. These studies indicate the prevalence and functionality of the HGF/Met signaling pathway in UC cells, suggest that paracrine HGF may contribute to UC tumor growth and progression, and that support further preclinical investigation of Met inhibitors for the treatment of UC is warranted.

  6. A Putative Association of COMT Val(108/158)Met with Impulsivity in Binge Eating Disorder.

    Science.gov (United States)

    Leehr, Elisabeth J; Schag, Kathrin; Brückmann, Christof; Plewnia, Christian; Zipfel, Stephan; Nieratschker, Vanessa; Giel, Katrin E

    2016-03-01

    This study aims to investigate the influence of the COMT Val(108/158)Met polymorphism on trait and behavioural impulsivity in binge eating disorder (BED). COMT Val(108/158)Met has been related to impulsivity in previous studies, but so far no study has investigated the role of this polymorphism in the context of BED. Impulsivity was assessed via a questionnaire (trait) and on a behavioural level via the antisaccade task in a sample of 69 participants classified into one out of three age-matched groups: (1) obese individuals with BED according to DMS-IV (BED+); (2) obese individuals without BED, matched with the BED+ sample according to body weight (OBED-); and (3) normal-weight healthy controls (NWC). The COMT Val(108/158)Met polymorphism was genotyped in all samples. As expected, the BED+ sample showed higher trait and behavioural impulsivity. Furthermore, within the BED+ group, COMT Met/Met homozygous individuals showed stronger deficits in inhibitory control. COMT Met/Met homozygous individuals with BED might represent a specific group in the BED spectrum, which shows a higher behavioural impulsivity. The association between COMT Val(108/158)Met with inhibitory control should be interpreted with caution because of the small sample size. Larger replication studies are needed to further elucidate the role of the COMT Val(108/158)Met polymorphism in the regulation of disordered eating behaviour. Copyright © 2015 John Wiley & Sons, Ltd and Eating Disorders Association.

  7. MET overexpression, gene amplification and relevant clinicopathological features in gastric adenocarcinoma.

    Science.gov (United States)

    Zhang, Jing; Guo, Lei; Liu, Xiuyun; Li, Wenbin; Ying, Jianming

    2017-02-07

    This study was conducted to investigate the expression of MET in Chinese gastric adenocarcinoma cohort, the correlation between MET overexpression and clinical pathological features, HER2 expression and MET gene amplification. A total of 816 gastric adenocarcinoma patients were included and MET and HER2 immunohistochemical (IHC) staining were performed. IHC and dual-color silver in situ hybridization analysis were performed in the tissue microarrays, constructed from the 240 patients who were randomly selected. MET overexpression (IHC 3+) was observed in 6.0% (49/816) of the cohort. MET overexpression rate was higher in patients with poor prognostic factors, such as clinical stages III/IV (p =0.012) and pathologic stages T3/T4 (p =0.027). The HER2 overexpression (IHC 3+) rate was 8.8% (72/816) and MET overexpression rate was higher in HER2 positive patients (9.7%, 7/72). A high concordance rate (94.6%) between MET overexpression and gene amplification was demonstrated. Therefore, MET overexpression could serve as a prognostic biomarker and a potential therapeutic target for gastric cancer.

  8. Effect of met on regulation of population and distribution of CO2 assimilates in soybean plant

    International Nuclear Information System (INIS)

    Yu Meiyu; Tao Longxing; Yao Fude; Wang Xi

    1991-01-01

    MET (Multi-Effects Triazole) is a new type of plant growth retardant. Spraying MET (200 ppm) on soybean plant at initial flowering stage controled plant height and promoted the growth of lateral branches. The experimental results showed that the rate of photosynthesis of the plant sprayed with MET was higher than that of the control. The regulation effect of MET on distribution of 14 CO 2 -assimilates was expressed by the increase of assimilates in root and seed of soybean. More 14 CO 2 -assimilates in seed were found at rapid seed development stage when 14 CO 2 was fed at initial flowering and pod development stages

  9. Neurokinin-1 receptor activation in globus pallidus

    Directory of Open Access Journals (Sweden)

    Lei Chen

    2009-10-01

    Full Text Available The undecapeptide substance P has been demonstrated to modulate neuronal activity in a number of brain regions by acting on neurokinin-1 receptors. Anatomical studies revealed a moderate level of neurokinin-1 receptor in rat globus pallidus. To determine the electrophysiological effects of neurokinin-1 receptor activation in globus pallidus, whole-cell patch-clamp recordings were performed in the present study. Under current-clamp recordings, neurokinin-1 receptor agonist, [Sar9, Met(O211] substance P (SM-SP at 1 μM, depolarized globus pallidus neurons and increased their firing rate. Consistently, SM-SP induced an inward current under voltage-clamp recording. The depolarization evoked by SM-SP persisted in the presence of tetrodotoxin, glutamate and GABA receptor antagonists, indicating its direct postsynaptic effects. The neurokinin-1 receptor antagonist, SR140333B, could block SM-SP-induced depolarization. Further experiments showed that suppression of potassium conductance was the predominant ionic mechanism of SM-SP-induced depolarization. To determine if neurokinin-1 receptor activation exerts any effects on GABAergic and glutamatergic neurotransmission, the action of SM-SP on synaptic currents was studied. SM-SP significantly increased the frequency of spontaneous inhibitory postsynaptic currents, but only induced a transient increase in the frequency of miniature inhibitory postsynaptic currents. No change was observed in both spontaneous and miniature excitatory postsynaptic currents. Based on the direct excitatory effects of SM-SP on pallidal neurons, we hypothesize that neurokinin-1 receptor activation in globus pallidus may be involved in the beneficial effect of substance P in Parkinson’s disease.

  10. Influence of the metabolic syndrome on leptin and leptin receptor in breast cancer.

    Science.gov (United States)

    Carroll, Paul A; Healy, Laura; Lysaght, Joanne; Boyle, Terry; Reynolds, John V; Kennedy, M John; Pidgeon, Graham; Connolly, Elizabeth M

    2011-08-01

    Obesity and its associated metabolic syndrome (MetS) are recognized risk factors for breast cancer. The molecular basis for this association remains largely unknown. Adipokines, in particular leptin and adiponectin, are thought to form part of the mechanism linking obesity with cancer through their altered expression/production either systemically (endocrine pathway) or locally (paracrine/autocrine pathway). Using quantitative PCR, mRNA expression of adiponectin (AdipoQ) and leptin (Ob) in mammary adipose tissue (MAT), intratumoral leptin and associated ligand receptors (ObR, AdipoR1, and AdipoR2) was examined in 77 patients with complete anthropomorphic and serological data. Expression of Ob in MAT, and ObR in matched tumor tissue was significantly higher in patients with MetS compared to obese only or normal weight cancer patients (P < 0.005). There was no difference in intratumoral leptin adiponectin or its ligand receptors in the same groups. Individual features of MetS correlated with Ob and ObR expression, but not obesity markers (BMI, waist circumference). mRNA expression of leptin (Ob) and ObR, in adipose tissue and matched tumor samples, respectively, appear to be associated with obesity status in breast cancer. Increasing insulin resistance is a predominant feature of this higher Ob/ObR expression observed. These novel data indicate that the MetS may be an amenable risk factor for breast cancer. Copyright © 2011 Wiley-Liss, Inc.

  11. Peroxisome Proliferator–Activated Receptors and The Metabolic Syndrome

    Directory of Open Access Journals (Sweden)

    Anna Meiliana

    2009-04-01

    Full Text Available BACKGROUND: Obesity is a growing threat to global health by virtue of its association with insulin resistance, inflammation, hypertension, and dyslipidemia, collectively known as the metabolic syndrome (MetS. The nuclear receptors PPARα and PPARγ are therapeutic targets for hypertriglyceridemia and insulin resistance, respectively, and drugs that modulate these receptors are currently in clinical use. More recent work on the PPARδ has uncovered a dual benefit for both hypertriglyceridemia and insulin resistance, highlighting the broad potential of PPARs in the treatment of metabolic disease. CONTENT: We have learned much about PPARs, the metabolic fat sensors, and the molecular pathways they regulate. Through their distinct tissue distribution and specific target gene activation, the three PPARs together control diverse aspects of fatty acid metabolism, energy balance, insulin sensitivity glucose homeostasis, inflammation, hypertension and atherosclerosis. These studies have advanced our understanding of the etiology for the MetS. Mechanisms revealed by these studies highlight the importance of emerging concepts, such as the endocrine function of adipose tissue, tissue-tissue cross-talk and lipotoxicity, in the pathogenesis of type 2 diabetes mellitus and CVD. SUMMARY: The elucidation of key regulators of energy balance and insulin signaling have revolutionized our understanding of fat and sugar metabolism and their intimate link. The three ‘lipidsensing’ (PPARα, PPARγ and PPARδ exemplify this connection, regulating diverse aspects of lipid and glucose homeostasis, and serving as bonafide therapeutic targets. KEYWORDS: peroxisome proliferator, activated receptor, metabolic syndrome.

  12. Genetic evidence for function of the bHLH-PAS protein Gce/Met as a juvenile hormone receptor

    Czech Academy of Sciences Publication Activity Database

    Jindra, Marek; Uhlířová, M.; Charles, J.-P.; Smýkal, V.; Hill, R. J.

    2015-01-01

    Roč. 11, č. 7 (2015), e1005394 ISSN 1553-7404 Grant - others:Marie Curie International Outgoing Fellowship Award(CZ) 276569 Institutional support: RVO:60077344 Keywords : juvenile hormone Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 6.661, year: 2015 http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1005394

  13. 42 CFR 59.5 - What requirements must be met by a family planning project?

    Science.gov (United States)

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false What requirements must be met by a family planning... GRANTS GRANTS FOR FAMILY PLANNING SERVICES Project Grants for Family Planning Services § 59.5 What requirements must be met by a family planning project? (a) Each project supported under this part must: (1...

  14. BDNF Val66Met homozygosity does not influence plasma BDNF levels in healthy human subjects

    NARCIS (Netherlands)

    Luykx, J.J.; Boks, M.P.M.; Breetvelt, E.J.; Aukes, M.F.; Strengman, E.; da Pozzo, E.; Dell'osso, L.; Marazziti, D.; van Leeuwen, A.; Vreeker, A.; Abramovic, L.; Martini, C.; Numans, M.E.; Kahn, R. S.; Ophoff, R. A.

    2013-01-01

    A putative pathway by which the BDNF Val66Met polymorphism (rs6265) leads to aberrant phenotypes is its influence on plasma BDNF. Research into the impact of rs6265 on plasma BDNF has given rise to conflicting results. Moreover, most such studies have compared Met-carriers with Val-homozygous

  15. Anxiolytic effect of music exposure on BDNFMet/Met transgenic mice.

    Science.gov (United States)

    Li, Wen-Jing; Yu, Hui; Yang, Jian-Min; Gao, Jing; Jiang, Hong; Feng, Min; Zhao, Yu-Xia; Chen, Zhe-Yu

    2010-08-06

    Brain-derived neurotrophic factor (BDNF) has been reported to play important roles in the modulation of anxiety, mood stabilizers, and pathophysiology of affective disorders. Recently, a single nucleotide polymorphism (SNP) in the BDNF gene (Val66Met) has been found to be associated with depression and anxiety disorders. The humanized BDNF(Met/Met) knock-in transgenic mice exhibited increased anxiety-related behaviors that were unresponsive to serotonin reuptake inhibitors, fluoxetine. Music is known to be able to elicit emotional changes, including anxiolytic effects. In this study, we found that music treatment could significantly decrease anxiety state in BDNF(Met/Met) mice, but not in BDNF(+/)(-), mice compared with white noise exposure in open field and elevated plus maze test. Moreover, in contrast to white noise exposure, BDNF expression levels in the prefrontal cortex (PFC), amygdala and hippocampus were significantly increased in music-exposed adult BDNF(Met/Met) mice. However, music treatment could not upregulate BDNF levels in the PFC, amygdala, and hippocampus in BDNF(+/)(-) mice, which suggests the essential role of BDNF in the anxiolytic effect of music. Together, our results imply that music may provide an effective therapeutic intervention for anxiety disorders in humans with this genetic BDNF(Met) variant. Copyright 2010 Elsevier B.V. All rights reserved.

  16. Kas Eesti Mets on vanim praegu ilmuv eestikeelne ajakiri? / Rosmarii Kurvits

    Index Scriptorium Estoniae

    Kurvits, Roosmarii, 1969-

    2015-01-01

    Artiklist selgub, et vanim tänini ilmuv eestikeelne ajakiri on baptistide häälekandja Teekäija. Kuid vanuselt järgmine ongi 1921. aastast ilmuv Eesti Mets. Ühtlasi on Eesti Mets vanim kodumaine loodusajakiri

  17. "Met" Made Simple: Building Research-Based Teacher Evaluations. Issue Analysis Report

    Science.gov (United States)

    New Teacher Project, 2012

    2012-01-01

    Groundbreaking new findings from the Bill and Melinda Gates Foundation's Measures of Effective Teaching (MET) project hold the potential to answer crucial questions about how to assess teachers' performance. For the past two years, MET researchers have conducted a research project of unprecedented scope, involving 3,000 teachers in six school…

  18. Working with Teachers to Develop Fair and Reliable Measures of Effective Teaching. MET Project

    Science.gov (United States)

    Bill & Melinda Gates Foundation, 2010

    2010-01-01

    In fall 2009, the Bill & Melinda Gates Foundation launched the Measures of Effective Teaching (MET) project to develop and test multiple measures of teacher effectiveness. The goal of the MET project is to improve the quality of information about teaching effectiveness available to education professionals within states and districts--information…

  19. Evaluatie van individuele happy games op de iPad voor mensen met dementie

    NARCIS (Netherlands)

    Dr. J.H. Groenewoud; Dr. J. de Lange

    2014-01-01

    Er is veel belangstelling voor de kwaliteit van zorg voor mensen met dementie. Ook hun kwaliteit van leven krijgt steeds meer aandacht. Een zinvolle en plezierige dagbesteding hoort daarbij. Zorgprofessionals willen mensen met dementie graag ondersteunen bij het doen van activiteiten. Het huidige

  20. Patienten met diabetes Mellitus type 1 screenen op coeliakie; Ja of nee

    NARCIS (Netherlands)

    Greijdanus, T.

    2005-01-01

    Diabetes mellitus type 1 is een veelvoorkomende ziekte. Deze ziekte blijkt niet op zichzelf te staan maar is onder andere geassocieerd met coeliakie. Coeliakie wordt behandeld middels een glutenvrij dieet. De diabetespatiënten die aan coeliakie lijden blijken zich niet altijd bij de huisarts met

  1. De bepaling van aluminium in slib met behulp van een nieuwe smelttechniek en XRF

    NARCIS (Netherlands)

    Boer JLM de; Boogerd JP

    1987-01-01

    Dit rapport beschrijft de monstervoorbereiding met behulp van een nieuwe smelttechniek en de analytische aspecten van de bepaling met behulp van rontgenfluorescentiespectrometrie (XRF) van aluminium en slib. De aanleiding tot dit onderzoek was de noodzaak om analytisch-chemische bijstand te

  2. OTULIN antagonizes LUBAC signaling by specifically hydrolyzing met1-linked polyubiquitin

    DEFF Research Database (Denmark)

    Keusekotten, K.; Elliott, P.R.; Kulathu, Y.

    2013-01-01

    The linear ubiquitin (Ub) chain assembly complex (LUBAC) is an E3 ligase that specifically assembles Met1-linked (also known as linear) Ub chains that regulate nuclear factor κB (NF-κB) signaling. Deubiquitinases (DUBs) are key regulators of Ub signaling, but a dedicated DUB for Met1 linkages has...

  3. Fasciitis necroticans ten gevolge van een infectie met in een palingkwekerij

    NARCIS (Netherlands)

    Dijkstra, A.; Ingen, van J.; Lubbert, P.H.W.; Haenen, O.L.M.; Möller, A.V.M.

    2009-01-01

    Een 41-jarige man presenteerde zich met een pijnlijke infectie van zijn rechter hand. Hij werkte in een palingkwekerij, waar op dat moment een infectie met Vibrio vulnificus onder de palingen heerste. Vibrio vulnificus als veroorzaker van een wondinfectie, een sepsis of een gastro-enteritis is een

  4. Metáfora sinestésica en el Quijote

    Directory of Open Access Journals (Sweden)

    Mitja Skubic

    1995-12-01

    Full Text Available En la metáfora sinestésica, la metáfora viene considerada como el translado de una esfera sensorial a otra. Si cada metáfora es una transposición de sentido de un término a un otro, basada en una comparación no expresada, la llamada sinestésica incluye dos esferas sensoriales distintas (voz cálida, lágrimas amargas. Es aceptado por todos los semantistas que una de las condiciones de la eficacia de la metáfora sinestésica, para algunos la más importante, es la distancia semántica entre los dos conceptos; al estar los dos conceptos demasiado cercanos o pertenecer a semejante campo nocional, la metáfora pierde vigor. Comparar dos seres o cosas (casi idénticas, es posible; es, de alguna manera, una comparación pálida, inexpresiva. La metáfora sinestésica es eficaz, porque llega inesperadamente, sorprende, como postulaba el surrealismo francés (A Breton. Si hoy día muchas metáforas sinestésicas no provocan ningun asombro, es debido a la suerte que toda metáfora sufre cuando llega a ser patrimonio lexical de una lengua.

  5. Clinical and prognostic value of the C-Met/HGF signaling pathway in cervical cancer.

    Science.gov (United States)

    Boromand, Nadia; Hasanzadeh, Malihe; ShahidSales, Soodabeh; Farazestanian, Marjaneh; Gharib, Masoumeh; Fiuji, Hamid; Behboodi, Negin; Ghobadi, Niloofar; Hassanian, Seyed Mahdi; Ferns, Gordon A; Avan, Amir

    2018-06-01

    Aberrant activation of the HGF/c-Met signalling pathway is reported to be associated with cell proliferation, progression, and metastasis features of several tumor types, including cervical cancer, suggesting that it may be of potential value as a novel therapeutic target. Furthermore, HPV-positive patients had a higher serum level of HGF or c-Met protein, compared with HPV-negative patients. c-Met or HGF overexpression in lesions of cervical cancer is reported to be related to a poorer prognosis, and hence this may be of value as a prognostic and predictive biomarker. Several approaches have been developed for targeting HGF and/or c-Met. One of these is crizotinib (a dual c-Met/ALK inhibitor). This has been approved by FDA for the treatment of lung-cancer. Further investigations are required to evaluate and optimize the use of c-Met inhibitors in cervical cancer or parallel targeting signalling pathway associated/activated via MET/HGF pathway. The main aim of current review was to give an overview of the potential of the c-Met/HGF pathway as a prognostic, or predictive biomarker in cervical cancer. © 2017 Wiley Periodicals, Inc.

  6. KLF4 promotes c-Met amplification-mediated gefitinib resistance in NSCLC.

    Science.gov (United States)

    Feng, Wei; Xie, Qianyi; Liu, Suo; Ji, Ying; Li, Chunyun; Wang, Chunle; Jin, Longyu

    2018-04-06

    Gefitinib have been widely used in the first-line treatment of advanced EGFR-mutated non-small-cell lung cancer (NSCLC). However, many NSCLC patients will acquire resistance to gefitinib after 9-14 months of treatment. This study revealed that Krüppel-like factor 4 (KLF4) contributes to the formation of gefitinib resistance in c-Met overexpressing NSCLC cells. We observed that KLF4 was overexpressed in c-Met overexpressing NSCLC cells and tissues. Knockdown of KLF4 increased tumorigenic properties in gefitinib-resistant NSCLC cell lines without c-Met overexpression, but it reduced tumorigenic properties and increased gefitinib sensitivity in gefitinib-resistant NSCLC cells with c-Met overexpression, whereas overexpression of KLF4 reduced gefitinib sensitivity in gefitinib-sensitive NSCLC cells. Furthermore, Western blot analysis revealed that KLF4 contributed to the formation of gefitinib resistance in c-Met overexpressing NSCLC cells by inhibiting the expression of apoptosis-related proteins under gefitinib treatment and activating the c-Met/Akt signaling pathway by decreasing the inhibition of β-Catenin on phosphorylation of c-Met to prevent blockade by gefitinib. In summary, this study's results suggest that KLF4 is a promising candidate molecular target for both prevention and therapy of NSCLC with c-Met overexpression. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  7. 34 CFR 692.101 - What requirements must be met by a State partnership?

    Science.gov (United States)

    2010-07-01

    ... 34 Education 3 2010-07-01 2010-07-01 false What requirements must be met by a State partnership...) OFFICE OF POSTSECONDARY EDUCATION, DEPARTMENT OF EDUCATION LEVERAGING EDUCATIONAL ASSISTANCE PARTNERSHIP... What requirements must be met by a State partnership? (a) State. A State that is receiving an allotment...

  8. Hergroeivertraging tijdens de veldperiode : door: lengte veldperiode, bedekking met gemaaid gras, zwaarte vorige snede, berijden

    NARCIS (Netherlands)

    Overvest, J.

    1977-01-01

    In 1971 en 1972 zijn vier proeven uitgevoerd, waarbij nagegaan werd in hoeverre de hergroei na maaien wordt beïnvloed door een tijdelijke bedekking van de stoppel met gras. Bij de proeven in 1971 is dat gebeurd bij één opbrengstniveau. In 1972 werd tegelijkertijd met twee opbrengstniveaus gewerkt.

  9. 75 FR 16205 - MetLife Insurance Company of Connecticut, et al.

    Science.gov (United States)

    2010-03-31

    ... Funds' adviser, profit distributions from the adviser. These profits from investment advisory fees may...''). ACTION: Notice of application for an order pursuant to Section 26(c) of the Investment Company Act of...''), MetLife of CT Fund UL for Variable Life Insurance (``Fund UL''), MetLife Investors Insurance Company...

  10. BDNF Val66Met polymorphism and protein levels in Amniotic Fluid

    Directory of Open Access Journals (Sweden)

    Calabrese Francesca

    2010-02-01

    Full Text Available Abstract Background Brain-Derived Neurotrophic Factor (BDNF is a neurotrophin which plays survival- and growth-promoting activity in neuronal cells and it is involved in cellular plasticity mechanisms as it controls activity dependent synaptic transmission. A functional polymorphism (Val66Met in the pro-region of BDNF, which affects the intracellular trafficking of proBDNF has been associated with memory and cognitive deficits as well as to an increased susceptibility for several psychiatric disorders especially those with a neurodevelopmental origin. To date, no study has evaluated the influence of the Val66Met polymorphism on BDNF levels in a peripheral system that may reflect fetal neurodevelopment. Therefore we investigated in amniotic fluids (AF obtained from 139 healthy women during 15-17 week of pregnancy, BDNF protein levels in correlation with the Val66Met polymorphism. Results Interestingly we found a significant BDNF protein levels reduction in 55 Met carriers (Val/Met and Met/Met (p = 0.002 as compared to 84 non carriers (Val/Val, and no effect of fetus gender, maternal age or gestation week on BDNF levels has been observed. Conclusion These results, although explorative, indicate that during fetal life the Val66Met genotype might influences BDNF protein levels in AF supporting the involvement of this polymorphism in behavioral and functional brain individual differences in the adulthood.

  11. Het effect van gedragsmatige oefentherapie bij patiënten met artrose van heup of knie.

    NARCIS (Netherlands)

    Veenhof, C.; Dekker, J.; Bijlsma, H.; Ende, E. van den

    2008-01-01

    In dit hoofdstuk wordt de effectiviteit van gedragsmatige oefentherapie, genaamd GRADIT, beschreven en vergeleken met behandeling volgens de huidige fysiotherapeutische richtlijn, bij patiënten met artrose van heup of knie. De GRADIT-behandeling is gebaseerd op de behandelprincipes van operant leren

  12. Een vergelijking van de voorjaarstrek van drie populaties Brandganzen met behulp van GPS-satellietzenders

    NARCIS (Netherlands)

    De Boer, R.; Bauer, Silke; Van der Jeugd, Henk; Ens, B.J.; Griffin, L.; Cabot, D.; Exo, K-M.; Nolet, Bart A.; Kölzsch, Andrea

    2014-01-01

    Onderzoek naar trekvogels heeft een grote vlucht genomen sinds de introductie van draagbare apparatuur met ingebouwde GPS-ontvangers, omdat we hiermee de trek van individuele vogels in groot detail kunnen volgen. In dit artikel brengen we met behulp van GPS-satellietzenders de voorjaarstrek van drie

  13. Beperkte evaluatie van een ELISA kit voor het bepalen van Diarrhetic Shellfish Poisons : met name okadainezuur

    NARCIS (Netherlands)

    Trijp, van J.M.P.; Traag, W.A.; Paulussen, R.J.A.; Tuinstra, L.G.M.Th.

    1988-01-01

    Naast een reeds in ontwikkeling zijnde methode me t gebruik van HPLC is er zeer recentelijk een ELISA-kit van Japanse origine op de markt gekomen voor de bepaling van DSP (Diarrhetic Shellfish Paisons). Deze kit is getest met een viertal mosselen welke positief waren bevonden met de rat bio-assay.

  14. NATO Rule of Law Field Support Mission (NROLFSM): Een concept met toekomst?

    NARCIS (Netherlands)

    Voetelink, J.

    2014-01-01

    Nederland heeft de afgelopen jaren met drie stafofficieren bijgedragen aan de NATO Rule of Law Field Support Mission die van 30 juni 2011 tot en met 30 september 2013 in Afghanistan actief is geweest. Dit commando heeft vanuit de Counter Insurgency gedachte een bijdrage geleverd aan de bestrijding

  15. 76 FR 53054 - Safety Zone; TriMet Bridge Project, Willamette River; Portland, OR

    Science.gov (United States)

    2011-08-25

    ... SECURITY Coast Guard 33 CFR Part 165 RIN 1625-AA00 Safety Zone; TriMet Bridge Project, Willamette River... safety zone during the construction of the TriMet Bridge on the Willamette River, in Portland, OR. This... close proximity to cranes and overhead work associated with this construction project. During the...

  16. Genetic contribution of catechol-O-methyltransferase polymorphism (Val158Met) in children with chronic tension-type headache.

    Science.gov (United States)

    Fernández-de-las-Peñas, César; Ambite-Quesada, Silvia; Rivas-Martínez, Inés; Ortega-Santiago, Ricardo; de-la-Llave-Rincón, Ana Isabel; Fernández-Mayoralas, Daniel M; Pareja, Juan A

    2011-10-01

    Our aim was to investigate the relationship between Val158Met polymorphisms, headache, and pressure hypersensitivity in children with chronic tension-type headache (CTTH). A case-control study with blinded assessor was conducted. Seventy children with CTTH associated with pericranial tenderness and 70 healthy children participated. After amplifying Val158Met polymorphism by polymerase chain reactions, we assessed genotype frequencies and allele distributions. We classified children according to their Val158Met polymorphism: Val/Val, Val/Met, Met/Met. Pressure pain thresholds (PPT) were bilaterally assessed over the temporalis, upper trapezius, second metacarpal, and tibialis anterior muscles. The distribution of Val158Met genotypes was not significantly different (p = 0.335), between children with CTTH and healthy children, and between boys and girls (p = 0.872). Children with CTTH with the Met/Met genotype showed a longer headache history compared with those with Met/Val (p = 0.001) or Val/Val (p = 0.002) genotype. Children with CTTH with Met/Met genotype showed lower PPT over upper trapezius and temporalis muscles than children with CTTH with Met/Val or Val/Val genotype (p < 0.01). The Val158Met catechol-O-methyltransferase (COMT) polymorphism does not appear to be involved in predisposition to suffer from CTTH in children; nevertheless, this genetic factor may be involved in the phenotypic expression, as pressure hypersensitivity was greater in those CTTH children with the Met/Met genotype.

  17. The reliability of the National Cholesterol Education Program's Adult Treatment Panel III (NCEP/ATP III) and the International Diabetes Federation (IDF) definitions in diagnosing metabolic syndrome (MetS) among Gaza Strip Palestinians.

    Science.gov (United States)

    Sirdah, Mahmoud M; Abu Ghali, Asmaa S; Al Laham, Nahed A

    2012-01-01

    Metabolic syndrome (MetS) which is a multifaceted syndrome, has been demonstrated as a common precursor for developing cardiovascular diseases and/or type 2 diabetes mellitus. Different diagnostic definitions for MetS have been proposed and recommended. We set up to evaluate the reliabilities of the National Cholesterol Education Program's Adult Treatment Panel III (NCEP/ATP III) and the International Diabetes Federation (IDF) definitions in diagnosing MetS among Gaza Strip Palestinians. This cross sectional study involved a randomly selected two hundred and thirty apparently healthy adults from the Gaza Strip. Anthropometric measurements, blood pressure, fasting plasma glucose, lipid profile, and questionnaire interviews were performed. The overall prevalence of MetS in our Gaza Strip cohort was 23.0% and 39.5% according to NCEP/ATP III and IDF definitions respectively (pdefinition (mean 3.42 ± 0.63 vs 3.52 ± 0.69 respectively, p=0.865). Both IDF and NCEP/ATP III showed an increased prevalence of MetS with age, and body mass index (BMI), however they revealed different prevalence trends with sex. Except for BMI, there were no significant differences in the general and metabolic related characteristics between subjects with MetS of IDF and NCEP/ATP III definitions. Independently of the definition used, MetS is highly prevalent in Gaza Strip population, with a steady increase in MetS prevalence through age and BMI. The IDF definition tends to give higher values for MetS prevalence, and therefore could be more appropriate for diagnosing MetS in Gaza Strip cohort. Copyright © 2012 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  18. Opioid-dependent growth of glial cultures: Suppression of astrocyte DNA synthesis by met-enkephalin

    Energy Technology Data Exchange (ETDEWEB)

    Stiene-Martin, A.; Hauser, K.F. (Univ. of Kentucky, Lexington (USA))

    1990-01-01

    The action of met-enkephalin on the growth of astrocytes in mixed-glial cultures was examined. Primary, mixed-glial cultures were isolated from 1 day-old mouse cerebral hemispheres and continuously treated with either basal growth media, 1 {mu}M met-enkephalin, 1 {mu}M met-enkephalin plus the opioid antagonist naloxone, or naloxone alone. Absolute numbers of neural cells were counted in unstained preparations, while combined ({sup 3}H)-thymidine autoradiography and glial fibrillary acid protein (GFAP) immunocytochemistry was performed to identify specific changes in astrocytes. When compared to control and naloxone treated cultures, met-enkephalin caused a significant decrease in both total cell numbers, and in ({sup 3}H)-thymidine incorporation by GFAP-positive cells with flat morphology. These results indicate that met-enkephalin suppresses astrocyte growth in culture.

  19. c-MET Overexpression in Colorectal Cancer: A Poor Prognostic Factor for Survival.

    Science.gov (United States)

    Lee, Su Jin; Lee, Jeeyun; Park, Se Hoon; Park, Joon Oh; Lim, Ho Yeong; Kang, Won Ki; Park, Young Suk; Kim, Seung Tae

    2018-03-02

    Increased mesenchymal-epithelial transition factor gene (c-MET) expression in several human malignancies is related to increased tumor progression and is a new potential drug target for several types of cancers. In the present study, we investigated the incidence of c-MET overexpression and its prognostic significance in patients with colorectal cancer (CRC). We retrospectively reviewed the data from 255 stage IV CRC patients who had results from a c-MET immunohistochemical test at Samsung Medical Center. We explored the relationships between c-MET overexpression and clinicopathological features and survival. Primary tumor sites were 67 right-sided colon, 98 left-sided colon, and 90 rectum. Forty-two patients (16.7%) had poorly differentiated or mucinous carcinoma. Among the 255 patients, 39 (15.3%) exhibited c-MET overexpression. There was no significant difference in the prevalence of c-MET overexpression according to primary site, histologic differentiation, molecular markers, or metastatic sites. In a comparison of the tumor response to first-line chemotherapy according to the level of c-MET expression, we found no significant difference in either partial response or disease control rate. In the survival analysis, patients with c-MET overexpression had significantly shorter overall survival (39 vs. 27 months; P = .018) and progression-free survival (PFS) during bevacizumab treatment (10 vs. 7 months; P = .024). c-MET overexpression, which was detected in 39 CRC patients (15.3%) irrespective of primary sites or molecular markers, indicated a poor survival prognosis and predicted shorter PFS during bevacizumab treatment in patients with CRC. Further studies are warranted to elucidate the value of c-MET-targeted therapy in CRC patients. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Catechol-O-Methyltransferase (COMT) Gene (Val158Met) and Brain-Derived Neurotropic Factor (BDNF) (Val66Met) Genes Polymorphism in Schizophrenia: A Case-Control Study.

    Science.gov (United States)

    Saravani, Ramin; Galavi, Hamid Reza; Lotfian Sargazi, Marzieh

    2017-10-01

    Objective: Several studies have shown that some polymorphisms of genes encoding catechol-O-methyltransferase (COMT), the key enzyme in degrading dopamine, and norepinephrine and the human brain-derived neurotropic factor (BDNF), a nerve growth factor, are strong candidates for risk of schizophrenia (SCZ). In the present study, we aimed at examining the effects of COMT Val158Met (G>A) and BDNF Val66Met (G>A) polymorphisms on SCZ risk in a sample of Iranian population. Method: This case- control study included 92 SCZ patients and 92 healthy controls (HCs). Genotyping of both variants (COMT Val158Met (G>A) and BDNF Val66Met (G>A)) were conducted using Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR). Results: The findings revealed that the COMT Val158Met (G>A) polymorphism was not associated with the risk/protective of SCZ in all models (OR=0.630, 95%CI=0.299-1.326, P=0.224, GA vs. GG, OR=1.416, 95%CI=0.719-2.793, P=0.314, AA vs. GG, OR=1.00, 95%CI=0.56-1.79, P=1.00 GA+AA vs. GG, OR=1.667, 95%CI=0.885-3.125, P=0.11, AA vs. GG+GA, OR=1.247, 95%CI=0.825-1.885, P=0.343, A vs. G,). However, BDNF Val66Met (G>A) variant increased the risk of SCZ (OR = 2.008 95%CI = 1.008-4.00, P = 0.047, GA vs. GG, OR = 3.876 95%CI = 1.001-14.925, P = 0.049. AA vs. GG, OR = 2.272. 95%CI = 1.204-4.347, P = 0.011, GA+AA vs. GG, OR = 2.22 95%CI = 1.29-3.82. P = 0.005, A vs. G). Conclusion: The results did not support an association between COMT Val158Met (G>A) variant and risk/protective of SCZ. Moreover, it was found that BDNF Val66Met (G>A) polymorphism may increase the risk of SCZ development. Further studies and different ethnicities are recommended to confirm the findings.

  1. ROCK I Has More Accurate Prognostic Value than MET in Predicting Patient Survival in Colorectal Cancer.

    Science.gov (United States)

    Li, Jian; Bharadwaj, Shruthi S; Guzman, Grace; Vishnubhotla, Ramana; Glover, Sarah C

    2015-06-01

    Colorectal cancer remains the second leading cause of death in the United States despite improvements in incidence rates and advancements in screening. The present study evaluated the prognostic value of two tumor markers, MET and ROCK I, which have been noted in other cancers to provide more accurate prognoses of patient outcomes than tumor staging alone. We constructed a tissue microarray from surgical specimens of adenocarcinomas from 108 colorectal cancer patients. Using immunohistochemistry, we examined the expression levels of tumor markers MET and ROCK I, with a pathologist blinded to patient identities and clinical outcomes providing the scoring of MET and ROCK I expression. We then used retrospective analysis of patients' survival data to provide correlations with expression levels of MET and ROCK I. Both MET and ROCK I were significantly over-expressed in colorectal cancer tissues, relative to the unaffected adjacent mucosa. Kaplan-Meier survival analysis revealed that patients' 5-year survival was inversely correlated with levels of expression of ROCK I. In contrast, MET was less strongly correlated with five-year survival. ROCK I provides better efficacy in predicting patient outcomes, compared to either tumor staging or MET expression. As a result, ROCK I may provide a less invasive method of assessing patient prognoses and directing therapeutic interventions. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  2. BDNF val66met genotype and schizotypal personality traits interact to influence probabilistic association learning.

    Science.gov (United States)

    Skilleter, Ashley Jayne; Weickert, Cynthia Shannon; Moustafa, Ahmed Abdelhalim; Gendy, Rasha; Chan, Mico; Arifin, Nur; Mitchell, Philip Bowden; Weickert, Thomas Wesley

    2014-11-01

    The brain derived neurotrophic factor (BDNF) val66met polymorphism rs6265 influences learning and may represent a risk factor for schizophrenia. Healthy people with high schizotypal personality traits display cognitive deficits that are similar to but not as severe as those observed in schizophrenia and they can be studied without confounds of antipsychotics or chronic illness. How genetic variation in BDNF may impact learning in individuals falling along the schizophrenia spectrum is unknown. We predicted that schizotypal personality traits would influence learning and that schizotypal personality-based differences in learning would vary depending on the BDNF val66met genotype. Eighty-nine healthy adults completed the Schizotypal Personality Questionnaire (SPQ) and a probabilistic association learning test. Blood samples were genotyped for the BDNF val66met polymorphism. An ANOVA was performed with BDNF genotype (val homozygotes and met-carriers) and SPQ score (high/low) as grouping variables and probabilistic association learning as the dependent variable. Participants with low SPQ scores (fewer schizotypal personality traits) showed significantly better learning than those with high SPQ scores. BDNF met-carriers displaying few schizotypal personality traits performed best, whereas BDNF met-carriers displaying high schizotypal personality traits performed worst. Thus, the BDNF val66met polymorphism appears to influence probabilistic association learning differently depending on the extent of schizotypal personality traits displayed. Crown Copyright © 2014. Published by Elsevier B.V. All rights reserved.

  3. Catechol-O-methyltransferase val158met polymorphism predicts placebo effect in irritable bowel syndrome.

    Directory of Open Access Journals (Sweden)

    Kathryn T Hall

    Full Text Available Identifying patients who are potential placebo responders has major implications for clinical practice and trial design. Catechol-O-methyltransferase (COMT, an important enzyme in dopamine catabolism plays a key role in processes associated with the placebo effect such as reward, pain, memory and learning. We hypothesized that the COMT functional val158met polymorphism, was a predictor of placebo effects and tested our hypothesis in a subset of 104 patients from a previously reported randomized controlled trial in irritable bowel syndrome (IBS. The three treatment arms from this study were: no-treatment ("waitlist", placebo treatment alone ("limited" and, placebo treatment "augmented" with a supportive patient-health care provider interaction. The primary outcome measure was change from baseline in IBS-Symptom Severity Scale (IBS-SSS after three weeks of treatment. In a regression model, the number of methionine alleles in COMT val158met was linearly related to placebo response as measured by changes in IBS-SSS (p = .035. The strongest placebo response occurred in met/met homozygotes treated in the augmented placebo arm. A smaller met/met associated effect was observed with limited placebo treatment and there was no effect in the waitlist control. These data support our hypothesis that the COMT val158met polymorphism is a potential biomarker of placebo response.

  4. Preliminary clinical application of 11C-MET PET/CT in the brain glioma patients

    International Nuclear Information System (INIS)

    Wang Quanshi; Wu Hubing; Wang Mingfang; Wang Xinlu; Guo Xiaojun

    2005-01-01

    Objective: To study the clinical value of 11 C-methionine (MET) PET/CT imaging in brain glioma. Methods: 27 cases were studied including 2 glioma, 23 operated glioma and 2 healthy volunteers. 11 C-MET PET/CT was performed in all cases but 18 F-fluorodeoxyglucose (FDG) PET/CT in only 17 cases. Follow-up period was within 3-17 months. Results: 11 C-MET was negative in 4 cases and 18 F-FDG negative in 3 cases in group without remnant or recurrent tumor after operation. In 2 cases of initial glioma and 19 cases with remnant or recurrent tumor group, 11 C-MET imaging was positive in 20 cases, tumor/gray matter ratio and tumor/white matter ratio were 2.02 ± 0.96, 3.01 ± 1.79, respectively, among them 14 cases also with 18 F-FDG imaging showed positive in 12 cases. Lesions showed by 11 C-MET were far more clear than that of 18 F-FDG. Also tumor/gray matter ratio and the tumor/white matter ratio of 11 C-MET imaging were significantly higher than 18 F-FDG (2.15 ± 1.16 vs 0.97 ± 0.43, P 11 C-MET PET/CT is superior to 18 F-FDG PET/CT in the diagnosis and localization of brain glioma. (authors)

  5. FAK is required for c-Met/β-catenin-driven hepatocarcinogenesis.

    Science.gov (United States)

    Shang, Na; Arteaga, Maribel; Zaidi, Ali; Stauffer, Jimmy; Cotler, Scott J; Zeleznik-Le, Nancy J; Zhang, Jiwang; Qiu, Wei

    2015-01-01

    Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide and most patients with HCC have limited treatment options. Focal adhesion kinase (FAK) is overexpressed in many HCC specimens, offering a potential target for HCC treatment. However, the role of FAK in hepatocarcinogenesis remains elusive. Establishing whether FAK expression plays a role in HCC development is necessary to determine whether it is a viable therapeutic target. In this study, we generated mice with hepatocyte-specific deletion of Fak and investigated the role of Fak in an oncogenic (c-MET/β-catenin, MET/CAT)-driven HCC model. We found that deletion of Fak in hepatocytes did not affect morphology, proliferation, or apoptosis. However, Fak deficiency significantly repressed MET/CAT-induced tumor development and prolonged survival of animals with MET/CAT-induced HCC. In mouse livers and HCC cell lines, Fak was activated by MET, which induced the activation of Akt/Erk and up-regulated cyclin D1 and tumor cell proliferation. CAT enhanced MET-stimulated FAK activation and synergistically induced the activation of the AKT/ERK-cyclin D1 signaling pathway in a FAK kinase-dependent manner. In addition, FAK was required for CAT-induced cyclin D1 expression in a kinase-independent fashion. Fak is required for c-Met/β-catenin-driven hepatocarcinogenesis. Inhibition of FAK provides a potential strategy to treat HCC. © 2014 by the American Association for the Study of Liver Diseases.

  6. COMT Val158Met polymorphism, cognitive stability and cognitive flexibility: an experimental examination

    Directory of Open Access Journals (Sweden)

    Rosa Elise C

    2010-09-01

    Full Text Available Abstract Background Dopamine in prefrontal cortex (PFC modulates core cognitive processes, notably working memory and executive control. Dopamine regulating genes and polymorphisms affecting PFC - including Catechol-O-Methyltransferase (COMT Val158Met - are crucial to understanding the molecular genetics of cognitive function and dysfunction. A mechanistic account of the COMT Val158Met effect associates the Met allele with increased tonic dopamine transmission underlying maintenance of relevant information, and the Val allele with increased phasic dopamine transmission underlying the flexibility of updating new information. Thus, consistent with some earlier work, we predicted that Val carriers would display poorer performance when the maintenance component was taxed, while Met carriers would be less efficient when rapid updating was required. Methods Using a Stroop task that manipulated level of required cognitive stability and flexibility, we examined reaction time performance of patients with schizophrenia (n = 67 and healthy controls (n = 186 genotyped for the Val/Met variation. Results In both groups we found a Met advantage for tasks requiring cognitive stability, but no COMT effect when a moderate level of cognitive flexibility was required, or when a conflict cost measure was calculated. Conclusions Our results do not support a simple stability/flexibility model of dopamine COMT Val/Met effects and suggest a somewhat different conceptualization and experimental operationalization of these cognitive components.

  7. Catechol-O-methyltransferase val158met polymorphism predicts placebo effect in irritable bowel syndrome.

    Science.gov (United States)

    Hall, Kathryn T; Lembo, Anthony J; Kirsch, Irving; Ziogas, Dimitrios C; Douaiher, Jeffrey; Jensen, Karin B; Conboy, Lisa A; Kelley, John M; Kokkotou, Efi; Kaptchuk, Ted J

    2012-01-01

    Identifying patients who are potential placebo responders has major implications for clinical practice and trial design. Catechol-O-methyltransferase (COMT), an important enzyme in dopamine catabolism plays a key role in processes associated with the placebo effect such as reward, pain, memory and learning. We hypothesized that the COMT functional val158met polymorphism, was a predictor of placebo effects and tested our hypothesis in a subset of 104 patients from a previously reported randomized controlled trial in irritable bowel syndrome (IBS). The three treatment arms from this study were: no-treatment ("waitlist"), placebo treatment alone ("limited") and, placebo treatment "augmented" with a supportive patient-health care provider interaction. The primary outcome measure was change from baseline in IBS-Symptom Severity Scale (IBS-SSS) after three weeks of treatment. In a regression model, the number of methionine alleles in COMT val158met was linearly related to placebo response as measured by changes in IBS-SSS (p = .035). The strongest placebo response occurred in met/met homozygotes treated in the augmented placebo arm. A smaller met/met associated effect was observed with limited placebo treatment and there was no effect in the waitlist control. These data support our hypothesis that the COMT val158met polymorphism is a potential biomarker of placebo response.

  8. Prevalence of 35delG and Met34Thr GJB2 variants in Portuguese samples.

    Science.gov (United States)

    Dória, Mariana; Neto, Ana Paula; Santos, Ana Cristina; Barros, Henrique; Fernandes, Susana; Moura, Carla Pinto

    2015-12-01

    To estimate the prevalence of 35delG and Met34Thr variants in a Portuguese children's community sample and to compare these frequencies with nonsyndromic hearing-loss patients. 502 children were randomly selected among the 8647 participants of the Portuguese birth cohort Generation XXI, and screened for Met34Thr and 35delG variants in the GJB2 gene. These variants were also studied on 89 index-cases, observed in the Clinic of "Hereditary Hearing-loss" in Saint John's Hospital Center, presenting a mild to profound nonsyndromic hearing-loss. Among the 502 children from Generation XXI, 10 were heterozygous for the 35delG variant (95% Confidence Interval 1.03-3.68) and 1 homozygous (95% Confidence Interval 0.01-1.24). Other 10 children presented heterozygosity for the Met34Thr variant (95% Confidence Interval 1.03-3.68). No homozygous for the Met34Thr or compound heterozygotes (35delG/Met34Thr) were found. In the total of 89 nonsyndromic hearing-loss patients, 5 (95% Confidence Interval 2.11-12.8) were heterozygous and 7 (95% Confidence Interval 3.61-15.6) were homozygous for the 35delG variant. The Met34Thr variant was found in 4 patients, 2 heterozygous (95% Confidence Interval 0.13-8.31) and 2 homozygous (95% Confidence Interval 0.13-8.31). The carrier frequency of 35delG and Met34Thr variants in a Portuguese sample was 1 in 50. Our data suggests that the 35delG mutation has an association with deafness. For the Met34Thr variant, no association was observed. However, Met34Thr seemed to conform to an additive model in hearing-loss. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  9. MetNet - In situ observational Network and Orbital platform to investigate the Martian environment

    Science.gov (United States)

    Harri, Ari-Matti; Leinonen, Jussi; Merikallio, Sini; Paton, Mark; Haukka, Harri; Polkko, Jouni

    2007-09-01

    MetNet Mars Mission is an in situ observational network and orbital platform mission to investigate the Martian environment and it has been proposed to European Space Agency in response to Call for proposals for the first planning cycle of Cosmic Vision 2015-2025 D/SCI/DJS/SV/val/21851. The MetNet Mars Mission is to be implemented in collaboration with ESA, FMI, LA, IKI and the payload providing science teams. The scope of the MetNet Mission is to deploy 16 MetNet Landers (MNLs) on the Martian surface by using inflatable descent system structures accompanied by an atmospheric sounder and data relay onboard the MetNet Orbiter (MNO), which is based on ESA Mars Express satellite platform. The MNLs are attached on the three sides of the satellite and most of the MNLs are deployed to Mars separately a few weeks prior to the arrival to Mars. The MetNet Orbiter will perform continuous atmospheric soundings thus complementing the accurate in situ observations at the Martian ground produced by the MetNet observation network, as well as the orbiter will serve as the primary data relay between the MetNet Landers and the Earth. The MNLs are equipped with a versatile science payload focused on the atmospheric science of Mars. Detailed characterisation of the Martian atmospheric circulation patterns, boundary layer phenomena, and climatological cycles, as well as interior investigations, require simultaneous in situ meteorological, seismic and magnetic measurements from networks of stations on the Martian surface. MetNet Mars Mission will also provide a crucial support for the safety of large landing missions in general and manned Mars missions in particular. Accurate knowledge of atmospheric conditions and weather data is essential to guarantee safe landings of the forthcoming Mars mission elements.

  10. Cysteine methylation controls radical generation in the Cfr radical AdoMet rRNA methyltransferase.

    Directory of Open Access Journals (Sweden)

    Martin R Challand

    Full Text Available The 'radical S-adenosyl-L-methionine (AdoMet' enzyme Cfr methylates adenosine 2503 of the 23S rRNA in the peptidyltransferase centre (P-site of the bacterial ribosome. This modification protects host bacteria, notably methicillin-resistant Staphylococcus aureus (MRSA, from numerous antibiotics, including agents (e.g. linezolid, retapamulin that were developed to treat such organisms. Cfr contains a single [4Fe-4S] cluster that binds two separate molecules of AdoMet during the reaction cycle. These are used sequentially to first methylate a cysteine residue, Cys338; and subsequently generate an oxidative radical intermediate that facilitates methyl transfer to the unreactive C8 (and/or C2 carbon centres of adenosine 2503. How the Cfr active site, with its single [4Fe-4S] cluster, catalyses these two distinct activities that each utilise AdoMet as a substrate remains to be established. Here, we use absorbance and electron paramagnetic resonance (EPR spectroscopy to investigate the interactions of AdoMet with the [4Fe-4S] clusters of wild-type Cfr and a Cys338 Ala mutant, which is unable to accept a methyl group. Cfr binds AdoMet with high (∼ 10 µM affinity notwithstanding the absence of the RNA cosubstrate. In wild-type Cfr, where Cys338 is methylated, AdoMet binding leads to rapid oxidation of the [4Fe-4S] cluster and production of 5'-deoxyadenosine (DOA. In contrast, while Cys338 Ala Cfr binds AdoMet with equivalent affinity, oxidation of the [4Fe-4S] cluster is not observed. Our results indicate that the presence of a methyl group on Cfr Cys338 is a key determinant of the activity of the enzyme towards AdoMet, thus enabling a single active site to support two distinct modes of AdoMet cleavage.

  11. Gefitinib inhibits invasive phenotype and epithelial-mesenchymal transition in drug-resistant NSCLC cells with MET amplification.

    Directory of Open Access Journals (Sweden)

    Silvia La Monica

    Full Text Available Despite the initial response, all patients with epidermal growth factor receptor (EGFR-mutant non-small cell lung cancer (NSCLC eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs. The EGFR-T790M secondary mutation is responsible for half of acquired resistance cases, while MET amplification has been associated with acquired resistance in about 5-15% of NSCLCs. Clinical findings indicate the retained addiction of resistant tumors on EGFR signaling. Therefore, we evaluated the molecular mechanisms supporting the therapeutic potential of gefitinib maintenance in the HCC827 GR5 NSCLC cell line harbouring MET amplification as acquired resistance mechanism. We demonstrated that resistant cells can proliferate and survive regardless of the presence of gefitinib, whereas the absence of the drug significantly enhanced cell migration and invasion. Moreover, the continuous exposure to gefitinib prevented the epithelial-mesenchymal transition (EMT with increased E-cadherin expression and down-regulation of vimentin and N-cadherin. Importantly, the inhibition of cellular migration was correlated with the suppression of EGFR-dependent Src, STAT5 and p38 signaling as assessed by a specific kinase array, western blot analysis and silencing functional studies. On the contrary, the lack of effect of gefitinib on EGFR phosphorylation in the H1975 cells (EGFR-T790M correlated with the absence of effects on cell migration and invasion. In conclusion, our findings suggest that certain EGFR-mutated patients may still benefit from a second-line therapy including gefitinib based on the specific mechanism underlying tumor cell resistance.

  12. Tratamiento quirúrgico de las metástasis vertebrales

    OpenAIRE

    Villas, C. (Carlos); Arriagada, C. (C.); Noain, E. (E.); Beguiristain, J. (José); Bascuñan, F. (F.)

    1998-01-01

    Las metástasis vertebrales causan dolor y déficit neurológico por la destrucción ósea y compresión medular. Las nuevas terapias oncológicas han prolongado la vida sobrevida de muchos pacientes afectos de tumores de distinto origen y el tratamiento de las metástasis es frecuentemente necesario para mejorar la calidad de vida. Se estudian 121 pacientes afectos de metástasis vertebrales de una variada etiología de tumores primarios, tratados quirúrgicamente entre 1982 y 1995; se utilizaron disti...

  13. Vigas de madera laminada Glulam reforzadas con pletinas metálicas dentadas

    OpenAIRE

    Cañola, Hernán Darío

    2015-01-01

    En esta tesis se estudian las propiedades mecánicas de vigas de madera maciza y de madera laminada Glulam reforzadas con pletinas metálicas dentadas. Se fabricaron y analizaron experimentalmente cuatro grupos diferentes de vigas: 30 vigas de madera maciza no reforzadas, 30 vigas de madera maciza reforzadas con pletinas metálicas dentadas, 30 vigas de madera laminada Glulam no reforzadas y 30 vigas de madera laminada Glulam reforzadas con pletinas metálicas dentadas. Las vigas de madera ...

  14. Inzet RTK-GPS in de teelt van een gewas : met RTK-GPS schoffelen in cichorei na zaaien met RTK-GPS

    OpenAIRE

    Bleeker, P.O.

    2009-01-01

    In juni 2008 werd op het proefbedrijf van PPO in Lelystad onderzoek gedaan naar de invloed van RTK-GPS stuursystemen op de rechtgeleiding van een werktuig. Met RTK-GPS (RTK staat voor Real Time Kinetic) kan op centimeters nauwkeurig gereden worden. De vraag die beantwoord moest worden was: is de afwijking die de fabrikant aangeeft haalbaar.

  15. Inzet RTK-GPS in de teelt van een gewas : met RTK-GPS schoffelen in cichorei na zaaien met RTK-GPS

    NARCIS (Netherlands)

    Bleeker, P.O.

    2009-01-01

    In juni 2008 werd op het proefbedrijf van PPO in Lelystad onderzoek gedaan naar de invloed van RTK-GPS stuursystemen op de rechtgeleiding van een werktuig. Met RTK-GPS (RTK staat voor Real Time Kinetic) kan op centimeters nauwkeurig gereden worden. De vraag die beantwoord moest worden was: is de

  16. HPA axis dysregulation, NR3C1 polymorphisms and glucocorticoid receptor isoforms imbalance in metabolic syndrome.

    Science.gov (United States)

    Martins, Clarissa Silva; Elias, Daniel; Colli, Leandro Machado; Couri, Carlos Eduardo; Souza, Manoel Carlos L A; Moreira, Ayrton C; Foss, Milton C; Elias, Lucila L K; de Castro, Margaret

    2017-03-01

    Metabolic syndrome (MetS) shares several similarities with hypercortisolism. To evaluate hypothalamic-pituitary-adrenal (HPA) axis sensitivity to dexamethasone (DEX), NR3C1 single nucleotide polymorphisms (SNPs), and expression of glucocorticoid receptor (GR) isoforms and cytokines in peripheral immune cells of MetS patients and controls. Prospective study with 40 MetS patients and 40 controls was conducted at the Ribeirão Preto Medical School University Hospital. Plasma and salivary cortisol were measured in basal conditions and after 0.25, 0.5, and 1 mg of DEX given at 2300 h. In addition, p.N363S (rs6195), p.ER22/23EK (rs6189-6190), and BclI (rs41423247) SNPs were evaluated by quantitative polymerase chain reaction allelic discrimination. Exons 3 to 9 and exon/intron boundaries of NR3C1 were sequenced. GR isoforms and cytokines (IL1B, IL2, IL4, IL6, IL8, IL10, IFNγ, TNFα) expression were assessed by quantitative polymerase chain reaction. Plasma and salivary cortisol (nmol/L) after 1-mg DEX were higher in MetS patients compared with controls (PF: 70.2 ± 17.3 vs 37.9 ± 2.6, P = .02, and SF: 4.9 ± 1.7 vs 2.2 ± 0.3, P molecular mechanism of glucocorticoid resistance in MetS. Thus, HPA axis dysregulation might contribute to MetS pathogenesis. Copyright © 2016 John Wiley & Sons, Ltd.

  17. GPM GROUND VALIDATION MET ONE RAIN GAUGE PAIRS IFLOODS V2

    Data.gov (United States)

    National Aeronautics and Space Administration — The GPM Ground Validation Met One Rain Gauge Pairs IFloodS V2 data measures the amount of fallen precipitation collected by a Model 380 tipping bucket rain gauge...

  18. The association of XRCC3 Thr241Met genetic variant with risk of ...

    African Journals Online (AJOL)

    complementing group 3 gene (XRCC3) Thr241Met genetic variant could be potentially associated with the risk of prostate cancer. However, results from these published studies were conflicting rather than conclusive. Objectives:This meta-analysis ...

  19. GPM Ground Validation Met One Rain Gauge Pairs OLYMPEX V1

    Data.gov (United States)

    National Aeronautics and Space Administration — The GPM Ground Validation Met One Rain Gauge Pairs OLYMPEX dataset was collected from January 1, 2015 to June 20, 2016 during the GPM Ground Validation Olympic...

  20. Alleen leven en geluk : Verhoogt onvrede met het leven de kans om alleen te komen staan?

    NARCIS (Netherlands)

    R. Veenhoven (Ruut)

    1987-01-01

    textabstractSAMENVATTING:
    Alleenstaanden beleven gemiddeld minder voldoening aan hun bestaan dan mensen die met een partner samenwonen. Vooral gescheidenen en verweduwden zijn naar verhouding ongelukkig. Dit verschil blijkt in tal van onderzoekingen in moderne westerse landen en heeft

  1. A metáfora na obra de arte – estudo 1

    Directory of Open Access Journals (Sweden)

    Diogo Gurgel

    2013-07-01

    Full Text Available Em A Transfiguração do Lugar-Comum , Arthur Danto elabora uma teoria da metáfora visando explicar como pode se dar a transfiguração de objetos comuns em obras de arte. Contudo, ele vai ainda mais longe, e afirma que sua concepção de metáfora abre espaço para importantes esclarecimentos sobre a revelação de verdades por meio de obras de arte. Neste artigo, procuro evidenciar alguns problemas decorrentes da proposta de Danto. Ao fim, delineio uma concepção de metáfora promissora no que diz respeito à elucidação das relações entre verdade e arte, a saber, a concepção desenvolvida por Paul Ricoeur em A Metáfora Viva.

  2. Using Remote Sensing and Radar MET Data to Support Watershed Assessments Comprising IEM

    Science.gov (United States)

    Meteorological (MET) data required by watershed assessments that comprise Integrated Environmental Modeling (IEM) have traditionally been provided by land-based weather (gauge) stations; although these data may not be most appropriate for describing adequate spatial and temporal...

  3. Complementaire interventies door verpleegkundigen bij kankerpatiënten met pijn.

    NARCIS (Netherlands)

    Francke, A.L.

    2002-01-01

    Doel van dit artikel is inzicht geven in welke complementaire interventies verpleegkundigen (kunnen) toepassen bij kankerpatiënten met pijn. In dit kader worden de volgende interventies besproken: ontspannende massages, het gebruik van ontspannings- en afleidingstechieken, koude- en

  4. Vergelijkend kortdurend onderzoek met waterorganismen ter bepaling van de acute toxiciteit van een aantal biociden

    NARCIS (Netherlands)

    Canton, J.H.; Mathijssen-Spiekman, E.A.M.

    1983-01-01

    Ter bepaling van de acute toxiciteit van een aantal biociden is vergelijkend kortdurend onderzoek met waterorganismen uitgevoerd. Daphnia magna en de twee geteste groene algen (Chlorella pyrenoidosa en Scenedesmus pannonicus) bleken voor alle onderzochte biociden gevoeliger te zijn dan de

  5. Statistical forecasting of met-ocean parameters in the Cochin estuarine system, southwest coast of India

    Digital Repository Service at National Institute of Oceanography (India)

    Srinivas, K.; Revichandran, C.; DineshKumar, P.K.

    Three different statistical forecasting techniques - autoregressive, sinusoidal and exponentially weighted moving average (EWMA) were used to forecast monthly values of meteorological and oceanographic (met-ocean) parameters viz. sea surface...

  6. Kaliumfosfiet helpt kalanchoë tegen phytophthora (interview met Filip van Noort)

    NARCIS (Netherlands)

    Neefjes, H.; Noort, van F.R.

    2009-01-01

    Toevoegen van plantversterker kaliumfosfiet maakt kalanchoë weerbaar tegen phytophthora. Onderzoek bij WUR Glastuinbouw heeft dit aangetoond in een deel van een proef. De praktijk is voorzichtig met het middel

  7. Agro Informatica beschikbaar via vias.nl : samenwerking met ARTIK Bibliotheek Wageningen UR

    NARCIS (Netherlands)

    Genderen, van R.A.

    2004-01-01

    Attendering op de totstandkoming van het Agro Informatica Archief met artikelen uit het tijdschrift Agro Informatica. Via dit Archief kan weer doorgeklikt worden naar het volledige artikelenbestand van ARTIK

  8. Techniek moet rijtaak ondersteunen : interview met Fred Wegman, directeur SWOV, over verkeersveiligheid.

    NARCIS (Netherlands)

    Ohm, R.

    2010-01-01

    Het gaat nog steeds goed, maar het kan altijd beter. Helaas is de problematiek ingewikkelder geworden en zijn er geen snelle oplossingen met veel effect meer voorhanden. Daarom moet het karakter van de aanpak van verkeersonveiligheid veranderen. (Author/publisher)

  9. Outreachend mentaliserend werken met moeilijk te bereiken jongeren - AMBIT : Uitgangspunten en basishouding

    NARCIS (Netherlands)

    Jessurun, Haiko; Bevington, Dickon; Fuggle, Peter; Anthonio, Gabriël

    2015-01-01

    De basishouding en uitgangspunten van de bij het Anna Freud Centre ontwikkelde werkwijze rondom jongeren met complexe problematiek, waaronder psychiatrische problemen, wordt besproken. AMBIT (Adolescent Mentalization-Based Integrative Therapy) richt zich op jongeren die moeilijk te bereiken zijn

  10. GPM GROUND VALIDATION MET ONE RAIN GAUGE PAIRS IPHEX V2

    Data.gov (United States)

    National Aeronautics and Space Administration — The GPM Ground Validation Met One Rain Gauge Pairs IPHEx V2 data measured the amount of fallen precipitation collected by a Model 380 tipping bucket rain gauge made...

  11. Een bloemstrook als leverancier van natuurlijke vijanden: Met luzerne minder groene perzikluis op ijsbergsla

    NARCIS (Netherlands)

    Schelling, G.C.; Belder, den E.

    2002-01-01

    PRI onderzocht het effect van stroken bloeiende luzerne tussen vollegronds ijsbergsla op het voorkomen van natuurlijke vijanden van bladluizen. In de luzernestroken bleken vele predatoren en parasieten van bladluizen voor te komen (zweefvliegen; sluipwespen; loopkevers; roofwantsen); met name de

  12. Maatschappelijk Verantwoord Ondernemen in Fryslân. Omgaan met stakeholders in theorie en praktijk

    NARCIS (Netherlands)

    Nijboer, Michiel

    2002-01-01

    Een bedrijf kan verschillend omgaan met haar stakeholders. In een ruwe tweedeling kan men onderscheid maken tussen bedrijven die sterk gericht zijn op de aandeelhouder als belangrijkste stakeholder en bedrijven die gericht zijn op bredere groepen stakeholders. Maatschappelijk verantwoord ondernemen

  13. Neuroprotection by NMDA receptor antagonists in a variety of neuropathologies.

    Science.gov (United States)

    Palmer, G C

    2001-09-01

    Because of adverse reactions, early efforts to introduce high affinity competitive or use-dependent NMDA receptor antagonists into patients suffering from stroke, head trauma or epilepsy met with failure. Later it was discovered that both low affinity use-dependent NMDA receptor antagonists and compounds with selective affinity for the NR2B receptor subunit met the criteria for safe administration into patients. Furthermore, these low affinity antagonists exhibit significant mechanistic differences from their higher affinity counterparts. Success of the latter is attested to the ability of the following low affinity compounds to be marketed: 1) Cough suppressant-dextromethorphan (available for decades); 2) Parkinson's disease--amantadine, memantine and budipine; 3) Dementia--memantine; and 4) Epilepsy--felbamate. Moreover, Phase III clinical trials are ongoing with remacemide for epilepsy and Huntington's disease and head trauma for HU-211. A host of compounds are or were under evaluation for the possible treatment of stroke, head trauma, hyperalgesia and various neurodegenerative disorders. Despite the fact that other drugs with associated NMDA receptor mechanisms have reached clinical status, this review focuses only on those competitive and use-dependent NMDA receptor antagonists that reached clinical trails. The ensuing discussions link the in vivo pharmacological investigations that led to the success/mistakes/ failures for eventual testing of promising compounds in the clinic.

  14. The BDNF Val66Met Polymorphism Affects the Vulnerability of the Brain Structural Network

    Directory of Open Access Journals (Sweden)

    Chang-hyun Park

    2017-08-01

    Full Text Available Val66Met, a naturally occurring polymorphism in the human brain-derived neurotrophic factor (BDNF gene resulting in a valine (Val to methionine (Met substitution at codon 66, plays an important role in neuroplasticity. While the effect of the BDNF Val66Met polymorphism on local brain structures has previously been examined, its impact on the configuration of the graph-based white matter structural networks is yet to be investigated. In the current study, we assessed the effect of the BDNF polymorphism on the network properties and robustness of the graph-based white matter structural networks. Graph theory was employed to investigate the structural connectivity derived from white matter tractography in two groups, Val homozygotes (n = 18 and Met-allele carriers (n = 55. Although there were no differences in the global network measures including global efficiency, local efficiency, and modularity between the two genotype groups, we found the effect of the BDNF Val66Met polymorphism on the robustness properties of the white matter structural networks. Specifically, the white matter structural networks of the Met-allele carrier group showed higher vulnerability to targeted removal of central nodes as compared with those of the Val homozygote group. These findings suggest that the central role of the BDNF Val66Met polymorphism in regards to neuroplasticity may be associated with inherent differences in the robustness of the white matter structural network according to the genetic variants. Furthermore, greater susceptibility to brain disorders in Met-allele carriers may be understood as being due to their limited stability in white matter structural connectivity.

  15. Influence of Met-Ocean Condition Forecasting Uncertainties on Weather Window Predictions for Offshore Operations

    DEFF Research Database (Denmark)

    Gintautas, Tomas; Sørensen, John Dalsgaard

    2017-01-01

    The article briefly presents a novel methodology of weather window estimation for offshore operations and mainly focuses on effects of met-ocean condition forecasting uncertainties on weather window predictions when using the proposed methodology. It is demonstrated that the proposed methodology...... to include stochastic variables, representing met-ocean forecasting uncertainties and the results of such modification are given in terms of predicted weather windows for a selected test case....

  16. MET-XAlign: a metabolite cross-alignment tool for LC/MS-based comparative metabolomics.

    Science.gov (United States)

    Zhang, Wenchao; Lei, Zhentian; Huhman, David; Sumner, Lloyd W; Zhao, Patrick X

    2015-09-15

    Liquid chromatography/mass spectrometry (LC/MS) metabolite profiling has been widely used in comparative metabolomics studies; however, LC/MS-based comparative metabolomics currently faces several critical challenges. One of the greatest challenges is how to effectively align metabolites across different LC/MS profiles; a single metabolite can give rise to multiple peak features, and the grouped peak features that can be used to construct a spectrum pattern of single metabolite can vary greatly between biochemical experiments and even between instrument runs. Another major challenge is that the observed retention time for a single metabolite can also be significantly affected by experimental conditions. To overcome these two key challenges, we present a novel metabolite-based alignment approach entitled MET-XAlign to align metabolites across LC/MS metabolomics profiles. MET-XAlign takes the deduced molecular mass and estimated compound retention time information that can be extracted by our previously published tool, MET-COFEA, and aligns metabolites based on this information. We demonstrate that MET-XAlign is able to cross-align metabolite compounds, either known or unknown, in LC/MS profiles not only across different samples but also across different biological experiments and different electrospray ionization modes. Therefore, our proposed metabolite-based cross-alignment approach is a great step forward and its implementation, MET-XAlign, is a very useful tool in LC/MS-based comparative metabolomics. MET-XAlign has been successfully implemented with core algorithm coding in C++, making it very efficient, and visualization interface coding in the Microsoft.NET Framework. The MET-XAlign software along with demonstrative data is freely available at http://bioinfo.noble.org/manuscript-support/met-xalign/ .

  17. PS O kke Jager : Interview met de Tijdgeest, JH Kok, NV, Kampen ...

    African Journals Online (AJOL)

    Test

    humor. Hy is nie suinig met die kritiek nie. Wie dit wil ervaar moet “ Een reis langs de Kerken” maar eens lees. Die skrywer sê dat hy „zo nog wel een tijd zou kunnen doorgaan. Maar het is beter dat wij eindigen.” Gelukkig is sy Interview met de Tijdgeest na die hoofstuk nog nie beeïndig nie. Alle fasette van die lewe — nie ...

  18. Lipophorin Receptor: The Insect Lipoprotein Receptor

    Indian Academy of Sciences (India)

    IAS Admin

    physiology and develop- mental biology of silkworms, and use of silk in industrial applications. The low-density lipoprotein receptor (LDLR), one of the best characterized cell-surface receptors, mediates cholesterol ho- meostasis and other functions in mammals. The members of the LDLR superfamily are structurally related ...

  19. Lipophorin Receptor: The Insect Lipoprotein Receptor

    Indian Academy of Sciences (India)

    Permanent link: http://www.ias.ac.in/article/fulltext/reso/018/08/0748-0755. Keywords. Low-density lipoprotein receptor; lipophorin; lipophorin receptor; insects. Author Affiliations. G Ravikumar1 N B Vijayaprakash1. Seri-biotech Research Laboratory Central Silk Board Kodathi, Carmelaram Post Bangalore 560 035, India.

  20. Brain-derived neurotrophic factor Val66Met genotype modulates amygdala habituation.

    Science.gov (United States)

    Perez-Rodriguez, M Mercedes; New, Antonia S; Goldstein, Kim E; Rosell, Daniel; Yuan, Qiaoping; Zhou, Zhifeng; Hodgkinson, Colin; Goldman, David; Siever, Larry J; Hazlett, Erin A

    2017-05-30

    A deficit in amygdala habituation to repeated emotional stimuli may be an endophenotype of disorders characterized by emotion dysregulation, such as borderline personality disorder (BPD). Amygdala reactivity to emotional stimuli is genetically modulated by brain-derived neurotrophic factor (BDNF) variants. Whether amygdala habituation itself is also modulated by BDNF genotypes remains unknown. We used imaging-genetics to examine the effect of BDNF Val66Met genotypes on amygdala habituation to repeated emotional stimuli. We used functional magnetic resonance imaging (fMRI) in 57 subjects (19 BPD patients, 18 patients with schizotypal personality disorder [SPD] and 20 healthy controls [HC]) during a task involving viewing of unpleasant, neutral, and pleasant pictures, each presented twice to measure habituation. Amygdala responses across genotypes (Val66Met SNP Met allele-carriers vs. Non-Met carriers) and diagnoses (HC, BPD, SPD) were examined with ANOVA. The BDNF 66Met allele was significantly associated with a deficit in amygdala habituation, particularly for emotional pictures. The association of the 66Met allele with a deficit in habituation to unpleasant emotional pictures remained significant in the subsample of BPD patients. Using imaging-genetics, we found preliminary evidence that deficient amygdala habituation may be modulated by BDNF genotype. Copyright © 2017. Published by Elsevier B.V.

  1. BDNF Val66Met homozygosity does not influence plasma BDNF levels in healthy human subjects.

    Science.gov (United States)

    Luykx, Jurjen J; Boks, Marco P M; Breetvelt, Elemi J; Aukes, Maartje F; Strengman, Eric; da Pozzo, Eleonora; Dell'osso, Liliana; Marazziti, Donatella; van Leeuwen, Annelies; Vreeker, Annabel; Abramovic, Lucija; Martini, Claudia; Numans, Mattijs E; Kahn, René S; Ophoff, Roel A

    2013-06-03

    A putative pathway by which the BDNF Val66Met polymorphism (rs6265) leads to aberrant phenotypes is its influence on plasma BDNF. Research into the impact of rs6265 on plasma BDNF has given rise to conflicting results. Moreover, most such studies have compared Met-carriers with Val-homozygous subjects. We therefore genotyped subjects from a population-based cohort (the Utrecht Health Project, N=2743) and assessed whether plasma BDNF differs between rs6265 homozygous groups. We maximized the number of Met-homozygous subjects in whom we measured plasma BDNF, resulting in plasma BDNF being available for 19 Met-homozygous and 42 matched Val-homozygous subjects. Mean concentrations (S.D.) were 1963.1 (750.1) and 2133.2 pg/ml (1164.3) for the Val/Val and Met/Met groups, respectively. Using ANOVA, no differences in plasma BDNF between the two groups were detected. In conclusion, these results add to a growing body of evidence indicating that allelic variation at rs6265 does not have medium to large effects on plasma BDNF concentrations. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. Differential effects of BDNF val(66)met in repetitive associative learning paradigms.

    Science.gov (United States)

    Freundlieb, Nils; Backhaus, Winifried; Brüggemann, Norbert; Gerloff, Christian; Klein, Christine; Pinnschmidt, Hans O; Hummel, Friedhelm C

    2015-09-01

    In healthy young subjects, the brain derived neurotropic factor (BDNF) val(66)met polymorphism negatively affects behavioural outcome in short-term motor cortex or hippocampus-based learning paradigms. In repetitive training paradigms over several days this effect can be overcome, in tests involving other brain areas even positive effects were found. To further specify the role of this polymorphism in cognitive processes, we used an associative vocabulary learning paradigm over four consecutive days and tested 38 young healthy subjects and 29 healthy elderly subjects. As a control paradigm, we designed a nonverbal haptic Braille letter-learning paradigm based on the same principles. Behavioural outcome was then associated with the BDNF-genotype. In the vocabulary learning task, met carrier (met/val and met/met) benefitted more from the repetitive training than val/val subjects. This was paralleled by a higher reduction of delayed answers during the course of the study, an effect that was also present in the haptic paradigm. However, in a group of healthy elderly subjects, no similar tendency was found. We conclude that the BDNF val(66)met polymorphism alters highly circumscribed answer behaviours in young healthy subjects. This might partly explain the high variability of previously published results. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Central pain sensitization, COMT Val158Met polymorphism, and emotional factors in fibromyalgia.

    Science.gov (United States)

    Desmeules, Jules; Chabert, Jocelyne; Rebsamen, Michela; Rapiti, Elisabetta; Piguet, Valerie; Besson, Marie; Dayer, Pierre; Cedraschi, Christine

    2014-02-01

    Neurobiological evidence points to altered central nervous system processing of nociceptive stimuli in fibromyalgia. Enzymes like catechol-O-methyl-transferase (COMT) are involved in the elimination of catecholamines playing a possible role in central sensitization and pain. We used quantitative sensory testing to evidence central sensitization in fibromyalgia patients and test whether COMTVal158Met polymorphism, associated with a reduction in enzyme activity, plays a role in sensitized patients. Pain evaluation and quantitative sensory testing were performed including the spinal nociceptive flexion reflex, a physiologic correlate for the evaluation of central nociceptive pathways. Quality of life and distress questionnaires were used. A total of 137 fibromyalgia patients were assessed and compared to 99 matched controls. Central sensitization (nociceptive flexion reflex pain was more likely to be associated with COMT Met/Met genotype. Patients showed important emotional distress compared to controls. In sensitized patients, the COMT Met/Met subgroup showed systematically-though not significantly-worse scores for all psychological variables. The association between COMT p.Val158Met polymorphism and central sensitization in fibromyalgia is essential as it refers to the severity of central sensitization and may be a risk factor for treatment outcome. Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.

  4. BDNFval66met affects neural activation pattern during fear conditioning and 24 h delayed fear recall.

    Science.gov (United States)

    Lonsdorf, Tina B; Golkar, Armita; Lindström, Kara M; Haaker, Jan; Öhman, Arne; Schalling, Martin; Ingvar, Martin

    2015-05-01

    Brain-derived neurotrophic factor (BDNF), the most abundant neutrophin in the mammalian central nervous system, is critically involved in synaptic plasticity. In both rodents and humans, BDNF has been implicated in hippocampus- and amygdala-dependent learning and memory and has more recently been linked to fear extinction processes. Fifty-nine healthy participants, genotyped for the functional BDNFval66met polymorphism, underwent a fear conditioning and 24h-delayed extinction protocol while skin conductance and blood oxygenation level dependent (BOLD) responses (functional magnetic resonance imaging) were acquired. We present the first report of neural activation pattern during fear acquisition 'and' extinction for the BDNFval66met polymorphism using a differential conditioned stimulus (CS)+ > CS- comparison. During conditioning, we observed heightened allele dose-dependent responses in the amygdala and reduced responses in the subgenual anterior cingulate cortex in BDNFval66met met-carriers. During early extinction, 24h later, we again observed heightened responses in several regions ascribed to the fear network in met-carriers as opposed to val-carriers (insula, amygdala, hippocampus), which likely reflects fear memory recall. No differences were observed during late extinction, which likely reflects learned extinction. Our data thus support previous associations of the BDNFval66met polymorphism with neural activation in the fear and extinction network, but speak against a specific association with fear extinction processes. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  5. FAK kinase activity is required for the progression of c-Met/β-catenin-driven HCC

    Science.gov (United States)

    Shang, Na; Arteaga, Maribel; Zaidi, Ali; Cotler, Scott J.; Breslin, Peter; Ding, Xianzhong; Kuo, Paul; Nishimura, Michael; Zhang, Jiwang; Qiu, Wei

    2016-01-01

    Background & Aims There is an urgent need to develop new and more effective therapeutic strategies and agents to treat hepatocellular carcinoma (HCC). We have recently found that deletion of Fak in hepatocytes before tumors form inhibits tumor development and prolongs survival of animals in a c-Met (MET)/β-catenin (CAT)-driven HCC mouse model. However, it has yet to be determined whether FAK expression in hepatocytes promotes MET/CAT-induced HCC progression after tumor initiation. In addition, it remains unclear whether FAK promotes HCC development through its kinase activity. Methods We generated hepatocyte-specific inducible Fak-deficient mice (Alb-creERT2; Fakflox/flox) to examine the role of FAK in HCC progression. We re-expressed wild-type and mutant FAK in Fak-deficient mice to determine FAK’s kinase activity in HCC development. We also examined the efficacy of a FAK kinase inhibitor PF-562271 on HCC inhibition. Results We found that deletion of Fak after tumors form significantly repressed MET/CAT-induced tumor progression. Ectopic FAK expression restored HCC formation in hepatocyte-specific Fak-deficient mice. However, overexpression of a FAK kinase-dead mutant led to reduced tumor load compared to mice which express wild-type FAK. Furthermore, PF-562271 significantly suppressed progression of MET/CAT-induced HCC. Conclusion Fak kinase activity is important for MET/CAT-induced HCC progression. Inhibiting FAK kinase activity provides a potential therapeutic strategy to treat HCC. PMID:27142958

  6. BDNF Val66Met Polymorphism Influences Visuomotor Associative Learning and the Sensitivity to Action Observation

    Science.gov (United States)

    Taschereau-Dumouchel, Vincent; Hétu, Sébastien; Michon, Pierre-Emmanuel; Vachon-Presseau, Etienne; Massicotte, Elsa; De Beaumont, Louis; Fecteau, Shirley; Poirier, Judes; Mercier, Catherine; Chagnon, Yvon C.; Jackson, Philip L.

    2016-01-01

    Motor representations in the human mirror neuron system are tuned to respond to specific observed actions. This ability is widely believed to be influenced by genetic factors, but no study has reported a genetic variant affecting this system so far. One possibility is that genetic variants might interact with visuomotor associative learning to configure the system to respond to novel observed actions. In this perspective, we conducted a candidate gene study on the Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism, a genetic variant linked to motor learning in regions of the mirror neuron system, and tested the effect of this polymorphism on motor facilitation and visuomotor associative learning. In a single-pulse TMS study carried on 16 Met (Val/Met and Met/Met) and 16 Val/Val participants selected from a large pool of healthy volunteers, Met participants showed significantly less muscle-specific corticospinal sensitivity during action observation, as well as reduced visuomotor associative learning, compared to Val homozygotes. These results are the first evidence of a genetic variant tuning sensitivity to action observation and bring to light the importance of considering the intricate relation between genetics and associative learning in order to further understand the origin and function of the human mirror neuron system. PMID:27703276

  7. The MetJ regulon in gammaproteobacteria determined by comparative genomics methods

    Directory of Open Access Journals (Sweden)

    Augustus Anne M

    2011-11-01

    Full Text Available Abstract Background Whole-genome sequencing of bacteria has proceeded at an exponential pace but annotation validation has lagged behind. For instance, the MetJ regulon, which controls methionine biosynthesis and transport, has been studied almost exclusively in E. coli and Salmonella, but homologs of MetJ exist in a variety of other species. These include some that are pathogenic (e.g. Yersinia and some that are important for environmental remediation (e.g. Shewanella but many of which have not been extensively characterized in the literature. Results We have determined the likely composition of the MetJ regulon in all species which have MetJ homologs using bioinformatics techniques. We show that the core genes known from E. coli are consistently regulated in other species, and we identify previously unknown members of the regulon. These include the cobalamin transporter, btuB; all the genes involved in the methionine salvage pathway; as well as several enzymes and transporters of unknown specificity. Conclusions The MetJ regulon is present and functional in five orders of gammaproteobacteria: Enterobacteriales, Pasteurellales, Vibrionales, Aeromonadales and Alteromonadales. New regulatory activity for MetJ was identified in the genomic data and verified experimentally. This strategy should be applicable for the elucidation of regulatory pathways in other systems by using the extensive sequencing data currently being generated.

  8. Acetylcholine receptor antibody

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/003576.htm Acetylcholine receptor antibody To use the sharing features on this page, please enable JavaScript. Acetylcholine receptor antibody is a protein found in the blood ...

  9. Dose-response met-RANTES treatment of experimental periodontitis: a narrow edge between the disease severity attenuation and infection control.

    Directory of Open Access Journals (Sweden)

    Carlos Eduardo Repeke

    Full Text Available Chemokines and chemokine receptors have been implicated in the selective migration of leukocyte subsets to periodontal tissues, which consequently influences the disease outcome. Among these chemoattractants, the chemokines CCL3, CCL4 and CCL5 and its receptors, CCR1 and CCR5, have been associated with increased disease severity in mice and humans. Therefore, in this study we investigated the modulation of experimental periodontitis outcome by the treatment with a specific antagonist of CCR1 and 5 receptors, called met-RANTES. C57Bl/6 mice was orally infected with Aggregatibacter actinomycetemcomitans and treated with 0.05, 0.1, 0.5, 1.5 and 5 mg doses of met-RANTES on alternate days, and evaluated by morphometric, cellular, enzymatic and molecular methods. At 0.5 mg up to 5 mg doses, a strong reduction in the alveolar bone loss and inflammatory cell migration were observed. Interestingly, 5 mg dose treatment resulted in the maximum inhibition of inflammatory cell migration, but resulted in a similar inhibition of bone loss when compared with the lower doses, and also resulted in increased bacterial load and CRP response. When 0.5 and 5 mg therapy regimens were compared it was observed that both therapeutic protocols were able to downregulate the levels of pro-inflammatory, Th1-type and osteoclastogenic cytokines, and CD3+ and F4/80+ cells migration to periodontal tissues, but the high dose modulates host response in a more pronounced and unspecific and excessive way, interfering also with the production of antimicrobial mediators such as MPO, iNOS and IgG, and with GR1+ and CD19+ cells migration. Our results demonstrate a thin line between beneficial immunoregulation and impaired host defense during experimental periodontitis, and the determination of the exact equilibrium point is mandatory for the improvement of immune-targeted therapy of periodontitis.

  10. Circulating pathogen-associated molecular pattern - binding proteins and High Mobility Group Box protein 1 in nascent metabolic syndrome: implications for cellular Toll-like receptor activity.

    Science.gov (United States)

    Jialal, I; Rajamani, U; Adams-Huet, B; Kaur, H

    2014-09-01

    The Metabolic Syndrome, (MetS) a global epidemic, is a state of low grade chronic inflammation and confers an increased risk for diabetes and CVD. We have previously reported increased activity of the pathogen recognition receptors, Toll-like receptors (TLRs), TLR2 and TLR4 in MetS. We hypothesized that increased TLR activity in MetS is due in part to increased levels of circulating PAMP-binding proteins, soluble CD14 (sCD14), lipopolysaccharide binding protein (LBP) and the damage associated molecular pattern (DAMP), High Mobility Group Box protein 1 (HMGB-1). We measured sCD14, LBP and HMGB-1 in fasting plasma from nascent MetS (n = 37) and healthy control subjects (n = 32) by ELISA. We also investigated the effects of sCD14 and LBP on TLR4 activity in human aortic endothelial cells (HAECs). Following adjustment for body mass index and waist circumference, sCD14, LBP and HMGB-1 levels remained significantly increased in MetS. Also their levels increased with increasing numbers of MetS risk factors. Only sCD14 correlated significantly with monocyte TLR4 protein and activity. None of these soluble biomarkers correlated with TLR2 protein. Both sCD14 and HMGB-1 correlated significantly with HOMA-IR. In LPS primed HAECs, sCD14 compared to LBP, resulted in a greater increase in both TLR4 abundance and inflammatory biomediators (NF-κB, IL-1β, IL-8 and TNF-α). Thus, we make the novel observation that sCD14 reflects increased monocyte TLR4 protein and activity in nascent MetS and by contributing to increased cellular inflammation could explain, in part, the increased risk for diabetes and CVD. Published by Elsevier Ireland Ltd.

  11. The effect of interaction between Melanocortin-4 receptor polymorphism and dietary factors on the risk of metabolic syndrome.

    Science.gov (United States)

    Koochakpoor, Gelareh; Daneshpour, Maryam S; Mirmiran, Parvin; Hosseini, Seyed Ahmad; Hosseini-Esfahani, Firoozeh; Sedaghatikhayat, Bahareh; Azizi, Fereidoun

    2016-01-01

    Controversial data is available on the effect of the Melanocortin-4 receptor (MC4R) gene variation on metabolic syndrome (MetS) and ineffectiveness of diet in managing MetS. Effects of the interaction between MC4R polymorphism and dietary factors on MetS were investigated in this study. Subjects of this nested case-control study were selected from among participants of Tehran Lipid and Glucose Study. Each case (n = 815) was pair matched randomly with a control by age (±5 years) and sex from among those who had not developed ≥1 MetS components at the time that the corresponding case developed MetS. Dietary patterns were determined using factor analysis on 25 foods groups using a valid and reliable, 168-item semi-quantitative food frequency questionnaire (FFQ). MC4R rs12970134 were genotyped by Tetra-Primer ARMS-polymerase chain reaction analysis. Adjusted conditional logistic regression was used to estimate the interactions of SNP with quartiles of dietary factors in relation to MetS. MetS was defined by the modified National Cholesterol Education Program/Adult Treatment panel III. Two dietary patterns were extracted. The healthy dietary pattern was loaded heavily on vegetables, legumes, low fat dairy, whole grains, liquid oils and fruits; the western dietary pattern consisted of a high intake of soft drinks, fast foods, sweets, solid oils, red meats, salty snacks, refined grains, high fat dairy, tea and coffee, eggs and poultry. Among A allele carriers, being in the highest quartiles of western dietary pattern score and saturated fatty acid intake had an increased risk of MetS, compared to those in the lowest quartile (P trend = 0.007). Saturated fatty acid intake could modulate the association of A allele carriers of MC4R with MetS (P interaction = 0.03). A significant interaction was observed between rs12970134 with total fat and iron intake on the risk of abdominal obesity (P interaction < 0.05). Our findings suggest an interaction between rs

  12. Androgen receptor abnormalities

    NARCIS (Netherlands)

    A.O. Brinkmann (Albert); G.G.J.M. Kuiper (George); C. Ris-Stalpers (Carolyn); H.C.J. van Rooij (Henri); G. Romalo (G.); G. Trifiro (Gianluca); E. Mulder (Eppo); L. Pinsky (L.); H.U. Schweikert (H.); J. Trapman (Jan)

    1991-01-01

    markdownabstract__Abstract__ The human androgen receptor is a member of the superfamily of steroid hormone receptors. Proper functioning of this protein is a prerequisite for normal male sexual differentiation and development. The cloning of the human androgen receptor cDNA and the elucidation of

  13. Androgen receptor abnormalities

    NARCIS (Netherlands)

    Brinkmann, A. O.; Kuiper, G. G.; Ris-Stalpers, C.; van Rooij, H. C.; Romalo, G.; Trifiro, M.; Mulder, E.; Pinsky, L.; Schweikert, H. U.; Trapman, J.

    1991-01-01

    The human androgen receptor is a member of the superfamily of steroid hormone receptors. Proper functioning of this protein is a prerequisite for normal male sexual differentiation and development. The cloning of the human androgen receptor cDNA and the elucidation of the genomic organization of the

  14. 11C-MET PET/MRI for detection of recurrent glioma.

    Science.gov (United States)

    Deuschl, C; Kirchner, J; Poeppel, T D; Schaarschmidt, B; Kebir, S; El Hindy, N; Hense, J; Quick, H H; Glas, M; Herrmann, K; Umutlu, L; Moenninghoff, C; Radbruch, A; Forsting, M; Schlamann, M

    2018-04-01

    Radiological assessment of brain tumors is widely based on the Radiology Assessment of Neuro-Oncology (RANO) criteria that consider non-specific T1 and T2 weighted images. Limitation of the RANO criteria is that they do not include metabolic imaging techniques that have been reported to be helpful to differentiate treatment related changes from true tumor progression. In the current study, we assessed if the combined use of MRI and PET with hybrid 11 C-MET PET/MRI can improve diagnostic accuracy and diagnostic confidence of the readers to differentiate treatment related changes from true progression in recurrent glioma. Fifty consecutive patients with histopathologically proven glioma were prospectively enrolled for a hybrid 11 C-MET PET/MRI to differentiate recurrent glioma from treatment induced changes. Sole MRI data were analyzed based on RANO. Sole PET data and in a third evaluation hybrid 11 C-MET-PET/MRI data were assessed for metabolic respectively metabolic and morphologic glioma recurrence. Diagnostic performance and diagnostic confidence of the reader were calculated for the different modalities, and the McNemar test and Mann-Whitney U Test were applied for statistical analysis. Hybrid 11 C-MET PET/MRI was successfully performed in all 50 patients. Glioma recurrence was diagnosed in 35 of the 50 patients (70%). Sensitivity and specificity were calculated for MRI (86.11% and 71.43%), for 11 C-MET PET (96.77% and 73.68%), and for hybrid 11 C-MET-PET/MRI (97.14% and 93.33%). For diagnostic accuracy hybrid 11 C-MET-PET/MRI (96%) showed significantly higher values than MRI alone (82%), whereas no significant difference was found for 11C-MET PET (88%). Furthermore, by rating on a five-point Likert scale significantly higher scores were found for diagnostic confidence when comparing 11 C-MET PET/MRI (4.26 ± 0,777) to either PET alone (3.44 ± 0.705) or MRI alone (3.56 ± 0.733). This feasibility study showed that hybrid PET/MRI might strengthen

  15. Tachykinins and tachykinin receptors in human uterus.

    Science.gov (United States)

    Patak, Eva; Candenas, M Luz; Pennefather, Jocelyn N; Ziccone, Sebastian; Lilley, Alison; Martín, Julio D; Flores, Carlos; Mantecón, Antonio G; Story, Margot E; Pinto, Francisco M

    2003-06-01

    (1) Studies were undertaken to determine the nature of the receptors mediating contractile effects of tachykinins in the uteri of nonpregnant women, and to analyse the expression of preprotachykinins (PPT), tachykinin receptors and the cell-surface peptidase, neprilysin (NEP), in the myometrium from pregnant and nonpregnant women. (2) The neurokinin B (NKB) precursor PPT-B was expressed in higher levels in the myometrium from nonpregnant than from pregnant women. Faint expression of PPT-A mRNA was detectable in the myometrium from nonpregnant but not pregnant women. PPT-C, the gene encoding the novel tachykinin peptide hemokinin-1 (HK-1), was present in trace amounts in the uteri from both pregnant and nonpregnant women. (3) Tachykinin NK(2) receptors were more strongly expressed in tissues from nonpregnant than from pregnant women. NK(1) receptor mRNA was present in low levels in tissues from both pregnant and nonpregnant women. A low abundance transcript corresponding to the NK(3) receptor was present only in tissues from nonpregnant women. (4) The mRNA expression of the tachykinin-degrading enzyme NEP was lower in tissues from nonpregnant than from pregnant women. (5) Substance P (SP), neurokinin A (NKA) and NKB, in the presence of the peptidase inhibitors thiorphan, captopril and bestatin, produced contractions of myometrium from nonpregnant women. The order of potency was NKA>SP>/=NKB. The potency of NKA was unchanged in the absence of peptidase inhibitors. (6) The tachykinin NK(2) receptor-selective agonist [Lys(5)MeLeu(9)Nle(10)]NKA(4-l0) was approximately equipotent with NKA, but the tachykinin NK(1) and NK(3) receptor-selective agonists [Sar(9)Met(O(2))(11)]SP and [MePhe(7)]NKB were ineffective in the myometrium from nonpregnant women. (7) The uterotonic effects of [Lys(5)MeLeu(9)Nle(10)]NKA(4-10) were antagonized by the tachykinin NK(2) receptor-selective antagonist SR48968. Neither atropine, nor phentolamine nor tetrodotoxin affected responses to [Lys(5

  16. XL-184, a MET, VEGFR-2 and RET kinase inhibitor for the treatment of thyroid cancer, glioblastoma multiforme and NSCLC.

    Science.gov (United States)

    Zhang, Ying; Guessous, Fadila; Kofman, Alex; Schiff, David; Abounader, Roger

    2010-02-01

    XL-184 (BMS-907351), under development by Exelixis Inc and Bristol-Myers Squibb Co, is a pan-tyrosine kinase inhibitor for the potential oral treatment of medullary thyroid cancer, glioblastoma multiforme and NSCLC. The prinicipal targets of XL-184 are MET, VEGFR-2 and RET, but the drug is also reported to display inhibitory activity against KIT, FLT3 and TEK. Preclinical studies demonstrated that XL-184 potently inhibited multiple receptor tyrosine kinases in various cancer cell lines and animal xenograft models, and that the drug exhibited significant oral bioavailability and blood-brain barrier penetration. A phase I clinical trial in patients with advanced solid malignancies indicated that XL-184 accumulated dose-dependently in the plasma and had a long terminal half-life. A phase II trial in patients with progressive or recurrent glioblastoma revealed modest but promising median progression-free survival. Toxicity and side effects for the drug have generally been of low-to-moderate severity. At the time of publication, three additional trials of XL-184 were recruiting patients, including a phase I trial in combination with standard of care in patients with glioblastoma, a phase I/II trial in combination with erlotinib in patients with NSCLC, and a phase III trial in patients with medullary thyroid cancer.

  17. Targeting the epithelial to mesenchymal transition in glioblastoma: the emerging role of MET signaling

    Directory of Open Access Journals (Sweden)

    Lee JK

    2014-10-01

    Full Text Available Jin-Ku Lee,1,2,* Kyeung Min Joo,3 Jeongwu Lee,4 Yeup Yoon,5,* Do-Hyun Nam2,5 1Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea; 2Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 3Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Korea; 4Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; 5Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, Korea  *These authors contributed equally to this work Abstract: Glioblastoma multiforme (GBM is the most common human primary brain malignancy and has a dismal prognosis. Aggressive treatments using maximal surgical resection, radiotherapy, and temozolomide result in median survival of only 14.6 months in patients with GBM. Numerous clinical approaches using small molecule inhibitors have shown disappointing results because of the genetic heterogeneity of GBM. The epithelial to mesenchymal transition (EMT is a crucial biological process occurring in the early development stages of many species. However, cancer cells often obtain the ability to invade and metastasize through the EMT, which triggers the scattering of cells. The hepatocyte growth factor (HGF/MET signaling pathway is indicative of the EMT during both embryogenesis and the invasive growth of tumors, because HGF potently induces mesenchymal transition in epithelial-driven cells. Activation of MET signaling or co-overexpression of HGF and MET frequently represents aggressive growth and poor prognosis of various cancers, including GBM. Thus, efforts to treat cancers by inhibiting MET signaling using neutralizing antibodies or small molecule inhibitors have progressed during the last decade. In this review, we discuss HGF/MET signaling in the development of diseases

  18. The global met need for emergency obstetric care: a systematic review.

    Science.gov (United States)

    Holmer, H; Oyerinde, K; Meara, J G; Gillies, R; Liljestrand, J; Hagander, L

    2015-01-01

    Of the 287,000 maternal deaths every year, 99% happen in low- and middle-income countries. The vast majority could be averted with timely access to appropriate emergency obstetric care (EmOC). The proportion of women with complications of pregnancy or childbirth who actually receive treatment is reported as 'Met need for EmOC'. To estimate the global met need for EmOC and to examine the correlation between met need, maternal mortality ratio and other indicators. A systematic review was performed according to the PRISMA guidelines. Searches were made in PubMed, EMBASE and Google Scholar. Studies containing data on met need in EmOC were selected. Analysis was performed with data extracted from 62 studies representing 51 countries. World Bank data were used for univariate and multiple linear regression. Global met need for EmOC was 45% (IQR: 28-57%), with significant disparity between low- (21% [12-31%]), middle- (32% [15-56%]), and high-income countries (99% [99-99%]), (P = 0.041). This corresponds to 11.4 million (8.8-14.8) untreated complications yearly and 951 million (645-1174 million) women without access to EmOC. We found an inverse correlation between met need and maternal mortality ratio (r = -0.42, P EmOC, with vast disparities between countries of different income levels. Met need is a powerful indicator of the response to maternal mortality and strategies to improve EmOC act in synergy with the expansion of skilled birth attendance. © 2014 Royal College of Obstetricians and Gynaecologists.

  19. The BDNF Val66Met Polymorphism Influences Reading Ability and Patterns of Neural Activation in Children.

    Directory of Open Access Journals (Sweden)

    Kaja K Jasińska

    Full Text Available Understanding how genes impact the brain's functional activation for learning and cognition during development remains limited. We asked whether a common genetic variant in the BDNF gene (the Val66Met polymorphism modulates neural activation in the young brain during a critical period for the emergence and maturation of the neural circuitry for reading. In animal models, the bdnf variation has been shown to be associated with the structure and function of the developing brain and in humans it has been associated with multiple aspects of cognition, particularly memory, which are relevant for the development of skilled reading. Yet, little is known about the impact of the Val66Met polymorphism on functional brain activation in development, either in animal models or in humans. Here, we examined whether the BDNF Val66Met polymorphism (dbSNP rs6265 is associated with children's (age 6-10 neural activation patterns during a reading task (n = 81 using functional magnetic resonance imaging (fMRI, genotyping, and standardized behavioral assessments of cognitive and reading development. Children homozygous for the Val allele at the SNP rs6265 of the BDNF gene outperformed Met allele carriers on reading comprehension and phonological memory, tasks that have a strong memory component. Consistent with these behavioral findings, Met allele carriers showed greater activation in reading-related brain regions including the fusiform gyrus, the left inferior frontal gyrus and left superior temporal gyrus as well as greater activation in the hippocampus during a word and pseudoword reading task. Increased engagement of memory and spoken language regions for Met allele carriers relative to Val/Val homozygotes during reading suggests that Met carriers have to exert greater effort required to retrieve phonological codes.

  20. BDNF val66met association with serotonin transporter binding in healthy humans.

    Science.gov (United States)

    Fisher, P M; Ozenne, B; Svarer, C; Adamsen, D; Lehel, S; Baaré, W F C; Jensen, P S; Knudsen, G M

    2017-02-14

    The serotonin transporter (5-HTT) is a key feature of the serotonin system, which is involved in behavior, cognition and personality and implicated in neuropsychiatric illnesses including depression. The brain-derived neurotrophic factor (BDNF) val66met and 5-HTTLPR polymorphisms have predicted differences in 5-HTT levels in humans but with equivocal results, possibly due to limited sample sizes. Within the current study we evaluated these genetic predictors of 5-HTT binding with [ 11 C]DASB positron emission tomography (PET) in a comparatively large cohort of 144 healthy individuals. We used a latent variable model to determine genetic effects on a latent variable (5-HTT LV ), reflecting shared correlation across regional 5-HTT binding (amygdala, caudate, hippocampus, midbrain, neocortex, putamen and thalamus). Our data supported a significant BDNF val66met effect on 5-HTT LV such that met-carriers showed 2-7% higher subcortical 5-HTT binding compared with val/val individuals (P=0.042). Our data did not support a BDNF val66met effect in neocortex and 5-HTTLPR did not significantly predict 5-HTT LV . We did not observe evidence for an interaction between genotypes. Our findings indicate that met-carriers have increased subcortical 5-HTT binding. The small difference suggests limited statistical power may explain previously reported null effects. Our finding adds to emerging evidence that BDNF val66met contributes to differences in the human brain serotonin system, informing how variability in the 5-HTT level emerges and may represent an important molecular mediator of BDNF val66met effects on behavior and related risk for neuropsychiatric illness.

  1. Targeting c-Met in Cancer by MicroRNAs: Potential Therapeutic Applications in Hepatocellular Carcinoma.

    Science.gov (United States)

    Karagonlar, Zeynep F; Korhan, Peyda; Atabey, Neşe

    2015-11-01

    Preclinical Research Cancer is one of the world's deadliest diseases, with very low survival rates and increased occurrence in the future. Successfully developed target-based therapies have significantly changed cancer treatment. However, primary and/or acquired resistance in the tumor is a major challenge in current therapies and novel combinational therapies are required. RNA interference-mediated gene inactivation, alone or in combination with other current therapies, provides novel promising therapeutics that can improve cure rate and overcome resistance mechanisms to conventional therapeutics. Hepatocyte Growth Factor/c-Met signaling is one of the most frequently dysregulated pathways in human cancers and abnormal c-Met activation is correlated with poor clinical outcomes and drug resistance in hepatocellular carcinoma (HCC). In recent years, a growing number of studies have identified several inhibitors and microRNAs (miRNAs), specifically targeting c-Met in various cancers, including HCC. In this review, we discuss current knowledge regarding miRNAs, focusing on their involvement in cancer and their potential as research tools and therapeutics. Then, we focus on the potential use of c-Met targeting miRNAs for suppressing aberrant c-Met signaling in HCC treatment. © 2015 Wiley Periodicals, Inc.

  2. The association between COMT Val158Met polymorphism and migraine risk: A meta-analysis.

    Science.gov (United States)

    Liao, Yao-Jun; Jiang, Jing-Ru; Jin, San-Qing

    2017-05-01

    Background The COMT Val158Met polymorphism has long been regarded as a risk factor for migraine. The possible association between COMT Val158Met polymorphism and migraine has been evaluated in several studies, but the results are not consistent. Therefore, we conduct this meta-analysis to address these issues. Methods The WEB OF SCIENCE and EMBASE databases were searched for eligible studies. The odds ratio (OR) with the corresponding 95% confidence interval (CI) was calculated to estimate the strength of the association between COMT Val158Met polymorphism and migraine. Results Five studies with 979 cases and 1870 controls were ultimately included in the present meta-analysis. The overall data showed no significant association between COMT Val158Met polymorphism and migraine in the multiplicative model (OR = 0.97, 95% CI: 0.78-1.21, p = 0.805) and dominant model (OR = 1.05, 95% CI: 0.75-1.48, p = 0.773), neither in the additive model (OR = 0.97, 95% CI: 0.77-1.23, p = 0.817) nor in the recessive model (OR = 0.88, 95% CI: 0.71-1.09, p = 0.246). In subgroup analysis, both for Caucasian and Asian populations, no statistically significant associations were observed in any genetic models. Conclusions Our meta-analysis suggested that the COMT Val158Met polymorphism was not associated with migraine risk.

  3. Analysis of BDNF Val66Met allele-specific mRNA levels in bipolar disorder.

    Science.gov (United States)

    De Luca, Vincenzo; Strauss, John; Semeralul, Mawahib; Huang, Sheeda; Li, Peter P; Warsh, Jerry J; Kennedy, James L; Wong, Albert H C

    2008-08-22

    We have previously reported an association between the BDNF Val66Met polymorphism and bipolar disorder (BD). However, the possibility that genomic imprinting in BDNF gene affects risk for BD has not been investigated. To examine the possibility of genomic imprinting in the BDNF gene in BD, we analyzed the parent-of-origin effect (POE) and differential expression of the BDNF Val66Met alleles in BD. We performed a family-based association study and ETDT analyses of the Val66Met polymorphism in 312 BD nuclear families, and compared allele-specific mRNA levels in both post-mortem brain samples and B lymphoblasts from BD patients and controls. The BDNF Val66 allele was transmitted significantly more often to patients with BD (maternal transmissions: 46/22, p=0.003; paternal transmissions: 55/30, p=0.006). There was no significant difference between maternal and paternal transmission ratios. There was no significant difference in the ratio of Val/Met-specific mRNA expression between BD and controls, in either brain or B lymphoblasts. The Val/Met ratio was much lower in the brain vs. B lymphoblasts. These data do not support a role for genomic imprinting as a modifier of the contribution of BDNF gene to risk of susceptibility to BD.

  4. Data driven polypharmacological drug design for lung cancer: analyses for targeting ALK, MET, and EGFR

    DEFF Research Database (Denmark)

    Narayanan, Dilip; Gani, Osman ABSM; Gruber, Franz XE

    2017-01-01

    Drug design of protein kinase inhibitors is now greatly enabled by thousands of publicly available X-ray structures, extensive ligand binding data, and optimized scaffolds coming off patent. The extensive data begin to enable design against a spectrum of targets (polypharmacology); however...... consider polypharmacological targeting of protein kinases ALK, MET, and EGFR (and its drug resistant mutant T790M) in non small cell lung cancer as an example. Both EGFR and ALK represent sources of primary oncogenic lesions, while drug resistance arises from MET amplification and EGFR mutation. A drug...... which inhibits these targets will expand relevant patient populations and forestall drug resistance. Crizotinib co-targets ALK and MET. Analysis of the crystal structures reveals few shared interaction types, highlighting proton-arene and key CH–O hydrogen bonding interactions. These are not typically...

  5. Influence of Met-Ocean Condition Forecasting Uncertainties on Weather Window Predictions for Offshore Operations

    DEFF Research Database (Denmark)

    Gintautas, Tomas; Sørensen, John Dalsgaard

    2017-01-01

    The article briefly presents a novel methodology of weather window estimation for offshore operations and mainly focuses on effects of met-ocean condition forecasting uncertainties on weather window predictions when using the proposed methodology. It is demonstrated that the proposed methodology...... to include stochastic variables, representing met-ocean forecasting uncertainties and the results of such modification are given in terms of predicted weather windows for a selected test case....... has the capacity to retain the uncertainties of met-ocean condition forecasting and transfer them into uncertainties of probability of operation failure. In addition to that, improvements to the failure function, used to define operation failure are presented. The failure function is modified...

  6. CoMET: A Mesquite package for comparing models of continuous character evolution on phylogenies

    Directory of Open Access Journals (Sweden)

    Chunghau Lee

    2006-01-01

    Full Text Available Continuously varying traits such as body size or gene expression level evolve during the history of species or gene lineages. To test hypotheses about the evolution of such traits, the maximum likelihood (ML method is often used. Here we introduce CoMET (Continuous-character Model Evaluation and Testing, which is module for Mesquite that automates likelihood computations for nine different models of trait evolution. Due to its few restrictions on input data, CoMET is applicable to testing a wide range of character evolution hypotheses. The CoMET homepage, which links to freely available software and more detailed usage instructions, is located at http://www.lifesci.ucsb.edu/eemb/labs/oakley/software/comet.htm.

  7. GABA receptor imaging

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jong Doo [Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2007-04-15

    GABA is primary an inhibitory neurotransmitter that is localized in inhibitory interneurons. GABA is released from presynaptic terminals and functions by binding to GABA receptors. There are two types of GABA receptors, GABA{sub A}-receptor that allows chloride to pass through a ligand gated ion channel and GABA{sub B}-receptor that uses G-proteins for signaling. The GABA{sub A}-receptor has a GABA binding site as well as a benzodiazepine binding sites, which modulate GABA{sub A}-receptor function. Benzodiazepine GABAA receptor imaging can be accomplished by radiolabeling derivates that activates benzodiazepine binding sites. There has been much research on flumazenil (FMZ) labeled with {sup 11}C-FMZ, a benzodiazepine derivate that is a selective, reversible antagonist to GABAA receptors. Recently, {sup 18}F-fluoroflumazenil (FFMZ) has been developed to overcome {sup 11}C's short half-life. {sup 18}F-FFMZ shows high selective affinity and good pharmacodynamics, and is a promising PET agent with better central benzodiazepine receptor imaging capabilities. In an epileptic focus, because the GABA/benzodiazepine receptor amount is decreased, using '1{sup 1}C-FMZ PET instead of {sup 18}F-FDG, PET, restrict the foci better and may also help find lesions better than high resolution MR. GABA{sub A} receptors are widely distributed in the cerebral cortex, and can be used as an viable neuronal marker. Therefore it can be used as a neuronal cell viability marker in cerebral ischemia. Also, GABA-receptors decrease in areas where neuronal plasticity develops, therefore, GABA imaging can be used to evaluate plasticity. Besides these usages, GABA receptors are related with psychological diseases, especially depression and schizophrenia as well as cerebral palsy, a motor-related disorder, so further in-depth studies are needed for these areas.

  8. GABA receptor imaging

    International Nuclear Information System (INIS)

    Lee, Jong Doo

    2007-01-01

    GABA is primary an inhibitory neurotransmitter that is localized in inhibitory interneurons. GABA is released from presynaptic terminals and functions by binding to GABA receptors. There are two types of GABA receptors, GABA A -receptor that allows chloride to pass through a ligand gated ion channel and GABA B -receptor that uses G-proteins for signaling. The GABA A -receptor has a GABA binding site as well as a benzodiazepine binding sites, which modulate GABA A -receptor function. Benzodiazepine GABAA receptor imaging can be accomplished by radiolabeling derivates that activates benzodiazepine binding sites. There has been much research on flumazenil (FMZ) labeled with 11 C-FMZ, a benzodiazepine derivate that is a selective, reversible antagonist to GABAA receptors. Recently, 18 F-fluoroflumazenil (FFMZ) has been developed to overcome 11 C's short half-life. 18 F-FFMZ shows high selective affinity and good pharmacodynamics, and is a promising PET agent with better central benzodiazepine receptor imaging capabilities. In an epileptic focus, because the GABA/benzodiazepine receptor amount is decreased, using '1 1 C-FMZ PET instead of 18 F-FDG, PET, restrict the foci better and may also help find lesions better than high resolution MR. GABA A receptors are widely distributed in the cerebral cortex, and can be used as an viable neuronal marker. Therefore it can be used as a neuronal cell viability marker in cerebral ischemia. Also, GABA-receptors decrease in areas where neuronal plasticity develops, therefore, GABA imaging can be used to evaluate plasticity. Besides these usages, GABA receptors are related with psychological diseases, especially depression and schizophrenia as well as cerebral palsy, a motor-related disorder, so further in-depth studies are needed for these areas

  9. Transmission of epi-alleles with MET1-dependent dense methylation in Arabidopsis thaliana.

    Directory of Open Access Journals (Sweden)

    Michael Watson

    Full Text Available DNA methylation in plants targets cytosines in three sequence contexts, CG, CHG and CHH (H representing A, C or T. Each of these patterns has traditionally been associated with distinct DNA methylation pathways with CHH methylation being controlled by the RNA dependent DNA methylation (RdDM pathway employing small RNAs as a guide for the de novo DOMAINS REARRANGED METHYLTRANSFERASE (DRM2, and maintenance DNA METHYLTRANSFERASE1 (MET1 being responsible for faithful propagation of CG methylation. Here we report an unusual 'dense methylation' pattern under the control of MET1, with methylation in all three sequence contexts. We identified epi-alleles of dense methylation at a non coding RNA locus (At4g15242 in Arabidopsis ecotypes, with distinct dense methylation and expression characteristics, which are stably maintained and transmitted in genetic crosses and which can be heritably altered by depletion of MET1. This suggests that, in addition to its classical CG maintenance function, at certain loci MET1 plays a role in creating transcriptional diversity based on the generation of independent epi-alleles. Database inspection identified several other loci with MET1-dependent dense methylation patterns. Arabidopsis ecotypes contain distinct epi-alleles of these loci with expression patterns that inversely correlate with methylation density, predominantly within the transcribed region. In Arabidopsis, dense methylation appears to be an exception as it is only found at a small number of loci. Its presence does, however, highlight the potential for MET1 as a contributor to epigenetic diversity, and it will be interesting to investigate the representation of dense methylation in other plant species.

  10. Effects of modafinil on the sleep EEG depend on Val158Met genotype of COMT.

    Science.gov (United States)

    Bodenmann, Sereina; Landolt, Hans-Peter

    2010-08-01

    Modafinil may promote wakefulness by increasing cerebral dopaminergic neurotransmission, which importantly depends on activity of catechol-O-methyltransferase (COMT) in prefrontal cortex. The effects of modafinil on sleep homeostasis in humans are unknown. Employing a novel sleep-pharmacogenetic approach, we investigated the interaction of modafinil with sleep deprivation to study dopaminergic mechanisms of sleep homeostasis. Placebo-controlled, double-blind, randomized crossover study. Sleep laboratory in temporal isolation unit. 22 healthy young men (23.4 +/- 0.5 years) prospectively enrolled based on genotype of the functional Val158Met polymorphism of COMT(10 Val/Val and 12 Met/Met homozygotes). 2 x 100 mg modafinil and placebo administered at 11 and 23 hours during 40 hours prolonged wakefulness. Subjective sleepiness and EEG markers of sleep homeostasis in wakefulness and sleep were equally affected by sleep deprivation in Val/Val and Met/Met allele carriers (placebo condition). Modafinil attenuated the evolution of sleepiness and EEG 5-8 Hz activity during sleep deprivation in both genotypes. In contrast to caffeine, modafinil did not reduce EEG slow wave activity (0.75-4.5 Hz) in recovery sleep, yet specifically increased 3.0-6.75 Hz and > 16.75 Hz activity in NREM sleep in the Val/Val genotype of COMT. The Val158Met polymorphism of COMT modulates the effects of modafinil on the NREM sleep EEG in recovery sleep after prolonged wakefulness. The sleep EEG changes induced by modafinil markedly differ from those of caffeine, showing that pharmacological interference with dopaminergic and adenosinergic neurotransmission during sleep deprivation differently affects sleep homeostasis.

  11. A comparative study between met & unmet need groups of contraception in rural area of Maharashtra, India

    Directory of Open Access Journals (Sweden)

    Harsha M Solanki

    2013-03-01

    Full Text Available Objectives To compare met & unmet need groups of contraception with socio-economic, demographic, accessibility & family Planning (FP related factors. Methods Community based cross-sectional, comparative study was conducted among 363 married women of reproductive age groups in rural area selected by stratified simple random technique. After collecting preliminary information, the study population then divided into two groups based on their contraceptive use i.e. MET Group & UNMET NEED Groups. Then the role of socio-economic, demographic, accessibility & family Planning (FP related factors were studies to determine contraceptive use between these groups. Results Mean age of study subjects was 24.12 ± 4.45 years & average number of children per women was 2.02. Males were more literate than females (69.1% Vs 47.2%. 51.8% women were belonging to lower socio-economic status. Early marriages were still prevalent in this study (53.7%. Prevalence of met group of contraception was 59.2% & that of unmet need for contraception was 44.1%. Met groups were mainly from 20-29 years age group (46.6%; most of them (46.8% were literate & were from high socio-economic group (30.9% compared to unmet need groups. On comparison to unmet groups, most of the met group (33.9% got married after 18 years of age, residing within 5km area (26.4%, had visited to FP centre (49.0% & ever visited by FP staff (43.3%. Conclusion Education, income, marriage age, accessibility, FP staff related factors definitely has role among met & unmet need groups in their contraceptive use.

  12. Coexistent genetic alterations involving ALK, RET, ROS1 or MET in 15 cases of lung adenocarcinoma.

    Science.gov (United States)

    Tang, Zhenya; Zhang, Jianjun; Lu, Xinyan; Wang, Wei; Chen, Hui; Robinson, Melissa K; Cheng, Joanne; Tang, Guilin; Medeiros, L Jeffrey

    2018-02-01

    In lung cancer, targetable activating alterations in cancer genes, such as EGFR, ALK, RET, ROS1 and MET, are usually mutually exclusive. Rare lung cancer cases with coexistent alterations of EGFR and ALK or EGFR mutations with RET or ROS1 rearrangements have been reported. In this study, we report 15 patients (3 men and 12 women; 14 Caucasians and 1 African American) with ages ranging from 43 to 81 years (median 60 years) with lung adenocarcinoma in which coexistent alterations of two cancer-associated genes, including ALK, ROS1, or RET rearrangement or MET amplification were present. The combination of alterations detected by fluorescence in situ hybridization included ALK combined with ROS1 (n=4), ALK with MET (n=3), ALK with RET (n=1); RET with MET (n=4), RET with ROS1 (n=2), and ROS1 combined with MET (n=1). The frequencies of involvement were similar for all 4 genes, 53% for both ALK and MET (n=8), 47% for both RET and ROS1 (n=7). Activating gene mutations were also detected by next-generation sequencing for TP53 (n=6), EGFR (n=5), KRAS (n=3) and STK11 (n=2). Nine patients reported a smoking history (8 heavy and 1 light) and 6 patients were non-smokers. These findings suggest the need for assessing a panel of genes in lung cancer. Since targetable agents are available for each of these activating alterations, treatment with more than one targeted agent may be beneficial for this rare group of patients.

  13. MetNet: Software to Build and Model the Biogenetic Lattice of Arabidopsis

    Directory of Open Access Journals (Sweden)

    Heike Hofmann

    2006-04-01

    Full Text Available MetNet (http://www.botany.iastate.edu/∼mash/metnetex/metabolicnetex.html is publicly available software in development for analysis of genome-wide RNA, protein and metabolite profiling data. The software is designed to enable the biologist to visualize, statistically analyse and model a metabolic and regulatory network map of Arabidopsis, combined with gene expression profiling data. It contains a JAVA interface to an interactions database (MetNetDB containing information on regulatory and metabolic interactions derived from a combination of web databases (TAIR, KEGG, BRENDA and input from biologists in their area of expertise. FCModeler captures input from MetNetDB in a graphical form. Sub-networks can be identified and interpreted using simple fuzzy cognitive maps. FCModeler is intended to develop and evaluate hypotheses, and provide a modelling framework for assessing the large amounts of data captured by high-throughput gene expression experiments. FCModeler and MetNetDB are currently being extended to three-dimensional virtual reality display. The MetNet map, together with gene expression data, can be viewed using multivariate graphics tools in GGobi linked with the data analytic tools in R. Users can highlight different parts of the metabolic network and see the relevant expression data highlighted in other data plots. Multi-dimensional expression data can be rotated through different dimensions. Statistical analysis can be computed alongside the visual. MetNet is designed to provide a framework for the formulation of testable hypotheses regarding the function of specific genes, and in the long term provide the basis for identification of metabolic and regulatory networks that control plant composition and development.

  14. Association study between COMT 158Met and creativity scores in bipolar disorder and healthy controls

    Directory of Open Access Journals (Sweden)

    Márcio Gerhardt Soeiro-de-Souza

    2014-03-01

    Full Text Available Background Bipolar disorder (BD patients have been reported to be associated higher creativity abilities, and recent data tend to support the hypothesis that dopaminergic system that could be associated with creativity. Catechol-O-methyltransferase (COMT is one of the major enzymes involved in the metabolic degradation of dopamine. The COMT gene polymorphism (rs4680 or Val158Met Met allele is reported to cause decreased activity of this enzyme in prefrontal cortex and improve performance in several cognitive domains. Objective The objective of this study was to evaluate the influence of Val158Met on creativity in BD type I and healthy controls. Methods Ninety-seven healthy volunteers and 120 BD type I were genotyped for COMT rs4680 and tested for creativity (Barrow Welsh Art Scale – BWAS and intelligence Wechsler Abbreviated Scale of Intelligence (WASI. Results COMT Met allele positively influenced creativity scores in healthy controls but not in BD subjects during mood episodes and euthymia. The presence of allele Met did not influence IQ scores. No influence of IQ total score on creativity was observed. Limitations control group presented higher IQ scores and euthymic group was under medication use. Discussion Our research suggests positive effect of COMT rs4680 (allele Met on creativity scores in healthy controls. One possible interpretation is that creativity is more likely to be associated with lesser degrees of bipolarity. The fact that the same results were not observed in BD may be associated to dysfunctions in the dopaminergic system that characterizes this disorder. Further studies with larger samples and other types of BD should explore the role of the dopaminergic system in creativity.

  15. La metáfora conceptual en el discurso psiquiátrico sobre la esquizofrenia

    Directory of Open Access Journals (Sweden)

    Salvador Climent

    2017-10-01

    Full Text Available Este estudio presenta el análisis de las metáforas conceptuales producidas por psiquiatras en el discurso sobre la esquizofrenia en un ámbito de divulgación. La investigación permite detectar las principales metáforas utilizadas por estos profesionales en el corpus de trabajo y deducir sus modelos subyacentes de conceptualización de la enfermedad. El corpus analizado consiste en un documental en español que recoge intervenciones en primera persona de afectados y profesionales especialistas en su tratamiento. Se han detectado, cuantificado y clasificado las expresiones metafóricas de los intervinientes psiquiatras y a continuación se han inferido las metáforas conceptuales a las que corresponden, las cuales, finalmente, se han clasificado en función de los dominios de destino. Las conclusiones muestran los principales patrones de conceptualización de la esquizofrenia revelados por las metáforas usadas por los psiquiatras del corpus y su relación con los modelos biomédico y social de interpretación de la enfermedad. Destacan los siguientes patrones: la conceptualización de la enfermedad como agente externo con capacidades volitivas; la enfermedad como enemigo explícito en metáforas de lucha, con el afectado como contendiente en situación de inferioridad; la cosificación del afectado; y, en general, uso de metáforas conceptuales contrarias al empoderamiento del afectado. Todo ello situaría mayoritariamente a los intervinientes en el modelo biomédico de conceptualización de la esquizofrenia.

  16. BDNF val66met Polymorphism Affects Aging of Multiple Types of Memory

    Science.gov (United States)

    Kennedy, Kristen M.; Reese, Elizabeth D.; Horn, Marci M.; Sizemore, April N.; Unni, Asha K.; Meerbrey, Michael E.; Kalich, Allan G.; Rodrigue, Karen M.

    2014-01-01

    The BDNF val66met polymorphism (rs6265) influences activity-dependent secretion of brain-derived neurotrophic factor in the synapse, which is crucial for learning and memory. Individuals homozygous or heterozygous for the met allele have lower BDNF secretion than val homozygotes and may be at risk for reduced declarative memory performance, but it remains unclear which types of declarative memory may be affected and how aging of memory across the lifespan is impacted by the BDNF val66met polymorphism. This cross-sectional study investigated the effects of BDNF polymorphism on multiple indices of memory (item, associative, prospective, subjective complaints) in a lifespan sample of 116 healthy adults aged 20-93 years. Advancing age showed a negative effect on item, associative and prospective memory, but not on subjective memory complaints. For item and prospective memory, there were significant age x BDNF group interactions, indicating the adverse effect of age on memory performance across the lifespan was much stronger in the BDNF met carriers than for the val homozygotes. BDNF met carriers also endorsed significantly greater subjective memory complaints, regardless of age, and showed a trend (p memory performance compared to val homozygotes. These results suggest that genetic predisposition to the availability of brain-derived neurotrophic factor, by way of the BDNF val66met polymorphism, exerts an influence on multiple indices of episodic memory – in some cases in all individuals regardless of age (subjective memory and perhaps associative memory), in others as an exacerbation of age-related differences in memory across the lifespan (item and prospective memory). PMID:25264352

  17. Die hermeneuse van die Skrif met die oog op hedendaagse kerklik-etiese vraagstukke

    Directory of Open Access Journals (Sweden)

    J. C. Coetzee

    1980-05-01

    Full Text Available Daar is basiese reëls wat vir alle verklaring van boeke geld. Maar die eie aard en karakter van die Bybel bring ook hiermee dat sy verklaring ’n eie aard sal hê. Wat ’n mens van ’n bron dink, bepaal hoe jy met die bron omgaan. Geen eksegeet is onbevooroordeeld nie. ’n Mens se Skrifbeskouing bepaal ten diepste ook jou wyse van Skrifverklaring. Wie in die Bybel ’n gewoon menslike boek sien, sal dit met gewoon menslike hulpmiddels probeer verklaar.

  18. High levels of c-Met is associated with poor prognosis in glioblastoma

    DEFF Research Database (Denmark)

    Petterson, Stine Asferg; Dahlrot, Rikke Hedegaard; Hermansen, Simon Kjær

    2015-01-01

    . Measurements of high c-Met intensity correlated with high WHO grade (p = 0.006) but no association with survival was observed in patients with WHO grade II (p = 0.09) or III (p = 0.17) tumors. High expression of c-Met was associated with shorter overall survival in patients with glioblastoma multiforme (p = 0...... and the clinical variables age (HR 1.01, 95 % CI 0.99-1.03, p = 0.30), performance status (HR 1.34, 95 % CI 1.17-1.53, p

  19. El arte de la metáfora indígena

    OpenAIRE

    Ferro, Luis E.

    2014-01-01

    Para el mundo indígena, la memoria es palabra viva que se manifiesta en relatos que se construyen a través de las transfiguraciones de la metáfora. La metáfora es, por tanto, el eje y recurso narrativo para evocar el sentido de sus manifestaciones sociales y estéticas que nacen, ritualizan y explican con la oralidad sus propias experiencias vivenciales en el devenir del tiempo. To the indigenous world, memory is alive word manifested in stories that are constructed through the transfigurat...

  20. Performance of Missing Transverse Momentum (MET) reconstruction with the ATLAS detector - LHCC poster 2017

    CERN Document Server

    Valente, Marco; The ATLAS collaboration

    2017-01-01

    Accurate and precise measurement of missing transverse momentum (MET) in an event is critical for many of the searches for new physics carried out by the ATLAS experiment. In the last year, several improvements have been introduced to the reconstruction of this quantity, such as distinguishing between jets and electrons, as well as mitigating the impact of jets from multiple proton-proton collisions, especially in the forward region of the detector. This poster aims to illustrate the MET reconstruction performance of the ATLAS experiment, with a particular emphasis on forward pileup jet suppression and systematic uncertainties derivation.

  1. Novel germline c-MET mutation in a family with hereditary papillary renal carcinoma

    DEFF Research Database (Denmark)

    Wadt, Karin; Gerdes, Anne-Marie; Hansen, Thomas V O

    2012-01-01

    Hereditary papillary renal carcinoma (HPRC) is a highly penetrant hereditary renal cancer syndrome caused by germline missense mutations in the c-MET proto-oncogene. HPRC is clinically characterized by multiple bilateral papillary renal-cell carcinomas. Here we report a family with a novel missense...... mutation in c-MET. The original pathology report of four primary kidney cancers (1988-1997) revealed renal-cell carcinoma. A revised report described multiple adenomas and papillary renal-cell carcinomas with focal clear cells and a mixture of type 1 and type 2 pattern, emphasizing the importance...

  2. BDNF val66met association with serotonin transporter binding in healthy humans

    DEFF Research Database (Denmark)

    Fisher, P. M.; Ozenne, B.; Svarer, C.

    2017-01-01

    -carriers have increased subcortical 5-HTT binding. The small difference suggests limited statistical power may explain previously reported null effects. Our finding adds to emerging evidence that BDNF val66met contributes to differences in the human brain serotonin system, informing how variability in the 5-HTT......The serotonin transporter (5-HTT) is a key feature of the serotonin system, which is involved in behavior, cognition and personality and implicated in neuropsychiatric illnesses including depression. The brain-derived neurotrophic factor (BDNF) val66met and 5-HTTLPR polymorphisms have predicted...

  3. Cerebro y metáfora en la novela "Pedro Páramo", de Juan Rulfo

    Directory of Open Access Journals (Sweden)

    CECILIA EDILMA DÍAZ DÍAZ

    2010-01-01

    Full Text Available Se trata de un avance de investigación que aplica la teoría neurolingüística de Omar Parra Rozo para leer y comprender la metáfora en un texto literario. Se toma como objeto de estudio la novela "Pedro Páramo" de Juan Rulfo, específicamente los fragmentos que hablan acerca de la imagen compleja (religión-poder y muerte. El ejercicio de investigación alcanzó a establecer la relación que existe entre imagen- cerebro y metáfora, en el discurso de esta novela.

  4. The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism.

    NARCIS (Netherlands)

    Klebe, S.; Golmard, J.L.; Nalls, M.A.; Saad, M.; Singleton, A.B.; Bras, J.M.; Hardy, J.; Simon Sanchez, J.; Heutink, P.; Kuhlenbäumer, G.; Charfi, R.; Klein, C.; Hagenah, J.; Gasser, T.; Wurster, I.; Lesage, S.; Lorenz, D.; Deuschl, G.; Durif, F.; Pollak, P.; Damier, P.; Tison, F.; Durr, A.; Amouyel, P.; Lambert, J.C.; Tzourio, C.; Maubaret, C.; Charbonnier-Beaupel, F.; Tahiri, K.; Vidailhet, M.; Martinez, M.; Brice, A.; Corvol, J.C.

    2013-01-01

    The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met

  5. The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism

    NARCIS (Netherlands)

    Klebe, S.; Golmard, J.L.; Nalls, M.A.; Saad, M.; Singleton, A.B.; Bras, J.M.; Hardy, J.; Simon-Sanchez, J.; Heutink, P.; Kuhlenbaumer, G.; Charfi, R.; Klein, C.; Hagenah, J.; Gasser, T.; Wurster, I.; Lesage, S.; Lorenz, D.; Deuschl, G.; Durif, F.; Pollak, P.; Damier, P.; Tison, F.; Durr, A.; Amouyel, P.; Lambert, J.C.; Tzourio, C.; Maubaret, C.; Charbonnier-Beaupel, F.; Tahiri, K.; Vidailhet, M.; Martinez, M.; Brice, A.; Corvol, J.C.; Bloem, B.R.; Post, B.; Scheffer, H.; Warrenburg, B.P.C. van de; et al.,

    2013-01-01

    The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met

  6. More with thermal energy storage. Report 1. Coupling with policy. Coupling of research results MMB with policy aspects. Final report; Meer met bodemenergie. Rapport 1. Koppeling met beleid. Koppeling onderzoeksresultaten MMB met beleidsaspecten. Eindrapport

    Energy Technology Data Exchange (ETDEWEB)

    Luitwieler, M. [Bioclear, Groningen (Netherlands); Van Beek, D.; De Boer, S.; Koenders, M. [IF Technology, Arnhem (Netherlands)

    2012-06-25

    The project More With Thermal Energy Storage (MMB, abbreviated in Dutch) focuses on knowledge gaps and potential opportunities regarding open systems. The main questions to be answered are: (1) What effects (hydrological, thermal, microbiological and chemical) occur in the soil system by application of thermal energy storage; (2) Which technical options are available for a sustainable integration of thermal energy storage in the water and energy chain?; (3) Is it possible to achieve multiple objectives by using smart combinations? The project is organized in different work packages. In work package 2, the effects of individual and collective thermal energy storage storage systems on subsoils and the environment are determined. In work package 3 the opportunities for thermal energy storage and soil remediation are examined, while in work package 4 the focus is on new sustainable combinations of heat and cold storage. Work package is the umbrella part where communication and policy of and participation in MMB are the main subjects. This final report provides (a) an overview of the activities that have taken place in the context of work package 1, (b) the results of the other work packages in the light of four policy frameworks, and (c) a view on future policy [Dutch] Het project Meer Met Bodemenergie (MMB) richt zich op het invullen van kennisleemtes en mogelijke kansen ten aanzien van open systemen. De belangrijkste vragen waarop het onderzoeksprogramma MMB antwoord geeft zijn: (1) Welke effecten (hydrologisch, thermisch, microbiologisch en chemisch) treden op in het bodemsysteem bij toepassing van bodemenergie?; (2) Welke technische mogelijkheden zijn er voor het duurzaam inpassen van bodem-energie in de water- en energieketen?; (3) Is het mogelijk om meerdere doelstellingen tegelijk te verwezenlijken door slimme combinaties te maken? Het project is ingericht met verschillende werkpakketten. In werkpakket 2 worden de effecten van individuele en collectieve

  7. Recombinant Collagen Engineered to Bind to Discoidin Domain Receptor Functions as a Receptor Inhibitor*

    Science.gov (United States)

    An, Bo; Abbonante, Vittorio; Xu, Huifang; Gavriilidou, Despoina; Yoshizumi, Ayumi; Bihan, Dominique; Farndale, Richard W.; Kaplan, David L.; Balduini, Alessandra; Leitinger, Birgit; Brodsky, Barbara

    2016-01-01

    A bacterial collagen-like protein Scl2 has been developed as a recombinant collagen model system to host human collagen ligand-binding sequences, with the goal of generating biomaterials with selective collagen bioactivities. Defined binding sites in human collagen for integrins, fibronectin, heparin, and MMP-1 have been introduced into the triple-helical domain of the bacterial collagen and led to the expected biological activities. The modular insertion of activities is extended here to the discoidin domain receptors (DDRs), which are collagen-activated receptor tyrosine kinases. Insertion of the DDR-binding sequence from human collagen III into bacterial collagen led to specific receptor binding. However, even at the highest testable concentrations, the construct was unable to stimulate DDR autophosphorylation. The recombinant collagen expressed in Escherichia coli does not contain hydroxyproline (Hyp), and complementary synthetic peptide studies showed that replacement of Hyp by Pro at the critical Gly-Val-Met-Gly-Phe-Hyp position decreased the DDR-binding affinity and consequently required a higher concentration for the induction of receptor activation. The ability of the recombinant bacterial collagen to bind the DDRs without inducing kinase activation suggested it could interfere with the interactions between animal collagen and the DDRs, and such an inhibitory role was confirmed in vitro and with a cell migration assay. This study illustrates that recombinant collagen can complement synthetic peptides in investigating structure-activity relationships, and this system has the potential for the introduction or inhibition of specific biological activities. PMID:26702058

  8. Dengue virus receptor

    OpenAIRE

    Hidari, Kazuya I.P.J.; Suzuki, Takashi

    2011-01-01

    Dengue virus is an arthropod-borne virus transmitted by Aedes mosquitoes. Dengue virus causes fever and hemorrhagic disorders in humans and non-human primates. Direct interaction of the virus introduced by a mosquito bite with host receptor molecule(s) is crucial for virus propagation and the pathological progression of dengue diseases. Therefore, elucidation of the molecular mechanisms underlying the interaction between dengue virus and its receptor(s) in both humans and mosquitoes is essent...

  9. Therapeutic androgen receptor ligands

    Science.gov (United States)

    Allan, George F.; Sui, Zhihua

    2003-01-01

    In the past several years, the concept of tissue-selective nuclear receptor ligands has emerged. This concept has come to fruition with estrogens, with the successful marketing of drugs such as raloxifene. The discovery of raloxifene and other selective estrogen receptor modulators (SERMs) has raised the possibility of generating selective compounds for other pathways, including androgens (that is, selective androgen receptor modulators, or SARMs). PMID:16604181

  10. Activation of neurokinin-1 receptors increases the excitability of guinea pig dorsal root ganglion cells.

    Science.gov (United States)

    Zhang, Xiulin; Pietra, Claudio; Lovati, Emanuela; de Groat, William C

    2012-10-01

    The suppression of overactive bladder symptoms in patients and overactive bladder reflexes in animal models by neurokinin (NK)-1 receptor antagonists raises the possibility that these drugs target sensory neurons. This mechanism was evaluated by examining the interactions between a specific NK-1 agonist, [Sar(9),Met(O(2))(11)]-substance P (Sar-Met-SP), and a potent NK-1 antagonist, netupitant (NTP), on small size (20-30 μm) dissociated L6 and S1 dorsal root ganglion (DRG) neurons from female guinea pigs. Current-clamp recording revealed that Sar-Met-SP (1 μM) elicited membrane depolarization (average 8.05 ± 1.38 mV) in 27% (18 of 65) of DRG neurons. In 74% of the remaining neurons (35 of 47) Sar-Met-SP decreased the rheobase for action potential (AP) generation and increased the response to a suprathreshold stimulus (3 times rheobase) without changing the membrane potential. Sar-Met-SP also induced changes in the action potential (AP) wave form, including 1) an increase in overshoot (average 5 mV, n = 35 neurons), 2) a prolongation of AP duration (from 4.64 to 5.29 ms, n = 34), and 3) a reduction in the maximal rate of AP repolarization. NTP (200 nM) reversed the Sar-Met-SP-induced changes. Ca(2+) imaging showed that application of Sar-Met-SP (1 μM) decreased the tachyphylaxis induced by repeated application of capsaicin (0.5 μM), an effect blocked by pretreatment with NTP (200 nM). These results raise the possibility that activation of NK-1 receptors in primary sensory neurons plays a role in the generation of overactive bladder and that block of NK-1 receptors in these neurons may contribute to efficacy of NK-1 antagonists in the treatment of overactive bladder symptoms.

  11. Immunohistochemical observations of methionine-enkephalin and delta opioid receptor in the digestive system of Octopus ocellatus.

    Science.gov (United States)

    Sha, Ailong; Sun, Hushan; Wang, Yiyan

    2013-02-01

    The study was designed to determine whether methionine-enkephalin (met-Enk) or delta opioid receptor was present in the digestive system of Octopus ocellatus. The results showed that they were both in the bulbus oris, esophagus, crop, stomach, gastric cecum, intestine, posterior salivary glands of O. ocellatus, one of them, met-Enk in the rectum, anterior salivary glands, digestive gland. And the distributions were extensive in the digestive system. Strong or general met-Enk immunoreactivity was observed in the inner epithelial cells of the bulbus oris, esophagus, stomach, gastric cecum, intestine, anterior salivary glands and the adventitia of the intestine and rectum, and so was the delta opioid receptor immunoreactivity in the inner epithelial cells of the bulbus oris, esophagus, and crop, however, they were weak in other parts. Combining with delta opioid receptor, met-Enk may be involved in the regulations of food intake, absorption, movement of gastrointestinal smooth muscle and secretion of digestive gland. The different densities of met-Enk and delta opioid receptor may be related to the different functions in the digestive system of O. ocellatus. Copyright © 2012 Elsevier Ltd. All rights reserved.

  12. Bufalin Reverses HGF-Induced Resistance to EGFR-TKIs in EGFR Mutant Lung Cancer Cells via Blockage of Met/PI3k/Akt Pathway and Induction of Apoptosis

    Directory of Open Access Journals (Sweden)

    Xiao-Hong Kang

    2013-01-01

    Full Text Available The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs, such as gefitinib and erlotinib, have shown promising therapeutic efficacy in nonsmall cell lung cancer (NSCLC patients harboring epidermal growth factor receptor- (EGFR- activating mutation. However, the inevitable recurrence resulting from acquired resistance has limited the clinical improvement in therapy outcomes. Many studies demonstrate that hepatocyte growth factor- (HGF- Met axis plays an important role in tumor progression and drug sensitivity. HGF may induce resistance to EGFR-TKIs in EGFR mutant lung cancer cells by Met/PI3K/Akt signaling. The purpose of this study was to determine whether bufalin, a major bioactive component of Venenum Bufonis, could reverse HGF-induced resistance to reversible and irreversible EGFR-TKIs in mutant lung cancer cells PC-9, HCC827, and H1975. Our studies showed that bufalin could reverse resistance to reversible and irreversible EGFR-TKIs induced by exogenous HGF in EGFR mutant lung cancer cells by inhibiting the Met/PI3K/Akt pathway and inducing death signaling. These results suggested that bufalin might have a potential to overcome HGF-induced resistance to molecular-targeted drugs for lung cancer.

  13. Plastic raakt zoek in de oceaan (interview met Jan Andries van Franeker)

    NARCIS (Netherlands)

    Kleis, R.; Franeker, van J.A.

    2015-01-01

    De plastic eilanden op de oceanen verliezen in hoog tempo .....plastic. Jan Andries van Franeker toont dat aan door plastic vangsten in die eilanden te vergelijken met de maaginhoud van Noordse stormvogels op de Noordzee. Waar al dat plastic blijft, is vooralsnog een raadsel.

  14. E-cadherin and c-Met expression in actinic cheilits and lip squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    A Martínez

    2011-12-01

    Full Text Available Objective: The aim of this study was to assess epithelial expression of E-cadherin and c-Met in normal lip, in actinic cheilitis and lip squamous cell carcinoma. Study Design: Biopsies of normal lip vermillion (NL, n=18, actinic cheilitis (AC, n=37, and lip SCC (n=22 were processed for E-cadherin and c-Met immunodetection. Epithelial and tumor cell expression was scored for each sample considering staining intensity and percentage. Results: E-cadherin expression was significantly reduced in AC and lip SCC as compared to normal lip (P<0.05, with a significant reduction in lip SCC as compared to AC (P=0.003. Expression of c-Met was significantly higher in AC and lip SCC as compared to NL (P<0.05, with a significant increase in lip SCC as compared to AC (P<0.0001. Conclusion: The results showed that epithelial E-cadherin expression is reduced and c-Met expression is increased as lip carcinogenesis progresses, suggesting that these proteins may be useful markers of malignant transformation.

  15. Iedereen eet en drinkt elke dag voedsel met E-nummers

    NARCIS (Netherlands)

    Hartemink, R.

    2010-01-01

    Soms krijgen mensen met overgevoeligheidsklachten het advies om alle E-nummers in levensmiddelen te mijden. Dat kan helemaal niet! 'Als je dat wilt doen, hou je een dieet over van water, zout en suiker', aldus levensmiddelentechnoloog dr. ir. Ralf Hartemink van Wageningen Universiteit. Dit artikel

  16. Association Between Smoking, Nicotine Dependence, and BDNF Val(66)Met Polymorphism with BDNF Concentrations in Serum

    NARCIS (Netherlands)

    Jamal, Mumtaz; Van der Does, Willem; Elzinga, Bernet M.; Molendijk, Marc L.; Penninx, Brenda W. J. H.

    Introduction: Nicotine use is associated with the upregulation of brain-derived neurotrophic factor (BDNF) in serum. An association between smoking and the BDNF Val(66)Met polymorphism has also been found. The aim of this study is to examine the levels of serum BDNF in never-smokers, former smokers,

  17. When Allport Met Freud: Using Anecdotes in the Teaching of Psychology.

    Science.gov (United States)

    Kaufman, James C.; Bristol, Adam S.

    2001-01-01

    Proposes using anecdotes in introductory psychology courses to teach key points, principles, and people. Offers theoretical and empirical support for anecdotes as teaching tools. Believes that anecdotes, such as when Gordon Allport met Sigmund Freud, provide an enjoyable experience and enable students to better remember information. (CMK)

  18. 21 CFR 111.73 - What is your responsibility for determining whether established specifications are met?

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 2 2010-04-01 2010-04-01 false What is your responsibility for determining whether established specifications are met? 111.73 Section 111.73 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION CURRENT GOOD...

  19. 21 CFR 111.77 - What must you do if established specifications are not met?

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 2 2010-04-01 2010-04-01 false What must you do if established specifications are not met? 111.77 Section 111.77 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION CURRENT GOOD MANUFACTURING PRACTICE IN...

  20. Collegiate Schemas: The Influence of Institutional Met Expectations on Tenure-Track Faculty Job Satisfaction

    Science.gov (United States)

    Pontius, Jason Lewis

    2012-01-01

    "Met expectations" research into job satisfaction (Locke, 1976; Porter & Steers, 1973) has shown that the expectations employees bring to their jobs influence their overall job satisfaction. At colleges and universities, faculty job satisfaction is important because it can provide a measure of overall institutional effectiveness…

  1. Dit is heel leuk!!! Wat doen beloningen met de kwaliteit van online reviews?

    NARCIS (Netherlands)

    Verlegh, P.

    2013-01-01

    U worstelt met een probleem. U zou graag willen dat uw product vaker gereviewd werd, maar u wilt het eerlijk spelen. U wilt niet dat de recensenten beïnvloed worden als u hen een beloning aanbiedt. Wat voor mogelijkheden heeft u dan nog? Nou, eigenlijk is die beloning misschien zo gek nog niet...

  2. The association of XRCC3 Thr241Met genetic variant with risk of ...

    African Journals Online (AJOL)

    Background: Previous studies suggest that the X-ray repair cross-complementing group 3 gene (XRCC3) Thr241Met genetic variant could be potentially associated with the risk of prostate cancer. However, results from these published studies were conflicting rather than conclusive. Objectives:This meta-analysis aimed to ...

  3. Robots niet langer Science Fiction: scenario's voor de samenwerking met robots

    NARCIS (Netherlands)

    Popma, J.

    2015-01-01

    Hoewel industriële robots al jaren bestaan, lijkt hun opmars nu toch echt begonnen. Diverse scenario's buitelen over elkaar: hoeveel banen gaat dit kosten? Maar zeker zo interessant is wat de robotisering betekent voor de werknemers die wél hun baan houden. Hoe gaan die samenwerken met robots? En

  4. Evaluation of the EuroMET Web-Based Course in Meteorology.

    Science.gov (United States)

    Phelps, Julia; Reynolds, Ross

    The EuroMET (European Meteorological Education and Training) project was created to address the education and training needs of professional meteorologists and students in tertiary education throughout Europe and more widely. Two courses, each modular in format, have been developed for the World Wide Web. The courses have been evaluated at three…

  5. Financiële verslaggeving door het Rijk vergeleken met IPSAS

    NARCIS (Netherlands)

    van Schaik, F.

    2014-01-01

    De Europese Commissie bereidt plannen voor om de financiële verslaggeving door de overheden van de lidstaten te harmoniseren met als doel een verbetering van transparantie en vergelijkbaarheid. De Europese schuldencrisis heeft duidelijk gemaakt dat de jaarrekeningen van de overheden van de lidstaten

  6. Military Training: DOD Met Annual Reporting Requirements in Its 2016 Sustainable Ranges Report

    Science.gov (United States)

    2016-06-01

    maritime or airspace restrictions, air quality, airborne noise, urban growth , physical obstructions, and renewable energy projects. 2Department of...MILITARY TRAINING DOD Met Annual Reporting Requirements in Its 2016 Sustainable Ranges Report Report to... Sustainable Ranges Report Why GAO Did This Study DOD relies on its training ranges within the United States and overseas to help prepare its

  7. Combihuisvesting van voedsters: Resultaat na een jaar draaien met dit systeem

    NARCIS (Netherlands)

    Rommers, J.M.; Jong, de I.C.

    2011-01-01

    In dit artikel wordt ingegaan op een proef waarin voedsters in groepen zijn gehouden in het zogenaamde combisysteem. De speenkonijnen van deze voedsters zijn gevolgd tot en met het slachten. Het huisvesten van voedsters in een combisysteem heeft geen nadelige invloed op de groei en uitval van de

  8. Patterns of learning organisation in Estonian companies / Tõnis Mets, Made Torokoff

    Index Scriptorium Estoniae

    Mets, Tõnis, 1952-

    2007-01-01

    Uuringu eesmärgiks on määratleda õppiva organisatsiooni põhiomadused ja hinnata organisatsioonilise õppimise olukorda Eesti tootmisettevõtetes. Empiirilise uuringu põhimudelid tulenevad Senge viiest distsipliinist ja Mets'ia kolmedimensioonilisest õppimise raamistikust. Tabelid

  9. al die tyd sy plek met eer volstaan in die studeerkamer. A. S. G eyser ...

    African Journals Online (AJOL)

    Test

    De Bijbel in Nieuwe Vertaling met verklarende Aantekeningen. Het Nieuwe. Testament. J. H. Kok, Kampen, 1957. GLD. 17.50. By die teks van die Nederlandse Bybelgenootskap se Nuwe Testament het Dr. N. J. Hommes, Dr. J. L. Koole, Dr. P. G. Kunst, Dr. H. N. Ridder bos en Dr. R. Schippers verklarende aantekeninge ...

  10. 21 CFR 111.75 - What must you do to determine whether specifications are met?

    Science.gov (United States)

    2010-04-01

    ... Production and Process Control System § 111.75 What must you do to determine whether specifications are met... where control is necessary to ensure the quality of the finished batch of dietary supplement to: (1... verify that the production and process control system is producing a dietary supplement that meets all...

  11. Instructional Coding System for Mathematics Program of Studies. MET, A Title IV-C Project.

    Science.gov (United States)

    Fairfax County Public Schools, VA. Dept. of Instructional Services.

    This document is part of the Management for Effective Teaching (MET) support kit, a pilot project designed by the Fairfax County (Virginia) Public Schools to assist elementary school teachers in planning, managing, and implementing the county's Program of Studies (POS). This document provides an alpha-numeric coding system to be used in…

  12. Vervoerwijzekeuze in woon-werkverkeer. Eerste analyses met het nieuwe Mobiliteitspanel Nederland

    NARCIS (Netherlands)

    Olde Kalter, Marie-José José Theresia; Geurs, Karst Teunis; Hoogendoorn-Lanser, Sascha

    2015-01-01

    In dit artikel presenteren we de resultaten van een aantal vervoerwijzekeuzemodellen die zijn geschat met data van het Mobiliteitspanel Nederland (MPN). Het MPN is erop gericht het inzicht te vergroten in factoren die een rol spelen bij veranderingen in het mobiliteitsgedrag. Het gaat daarbij om

  13. Onderzoek naar de mutagene werking van 2,3-epoxypropylmethacrylaat met microorganismen

    NARCIS (Netherlands)

    Voogd CE; van der Stel JJ; Verharen HW

    1984-01-01

    Glycidylmethacrylaat of 2,3-epoxypropylmethacrylaat bleek een mutagene werking uit te oefenen op Klebsiela pneumoniae (0,0002 mol en hoger), op Salmonella typhimurium TA 1535 (vanaf 0,004 mg per plaat) en Salmonella typhimurium TA 100 (vanaf 0,04 mg per plaat). Met de Salmonella typhimurium stammen

  14. Worstelen met Risk Appetite : Hoe de inkleuring van de risicomatrix de risicohouding verraadt

    NARCIS (Netherlands)

    dr. A.F. de Wild; V. Versluis

    2016-01-01

    Een risico-averse houding bij het prioriteren van risico’s is aan te bevelen volgens de besliskundige inzichten van Daniël Kahneman. Maar wat bedoelt de besliskunde eigenlijk met risicoaversie? En hoe kan het koppelen van het begrip risicohouding aan de risicomatrix helpen bij de onderbouwing van de

  15. Estructuras Metálicas. Prácticas de ordenador (curso 2014-2015)

    OpenAIRE

    Varona Moya, Francisco de Borja

    2015-01-01

    Cuaderno con enunciados y actividades correspondientes a las prácticas con ordenador de la asignatura "Estructuras Metálicas" del Grado en Ingeniería Civil. Cálculo de estructuras de pórtico de nave industrial y pasarela peatonal con el software SAP2000.

  16. Plant krijgt vorm door de regels te breken (interview met Dolf Weijers)

    NARCIS (Netherlands)

    Ramaker, R.; Weijers, D.

    2014-01-01

    Plantencellen blijken zich volgens een simpele regel in tweeën te delen; dit gebeurt in het midden, maar wel met een zo klein mogelijk deelvlak. Dit inzicht helpt te verklaren hoe planten hun definitieve vorm krijgen. Opvallend genoeg blijken cellen deze regel ook te overtreden.

  17. Met lure&kill-systeem vliegen motten vanzelf naar het insecticide

    NARCIS (Netherlands)

    Kierkels, T.; Griepink, F.C.

    2008-01-01

    Insecten worden zo sterk aangetrokken door feromonen - seksstoffen - dat je daar bij de bestrijding gebruik van kunt maken. Als het insect naar het insecticide toekomt, hoef je niet areaaldekkend te spuiten. Dat heeft veel voordelen. Plant Research International is al ver met de ontwikkeling van

  18. MetAnnotate: function-specific taxonomic profiling and comparison of metagenomes.

    Science.gov (United States)

    Petrenko, Pavel; Lobb, Briallen; Kurtz, Daniel A; Neufeld, Josh D; Doxey, Andrew C

    2015-11-05

    Metagenomes provide access to the taxonomic composition and functional capabilities of microbial communities. Although metagenomic analysis methods exist for estimating overall community composition or metabolic potential, identifying specific taxa that encode specific functions or pathways of interest can be more challenging. Here we present MetAnnotate, which addresses the common question: "which organisms perform my function of interest within my metagenome(s) of interest?" MetAnnotate uses profile hidden Markov models to analyze shotgun metagenomes for genes and pathways of interest, classifies retrieved sequences either through a phylogenetic placement or best hit approach, and enables comparison of these profiles between metagenomes. Based on a simulated metagenome dataset, the tool achieves high taxonomic classification accuracy for a broad range of genes, including both markers of community abundance and specific biological pathways. Lastly, we demonstrate MetAnnotate by analyzing for cobalamin (vitamin B12) synthesis genes across hundreds of aquatic metagenomes in a fraction of the time required by the commonly used Basic Local Alignment Search Tool top hit approach. MetAnnotate is multi-threaded and installable as a local web application or command-line tool on Linux systems. Metannotate is a useful framework for general and/or function-specific taxonomic profiling and comparison of metagenomes.

  19. Validation Engine for Observational Protocols. Measures of Effective Teaching (MET) Project

    Science.gov (United States)

    Bill & Melinda Gates Foundation, 2010

    2010-01-01

    In the fall of 2009, the Bill and Melinda Gates Foundation launched the two-year Measures of Effective Teaching (MET) project to rigorously develop and test multiple measures of teacher effectiveness. As part of the project, partners from more than a dozen reputable academic, non-profit and for-profit organizations collected and analyzed data from…

  20. Simple and effective procedure for conformational search of macromolecules. Application to Met- and Leu-Enkephalin

    Energy Technology Data Exchange (ETDEWEB)

    Meirovitch, H.; Meirovitch, E. (Florida State Univ., Tallahassee, FL (United States)); Michel, A.G. (Institut de Recherches Serrier, Suresnes (France)); Vasquez, M. (Protein Design Lab., Mountain View, CA (United States))

    1994-06-23

    A simple and efficient method for searching the conformational space of macromolecules is presented. With this method an initial set of relatively low-energy structures is generated, and their energies are further minimized with a procedure that enables escaping from local energy minima. Illustrative calculations are described for Met- and Leu-enkephalin. 37 refs., 1 tab.

  1. Metástasis coroidea como manifestación inicial de tumor germinal mixto testicular

    Directory of Open Access Journals (Sweden)

    Leticia E. Pacheco Quito

    2016-05-01

    El objetivo del oftalmólogo es establecer el diagnóstico ocular oportuno y realizar un correcto diagnóstico diferencial. Se debe considerar el diagnóstico de tumor testicular primario en un adulto joven con metástasis intraoculares.

  2. Kwaliteitsdocument inzake de bepaling van Cadmium in kunststoffen met behulp van Rontgenflurescentie

    NARCIS (Netherlands)

    Hoogerbrugge R; van de Wiel HJ; van de Beek ACW; Kliest JJG; IEM

    1999-01-01

    Bij de handhaving van het besluit Cadmium in Kunststoffen is gebleken, dat de analyse met behulp van Rvntgenfluorescentie (XRF) een snel en goedkoop alternatief zou kunnen zijn voor de op dit moment wettelijk voorgeschreven methoden. In opdracht van de Inspecteur Milieuhygikne is daarom door het

  3. Etnische diversiteit, sociaal vertrouwen in de buurt en contact van allochtonen en autochtonen met de buren

    NARCIS (Netherlands)

    Lancee, B.; Dronkers, J.

    2008-01-01

    Putnam (2007) toont aan dat in de Verenigde Staten etnische diversiteit samengaat met minder solidariteit en sociaal kapitaal: in etnisch diverse wijken hebben bewoners de neiging in ‘hun schulp te kruipen’. Het onderling vertrouwen (zelfs in de eigen etnische groep) is lager, altruı¨sme en

  4. Fluorescentievingerafdruk van Aardappel, Melganzenvoet en Mais : Eerste resultaten van plantonderscheid met behulp van fluorescentie

    NARCIS (Netherlands)

    Groot, T.T.; Nieuwenhuizen, A.T.

    2012-01-01

    Als het spectrum van één “soort” (gewas) vergeleken wordt met de rest (onkruid) neemt het onderscheid van het “gewas” af tot 70%. Het lijkt dus nodig ook de spectra van alle soorten onkruid in het veld te kennen om een goed onderscheid mogelijk te maken. De doelstelling voor deze metingen is een

  5. Wat is het geheim van ammonium? (interview met Bram van der Maas)

    NARCIS (Netherlands)

    Maas, van der A.A.

    2013-01-01

    Beter meten is meer weten. Dat is het uitgangspunt van de 'ion selectieve meter' die Horticoop en CleanGrow bezig zijn te ontwikkelen. Daarmee zijn zes elementen te controleren. Maar wat zegt bijvoorbeeld het gehalte ammonium over een gewas? Onderzoeker Bram van der Maas: 'Met ammonium is misschien

  6. To bee or not to bee (interview met T. Blacquière & J. Calis)

    NARCIS (Netherlands)

    Thoenes, E.; Blacquiere, T.; Calis, J.

    2009-01-01

    Het gaat slecht met de honingbij. Zowel in Europa als in Amerika zien imkers in toenemende mate hun bijenvolken ten prooi vallen aan de ‘verdwijnziekte’. Het symptoom, een lege kast zonder bijen – levend noch dood –, stelt wetenschappers voor een raadsel. Wageningse onderzoekers proberen de oorzaken

  7. Inbedding kennisarrangement Leren met Toekomst : succes- en faalfactoren bij de implementatie in Onderwijs en Onderzoek

    NARCIS (Netherlands)

    Os, van G.J.

    2008-01-01

    Het stage-concept van Leren met Toekomst (LmT-stage) behelst een onderzoeksstage waaraan een aantal extra aspecten zijn toegevoegd. De stage is in een breder kader geplaatst van een ondernemersnetwerk en leerlingen van MBO en HBO werken als team samen bij het vervullen van een opdracht. De docenten

  8. Radioimmunoassay of met-enkephalin in microdissected areas of paraformaldehyde-fixed rat brain

    International Nuclear Information System (INIS)

    Correa, F.M.A.; Saavedra, J.M.

    1984-01-01

    The effects were studied of various sample preparation procedures on rat brain met-enkephalin content, measured by radioimmunoassay. Whole brain met-enkephalin content of rats killed by decapitation followed by immediate tissue freezing was similar to that of rats killed by microwave irradiation and to those of rats anesthetized with pentobarbital or halothane before killing, whether previously perfused with paraformaldehyde or not. In contrast, a decrease (up to 80%) in met-enkephalin concentrations was observed when brain samples were frozen and thawed to mimic the procedure utilized in the ''punch'' technique for analysis of discrete brain nuclei. This decrease was totally prevented by paraformaldehyde perfusion of the brain prior to sacrifice. Brain perfusion did not alter the amount of immunoassayable met-enkephalin extracted from tissue or its profile after Sephadex chromatography. Paraformaldehyde perfusion results in better morphological tissue preservation and facilitates the ''punch'' dissecting technique. Paraformaldehyde perfusion may be the procedure of choice for the measurement of neuropeptides in specific brain nuclei dissected by the ''punch'' technique

  9. Vergelijkend kortdurend onderzoek met waterorganismen ter bepaling van de acute toxiciteit van een aantal biociden

    NARCIS (Netherlands)

    Canton JH; Mathijssen-Spiekman EAM

    1983-01-01

    Ter bepaling van de acute toxiciteit van een aantal biociden is vergelijkend kortdurend onderzoek met waterorganismen uitgevoerd. Daphnia magna en de twee geteste groene algen (Chlorella pyrenoidosa en Scenedesmus pannonicus) bleken voor alle onderzochte biociden gevoeliger te zijn dan de vissen

  10. De moraal van de tomaat : interview met techniekfilosoof Peter-Paul Verbeek

    NARCIS (Netherlands)

    Verbeek, Peter P.C.C.; Meijers, Erica

    2007-01-01

    De huidige land- en tuinbouw is in verregaande mate geïndustrialiseerd: de invoering van machines en technologie hebben het boerenbedrijf diepgaand veranderd. Een gesprek met de techniekfilosoof Peter-Paul Verbeek (1970) over de relatie tussen mens en machine, de vrijheid van het individu en de

  11. Biomarkers voor de voorspelling van nierfunctieafname bij patiënten met diabetes mellitus.

    NARCIS (Netherlands)

    Wilffert, Berend

    2017-01-01

    Chronische nierziekte bij patiënten met diabetes mellitus is een groot probleem voor de volksgezondheid en de pathologie is zeer complex. Bij het voorspellen van de renale prognose worden de glomerulaire filtratiesnelheid en albuminurie gebruikt, maar er is behoefte aan betere voorspellers. In dit

  12. Vergelijking van drie Wistarrattestammen met betrekking tot de werkingsduur en het farmacokinetisch profiel van desmethyldiazepam

    NARCIS (Netherlands)

    van der Laan JW; de Groot G

    1988-01-01

    In het kader van het onderzoek naar de afhankelijkheid van benzodiazepinen is een vergelijking gemaakt tussen drie rattestammen, namelijk Cpb: WU, Riv:TOX en Crl:(WI)BR met betrekking tot de werkingsduur van desmethyldiazepam (DMD) na orale toediening in een model waarbij de onderdrukking van de

  13. De eerste 'European Day Without A Road Death' : maak kennis met EDWARD.

    NARCIS (Netherlands)

    Preusting, G.

    2016-01-01

    Op 21 september 2016 vond de eerste European Day Without A Road Death plaats. Het project - naar goed Europees gebruik met een acronym 'EDWARD' gedoopt - is een initiatief van TISPOL, het European Traffic Police Network. TISPOL, waarbij dertig landen zijn aangesloten, vraagt nu aan elke Europese

  14. Kinderen met een motorische coördinatiestoornis (DCD) in de kinderrevalidatie: Motorische problematiek en comorbiditeit

    NARCIS (Netherlands)

    Flapper, Boudien C.T.; Scholten-Jaegers, S.; Schoemaker, M.M.

    2003-01-01

    The purpose of this study was to describe the developmental problems of children in school age, referred to the child rehabilitation centre because of clumsiness. The results show that 63% met the criteria for the classification of developmental coordination disorder and these children with DC:D

  15. Bestrijding spint op rozenstek : met behulp van warm water en mens- en milieuvriendelijke additieven

    NARCIS (Netherlands)

    Garcia Victoria, N.; Beerling, E.A.M.

    2004-01-01

    Een korte dompelbehandeling in water van 20°C geeft een goede spintbestrijding van de stek, vergelijkbaar met die van de chemische middelen. Dit resultaat wordt niet of onvoldoende verbeterd door het toevoegen van zepen, spiritus en andere GNO’s aan het dompelwater, of door langere dompeltijden. Er

  16. Biologische bestrijding van spint en trips in anjer : selectieproef met 6 soorten roofmijten

    NARCIS (Netherlands)

    Scholte-Wassink, G.M.; Berg, van den D.

    2005-01-01

    In de anjerteelt zijn de anjerspintmijt (Tetranychus cinnabarinus) en de californische trips (Frankliniella occi-dentalis) de twee belangrijkste plagen. Vanwege de gewasopbouw van anjer en de levenswijze van spint en trips zijn deze plagen met een bespuiting moeilijk te bestrijden. De ervaring tot

  17. Metáfora multimodal: representación mediática del despojo

    Directory of Open Access Journals (Sweden)

    Neyla Graciela Pardo Abril

    2012-01-01

    Full Text Available La interacción comunicativa ocurre con frecuencia cuando se acude a sistemas de signos múltiples que se soportan, de manera significativa, en tecnologías y pretende interlocutores impredecibles. Desde esta perspectiva, la lengua es apenas un sistema sígnico y sus modos de significación se han amplificado. En este trabajo, de acuerdo con las teorías cognitivas, se entiende que la metáfora, como recurso semiótico, supera el uso de la lengua, se estructura en diversos sistemas de signos y formula saberes, pensamiento y acción social. Se estudia la metáfora producida y comprendida en diversos modos semióticos y se aplica a un proceso de investigación en curso, en el que se analizan cuatro caricaturas del periódico digital eltiempo.com y tres de elespectador.com, que forman parte de un corpus más amplio compilado en medios virtuales. Se proponen algunas reflexiones sobre la metáfora multimodal, su relación con la metáfora verbal y los procesos de amplificación de los significados que se derivan de una posible interpretación. Finalmente, se presentan algunas conclusiones sobre la representación mediática del despojo.

  18. A meteorological distribution system for high-resolution terrestrial modeling (MicroMet)

    Science.gov (United States)

    Glen E. Liston; Kelly Elder

    2006-01-01

    An intermediate-complexity, quasi-physically based, meteorological model (MicroMet) has been developed to produce high-resolution (e.g., 30-m to 1-km horizontal grid increment) atmospheric forcings required to run spatially distributed terrestrial models over a wide variety of landscapes. The following eight variables, required to run most terrestrial models, are...

  19. Interactief implementeren: een praktijkvoorbeeld van preventieprogramma's voor ouderen met artrose van de knie en heup

    NARCIS (Netherlands)

    Jonge, O.R.W. de; Hopman-Rock, M.; Klazinga, N.S.

    2003-01-01

    In dit artikel wordt de interactieve (proef)implementatie beschreven van twee bewezen effectieve leefstijlprogramma's voor ouderen met artrose van de knie en de heup. De theoretische uitgangspunten van waaruit de implementatie is opgezet, worden kort besproken. Ook komt aan de orde welke factoren er

  20. LINH-cijfers: de patiënt met artrose in de huisartsenpraktijk.

    NARCIS (Netherlands)

    Jabaaij, L.

    2003-01-01

    De behandeling van artrose door de huisarts bestaat vooral uit 'pappen en nathouden'. Pas in een laat stadium van de ziekte kan de orthopeed chirurgisch ingrijpen: de huisarts verwijst per jaar één op de zeven patiënten met artroseklachten naar de tweede lijn. De overigen zijn aangewezen op

  1. Met and unmet palliative care needs of people living with HIV/AIDS ...

    African Journals Online (AJOL)

    The rising number of people living with HIV/AIDS (PLWHA) worldwide has made health care professionals and policy makers search for accessible health care that will meet the needs of people who are suffering from the disease and enhance their quality of life (QoL).This study investigated met and unmet palliative care ...

  2. Dierexperimentele behandeling van paraquat- toxiciteit met desferrioxamine, gewassen erythrocyten of erythrocyten-cytosol

    NARCIS (Netherlands)

    Boonen; H.C.M.*; Hillen; F.C.; Jong; Y.de; Timmerman; A.; Dormans; J.A.M.A.; Asbeck; B.S.van*

    1986-01-01

    Een paraquat intoxicatie bij de rat kon met de ijzerchelator desferrioxiamine via een chronisch infuus worden tegengegaan: het overlevingspercentage bleek tot 66,6% te stijgen na een desferrioxamine infuus van 100 mg/kg/24uur. Gewassen erythrocyten en cytosol hadden na intratracheale toediening

  3. ECO-driving met behulp van serious gaming en social media (fase 1)

    NARCIS (Netherlands)

    Kuiper, H.; Boonekamp, R.C.; Bijlsma, T.; Jansen, S.T.H.; Obdeijn, C.; Stuiver, A.; Spronkmans, S.; Bijnen, D.; Versteegh, T.

    2013-01-01

    Dit rapport beschrijft fase 1 van een EL&I cofinancieringstraject waarin onderzoek wordt gedaan naar gedragsbeïnvloeding bij automobilisten om CO2-reductie te bereiken met behulp van Serious gaming en Social Media. Het onderzoek sluit goed aan bij het overheidswerkprogramma “Schoon en Zuinig”

  4. Evaluatie van de voedingsstatus van Nederlandse patiënten met chronische inflammatoire darmziekten : een pilotonderzoek

    NARCIS (Netherlands)

    Berg, van den M.C.; Plas, M.; Mares, W.; Witteman, B.J.M.; Klein Gunnewiek, J.M.T.; Vries, de J.H.M.

    2014-01-01

    Introductie Het doel van deze pilotstudie was het verkrijgen van inzicht in de voedingsstatus van Nederlandse patiënten met chronische inflammatoire darmziekten (IBD). Methoden De voedingsstatus werd onderzocht op basis van MUST-score, handknijpkracht, micronutriëntstatus in het bloed en

  5. Operational assimilation of ASCAT surface soil wetness at the Met Office

    Directory of Open Access Journals (Sweden)

    I. Dharssi

    2011-08-01

    Full Text Available Currently, no extensive, near real time, global soil moisture observation network exists. Therefore, the Met Office global soil moisture analysis scheme has instead used observations of screen temperature and humidity. A number of new space-borne remote sensing systems, operating at microwave frequencies, have been developed that provide a more direct retrieval of surface soil moisture. These systems are attractive since they provide global data coverage and the horizontal resolution is similar to weather forecasting models. Several studies show that measurements of normalised backscatter (surface soil wetness from the Advanced Scatterometer (ASCAT on the meteorological operational (MetOp satellite contain good quality information about surface soil moisture. This study describes methods to convert ASCAT surface soil wetness measurements to volumetric surface soil moisture together with bias correction and quality control. A computationally efficient nudging scheme is used to assimilate the ASCAT volumetric surface soil moisture data into the Met Office global soil moisture analysis. This ASCAT nudging scheme works alongside a soil moisture nudging scheme that uses observations of screen temperature and humidity. Trials, using the Met Office global Unified Model, of the ASCAT nudging scheme show a positive impact on forecasts of screen temperature and humidity for the tropics, North America and Australia. A comparison with in-situ soil moisture measurements from the US also indicates that assimilation of ASCAT surface soil wetness improves the soil moisture analysis. Assimilation of ASCAT surface soil wetness measurements became operational during July 2010.

  6. 77 FR 25080 - Safety Zones; TriMet Bridge Project, Willamette River, Portland, OR

    Science.gov (United States)

    2012-04-27

    ... bridge construction cranes. (b) Regulation. In accordance with the general regulations in 33 CFR Part 165... SECURITY Coast Guard 33 CFR Part 165 RIN 1625-AA00 Safety Zones; TriMet Bridge Project, Willamette River... establishing safety zones encompassing the work trestles and construction cranes involved in the construction...

  7. Parent of origin effect and differential allelic expression of BDNF Val66Met in suicidal behaviour.

    Science.gov (United States)

    de Luca, Vincenzo; Souza, Renan P; Zai, Clement C; Panariello, Fabio; Javaid, Naima; Strauss, John; Kennedy, James L; Tallerico, Teresa; Wong, Albert H

    2011-02-01

    Brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of mood disorders and may also be involved in suicidal behaviour since BDNF levels are decreased in brain and plasma of suicide victims. Because the differential allelic expression of Val66Met BDNF gene on suicidal behaviour has not been investigated, we analyzed the parent-of-origin effect (POE) in suicide attempters and the differential expression of BDNF Val66Met alleles in suicide victims. We performed a family-based association study and ETDT analyses of the Val66Met polymorphism in nuclear families with at least one subject affected by major psychosis with suicidal behaviour, and compared allele-specific mRNA levels in post-mortem brain samples from suicide and non-suicide victims. The subjects included in this study have diagnosis of schizophrenia, bipolar disorder type I and type II. Allele 3 in the GT repeat polymorphism was transmitted significantly more often to patients who attempted suicide (maternal transmissions: 46/22, P = 0.003; paternal transmissions: 55/30, P = 0.006). There was no significant difference between maternal and paternal transmission ratios. Furthermore, there was no significant difference in the ratio of Val/Met-specific mRNA expression between suicide victims and controls. These data do not support a role for allelic imbalance or POE of BDNF for suicidal behaviour in major psychoses.

  8. Met expectations and supplies-values fit of Dutch young adults as determinants of work outcomes

    NARCIS (Netherlands)

    Taris, R.; Feij, J.A.; van Vianen, A.E.M.

    2005-01-01

    Many studies have shown that work outcomes, such as job satisfaction and turnover intentions, are affected by met expectations and the fit between the work values of an employee and the supplies offered by the organization. However, research that investigates their simultaneous effects on work

  9. Met expectations and supplies - values fit as determinants of work outcomes

    NARCIS (Netherlands)

    Taris, R.; Feij, J.A.; van Vianen, A.E.M.

    2005-01-01

    Many studies have shown that work outcomes, such as job satisfaction and turnover intentions, are affected by met expectations and the fit between the work values of an employee and the supplies offered by the organization. However, research that investigates their simultaneous effects on work

  10. Alz...muziek maken zo gewoon is als ademhalen : interview met Misha Mengelberg en Frans Hoogeveen

    NARCIS (Netherlands)

    Nederland Stichting Alzheimer

    2014-01-01

    Pianist Misha Mengelberg (79) wordt beschouwd als de meest invloedrijke jazzmusicus binnen de Nederlandse jazzmuziek. Maar Mengelberg heeft dementie en kampt de laatste jaren met toenemende geheugen- en taalproblemen. Al zal de rol van muziek in zijn leven nooit veranderen, ook niet nu hij de ziekte

  11. Máquinas e mentes: interpretando a metáfora

    Directory of Open Access Journals (Sweden)

    Ivelã Pereira

    2008-04-01

    O artigo tem por objetivo testar a hipótese de Moura (2007 de que as metáforas possuem uma estrutura léxico-conceptual e de que há sistematicidade na interpretação metafórica, ou seja, há uma regularidade interpretativa conforme a classe verbal (ou nominal dos veículos das metáforas. Para chegar ao objetivo, selecionamos alguns verbos de atitude proposicional e procuramos na web exemplos do uso desses verbos em relação a máquinas. Os verbos escolhidos como veículos das metáforas foram: pensar, raciocinar, surtar, pirar, enlouquecer, inventar, criar, decidir, saber, acreditar, entender, aceitar, querer, achar; e os tópicos selecionados: computador, celular, aparelho, televisão, microondas, avião, carro, piloto automático, termostato, aparelho e máquinas. A coleta resultou em 51 exemplos que constituem metáforas ontológicas de personificação e, por causa da relação estreita desse tipo de metáfora com a discussão sobre Inteligência Artificial, foi feita uma breve seção sobre este assunto. A partir dos dados coletados, a análise foi efetuada objetivando parafrasear e buscar relações paradigmáticas e sintagmáticas relativas às metáforas selecionadas. Após a discussão dos resultados, a hipótese pôde ser confirmada e, através da análise, é possível mostrar que há regularidade na interpretação de metáforas cujos tópicos são máquinas e os veículos são verbos de atitude proposicional. Foi averiguado que, quando verbos de atitude proposicional são aplicados metaforicamente a máquinas, visa-se basicamente o funcionamento dos equipamentos e a manipulação de símbolos pelas máquinas, mas não atitudes conscientes ou estados da “mente” das máquinas, o que mostra a limitação da analogia metafórica entre máquinas e mentes.

  12. Oxidative stress inactivates cobalamin-independent methionine synthase (MetE in Escherichia coli.

    Directory of Open Access Journals (Sweden)

    Elise R Hondorp

    2004-11-01

    Full Text Available In nature, Escherichia coli are exposed to harsh and non-ideal growth environments-nutrients may be limiting, and cells are often challenged by oxidative stress. For E. coli cells confronting these realities, there appears to be a link between oxidative stress, methionine availability, and the enzyme that catalyzes the final step of methionine biosynthesis, cobalamin-independent methionine synthase (MetE. We found that E. coli cells subjected to transient oxidative stress during growth in minimal medium develop a methionine auxotrophy, which can be traced to an effect on MetE. Further experiments demonstrated that the purified enzyme is inactivated by oxidized glutathione (GSSG at a rate that correlates with protein oxidation. The unique site of oxidation was identified by selectively cleaving N-terminally to each reduced cysteine and analyzing the results by liquid chromatography mass spectrometry. Stoichiometric glutathionylation of MetE by GSSG occurs at cysteine 645, which is strategically located at the entrance to the active site. Direct evidence of MetE oxidation in vivo was obtained from thiol-trapping experiments in two different E. coli strains that contain highly oxidizing cytoplasmic environments. Moreover, MetE is completely oxidized in wild-type E. coli treated with the thiol-oxidizing agent diamide; reduced enzyme reappears just prior to the cells resuming normal growth. We argue that for E. coli experiencing oxidizing conditions in minimal medium, MetE is readily inactivated, resulting in cellular methionine limitation. Glutathionylation of the protein provides a strategy to modulate in vivo activity of the enzyme while protecting the active site from further damage, in an easily reversible manner. While glutathionylation of proteins is a fairly common mode of redox regulation in eukaryotes, very few proteins in E. coli are known to be modified in this manner. Our results are complementary to the independent findings of Leichert

  13. Met is the most frequently amplified gene in endometriosis-associated ovarian clear cell adenocarcinoma and correlates with worsened prognosis.

    Directory of Open Access Journals (Sweden)

    Yoriko Yamashita

    Full Text Available Clear cell adenocarcinoma of the ovary (OCC is a chemo-resistant tumor with a relatively poor prognosis and is frequently associated with endometriosis. Although it is assumed that oxidative stress plays some role in the malignant transformation of this tumor, the characteristic molecular events leading to carcinogenesis remain unknown. In this study, an array-based comparative genomic hybridization (CGH analysis revealed Met gene amplification in 4/13 OCC primary tumors and 2/8 OCC cell lines. Amplification of the AKT2 gene, which is a downstream component of the Met/PI3K signaling pathway, was also observed in 5/21 samples by array-based CGH analysis. In one patient, both the Met and AKT2 genes were amplified. These findings were confirmed using fluorescence in situ hybridization, real-time quantitative PCR, immunoblotting, and immunohistochemistry. In total, 73 OCC cases were evaluated using real-time quantitative PCR; 37.0% demonstrated Met gene amplification (>4 copies, and 8.2% had AKT2 amplification. Furthermore, stage 1 and 2 patients with Met gene amplification had significantly worse survival than patients without Met gene amplification (p<0.05. Met knockdown by shRNA resulted in reduced viability of OCC cells with Met amplification due to increased apoptosis and cellular senescence, suggesting that the Met signaling pathway plays an important role in OCC carcinogenesis. Thus, we believe that targeted inhibition of the Met pathway may be a promising treatment for OCC.

  14. Correlation among genetic variations of c-MET in Chinese patients with non-small cell lung cancer.

    Science.gov (United States)

    Duan, Jianchun; Yang, Xiaodan; Zhao, Jun; Zhuo, Minglei; Wang, Zhijie; An, Tongtong; Bai, Hua; Wang, Jie

    2018-01-05

    The purpose of our research was to determine the correlation of amplification, protein expression and somatic mutation of c-MET in IIIb-IV stage NSCLC (Non-small cell lung cancer). We also explored correlation of c-MET variation with clinical outcome. c-MET expression was observed in 28.6% (56/196) cases, and among those 13.8% (27/196) were shown to be FISH positive. Only 2.67% patients in this study carried the c-MET mutation. Cases with c-MET FISH positive were all IHC positive ,but in IHC positive cases, only half were FISH positive. Among patients with IHC 2+ staining, 35.5% was FISH positive, while cases with IHC 3+ staining,64% was FISH positive. Both protein expression and copy number of c-MET did not significantly correlate with clinical prognosis in these patients treated with EGFR-TKIs. IHC could be used as a preliminary screening method for c-MET copy number amplification and should be confirmed by FISH only in IHC positive case which facilitate selection of ALK or MET inhibitor therapy. c-MET gene copy number, protein expression and somatic mutation for exon 14 were detected by fluorescent- In-Situ -Hybridization (FISH), Immunohistochemistry (IHC), and Denaturing-High-Performance-Liquid-Chromatography (DHPLC), respectively, in 196 NSCLC patients. The relationship between c-MET abnormalities and clinical outcome of targeted therapy was analyzed by McNemar's test.

  15. On the genetics of loss aversion: An interaction effect of BDNF Val66Met and DRD2/ANKK1 Taq1a.

    Science.gov (United States)

    Voigt, Gesine; Montag, Christian; Markett, Sebastian; Reuter, Martin

    2015-12-01

    Loss aversion is the tendency to overweight losses compared with gains in decision situations. Several studies have investigated the neurobiological background of this phenomenon and it was found that activation in the mesolimbic-mesocortical dopamine system during a gambling decision correlates with loss aversion. In a behavioral experiment with N = 143 subjects, the present study investigates the influence of 2 functional single-nucleotide polymorphisms on the BDNF gene (BDNF Val66Met polymorphism) and ANKK1 gene (DRD2 Taq1a/ANKK1 polymorphism), that are known to affect the dopamine system, on loss aversion. Additionally, associations of alexithymia, a personality construct describing the disability to consciously experience emotions in the self, with loss aversion and with the mentioned polymorphisms were assessed using the TAS-20 questionnaire, to replicate associations that have been reported before. Results revealed a significant interaction effect of the 2 polymorphisms on loss aversion. Carriers of the genetic constellation 66Met+/A1+ had the lowest loss aversion scores, compared with all other allelic groups. According to the literature this allelic configuration is characterized by a relatively low D2/3 receptor binding in the striatum and an impaired activity-dependent secretion of BDNF. This is the first study showing that loss aversion is related to naturally occurring differences in dopamine function. (c) 2015 APA, all rights reserved).

  16. A Meteorological Distribution System for High Resolution Terrestrial Modeling (MicroMet)

    Science.gov (United States)

    Liston, G. E.; Elder, K.

    2004-12-01

    Spatially distributed terrestrial models generally require atmospheric forcing data on horizontal grids that are of higher resolution than available meteorological data. Furthermore, the meteorological data collected may not necessarily represent the area of interest's meteorological variability. To address these deficiencies, computationally efficient and physically realistic methods must be developed to take available meteorological data sets (e.g., meteorological tower observations) and generate high-resolution atmospheric-forcing distributions. This poster describes MicroMet, a quasi-physically-based, but simple meteorological distribution model designed to produce high-resolution (e.g., 5-m to 1-km horizontal grid increments) meteorological data distributions required to run spatially distributed terrestrial models over a wide variety of landscapes. The model produces distributions of the seven fundamental atmospheric forcing variables required to run most terrestrial models: air temperature, relative humidity, wind speed, wind direction, incoming solar radiation, incoming longwave radiation, and precipitation. MicroMet includes a preprocessor that analyzes meteorological station data and identifies and repairs potential data deficiencies. The model uses known relationships between meteorological variables and the surrounding area (primarily topography) to distribute those variables over any given landscape. MicroMet performs two kinds of adjustments to available meteorological data: 1) when there are data at more than one location, at a given time, the data are spatially interpolated over the domain using a Barnes objective analysis scheme, and 2) physical sub-models are applied to each MicroMet variable to improve its realism at a given point in space and time with respect to the terrain. The three, 25-km by 25-km, Cold Land Processes Experiment (CLPX) mesoscale study areas (MSAs: Fraser, North Park, and Rabbit Ears) will be used as example MicroMet

  17. Human β-defensin-2 production from S. cerevisiae using the repressible MET17 promoter.

    Science.gov (United States)

    Møller, Thea S B; Hay, Joanna; Saxton, Malcolm J; Bunting, Karen; Petersen, Evamaria I; Kjærulff, Søren; Finnis, Christopher J A

    2017-01-18

    Baker's yeast Saccharomyces cerevisiae is a proven host for the commercial production of recombinant biopharmaceutical proteins. For the manufacture of heterologous proteins with activities deleterious to the host it can be desirable to minimise production during the growth phase and induce production late in the exponential phase. Protein expression by regulated promoter systems offers the possibility of improving productivity in this way by separating the recombinant protein production phase from the yeast growth phase. Commonly used inducible promoters do not always offer convenient solutions for industrial scale biopharmaceutical production with engineered yeast systems. Here we show improved secretion of the antimicrobial protein, human β-defensin-2, (hBD2), using the S. cerevisiae MET17 promoter by repressing expression during the growth phase. In shake flask culture, a higher final concentration of human β-defensin-2 was obtained using the repressible MET17 promoter system than when using the strong constitutive promoter from proteinase B (PRB1) in a yeast strain developed for high-level commercial production of recombinant proteins. Furthermore, this was achieved in under half the time using the MET17 promoter compared to the PRB1 promoter. Cell density, plasmid copy-number, transcript level and protein concentration in the culture supernatant were used to study the effects of different initial methionine concentrations in the culture media for the production of human β-defensin-2 secreted from S. cerevisiae. The repressible S. cerevisiae MET17 promoter was more efficient than a strong constitutive promoter for the production of human β-defensin-2 from S. cerevisiae in small-scale culture and offers advantages for the commercial production of this and other heterologous proteins which are deleterious to the host organism. Furthermore, the MET17 promoter activity can be modulated by methionine alone, which has a safety profile applicable to

  18. Standardized MET Value Underestimates the Energy Cost of Treadmill Running in Men.

    Science.gov (United States)

    Ázara, Helouane M; Farinatti, Paulo T V; Midgley, Adrian W; Vasconcellos, Fabrício; Vigário, Patrícia; Cunha, Felipe A

    2017-11-01

    The main purpose of the present study was to compare the reference metabolic equivalent (MET) value and observed resting oxygen uptake (VO 2 ) for defining cardiorespiratory fitness (VO 2max ) and characterizing the energy cost of treadmill running. A heterogeneous cohort of 114 healthy men volunteered to participate. In Part 1 of the study, 114 men [mean±SD, age: 24±5 years; height: 177.1±7.9 cm; body mass: 75.0±10.0 kg] visited the laboratory twice for assessment of resting and maximal VO 2 values to compare the reference MET value vs. observed resting VO 2 and to investigate the association between resting VO 2 and VO 2max . In Part 2, 14 of the 114 men visited the laboratory once more to perform a 30-min bout of running at 8.0 km∙h -1 /8.3 METs. The mean observed resting VO 2 of 3.26 mL·kg -1 ·min -1 was lower than the reference MET value of 3.5 mL·kg -1 ·min -1 (Pvalues relative to total body mass and fat-free mass were positively correlated (R=0.71 and 0.60, respectively; Pvalue only for those with low VO 2max (P=0.005 to Pvalue considerably overestimated observed resting VO 2 in men with low VO 2max , resulting in underestimations of the maximal MET, exercise intensity prescription, and the energy cost of running. © Georg Thieme Verlag KG Stuttgart · New York.

  19. Opioid mediated activity and expression of mu and delta opioid receptors in isolated human term non-labouring myometrium.

    LENUS (Irish Health Repository)

    Fanning, Rebecca A

    2013-01-05

    The existence of opioid receptors in mammalian myometrial tissue is now widely accepted. Previously enkephalin degrading enzymes have been shown to be elevated in pregnant rat uterus and a met-enkephalin analogue has been shown to alter spontaneous contractility of rat myometrium. Here we have undertaken studies to determine the effects of met-enkephalin on in vitro human myometrial contractility and investigate the expression of opioid receptors in pregnant myometrium. Myometrial biopsies were taken from women undergoing elective caesarean delivery at term. Organ bath experiments were used to investigate the effect of the met-enkephalin analogue [d-Ala 2, d-met 5] enkephalin (DAMEA) on spontaneous contractility. A confocal immunofluorescent technique and real time PCR were used to determine the expression of protein and mRNA, respectively for two opioid receptor subtypes, mu and delta. DAMEA had a concentration dependent inhibitory effect on contractile activity (1 × 10(-7)M-1 × 10(-4)M; 54% reduction in contractile activity, P<0.001 at 1 × 10(-4)M concentration). Mu and delta opioid receptor protein sub-types and their respective mRNA were identified in all tissues sampled. This is the first report of opioid receptor expression and of an opioid mediated uterorelaxant action in term human non-labouring myometrium in vitro.

  20. AMPA receptor ligands

    DEFF Research Database (Denmark)

    Strømgaard, Kristian; Mellor, Ian

    2004-01-01

    Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR), subtype of the ionotropic glutamate receptors (IGRs), mediate fast synaptic transmission in the central nervous system (CNS), and are involved in many neurological disorders, as well as being a key player...