Werkbelasting Bij Verkeers-En Gevechtsleiding. Deel 2 (Workload of Air Traffic and Air Combat Personnel. Part 2)

DTIC Science & Technology

1989-07-31

de onderzaeker nadig had am van bet instituut naar de werkplek te reizen . Genaemde diensten waren er niet zeker van dat bet nag steeds druk zau zijn...tegen de tijd dat anderzoeker ter plaatse zau zijn. Daarap werd beslaten bij deze diensten twee midweken (dinsdag t/m donderdag) cantinu te observeren...eon onderzoek to doen. Do tijd tussen oproep en begin van het onderzoek was 30 tot 40 minuten. Hot onderzoek word afgebroken als do werkpiek vaorbij was

75 FR 1007 - MetLife, Inc. and MetLife Capital Trust V; Notice of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-07

... SECURITIES AND EXCHANGE COMMISSION [Release No. IC-29101; 812-13549] MetLife, Inc. and MetLife... ``Act'') for an exemption from all provisions of the Act. Summary of Application: MetLife Capital Trust V (the ``Trust'') and MetLife, Inc. (``MetLife'') request an order that would permit the Trust to...

Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer.

PubMed

Oddo, Daniele; Siravegna, Giulia; Gloghini, Annunziata; Vernieri, Claudio; Mussolin, Benedetta; Morano, Federica; Crisafulli, Giovanni; Berenato, Rosa; Corti, Giorgio; Volpi, Chiara Costanza; Buscarino, Michela; Niger, Monica; Dunne, Philip D; Rospo, Giuseppe; Valtorta, Emanuele; Bartolini, Alice; Fucà, Giovanni; Lamba, Simona; Martinetti, Antonia; Di Bartolomeo, Maria; de Braud, Filippo; Bardelli, Alberto; Pietrantonio, Filippo; Di Nicolantonio, Federica

2017-07-25

Combined MET and BRAF inhibition showed clinical benefit in a patient with rectal cancer carrying BRAF V600E and MET amplification. However after 4 months, acquired resistance emerged and the patient deceased shortly after disease progression. The mechanism of resistance to this drug combination is unknown. We analysed plasma circulating tumour DNA obtained at progression by exome sequencing and digital PCR. MET gene and mRNA in situ hybridisation analyses in two bioptic specimens obtained at progression were used to confirm the plasma data. We identified in plasma MET gene hyper-amplification as a potential mechanism underlying therapy resistance. Increased MET gene copy and transcript levels were detected in liver and lymph node metastatic biopsies. Finally, transduction of MET in BRAF mutant colorectal cancer cells conferred refractoriness to BRAF and MET inhibition. We identified in a rectal cancer patient MET gene hyper-amplification as mechanism of resistance to dual BRAF and MET inhibition.

MET ONE 831

EPA Science Inventory

The Met One 831 sensor measures particulate matter (PM) by counting and sizing individual particles using scattered laser light. The unit then converts the count data to mass measurements in micrograms per cubic meter (µg/m3). The Met One 831 counts particles in four different PM...

Lipid ratio as a suitable tool to identify individuals with MetS risk: A case- control study.

PubMed

Abbasian, Maryam; Delvarianzadeh, Mehri; Ebrahimi, Hossein; Khosravi, Farideh

2017-11-01

This study aimed to compare the serum lipids ratio in staff with and without metabolic syndrome (MetS) who were working in Shahroud University of Medical Sciences. This case-control study was conducted in 2015 on 499 personnel aged 30-60 years old. ATP III criteria were used to diagnose patients with MetS. The data were analyzed by using logistic regression and ROC curve. Mean lipid ratio was higher in individuals having the MetS in both sexes compared with those without. In addition, the mean levels of lipid ratios significantly increased with increasing number of MetS components in both sexes. Also it could be concluded that TG/HDL-C ratio is the best marker for the diagnosis of MetS in men and women. Moreover, the cut-off point for the TG/HDL-C was 2.86 in women and 4.03 in men. It was found that for any unit of increases in the TG/HDL-C, the risk of developing the MetS will increase by 2.12 times. TG/HDL-C ratio is found to be the best clinical marker for the diagnosis of MetS compare with other lipid ratios, therefore it is recommended to be used as a feasible tool to identify individuals with MetS risk. Copyright © 2016 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Study of MET protein levels and MET gene copy number in 72 sinonasal intestinal-type adenocarcinomas.

PubMed

Projetti, Fabrice; Mesturoux, Laura; Coulibaly, Béma; Durand, Karine; Chaunavel, Alain; Léobon, Sophie; Gadeaud, Emilie; Caire, François; Bessède, Jean-Pierre; Labrousse, François

2015-11-01

Sinonasal intestinal-type adenocarcinomas (ITACs) have a poor prognosis, and are defined on the basis of their morphological similarities to colorectal adenocarcinomas. MET signaling pathway is involved in oncogenesis in various cancers. Nothing is currently known about the role of MET in ITACs. In a series of 72 ITACs, we investigated MET protein levels by immunohistochemistry (IHC) and gene copy number by in situ hybridization. These findings were analyzed as a function of clinical data, histological typing, and patient outcome. MET protein was overproduced in 64% of cases and chromosome 7 polysomy was observed in 52% of cases. No tumor displayed MET amplification. The presence of mucinous or solid histological components, T3/T4 tumors, and incomplete resection were associated with a poor outcome. MET is overproduced in about two third of ITACs, suggesting a role for the MET signaling pathway in the oncogenesis of these tumors. © 2014 Wiley Periodicals, Inc.

Simm530, a novel and highly selective c-Met inhibitor, blocks c-Met-stimulated signaling and neoplastic activities

PubMed Central

Peng, Xia; Shen, Yanyan; Chen, Fang; Ji, Yinchun; Liu, Weiren; Shi, Yinghong; Duan, Wenhu; Ding, Jian; Ai, Jing; Geng, Meiyu

2016-01-01

The aberrant c-Met activation has been implicated in a variety of human cancers for its critical role in tumor growth, metastasis and tumor angiogenesis. Thus, c-Met axis presents as an attractive therapeutic target. Notably, most of these c-Met inhibitors currently being evaluated in clinical trials lack selectivity and target multiple kinases, often accounting for the undesirable toxicities. Here we described Simm530 as a potent and selective c-Met inhibitor. Simm530 demonstrated >2,000 fold selectivity for c-Met compared with other 282 kinases, making it one of the most selective c-Met inhibitors described to date. This inhibitor significantly blocked c-Met signaling pathways regardless of mechanistic complexity implicated in c-Met activation. As a result, Simm530 led to substantial inhibition of c-Met-promoted cell proliferation, migration, invasion, ECM degradation, cell scattering and invasive growth. In addition, Simm530 inhibited primary human umbilical vascular endothelial cell (HUVEC) proliferation, decreased intratumoral CD31 expression and plasma pro-angiogenic factor interleukin-8 secretion, suggesting its significant anti-angiogenic properties. Simm530 resulted in dose-dependent inhibition of c-Met phosphorylation and tumor growth in c-Met-driven lung and gastric cancer xenografts. And, the inhibitor is well tolerated even at doses that achieve complete tumor regression. Together, Simm530 is a potent and highly selective c-Met kinase inhibitor that may have promising therapeutic potential in c-Met-driven cancer treatment. PMID:27191264

Tactisch Optreden van kleine eenheden (Small Unit Tactics)

DTIC Science & Technology

2007-08-01

Marechaussee KTS Knock, Talk and Search MB Mercedes Benz MND(SE) Multinational Division (South East) NAVO Noord Atlantische Verdrag Organisatie NGO Non...patrouilles had men de beschikking over Mercedes Benz (MB) soft top wielvoertuigen, met een mitrailleur MAG 7.62 mm op affuit. Als extra bescherming was het... Mercedes Benz 5 IkN/ 7.5 kN soft top) voorzien van een voertuigaffuit met een mitrailleur MAG 7,62mm, uitgevoerd (zie Figuur 8). Bij verhoogde dreiging

MetNet - Martian Network Mission

NASA Astrophysics Data System (ADS)

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.

Mars MetNet Mission Status

NASA Astrophysics Data System (ADS)

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.

Mars MetNet Mission Status

NASA Astrophysics Data System (ADS)

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

Nonclinical evaluation of the serum pharmacodynamic biomarkers HGF and shed MET following dosing with the anti-MET monovalent monoclonal antibody onartuzumab.

PubMed

Mai, Elaine; Zheng, Zhong; Chen, Youjun; Peng, Jing; Severin, Christophe; Filvaroff, Ellen; Romero, Mally; Mallet, William; Kaur, Surinder; Gelzleichter, Thomas; Nijem, Ihsan; Merchant, Mark; Young, Judy C

2014-02-01

Onartuzumab, a humanized, monovalent monoclonal anti-MET antibody, antagonizes MET signaling by inhibiting binding of its ligand, hepatocyte growth factor (HGF). We investigated the effects of onartuzumab on cell-associated and circulating (shed) MET (sMET) and circulating HGF in vitro and nonclinically to determine their utility as pharmacodynamic biomarkers for onartuzumab. Effects of onartuzumab on cell-associated MET were assessed by flow cytometry and immunofluorescence. sMET and HGF were measured in cell supernatants and in serum or plasma from multiple species (mouse, cynomolgus monkey, and human) using plate-based immunoassays. Unlike bivalent anti-MET antibodies, onartuzumab stably associates with MET on the surface of cells without inducing MET internalization or shedding. Onartuzumab delayed the clearance of human xenograft tumor-produced sMET from the circulation of mice, and endogenous sMET in cynomolgus monkeys. In mice harboring MET-expressing xenograft tumors, in the absence of onartuzumab, levels of human sMET correlated with tumor size, and may be predictive of MET-expressing tumor burden. Because binding of sMET to onartuzumab in circulation resulted in increasing sMET serum concentrations due to reduced clearance, this likely renders sMET unsuitable as a pharmacodynamic biomarker for onartuzumab. There was no observed effect of onartuzumab on circulating HGF levels in xenograft tumor-bearing mice or endogenous HGF in cynomolgus monkeys. Although sMET and HGF may serve as predictive biomarkers for MET therapeutics, these data do not support their use as pharmacodynamic biomarkers for onartuzumab.

Optimalisatie Draagsysteem (Optimization of the Load Carriage System)

DTIC Science & Technology

2008-06-01

nadelige gevolgen beeft voor de beweeglijkheid. In bet prototype draagsysteem uit figuur 9 ’hangt’ bet scberfwerende vest met kogelwerende platen niet...Soesterberg TNO-rapport wwton T +31 346 35 62 11 TNO-DV 2008 A230 F +31 346 35 39 77Info-DenV@tno.nI Optimalisatie draagsysteem D)atun juni 2008 0 Autcur(s...de draagconstructie. Bij bet ILCS- 11 is gevarieerd met de hoeveelheid afsteuning op heupen en Beschrijving van de werkzaamhleden schouders, alsmede

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

PubMed

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

2018-06-01

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

[c-MET Oncogene in Renal Cell Carcinomas].

PubMed

Erlmeier, F; Weichert, W; Autenrieth, M; Ivanyi, P; Hartmann, A; Steffens, S

2016-12-01

c-Met plays a significant role in multiple cellular processes. Being encoded by a proto-oncogene, tyrosine kinase supports aggressive tumour behaviour such as tumour invasiveness and formation of metastases. For some subtypes of renal cell carcinoma studies have shown a association between c-Met expression and clinical outcome or prognosis. Therefore, c-Met represents a prognostic marker in renal cell carcinoma.Furthermore, c-MET will play a decisive role as a possible target for targeted therapies in the era of personalised medicine. Especially for RCC, the dual inhibition of VEGF and c-MET tyrosine kinase in cases of metastatic, treatment-resistant tumours is gaining clinical relevance. The role of c-Met has not been fully elucidated for all subtypes of renal cell carcinomas. The relevance of c-Met for the remaining subtypes of renal tumours has yet to be clarified. © Georg Thieme Verlag KG Stuttgart · New York.

A comparison of metabolic syndrome (MetS) risk factors in Filipino women and Filipino American women: a pilot study.

PubMed

Ancheta, Irma B; Battie, Cynthia A; Tuason, Teresa; Ancheta, Christine V

2012-01-01

Cardiovascular disease (CVD) is a significant cause of morbidity and mortality in women of Filipino ethnicity. The objective of our work was to determine if metabolic syndrome (MetS), a modifiable CVD risk factor, differs in women as a function of country of residency and to determine if, CVD prevention strategies need to differ for these groups of Filipino women. Data were collected in community-based health screenings for this cross-sectional study. PARTICIPANTS were recruited at places of worship in southeast United States (n=60) and Central Visayas, Philippines (n=56). Prevalence of MetS and its component factors as defined by the International Diabetes Federation criteria. The prevalence of MetS in Filipino women (FW) and Filipino American women (FAW) groups was similar (52% vs 55%, P=.08) although the prevalence of elevated waist circumference was greater for FAW (78% vs 59%, P=.03). Conversely, the percentage of FW women with risk-associated high-density lipoprotein (HDL) levels was higher than the FAW group (84% vs 42%, P<.001). Other MetS component factors (blood pressure, glucose and triglycerides) did not significantly differ between groups. Similar high rates of MetS were observed in Filipino women regardless of the country of residency although the FAW tended to have higher rates of central obesity while the FW tended to have higher rates of risk-associated HDL levels. Further research should examine the cause of these differences in order to develop better cardiovascular screening and intervention strategies.

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

PubMed

Dodds, Chris M; Henson, Richard N; Suckling, John; Miskowiak, Kamilla W; Ooi, Cinly; Tait, Roger; Soltesz, Fruzsina; Lawrence, Phil; Bentley, Graham; Maltby, Kay; Skeggs, Andrew; Miller, Sam R; McHugh, Simon; Bullmore, Edward T; Nathan, Pradeep J

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 suggest that the BDNF Val66Met polymorphism does not, as previously claimed, exert an observable effect on neural systems underlying encoding of new information into episodic memory but may exert a subtle effect on the efficiency with which such information can be retrieved.

MET exon 14 skipping mutation in triple-negative pulmonary adenocarcinomas and pleomorphic carcinomas: An analysis of intratumoral MET status heterogeneity and clinicopathological characteristics.

PubMed

Kwon, Dohee; Koh, Jaemoon; Kim, Sehui; Go, Heounjeong; Kim, Young A; Keam, Bhumsuk; Kim, Tae Min; Kim, Dong-Wan; Jeon, Yoon Kyung; Chung, Doo Hyun

2017-04-01

MET mutations leading to exon 14 skipping rarely occur in non-small cell lung cancer (NSCLC). Recently, small molecule inhibitors targeting MET mutations showed clinical benefit. However, the clinicopathological characteristics of NSCLC harboring MET mutations, and the correlation among mutations, protein expression, and gene copy number of MET in NSCLC remain unclear. Therefore, we address these issues. MET exon 14 skipping mutations were evaluated using real-time quantitative reverse-transcription-PCR (qRT-PCR) in 102 triple-negative (i.e., EGFR mutation (-)/ALK translocation (-)/KRAS mutation (-)) pulmonary adenocarcinomas, and 45 pleomorphic carcinomas. MET mutation and gene copy were also examined in microdissected tissues obtained from tumor areas with heterogeneous MET immunohistochemical expression. MET mutations were detected in 8.8% (9/102) of triple-negative adenocarcinomas and 20% (9/45) of pleomorphic carcinomas of the lung. Patients with MET-mutated adenocarcinomas was significantly older than those without MET mutations (P=0.015). The male to female and ever-to never-smoker ratios were 3:6 and 2:7, respectively, among patients with MET-mutated adenocarcinomas. All (9/9) of the MET-mutated adenocarcinomas showed acinar predominant histology with associated lepidic patterns. In contrast, the male to female and ever- to never-smoker ratios were 8:1 and 7:1, respectively, among patients with MET-mutated pleomorphic carcinomas. The carcinoma component of MET-mutated pleomorphic carcinomas was mostly adenocarcinoma of acinar pattern (8/9). MET mutation was detected by qRT-PCR in all samples with heterogeneous MET expression microdissected from five cases with MET-mutated adenocarcinoma, while MET gene amplification was detected in tumor areas expressing high MET protein levels among MET-mutated adenocarcinomas. MET-mutated NSCLC is characterized by older age in patients with adenocarcinoma and by an acinar histology and variable MET expression in patients

Mars MetNet Precursor Mission Status

NASA Astrophysics Data System (ADS)

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.

Genomic status of MET potentiates sensitivity to MET and MEK inhibition in NF1-related malignant peripheral nerve sheath tumors.

PubMed

Peacock, Jacqueline D; Pridgeon, Matthew G; Tovar, Elizabeth A; Essenburg, Curt J; Bowman, Megan J; Madaj, Zachary B; Koeman, Julie; Boguslawski, Elissa A; Grit, Jamie; Dodd, Rebecca D; Khachaturov, Vadim; Cardona, Diana M; Chen, Mark; Kirsch, David G; Maina, Flavio; Dono, Rosanna; Winn, Mary E; Graveel, Carrie R; Steensma, Matthew R

2018-05-02

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are highly resistant sarcomas that occur in up to 13% of individuals with Neurofibromatosis Type 1 (NF1). Genomic analysis of longitudinally collected tumor samples in a case of MPNST disease progression revealed early hemizygous microdeletions in NF1 and TP53, with progressive amplifications of MET, HGF, and EGFR. To examine the role of MET in MPNST progression, we developed mice with enhanced MET expression and Nf1 ablation (Nf1fl/KO;lox-stop-loxMETtg/+;Plp-creERTtg/+; referred to as NF1 MET). NF1-MET mice express a robust MPNST phenotype in the absence of additional mutations. A comparison of NF1-MET MPNSTs with MPNSTs derived from Nf1KO/+;p53R172H;Plp-creERTtg/+ (NF1-P53) and Nf1KO/+;Plp-creERTtg/+ (NF1) mice revealed unique Met, Ras, and PI3K signaling patterns. NF1-MET MPNSTs were uniformly sensitive to the highly selective MET inhibitor, capmatinib, whereas a heterogeneous response to MET inhibition was observed in NF1-P53 and NF1 MPNSTs. Combination therapy of capmatinib and the MEK inhibitor trametinib resulted in reduced response variability, enhanced suppression of tumor growth, and suppressed RAS/ERK and PI3K/AKT signaling. These results highlight the influence of concurrent genomic alterations on RAS effector signaling and therapy response to tyrosine kinase inhibitors. Moreover, these findings expand our current understanding of the role of MET signaling in MPNST progression and identify a potential therapeutic niche for NF1-related MPNSTs. Copyright ©2018, American Association for Cancer Research.

MetNet Precursor - Network Mission to Mars

NASA Astrophysics Data System (ADS)

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

Alkaline transition of pseudoazurin Met16X mutant proteins: protein stability influenced by the substitution of Met16 in the second sphere coordination.

PubMed

Abdelhamid, Rehab F; Obara, Yuji; Kohzuma, Takamitsu

2008-01-01

Several blue copper proteins are known to change the active site structure at alkaline pH (alkaline transition). Spectroscopic studies of Met16Phe, Met16Tyr, Met16Trp, and Met16Val pseudoazurin variants were performed to investigate the second sphere role through alkaline transition. The visible electronic absorption and resonance Raman spectra of Met16Phe, Met16Tyr, and Met16Trp variants showed the increasing of axial component at pH approximately 11 like wild-type PAz. The visible electronic absorption and far-UV CD spectra of Met16Val demonstrated that the destabilization of the protein structure was triggered at pH>11. Resonance Raman (RR) spectra of PAz showed that the intensity-weighted averaged Cu-S(Cys) stretching frequency was shifted to higher frequency region at pH approximately 11. The higher frequency shift of Cu-S(Cys) bond is implied the stronger Cu-S(Cys) bond at alkaline transition pH approximately 11. The visible electronic absorption and far-UV CD spectra of Met16X PAz revealed that the Met16Val variant is denatured at pH>11, but Met16Phe, Met16Tyr, and Met16Trp mutant proteins are not denatured even at pH>11. These observations suggest that Met16 is important to maintain the protein structure through the possible weak interaction between methionine -SCH3 part and coordinated histidine imidazole moiety. The introduction of pi-pi interaction in the second coordination sphere may be contributed to the enhancement of protein structure stability.

MET amplification as a potential therapeutic target in gastric cancer

PubMed Central

Kawakami, Hisato; Okamoto, Isamu; Arao, Tokuzo; Okamoto, Wataru; Matsumoto, Kazuko; Taniguchi, Hirokazu; Kuwata, Kiyoko; Yamaguchi, Haruka; Nishio, Kazuto; Nakagawa, Kazuhiko; Yamada, Yasuhide

2013-01-01

Our aim was to investigate both the prevalence of MET amplification in gastric cancer as well as the potential of this genetic alteration to serve as a therapeutic target in gastric cancer. MET amplification was assessed by initial screening with a PCR-based copy number assay followed by confirmatory FISH analysis in formalin-fixed, paraffin-embedded specimens of gastric cancer obtained at surgery. The effects of MET tyrosine kinase inhibitors (MET-TKIs) in gastric cancer cells with or without MET amplification were also examined. The median MET copy number in 266 cases of gastric cancer was 1.7, with a range of 0.41 to 21.3. We performed FISH analysis for the 15 cases with the highest MET copy numbers. MET amplification was confirmed in the four assessable cases with a MET copy number of at least 4, whereas MET amplification was not detected in those with a gene copy number of <4. The prevalence of MET amplification was thus 1.5% (4 out of 266 cases). Inhibition of MET by MET-TKIs resulted in the induction of apoptosis accompanied by attenuation of downstream MET signaling in gastric cancer cell lines with MET amplification but not in those without this genetic change. MET amplification identifies a small but clinically important subgroup of gastric cancer patients who are likely to respond to MET-TKIs. Furthermore, screening with a PCR-based copy number assay is an efficient way to reduce the number of patients requiring confirmation of MET amplification by FISH analysis. PMID:23327903

MET expression and amplification in patients with localized gastric cancer

PubMed Central

Janjigian, Yelena Y.; Tang, Laura H.; Coit, Daniel G.; Kelsen, David P.; Francone, Todd D.; Weiser, Martin R.; Jhanwar, Suresh C.; Shah, Manish A.

2013-01-01

Background MET, the receptor for hepatocyte growth factor has been proposed as a therapeutic target in gastric cancer. This study assessed the incidence of MET expression and gene amplification in tumors of Western patients with gastric cancer. Methods Tumor specimens from patients enrolled on a preoperative chemotherapy study (NCI 5700) were examined for presence of MET gene amplification by fluorescence in situ hybridization (FISH), MET mRNA expression by quantitative polymerase chain reaction, MET overexpression by immunohistochemistry (IHC), and for evidence of MET pathway activation by p-MET IHC. Results Although high-level of MET protein and mRNA were commonly encountered (in 63% and 50% of resected tumor specimens, respectively), none of these tumors had MET gene amplification by FISH, and only 6.6% had evidence of MET tyrosine kinase activity by p-MET IHC. Conclusions In this cohort of patients with localized gastric cancer, the presence of high MET protein and RNA expression does not correlate with MET gene amplification or pathway activation as evidenced by the absence of amplification by FISH and negative p-MET IHC analysis. Impact This paper demonstrates a lack of MET amplification and pathway activation in a cohort of 38 patients with localized gastric cancer, suggesting that MET-driven gastric cancers are relatively rare in Western patients. PMID:21393565

Heat-shock protein 27 (HSP27, HSPB1) is up-regulated by MET kinase inhibitors and confers resistance to MET-targeted therapy

PubMed Central

Musiani, Daniele; Konda, John David; Pavan, Simona; Torchiaro, Erica; Sassi, Francesco; Noghero, Alessio; Erriquez, Jessica; Perera, Timothy; Olivero, Martina; Di Renzo, Maria Flavia

2014-01-01

The tyrosine kinase encoded by the MET oncogene is activated by gene mutation or amplification in tumors, which in most instances maintain addiction, i.e., dependency, to MET activation. This makes MET an attractive candidate for targeted therapies. Here we show that, in 3/3 MET-addicted human gastric cancer cell lines, MET kinase inhibition resulted in a 3- to 4-fold increased expression of the antiapoptotic small heat-shock protein of 27 kDa (HSP27, HSPB1). HSP27 increase depended on the inhibition of the MEK/ERK pathway and on heat-shock factor 1 (HSF1) and hypoxia-inducible factor-1α (HIF-1α) regulation. Importantly, HSP27-silenced MET-addicted cells underwent 2- and 3-fold more apoptosis following MET inhibition in vitro and in vivo, respectively. Likewise, in human cancer cells susceptible to epidermal growth factor receptor (EGFR) inhibition, EGFR inhibitors induced HSP27 expression and were strengthened by HSP27 suppression. In control cell lines that were not affected by drugs targeting MET or EGFR, these drugs did not induce HSP27 increase. Therefore, in cancer therapies targeting the MET pathway, the induction of HSP27 might limit the efficacy of anti-MET agents. As HSP27 increase also impairs the effectiveness of EGFR inhibitors and is known to protect cells from chemotherapeutics, the induction of HSP27 by targeted agents might strongly affect the success of combination treatments.—Musiani, D., Konda, J. D., Pavan, S., Torchiaro, E., Sassi, F., Noghero, A., Erriquez, J., Perera, T., Olivero, M., Di Renzo, M. F. Heat-shock protein 27 (HSP27, HSPB1) is up-regulated by MET kinase inhibitors and confers resistance to MET-targeted therapy. PMID:24903273

Heat-shock protein 27 (HSP27, HSPB1) is up-regulated by MET kinase inhibitors and confers resistance to MET-targeted therapy.

PubMed

Musiani, Daniele; Konda, John David; Pavan, Simona; Torchiaro, Erica; Sassi, Francesco; Noghero, Alessio; Erriquez, Jessica; Perera, Timothy; Olivero, Martina; Di Renzo, Maria Flavia

2014-09-01

The tyrosine kinase encoded by the MET oncogene is activated by gene mutation or amplification in tumors, which in most instances maintain addiction, i.e., dependency, to MET activation. This makes MET an attractive candidate for targeted therapies. Here we show that, in 3/3 MET-addicted human gastric cancer cell lines, MET kinase inhibition resulted in a 3- to 4-fold increased expression of the antiapoptotic small heat-shock protein of 27 kDa (HSP27, HSPB1). HSP27 increase depended on the inhibition of the MEK/ERK pathway and on heat-shock factor 1 (HSF1) and hypoxia-inducible factor-1α (HIF-1α) regulation. Importantly, HSP27-silenced MET-addicted cells underwent 2- and 3-fold more apoptosis following MET inhibition in vitro and in vivo, respectively. Likewise, in human cancer cells susceptible to epidermal growth factor receptor (EGFR) inhibition, EGFR inhibitors induced HSP27 expression and were strengthened by HSP27 suppression. In control cell lines that were not affected by drugs targeting MET or EGFR, these drugs did not induce HSP27 increase. Therefore, in cancer therapies targeting the MET pathway, the induction of HSP27 might limit the efficacy of anti-MET agents. As HSP27 increase also impairs the effectiveness of EGFR inhibitors and is known to protect cells from chemotherapeutics, the induction of HSP27 by targeted agents might strongly affect the success of combination treatments. © FASEB.

MET amplification, expression, and exon 14 mutations in colorectal adenocarcinoma.

PubMed

Zhang, Meng; Li, Guichao; Sun, Xiangjie; Ni, Shujuan; Tan, Cong; Xu, Midie; Huang, Dan; Ren, Fei; Li, Dawei; Wei, Ping; Du, Xiang

2018-04-08

MET amplification, expression, and splice mutations at exon 14 result in dysregulation of the MET signaling pathway. The aim of this study was to identify the relationship between MET amplification, protein or mRNA expression, and mutations in colorectal cancer (CRC). MET immunohistochemistry (IHC) was used for MET protein expression analysis and fluorescence in situ hybridization (FISH) was used for MET amplification detection. Both analyses were performed in tissue microarrays (TMA) containing 294 of colorectal adenocarcinoma tissue samples and 131 samples of adjacent normal epithelial tissue. MET mRNA expression was examined by real-time quantitative polymerase chain reaction (qRT-PCR) in 72 fresh colorectal adenocarcinoma tissue samples and adjacent normal colon tissue. PCR sequencing was performed to screen for MET exon 14 splice mutations in 59 fresh CRC tissue samples. Our results showed that MET protein expression was higher in colorectal tumor tissue than in adjacent normal intestinal epithelium. Positive MET protein expression was associated with significantly poorer overall survival (OS) and disease-free survival (DFS). Multivariate analysis revealed that positive MET protein expression was an independent risk factor for DFS, but not for OS. MET mRNA expression was upregulated in tumor tissues compared with the adjacent normal tissues. The incidence of MET amplification was 4.4%. None of the patients was positive for MET mutation. Collectively, MET was overexpressed in colorectal adenocarcinoma, and its positive protein expression predicted a poorer outcome in CRC patients. Furthermore, according to our results, MET amplification and 14 exon mutation are extremely rare events in colorectal adenocarcinoma. Copyright © 2018. Published by Elsevier Inc.

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

PubMed

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

2009-11-25

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-gamma 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

Dissection of combinatorial control by the Met4 transcriptional complex.

PubMed

Lee, Traci A; Jorgensen, Paul; Bognar, Andrew L; Peyraud, Caroline; Thomas, Dominique; Tyers, Mike

2010-02-01

Met4 is the transcriptional activator of the sulfur metabolic network in Saccharomyces cerevisiae. Lacking DNA-binding ability, Met4 must interact with proteins called Met4 cofactors to target promoters for transcription. Two types of DNA-binding cofactors (Cbf1 and Met31/Met32) recruit Met4 to promoters and one cofactor (Met28) stabilizes the DNA-bound Met4 complexes. To dissect this combinatorial system, we systematically deleted each category of cofactor(s) and analyzed Met4-activated transcription on a genome-wide scale. We defined a core regulon for Met4, consisting of 45 target genes. Deletion of both Met31 and Met32 eliminated activation of the core regulon, whereas loss of Met28 or Cbf1 interfered with only a subset of targets that map to distinct sectors of the sulfur metabolic network. These transcriptional dependencies roughly correlated with the presence of Cbf1 promoter motifs. Quantitative analysis of in vivo promoter binding properties indicated varying levels of cooperativity and interdependency exists between members of this combinatorial system. Cbf1 was the only cofactor to remain fully bound to target promoters under all conditions, whereas other factors exhibited different degrees of regulated binding in a promoter-specific fashion. Taken together, Met4 cofactors use a variety of mechanisms to allow differential transcription of target genes in response to various cues.

Acquired Resistance Mechanisms to Combination Met-TKI/EGFR-TKI Exposure in Met-Amplified EGFR-TKI-Resistant Lung Adenocarcinoma Harboring an Activating EGFR Mutation.

PubMed

Yamaoka, Toshimitsu; Ohmori, Tohru; Ohba, Motoi; Arata, Satoru; Kishino, Yasunari; Murata, Yasunori; Kusumoto, Sojiro; Ishida, Hiroo; Shirai, Takao; Hirose, Takashi; Ohnishi, Tsukasa; Sasaki, Yasutsuna

2016-12-01

Met-amplified EGFR-tyrosine kinase inhibitor (TKI)-resistant non-small cell lung cancer (NSCLC) harboring an activating EGFR mutation is responsive to concurrent EGFR-TKI and Met-TKI treatment in a preclinical model. Here, we determined that Met-amplified gefitinib-resistant cells acquire dual resistance to inhibition of EGFR and Met tyrosine kinase activities. PC-9 lung adenocarcinoma cells harboring 15-bp deletions (Del E746_A750) in EGFR exon 19 were treated with increasing concentrations of the Met-TKI PHA665752 and 1 μmol/L gefitinib for 1 year; three resistant clones were established via Met amplification. The three dual-resistance cell lines (PC-9DR2, PC-9DR4, and PC-9DR6, designated as DR2, DR4, and DR6, respectively) exhibited different mechanisms for evading both EGFR and Met inhibition. None of the clones harbored a secondary mutation of EGFR T790M or a Met mutation. Insulin-like growth factor (IGF)/IGF1 receptor activation in DR2 and DR4 cells acted as a bypass signaling pathway. Met expression was attenuated to a greater extent in DR2 than in PC-9 cells, but was maintained in DR4 cells by overexpression of IGF-binding protein 3. In DR6 cells, Met was further amplified by association with HSP90, which protected Met from degradation and induced SET and MYND domain-containing 3 (SMYD3)-mediated Met transcription. This is the first report describing the acquisition of dual resistance mechanisms in NSCLC harboring an activating EGFR mutation to Met-TKI and EGFR-TKI following previous EGFR-TKI treatment. These results might inform the development of more effective therapeutic strategies for NSCLC treatment. Mol Cancer Ther; 15(12); 3040-54. ©2016 AACR. ©2016 American Association for Cancer Research.

Detection of MET amplification in gastroesophageal tumor specimens using IQFISH

PubMed Central

Nielsen, Karsten Bork; Mollerup, Jens; Jepsen, Anna; Go, Ning

2017-01-01

Background The gene mesenchymal epithelial transition factor (MET) is a proto-oncogene that encodes a transmembrane receptor with intrinsic tyrosine kinase activity known as Met or cMet. MET is found to be amplified in several human cancers including gastroesophageal cancer. Methods Here we report the MET amplification prevalence data from 159 consecutive tumor specimens from patients with gastric (G), gastroesophageal junction (GEJ) and esophageal (E) adenocarcinoma, using a novel fluorescence in situ hybridization (FISH) assay, MET/CEN-7 IQFISH Probe Mix [an investigational use only (IUO) assay]. MET amplification was defined as a MET/CEN-7 ratio ≥2.0. Furthermore, the link between the MET signal distribution and amplification status was investigated. Results The prevalence of MET amplification was found to be 6.9%. The FISH assay demonstrated a high inter-observer reproducibility. The inter-observer results showed a 100% overall agreement with respect to the MET status (amplified/non-amplified). The inter-observer CV was estimated to 11.8% (95% CI: 10.2–13.4). For the signal distribution, the inter-observer agreement was reported to be 98.7%. We also report an association of MET amplification and a unique signal distribution pattern in the G/GEJ/E tumor specimens. We found that the prevalence of MET amplification was markedly higher in tumors specimens with a heterogeneous (66.7%) versus homogeneous (2.0%) signal distribution. Furthermore, specimens with a heterogeneous signal distribution had a statically significantly higher median MET/CEN-7 ratio (2.35 versus 1.04; P<0.0001). Conclusions The novel FISH assay showed a high inter-observer reproducibility both with respect to amplification status and signal distribution. Based on the finding in the study it is suggested that MET amplification mainly is associated with tumor cells that is represented by a heterogonous growth pattern. PMID:29285491

Detection of MET amplification in gastroesophageal tumor specimens using IQFISH.

PubMed

Jørgensen, Jan Trøst; Nielsen, Karsten Bork; Mollerup, Jens; Jepsen, Anna; Go, Ning

2017-12-01

The gene mesenchymal epithelial transition factor ( MET ) is a proto-oncogene that encodes a transmembrane receptor with intrinsic tyrosine kinase activity known as Met or cMet. MET is found to be amplified in several human cancers including gastroesophageal cancer. Here we report the MET amplification prevalence data from 159 consecutive tumor specimens from patients with gastric (G), gastroesophageal junction (GEJ) and esophageal (E) adenocarcinoma, using a novel fluorescence in situ hybridization (FISH) assay, MET /CEN-7 IQFISH Probe Mix [an investigational use only (IUO) assay]. MET amplification was defined as a MET /CEN-7 ratio ≥2.0. Furthermore, the link between the MET signal distribution and amplification status was investigated. The prevalence of MET amplification was found to be 6.9%. The FISH assay demonstrated a high inter-observer reproducibility. The inter-observer results showed a 100% overall agreement with respect to the MET status (amplified/non-amplified). The inter-observer CV was estimated to 11.8% (95% CI: 10.2-13.4). For the signal distribution, the inter-observer agreement was reported to be 98.7%. We also report an association of MET amplification and a unique signal distribution pattern in the G/GEJ/E tumor specimens. We found that the prevalence of MET amplification was markedly higher in tumors specimens with a heterogeneous (66.7%) versus homogeneous (2.0%) signal distribution. Furthermore, specimens with a heterogeneous signal distribution had a statically significantly higher median MET /CEN-7 ratio (2.35 versus 1.04; P<0.0001). The novel FISH assay showed a high inter-observer reproducibility both with respect to amplification status and signal distribution. Based on the finding in the study it is suggested that MET amplification mainly is associated with tumor cells that is represented by a heterogonous growth pattern.

MMPM - Mission implementation of Mars MetNet Precursor

NASA Astrophysics Data System (ADS)

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.

Tumor and Plasma Met Levels in Non-Metastatic Prostate Cancer.

PubMed

Kaye, Deborah R; Pinto, Peter A; Cecchi, Fabiola; Reilly, Joseph; Semerjian, Alice; Rabe, Daniel C; Gupta, Gopal; Choyke, Peter L; Bottaro, Donald P

2016-01-01

To measure Met protein content in prostate biopsies guided by fused magnetic resonance and ultrasound imaging, and to measure soluble Met (sMet) protein concentration in plasma samples from patients presenting evidence of prostate cancer. 345 patients had plasma samples drawn prior to image-guided biopsy of the prostate. Of these, 32% had benign biopsies. Of the 236 that were positive for prostate adenocarcinoma (PCa), 132 treated by total prostatectomy had Gleason scores of 6 (17%), 7, (55%), 8 (16%), or 9-10 (12%). 23% had evidence of local invasion. Plasma samples were also obtained from 80 healthy volunteers. Tissue Met and plasma sMet were measured by two-site immunoassay; values were compared among clinically defined groups using non-parametric statistical tests to determine significant differences or correlations. PCa tumor Met correlated significantly with plasma sMet, but median values were similar among benign and malignant groups. Median plasma sMet values were also similar among those groups, although both medians were significantly above normal. Median Met content in primary PCa tumors and sMet concentrations were independent of Gleason score, final pathologic stage and age. Plasma sMet is not predictive of PCa or its severity in patients with organ-confined or locally invasive disease. Quantitative analysis of Met protein content and activation state in PCa tumor biopsy samples was highly feasible and may have value in follow-up to genomic and/or transcriptomic-based screens that show evidence of oncogenically relevant MET gene features that occur at relatively low frequency in non-metastatic PCa.

Constitutively active c-Met kinase in PC-3 cells is autocrine-independent and can be blocked by the Met kinase inhibitor BMS-777607

PubMed Central

2012-01-01

Background The c-Met receptor tyrosine kinase is aberrantly activated in many solid tumors. In a prior study we showed that prostate cancer PC-3 cells exhibit constitutively activated c-Met without exogenous hepatocyte growth factor (HGF); however whether this characteristic is due to an endogenous HGF/c-Met autocrine loop remains controversial. In the current study we examined the response of PC-3 cells to an anti-HGF neutralizing antibody or a small molecule Met kinase inhibitor (BMS-777607). Methods Cell scattering was tested by monitoring cell morphology after HGF stimulation. Cell migration was examined by both “wound-healing” and transwell assasy and invasion was detected by Matrigel-coated transwell assay. Proliferation, survival and anoikis were determined by MTT, colony formation and trypan blue exclusion assay, respectively. Gene and protein expression were assessed by real-time PCR and Western blot, respectively. Results Although HGF mRNA could be detected in PC-3 cells, the molecular weight of secreted “HGF” protein was inconsistent with the functional recombinant HGF. Furthermore, conditioned medium from PC-3 cell cultures was ineffective at triggering either motogenic behavior or c-Met signaling in DU145, another prostate cancer cell line expressing c-Met but lacking basal c-Met activation. PC-3 cells also were not responsive to the anti-HGF neutralizing antibody in experiments assessing proliferation, migration, or c-Met signaling. BMS-777607 treatment with micromolar doses nonetheless led to significant inhibition of multiple PC-3 cell functions including proliferation, clonogenicity, migration and invasion. At the molecular level, BMS-777607 suppressed autophosphorylated c-Met and downstream c-Src and Akt pathways. Conclusions These results suggest that the constitutive c-Met activation in PC-3 is independent of autocrine stimulation. Because PC-3 cells were responsive to BMS-777607 but not the anti-HGF antibody, the findings also indicate

Physical Protection: the State of the Art

DTIC Science & Technology

2005-02-01

fundamentele mechanisme van adsorptie van water beschrijft; dit is ingewikkeld en kost veel tijd ; een tweede benadering is het opstellen van een eenvoudig...gasscheidingsmethoden, bij voorkeur regeneratief, zijn zeer wenselijk vanwege de logistieke voordelen en de gegarandeerde langere operatie tijd . P(T)SA is meer...in de loop van de tijd ) met vrij simpele middelen en technieken sterk worden verbeterd. Deze technieken, zoals micro-encapsulatie en toevoeging van

Job Oriented Training: Onderwijskundige Grondslag en Onderbouwing (Job Oriented Training: Foundation and Empirical Support)

DTIC Science & Technology

2008-07-01

die binmen defensie tot aanzien van de effecten van JOT onderwijs met het nieuwe leren terug te dan toe in gebruik waren bij het theorie - voeren is op...problemen in de uitvoerings- onderwijs; toepassing van JOT impliceerde Grondslag praktijk van datzeltde regulier onderwijs. dat er geen theorie meer...het rechte eind Opdrachtnummer Datum PROGRAMMA PROJECT juli 2008 Program mabegeleider Projectbegeleider Auteur (s) IkolP.M.. Bonen,dr. A.H. van der

Bewegingshinder van Impactbeschermingsmiddelen voor de ME van de KMar (Restriction of Movement of Impact Protective Clothing for the Anti-Riot Squad of the Dutch Military Police)

DTIC Science & Technology

2007-12-01

kleding. omnstandigheden. zoals borst. armen en benen. Omdat er geen De nieuwe kieding met impactbLscherming bestaand testprotocol voor het testen van...verschillende onderdelen die bescherming biedt op diverse plaatsen op bet lichaam zoals borst, armen en benen. Orndat er geen bestaand testprotocol voor bet... armen en benen, Hieronder wordt kort omischreven welke ergonomische testen uitgevoerd moesten worden. 2.6.1 Sprint Bij een korte sprint (10 meter

MET: roles in epithelial-mesenchymal transition and cancer stemness

PubMed Central

Jeon, Hye-Min

2017-01-01

In a number of cancers, deregulated MET pathway leads to aberrantly activated proliferative and invasive signaling programs that promote malignant transformation, cell motility and migration, angiogenesis, survival in hypoxia, and invasion. A better understanding of oncogenic MET signaling will help us to discover effective therapeutic approaches and to identify which tumors are likely to respond to MET-targeted cancer therapy. In this review, we will summarize the roles of MET signaling in cancer, with particular focus on epithelial-mesenchymal transition (EMT) and cancer stemness. Then, we will provide update on MET targeting agents and discuss the challenges that should be overcome for the development of an effective therapy. PMID:28164090

A first-in-human phase I study of SAR125844, a selective MET tyrosine kinase inhibitor, in patients with advanced solid tumours with MET amplification.

PubMed

Angevin, Eric; Spitaleri, Gianluca; Rodon, Jordi; Dotti, Katia; Isambert, Nicolas; Salvagni, Stefania; Moreno, Victor; Assadourian, Sylvie; Gomez, Corinne; Harnois, Marzia; Hollebecque, Antoine; Azaro, Analia; Hervieu, Alice; Rihawi, Karim; De Marinis, Filippo

2017-12-01

Dysregulated MET signalling is implicated in oncogenesis. The safety and preliminary efficacy of a highly selective MET kinase inhibitor (SAR125844) was investigated in patients with advanced solid tumours and MET dysregulation. This was a phase I dose-escalation (3 + 3 design [50-740 mg/m 2 ]) and dose-expansion study. In the dose escalation, patients had high total MET (t-MET) expression by immunohistochemistry (IHC) or MET amplification by fluorescence in situ hybridisation. In the dose expansion, patients had MET amplification (including a subset of patients with non-small cell lung cancer [NSCLC]) or phosphorylated-MET (p-MET) expression (IHC). Objectives were determination of maximum tolerated dose (MTD) of once-weekly intravenous SAR125844 based on dose-limiting toxicities; safety and pharmacokinetic profile; preliminary efficacy of SAR125844 MTD in the expansion cohort. In total, 72 patients were enrolled: dose escalation, N = 33; dose expansion, N = 39; 570 mg/m 2 was established as the MTD. Most frequent treatment-emergent adverse events (AEs) were asthenia/fatigue (58.3%), nausea (31.9%), and abdominal pain, constipation, and dyspnea (27.8% for each); 58.3% of patients reported grade 3 AEs (19.4% were treatment related). Of the 29 evaluable patients with MET amplification treated at 570 mg/m 2 , five achieved a partial response, including four of 22 with NSCLC; 17 patients had stable disease. No response was observed in patients with high p-MET solid tumours. There was no correlation between tumour response and t-MET status or MET gene copy number. The MTD of once-weekly SAR125844 was 570 mg/m 2 ; SAR125844 was well tolerated, with significant antitumour activity in patients with MET-amplified NSCLC. NCT01391533. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Effective implementation of novel MET pharmacodynamic assays in translational studies.

PubMed

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.

Microenvironment-derived HGF overcomes genetically determined sensitivity to anti-MET drugs.

PubMed

Pennacchietti, Selma; Cazzanti, Manuela; Bertotti, Andrea; Rideout, William M; Han, May; Gyuris, Jeno; Perera, Timothy; Comoglio, Paolo M; Trusolino, Livio; Michieli, Paolo

2014-11-15

Cell-based drug screenings indicate that tumors displaying c-MET gene amplification are "addicted" to MET signaling and therefore are very sensitive to MET-targeted agents. However, these screenings were conducted in the absence of the MET ligand, hepatocyte growth factor (HGF), which is abundant in the tumor microenvironment. Sensitivity of six MET-addicted human tumor cells to three MET kinase inhibitors (JNJ-38877605, PHA-665752, crizotinib) and one antagonistic anti-MET antibody (DN30 Fab) was analyzed in the absence or presence of HGF, in a stroma-tumor coculture system, and by combining anti-MET drugs with an HGF neutralizing antibody (ficlatuzumab) in human HGF knock-in mice bearing c-MET-amplified tumors. In all models examined, HGF promoted resistance to MET-targeted agents, affecting both their potency and efficacy. HGF-induced resistance was due to restoration of physiologic GAB1-mediated PI3K activation that compensated for loss of aberrant HER3-dependent PI3K signaling. Ficlatuzumab restored sensitivity to MET-targeted agents in coculture systems and overcame resistance to JNJ-38877605, crizotinib, and DN30 Fab in human HGF knock-in mice. These data suggest that c-MET-amplified tumor cells-which normally exhibit ligand-independent, constitutive MET activation-become dependent on HGF for survival upon pharmacologic MET inhibition. Because HGF is frequently overexpressed in human cancer, this mechanism may represent a major cause of resistance to anti-MET therapies. The ability of ficlatuzumab to overcome HGF-mediated resistance generates proof of principle that vertical inhibition of both a tyrosine kinase receptor and its ligand can be therapeutically beneficial and opens new perspectives for the treatment of MET-dependent tumors. ©2014 American Association for Cancer Research.

Vrouwen bij de Koninklijke Landmacht: Een Onderzoek naar de Maatregelen die het Behoud en de Doorstroom van Vrouwelijke Militairen Verbeteren (Women in the Royal Netherlands Army: Measures for Retention and Career Development)

DTIC Science & Technology

2007-02-01

mannencultuur. Uit onderzoek blijkt dat vrouwelijke BBT-ers (Beroeps Bepaalde Tijd ) zicb goed tbuis voelen bij de (masculiene) organisatiecultuur van...de KL. Zij ervaren bovendien geen benadeling of negatieve bejegening. Vrouwelijke BOT-ers (Beroeps Onbepaalde Tijd ) geven daarentegen wel aan dat zij...arbeid en zorg. Meer tijd voor de thuissituatie, waarbij de werknemner zelf kan beslissen hoe zij deze fijd bet beste kan aanpassen aan de behoefte van

The HGF Receptor c-Met Is Overexpressed in Esophageal Adenocarcinoma1

PubMed Central

Herrera, Luis J; El-Hefnawy, Talal; Queiroz de Oliveira, Pierre E; Raja, Siva; Finkelstein, Sydney; Gooding, William; Luketich, James D; Godfrey, Tony E; Hughes, Steven J

2005-01-01

Abstract The hepatocyte growth factor (HGF) receptor, Met, has established oncogenic properties; however, its expression and function in esophageal adenocarcinoma (EA) remain poorly understood. We aimed to determine the expression and potential alterations in Met expression in EA. Met expression was investigated in surgical specimens of EA, Barrett's esophagus (BE), and normal esophagus (NE) using immunohistochemistry (IHC) and quantitative reverse transcriptase polymerase chain reaction. Met expression, phosphorylation, and the effect of COX-2 inhibition on expression were examined in EA cell lines. IHC demonstrated intense Met immunoreactivity in all (100%) EA and dysplastic BE specimens. In contrast, minimal immunostaining was observed in BE without dysplasia or NE specimens. Met mRNA and protein levels were increased in three EA cell lines, and Met protein was phosphorylated in the absence of serum. Sequence analysis found the kinase domain of c-met to be wild type in all three EA cell lines. HGF mRNA expression was identified in two EA cell lines. In COX-2-overexpressing cells, COX-2 inhibition decreased Met expression. Met is consistently overexpressed in EA surgical specimens and in three EA cell lines. Met dysregulation occurs early in Barrett's dysplasia to adenocarcinoma sequence. Future study of Met inhibition as a potential biologic therapy for EA is warranted. PMID:15720819

A protective effect of the BDNF Met/Met genotype in obesity in healthy Caucasian subjects but not in patients with coronary heart disease.

PubMed

Sustar, A; Nikolac Perkovic, M; Nedic Erjavec, G; Svob Strac, D; Pivac, N

2016-08-01

Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor with an important role in the regulation of body weight, body mass index (BMI) and obesity. Increased BMI that leads to obesity is a substantial risk factor for coronary heart disease (CHD). The functional BDNF Val66Met polymorphism (rs6265) has been associated with CHD, obesity and BMI. The aim of the study was to determine the association between BDNF rs6265 polymorphism and CHD and/or BMI in patients with CHD and healthy control subjects. The study included 704 Caucasian subjects: 206 subjects with CHD and 498 healthy control subjects. The BDNF rs6265 genotype frequency was similar in male and female subjects, and there were no differences in the frequency of the BDNF rs6265 genotypes in 206 patients with CHD and in 498 healthy subjects. When study participants were subdivided according to the BMI categories into normal weight, overweight and obese subjects, significantly different BDNF rs6265 genotype frequency was found within healthy subjects, but not within patients with CHD. Healthy subjects, but not patients with CHD, subdivided into carriers of the Met/Met, Met/Val and Val/Val genotype, had different BMI scores. The BDNF rs6265 genotype frequency was similar in male and female subjects, and there were no differences in the frequency of the BDNF rs6265 genotypes in 206 patients with CHD and in 498 healthy subjects. When study participants were subdivided according to the BMI categories into normal weight, overweight and obese subjects, significantly different BDNF rs6265 genotype frequency was found within healthy subjects, but not within patients with CHD. Healthy subjects, but not patients with CHD, subdivided into carriers of the Met/Met, Met/Val and Val/Val genotype, had different BMI scores. BDNF rs6265 polymorphism was not associated with a diagnosis of CHD or with BMI categories among patients with CHD. In contrast, healthy Caucasians, carriers of the BDNF Met/Met genotype, had more

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

PubMed

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

Mars MetNet Mission - Martian Atmospheric Observational Post Network

NASA Astrophysics Data System (ADS)

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

Radiation chemical studies of Gly-Met-Gly in aqueous solution

DOE PAGES

Barata-Vallejo, Sebastian; Ferreri, Carla; Zhang, Tao; ...

2016-10-25

Important biological consequences are related to the reaction of HO radicals with methionine (Met). Several fundamental aspects remain to be defined when Met is an amino acid residue incorporated in the interior of peptides and proteins. The present study focuses on Gly-Met-Gly, the simplest peptide where Met is not a terminal residue. The reactions of HO with Gly-Met-Gly and its N-acetyl derivative were studied by pulse radiolysis technique. The transient absorption spectra were resolved into contributions from specific components of radical intermediates. Moreover, a detailed product analysis is provided for the first time for Met-containing peptides in radiolytic studies tomore » support the mechanistic proposal. By parallel radiolytical and electrochemical reactions and consequent product identification, the formation of sulfoxide attributed to the direct HO radical attack on the sulfide functionality of the Met residue could be excluded, with the in situ generated hydrogen peroxide responsible for this oxidation. LC–MS and high resolution MS/MS were powerful analytical tools to envisage the structures of five products, thus allowing to complete the mechanistic picture of the overall Met-containing peptide reactivity.« less

Scatterometry

NASA Astrophysics Data System (ADS)

Stoffelen, Adrianus Cornelis Maria

1996-10-01

Een veelheid aan meteorologische metingen is dagelijks beschikbaar. De meeste van deze waarnemingen bevinden zich echter boven land, en met name windwaarnemingen boven de (Noord Atlantische) oceaan zijn schaars. Bij een westelijke luchtstroming is dit een duidelijke beperking voor de weers- en golfverwachtingen ten behoeve van Nederland. Juist dan is het gevaar voor bijvoorbeeld storm of overstroming het grootst. Ook in het aardse klimaatsysteem speelt de wind aan het oppervlak een grote rol en is de belangrijkste factor voor de aandrijving van de oceaancirculatie. De oceaancirculatie op zijn beurt is cruciaal voor de verschijnselen die samenhangen met bijvoorbeeld El Niño. Dit proefschift gaat over het scatterometer instrument dat vanuit de ruimte, zelfs onder een wolkendek, nauwkeurige en betrouwbare informatie geeft over de wind aan het oceaanoppervlak met een hoge mate van ruimtelijke consistentie. Tijdens de tweede wereldoorlog werden radars aan boord van schepen veelvuldig gebruikt voor de opsporing van vijandige vaartuigen. Hierbij werd vastgesteld dat de detectie slechter werd naarmate de wind aan het zeeoppervlak groter was. Proefondervindelijk was hiermee het principe van een wind scatterometer aangetoond. Al snel ontwikkelde zich dan ook de idee de wind aan het zeeoppervlak te meten met behulp van radar. Vanuit een vliegtuig of een satelliet word dan een microgolfbundel onder een schuine hoek naar het zeeoppervlak gestuurd. De microgolfstraling, met gewoonlijk een golflengte van enkele centimeters, wordt verstrooid aan het ruwe oppervlak, en een klein gedeelte van de uitgezonden puls keert terug naar het detectorgedeelte van de scatterometer. Het fysische fenomeen van belang voor de werking van de scatterometer is de aanwezigheid van zogeheten capillaire gavitatiegolven op het zeeoppervlak. Deze golven hebben een golflengte van enkele centimeters en reageren vrijwel instantaan op de sterkte van de wind. De verstrooiing van microgolven is op zijn beurt

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

PubMed

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.

Preproghrelin Leu72Met polymorphism in obese Korean children.

PubMed

Jo, Dae-Sun; Kim, Se-Lim; Kim, Sun-Young; Hwang, Pyoung Han; Lee, Kee-Hyoung; Lee, Dae-Yeol

2005-11-01

Ghrelin is a novel gut-brain peptide that has somatotropic, orexigenic, and adipogenic effects. We examined the preproghrelin Leu72Met polymorphism in 222 obese Korean children to determine whether it is associated with obesity. The frequencies of the Leu72Met polymorphism were 29.3% in obese, 32.3% in overweight, and 32.5% in lean Korean children. No significant difference was found between Met72 carrier and non-carrier obese children with respect to BMI, total body fat, serum triglycerides, total cholesterol, or LDL-cholesterol levels. Our data suggest that the preproghrelin Leu72Met polymorphism is not associated with obesity in children.

Cellular and molecular mechanisms of HGF/Met in the cardiovascular system.

PubMed

Gallo, Simona; Sala, Valentina; Gatti, Stefano; Crepaldi, Tiziana

2015-12-01

Met tyrosine kinase receptor, also known as c-Met, is the HGF (hepatocyte growth factor) receptor. The HGF/Met pathway has a prominent role in cardiovascular remodelling after tissue injury. The present review provides a synopsis of the cellular and molecular mechanisms underlying the effects of HGF/Met in the heart and blood vessels. In vivo, HGF/Met function is particularly important for the protection of the heart in response to both acute and chronic insults, including ischaemic injury and doxorubicin-induced cardiotoxicity. Accordingly, conditional deletion of Met in cardiomyocytes results in impaired organ defence against oxidative stress. After ischaemic injury, activation of Met provides strong anti-apoptotic stimuli for cardiomyocytes through PI3K (phosphoinositide 3-kinase)/Akt and MAPK (mitogen-activated protein kinase) cascades. Recently, we found that HGF/Met is also important for autophagy regulation in cardiomyocytes via the mTOR (mammalian target of rapamycin) pathway. HGF/Met induces proliferation and migration of endothelial cells through Rac1 (Ras-related C3 botulinum toxin substrate 1) activation. In fibroblasts, HGF/Met antagonizes the actions of TGFβ1 (transforming growth factor β1) and AngII (angiotensin II), thus preventing fibrosis. Moreover, HGF/Met influences the inflammatory response of macrophages and the immune response of dendritic cells, indicating its protective function against atherosclerotic and autoimmune diseases. The HGF/Met axis also plays an important role in regulating self-renewal and myocardial regeneration through the enhancement of cardiac progenitor cells. HGF/Met has beneficial effects against myocardial infarction and endothelial dysfunction: the cellular and molecular mechanisms underlying repair function in the heart and blood vessels are common and include pro-angiogenic, anti-inflammatory and anti-fibrotic actions. Thus administration of HGF or HGF mimetics may represent a promising therapeutic agent for the

Triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) index as a reference criterion of risk for metabolic syndrome (MetS) and low insulin sensitivity in apparently healthy subjects.

PubMed

Baez-Duarte, Blanca Guadalupe; Zamora-Gínez, Irma; González-Duarte, Ramiro; Torres-Rasgado, Enrique; Ruiz-Vivanco, Guadalupe; Pérez-Fuentes, Ricardo; Celis, The Multidisciplinary Research Group Of Diabetes

To evaluate if the TG/HDL-C index can be considered as a reference criterion of MetS and low insulin sensitivity in apparently healthy subjects. The subjects were Mexican mestizos who resided in Puebla City, Mexico, who were anthropometrically, biochemically, and clinically characterized. The TG/HDL-C index was calculated by dividing triglyceride (TG) levels by HDL-C levels. MetS was diagnosed by the Third Report from the Adult Treatment Panel-National Cholesterol Education Program (ATP-III NCEP) criteria, while insulin sensitivity was evaluated by the Quantitative Insulin sensitivity Check Index (QUICKI). The study included 813 subjects, with an average age of 38.6 ± 12.1 years, of which 564 were women and 249 men. An association was found between high TG/HDL-C index and low insulin sensitivity (Odds ratio [OR]: 4.09; p < 0.01) and with MetS (OR: 15.29; p < 0.01). A correlation was found between the TG/HDL-C index and QUICKI (rho: -0.4989; p < 0.01) and with MetS (rho: 0.6581; p < 0.01). The results indicate that the TG/HDL-C index is associated with low insulin sensitivity and MetS in apparently healthy subjects, suggesting this index as a reference criterion of risk for low insulin sensitivity and MetS.

Ran GTPase promotes cancer progression via Met receptor-mediated downstream signaling

PubMed Central

Yuen, Hiu-Fung; Chan, Ka-Kui; Platt-Higgins, Angela; Dakir, El-Habib; Matchett, Kyle B.; Haggag, Yusuf Ahmed; Jithesh, Puthen V.; Habib, Tanwir; Faheem, Ahmed; Dean, Fennell A.; Morgan, Richard; Rudland, Philip S.; El-Tanani, Mohamed

2016-01-01

It has been shown previously that cancer cells with an activated oncogenic pathway, including Met activation, require Ran for growth and survival. Here, we show that knockdown of Ran leads to a reduction of Met receptor expression in several breast and lung cancer cell lines. This, in turn suppressed HGF expression and the Met-mediated activation of the Akt pathway, as well as cell adhesion, migration, and invasion. In a cell line model where Met amplification has previously been shown to contribute to gefitinib resistance, Ran knockdown sensitized cells to gefitinib-mediated inhibition of Akt and ERK1/2 phosphorylation and consequently reduced cell proliferation. We further demonstrate that Met reduction-mediated by knockdown of Ran, occurs at the post-transcriptional level, probably via a matrix metalloproteinase. Moreover, the level of immunoreactive Ran and Met are positively associated in human breast cancer specimens, suggesting that a high level of Ran may be a pre-requisite for Met overexpression. Interestingly, a high level of immunoreactive Ran dictates the prognostic significance of Met, indicating that the co-overexpression of Met and Ran may be associated with cancer progression and could be used in combination as a prognostic indicator. PMID:27716616

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

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-04

... SECURITIES AND EXCHANGE COMMISSION [Release No. IC-29544; File No. 812-13816] MetLife Insurance... Section 17(b) of the Act from Section 17(a) of the Act. Applicants: MetLife Insurance Company of Connecticut (``MetLife of CT''), MetLife of CT Separate Account Eleven for Variable Annuities (``Separate...

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

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-31

... SECURITIES AND EXCHANGE COMMISSION [Release No. IC-29190; File No. 812-13700] MetLife Insurance... Section 17(b) of the Act from Section 17(a) of the Act. Applicants: MetLife Insurance Company of Connecticut (``MetLife of CT''), MetLife of CT Separate Account Eleven for Variable Annuities (``Separate...

Lack of neural compensatory mechanisms of BDNF val66met met carriers and APOE E4 carriers in healthy aging, mild cognitive impairment, and Alzheimer's disease.

PubMed

Gomar, Jesus J; Conejero-Goldberg, Concepcion; Huey, Edward D; Davies, Peter; Goldberg, Terry E

2016-03-01

Compromises in compensatory neurobiologic mechanisms due to aging and/or genetic factors (i.e., APOE gene) may influence brain-derived neurotrophic factor (BDNF) val66met polymorphism effects on temporal lobe morphometry and memory performance. We studied 2 cohorts from Alzheimer's Disease Neuroimaging Initiative: 175 healthy subjects and 222 with prodromal and established Alzheimer's disease. Yearly structural magnetic resonance imaging and cognitive performance assessments were carried out over 3 years of follow-up. Both cohorts had similar BDNF Val/Val and Met allele carriers' (including both Val/Met and Met/Met individuals) distribution. In healthy subjects, a significant trend for thinner posterior cingulate and precuneus cortices was detected in Met carriers compared to Val homozygotes in APOE E4 carriers, with large and medium effect sizes, respectively. The mild cognitive impairment/Alzheimer's disease cohort showed a longitudinal decline in entorhinal thickness in BDNF Met carriers compared to Val/Val in APOE E4 carriers, with effect sizes ranging from medium to large. In addition, an effect of BDNF genotype was found in APOE E4 carriers for episodic memory (logical memory and ADAS-Cog) and semantic fluency measures, with Met carriers performing worse in all cases. These findings suggest a lack of compensatory mechanisms in BDNF Met carriers and APOE E4 carriers in healthy and pathological aging. Copyright © 2016 Elsevier Inc. All rights reserved.

Early application of Met-RANTES ameliorates chronic allograft nephropathy.

PubMed

Song, Erwei; Zou, Hequn; Yao, Yousheng; Proudfoot, Amanda; Antus, Balazs; Liu, Shanying; Jens, Lutz; Heemann, Uwe

2002-02-01

Initial insults to kidney allografts, characterized by infiltration of mononuclear inflammatory cells, contribute to chronic allograft nephropathy. Chemokines such as RANTES (regulated upon activation, normal T cell expressed) are thought to be responsible for the recruitment and activation of infiltrating cells. The present study investigated whether early application of Met-RANTES, a chemokine receptor antagonist that blocks the effects of RANTES, can protect renal allografts from long-term deterioration. Fisher (F344) rat kidneys were orthotopically transplanted into Lewis recipients and treated with cyclosporine A (1.5 mg/kg/day) for the first 10 days following transplantation, together with either Met-RANTES at 40 microg/day, 200 microg/day or vehicle for the first 7 days. Animals were harvested at 2 and 28 weeks after transplantation for histologic, immunohistologic and molecular analysis. Met-RANTES treatment reduced the infiltration of lymphocytes and macrophages in allografts at 2 weeks after transplantation, accompanied by decreased mRNA expression of interleukin (IL)-2, IL-1beta, tumor necrosis factor-alpha (TNF-alpha) and RANTES. At post-transplantation week 28, Met-RANTES treatment at high and low doses reduced urinary protein excretion and significantly ameliorated glomerulosclerosis, interstitial fibrosis, tubular atrophy, intimal proliferation of graft arteries and mononuclear cell infiltration. However, creatinine clearance was not influenced by Met-RANTES. Furthermore, Met-RANTES suppressed the mRNA expression of transforming growth factor-beta (TGF-beta) and platelet-derived growth factor-B (PDGF-B). Blockade of chemokine receptors by Met-RANTES diminishes early infiltration and activation of mononuclear cells in the grafts, and thus reduces the pace of chronic allograft nephropathy.

Mars MetNet Mission - Martian Atmospheric Observational Post Network

NASA Astrophysics Data System (ADS)

Harri, Ari-Matti; Aleksashkin, Sergey; Arruego, Ignacio; Schmidt, Walter; Ponomarenko, Andrey; Apestigue, Victor; Genzer, Maria; Vazquez, Luis; Uspensky, Mikhail; Haukka, Harri

2016-04-01

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. 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. 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

Mars MetNet Mission - Martian Atmospheric Observational Post Network

NASA Astrophysics Data System (ADS)

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.

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.

PubMed

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 (p<0.001). No significant differences were seen in the number of MetS components in individuals having MetS by either definition (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.

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

PubMed Central

Watson, Gregory A; Zhang, Xinglu; Stang, Michael T; Levy, Ryan M; Queiroz de Oliveira, Pierre E; Gooding, William E; Christensen, James G; Hughes, Steven J

2006-01-01

Abstract 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-overexpressing EA cell lines (Seg-1, Bic-1, and Flo-1) were used to examine the effects of a c-Met-specific small molecule inhibitor (PHA665752) on cell viability, apoptosis, motility, invasion, and 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. PMID:17132227

Quantitation of Met tyrosine phosphorylation using MRM-MS.

PubMed

Meng, Zhaojing; Srivastava, Apurva K; Zhou, Ming; Veenstra, Timothy

2013-01-01

Phosphorylation has long been accepted as a key cellular regulator of cell signaling pathways. The recent development of multiple-reaction monitoring mass spectrometry (MRM-MS) provides a useful tool for measuring the absolute quantity of phosphorylation occupancy at pivotal sites within signaling proteins, even when the phosphorylation sites are in close proximity. Here, we described a targeted quantitation approach to measure the absolute phosphorylation occupancy at Y1234 and Y1235 of Met. The approach is utilized to obtain absolute occupancy of the two phosphorylation sites in the full-length recombinant Met. It is further applied to quantitate the phosphorylation state of these two sites in SNU-5 cells treated with a Met inhibitor.

OMEGACAM and Gravitational Lensing

NASA Astrophysics Data System (ADS)

Christen, Fabrice Frédéric Thiébaut

2007-04-01

Het proefschrift van Fabrice Christen gaat over de ontwikkeling van nieuwe methoden voor het corrigeren van (digitale) foto's van melkwegstelsels. Met deze methoden kunnen de beelden uit het heelal beter worden geanalyseerd. Het eerste gedeelte is gewijd aan het werk dat bij ESO is uitgevoerd aan de CCD's van de OmegaCAM camera, het enige instrument van de VST. OmegaCAM is een optische groothoekcamera met een beeldveld van een vierkante graad, opgebouwd uit een mozaiek van 8 bij 4 CCD's. Van elk onderdeel moeten alle kenmerken volledig bekend zijn voordat het in het CCD mozaiek geplaatst kan worden. In het tweede deel van dit proefschrift wordt de ontwikkeling van een nieuwe methode voor het corrigeren van de ``point-spread function'' (PSF) en schatten van de ellipticiteit van de melkwegstelsels besproken. De nieuwe techniek wordt getest en vergeleken met een door sterrenkundigen algemeen gebruikte methode in het veld van zwaartekrachtslenzen, de Kaiser, Squire en Broadhurst (KSB) methode. De nieuwe methode, gebaseerd op shapelet ontleding (vergelijkbaar met wavelet ontleding), gaat verder, en is sneller en theoretisch preciezer dan de KSB methode. Door gebruik te maken van de gecorrigeerde ellipticiteit, kunnen we een statistische analyse uitvoeren om er een kosmisch vervormingssignaal uit te halen. De licht vervormde beelden van de melkwegstelsels bewij zen dat de niet-homogene massaverdeling op megaparsec-schaal voornamelijk bestaat uit grote hoeveelheden donkere materie. Verder vergelijken we de schattingen van de ellipticiteit van de shapelet en KSB methode. Bovendien voeren we ook nog een melkwegstelsel-melkwegstelsel lens analyse uit op de 50 VLT Fors1 afbeeldingen en slagen we erin de belangrijkste eigenschappen van de halo's van de stelsels, die zich op een afstand van een- tot tweeduizend megaparsec (1 parsec = 3,26 lichtjaar = 3,085 x 10^16 meter) bevinden, te bepalen door gebruik te maken van twee modellen van melkwegstelselhalo's. Vergeleken met andere

Success, but Slowly, as Met School Redefines Learning

ERIC Educational Resources Information Center

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…

Mars MetNet Mission - Martian Atmospheric Observational Post Network

NASA Astrophysics Data System (ADS)

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

2016-10-01

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 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.Full Qualification Model (QM) of the MetNet landing unit with the Precursor Mission payload is currently under functional tests. In the near future the QM unit will be exposed to environmental tests with qualification levels including vibrations, thermal balance, thermal cycling and mechanical impact shock. One complete flight unit of the entry, descent and landing systems (EDLS) has been manufactured and tested with acceptance levels. Another flight-like EDLS has been exposed to most of the qualification tests, and hence it may be used for flight after refurbishments. Accordingly two flight-capable EDLS systems exist. The eventual goal is to create a network of atmospheric observational posts around the Martian surface. The next step in the MetNet Precursor Mission is the demonstration of the technical robustness and scientific capabilities of the MetNet type of landing vehicle. Definition of the Precursor Mission and discussions on launch opportunities are currently under way. The baseline program development funding exists for the next five years. Flight unit manufacture of the payload bay takes about 18 months, and it will be commenced after the Precursor Mission has been defined.

Sequential EMT-MET induces neuronal conversion through Sox2

PubMed Central

He, Songwei; Chen, Jinlong; Zhang, Yixin; Zhang, Mengdan; Yang, Xiao; Li, Yuan; Sun, Hao; Lin, Lilong; Fan, Ke; Liang, Lining; Feng, Chengqian; Wang, Fuhui; Zhang, Xiao; Guo, Yiping; Pei, Duanqing; Zheng, Hui

2017-01-01

Direct neuronal conversion can be achieved with combinations of small-molecule compounds and growth factors. Here, by studying the first or induction phase of the neuronal conversion induced by defined 5C medium, we show that the Sox2-mediated switch from early epithelial–mesenchymal transition (EMT) to late mesenchymal–epithelial transition (MET) within a high proliferation context is essential and sufficient for the conversion from mouse embryonic fibroblasts (MEFs) to TuJ+ cells. At the early stage, insulin and basic fibroblast growth factor (bFGF)-induced cell proliferation, early EMT, the up-regulation of Stat3 and Sox2, and the subsequent activation of neuron projection. Up-regulated Sox2 then induced MET and directed cells towards a neuronal fate at the late stage. Inhibiting either stage of this sequential EMT-MET impaired the conversion. In addition, Sox2 could replace sequential EMT-MET to induce a similar conversion within a high proliferation context, and its functions were confirmed with other neuronal conversion protocols and MEFs reprogramming. Therefore, the critical roles of the sequential EMT-MET were implicated in direct cell fate conversion in addition to reprogramming, embryonic development and cancer progression. PMID:28580167

MetReS, an Efficient Database for Genomic Applications.

PubMed

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.

Cell membrane organization is important for inner hair cell MET-channel gating

NASA Astrophysics Data System (ADS)

Effertz, Thomas; Scharr, Alexandra L.; Ricci, Anthony J.

2018-05-01

Specialized sensory cells, hair cells, translate mechanical stimuli into electro/chemical responses. This process, termed mechano-electrical transduction (MET), is localized to the hair cell's sensory organelle, the hair bundle. The mature hair bundle comprises three rows of actin filled stereocilia, arranged in a staircase pattern. Deflections towards the tallest row of stereocilia activate MET channels, residing at the top of stereocilia. While other MET channels can be activated or modulated by changes to their lipid environment, this remains unknown for the mammalian auditory MET channel. We show here that the effect of lipid and cholesterol depletion from the cell membrane affect the MET current as well. We used γ-cyclodextrin to extract lipids form the membrane, reversibly reducing the peak MET current, current adaptation, and decreasing the channels resting open probability. The recovery after γ-cyclodextrin treatment was slower than the initial peak current reduction, suggesting that a specific lipid organization is required for normal MET channel function, which requires time reestablish. Extraction of cholesterol, using Mβ-cyclodextrin, irreversibly reduces the peak MET current and reversibly increases the channel resting open probability, suggesting that cholesterol restricts MET channel opening. This restriction could be useful to increase the channel's signal to noise ratio. Together this data suggests that the cell membrane is part of the force relay machinery to the MET channel and could possibly restrict gating associated conformational changes of the MET channel.

Have Clinical Trials Properly Assessed c-Met Inhibitors?

PubMed

Hughes, Veronica S; Siemann, Dietmar W

2018-02-01

The c-Met/HGF pathway is implicated in cancer progression and dissemination. Many inhibitors have been developed to target this pathway. Unfortunately, most trials have failed to demonstrate efficacy. However, clinical trials have not adequately tested the concept of c-Met pathway inhibition due to the lack of appropriate patient selection criteria. Copyright © 2017 Elsevier Inc. All rights reserved.

Design and synthesis of 3,3'-biscoumarin-based c-Met inhibitors.

PubMed

Xu, Jimin; Ai, Jing; Liu, Sheng; Peng, Xia; Yu, Linqian; Geng, Meiyu; Nan, Fajun

2014-06-14

A library of biscoumarin-based c-Met inhibitors was synthesized, based on optimization of 3,3'-biscoumarin hit 3, which was identified as a non-ATP competitive inhibitor of c-Met from a diverse library of coumarin derivatives. Among these compounds, 38 and 40 not only showed potent enzyme activities with IC50 values of 107 nM and 30 nM, respectively, but also inhibited c-Met phosphorylation in BaF3/TPR-Met and EBC-1 cells.

The oleocanthal-based homovanillyl sinapate as a novel c-Met inhibitor

PubMed Central

Mohyeldin, Mohamed M.; Akl, Mohamed R.; Ebrahim, Hassan Y.; Dragoi, Ana Maria; Dykes, Samantha; Cardelli, James A.; El Sayed, Khalid A.

2016-01-01

The hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-Met) signaling axis has gained considerable attention as an attractive molecular target for therapeutic blockade of cancer. Inspired by the chemical structure of S (−)-oleocanthal, a natural secoiridoid from extra-virgin olive oil with documented anticancer activity against c-Met-dependent malignancies, the research presented herein reports on the discovery of the novel olive-derived homovanillyl sinapate (HVS) as a promising c-Met inhibitor. HVS was distinguished for its remarkable potency against wild-type c-Met and its oncogenic variant in cell-free assays and confirmed by in silico docking studies. Furthermore, HVS substantially impaired the c-Met-mediated growth across a broad spectrum of breast cancer cells, while similar treatment doses had no effect on the non-tumorigenic mammary epithelial cell growth. In addition, HVS caused a dose-dependent inhibition of HGF-induced, but not epidermal growth factor (EGF)-induced, cell scattering in addition to HGF-mediated migration, invasion, and 3-dimensional (3D) proliferation of tumor cell spheroids. HVS treatment effects were mediated via inhibition of ligand-mediated c-Met activation and its downstream mitogenic signaling and blocking molecular mediators involved in cellular motility across different cellular contexts. An interesting feature of HVS is its good selectivity for c-Met and Abelson murine leukemia viral oncogene homolog 1 (ABL1) when profiled against a panel of kinases. Docking studies revealed interactions likely to impart high dual affinity for both ABL1 and c-Met kinases. HVS markedly reduced tumor growth, showed excellent pharmacodynamics, and suppressed cell proliferation and microvessel density in an orthotopic model of triple negative breast cancer. Collectively, the present findings suggested that the oleocanthal-based HVS is a promising c-Met inhibitor lead entity with excellent therapeutic potential to control

Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia

PubMed Central

Gray, Mary J.; Kannu, Peter; Sharma, Swarkar; Neyt, Christine; Zhang, Dongping; Paria, Nandina; Daniel, Philip B.; Whetstone, Heather; Sprenger, Hans-Georg; Hammerschmidt, Philipp; Weng, Angela; Dupuis, Lucie; Jobling, Rebekah; Mendoza-Londono, Roberto; Dray, Michael; Su, Peiqiang; Wilson, Megan J.; Kapur, Raj P.; McCarthy, Edward F.; Alman, Benjamin A.; Howard, Andrew; Somers, Gino R.; Marshall, Christian R.; Manners, Simon; Flanagan, Adrienne M.; Rathjen, Karl E.; Karol, Lori A.; Crawford, Haemish; Markie, David M.; Rios, Jonathan J.; Wise, Carol A.; Robertson, Stephen P.

2015-01-01

The periosteum contributes to bone repair and maintenance of cortical bone mass. In contrast to the understanding of bone development within the epiphyseal growth plate, factors that regulate periosteal osteogenesis have not been studied as intensively. Osteofibrous dysplasia (OFD) is a congenital disorder of osteogenesis and is typically sporadic and characterized by radiolucent lesions affecting the cortical bone immediately under the periosteum of the tibia and fibula. We identified germline mutations in MET, encoding a receptor tyrosine kinase, that segregate with an autosomal-dominant form of OFD in three families and a mutation in a fourth affected subject from a simplex family and with bilateral disease. Mutations identified in all families with dominant inheritance and in the one simplex subject with bilateral disease abolished the splice inclusion of exon 14 in MET transcripts, which resulted in a MET receptor (METΔ14) lacking a cytoplasmic juxtamembrane domain. Splice exclusion of this domain occurs during normal embryonic development, and forced induction of this exon-exclusion event retarded osteoblastic differentiation in vitro and inhibited bone-matrix mineralization. In an additional subject with unilateral OFD, we identified a somatic MET mutation, also affecting exon 14, that substituted a tyrosine residue critical for MET receptor turnover and, as in the case of the METΔ14 mutations, had a stabilizing effect on the mature protein. Taken together, these data show that aberrant MET regulation via the juxtamembrane domain subverts core MET receptor functions that regulate osteogenesis within cortical diaphyseal bone. PMID:26637977

MetAMOS: a modular and open source metagenomic assembly and analysis pipeline

PubMed Central

2013-01-01

We describe MetAMOS, an open source and modular metagenomic assembly and analysis pipeline. MetAMOS represents an important step towards fully automated metagenomic analysis, starting with next-generation sequencing reads and producing genomic scaffolds, open-reading frames and taxonomic or functional annotations. MetAMOS can aid in reducing assembly errors, commonly encountered when assembling metagenomic samples, and improves taxonomic assignment accuracy while also reducing computational cost. MetAMOS can be downloaded from: https://github.com/treangen/MetAMOS. PMID:23320958

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

PubMed Central

Arnold, Levi; Enders, Jonathan; Thomas, Sufi Mary

2017-01-01

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. PMID:29231907

MET Receptor Tyrosine Kinase as an Autism Genetic Risk Factor

PubMed Central

Peng, Yun; Huentelman, Matthew; Smith, Christopher; Qiu, Shenfeng

2014-01-01

In this chapter, we will briefly discuss recent literature on the role of MET receptor tyrosine kinase (RTK) in brain development and how perturbation of MET signaling may alter normal neurodevelopmental outcomes. Recent human genetic studies have established MET as a risk factor for autism, and the molecular and cellular underpinnings of this genetic risk are only beginning to emerge from obscurity. Unlike many autism risk genes that encode synaptic proteins, the spatial and temporal expression pattern of MET RTK indicates this signaling system is ideally situated to regulate neuronal growth, functional maturation, and establishment of functional brain circuits, particularly in those brain structures involved in higher levels of cognition, social skills, and executive functions. PMID:24290385

Prototype of the Modular Equipment Transporter (MET)

NASA Technical Reports Server (NTRS)

1970-01-01

A prototype of the Modular Equipment Transporter (MET), nicknamed the 'Rickshaw' after its shape and method of propulsion. This equipment was used by the Apollo 14 astronauts during their geological and lunar surface simulation training in the Pinacate volcanic area of northwestern Sonora, Mexico. The Apollo 14 crew will be the first one to use the MET. It will be a portable workbench with a place for the lunar handtools and their carrier, three cameras, two sample container bags, a Special Environmental Sample Container, spare film magazines, and a Lunar Surface Penetrometer.

MET receptor tyrosine kinase as an autism genetic risk factor.

PubMed

Peng, Yun; Huentelman, Matthew; Smith, Christopher; Qiu, Shenfeng

2013-01-01

In this chapter, we will briefly discuss recent literature on the role of MET receptor tyrosine kinase (RTK) in brain development and how perturbation of MET signaling may alter normal neurodevelopmental outcomes. Recent human genetic studies have established MET as a risk factor for autism, and the molecular and cellular underpinnings of this genetic risk are only beginning to emerge from obscurity. Unlike many autism risk genes that encode synaptic proteins, the spatial and temporal expression pattern of MET RTK indicates this signaling system is ideally situated to regulate neuronal growth, functional maturation, and establishment of functional brain circuits, particularly in those brain structures involved in higher levels of cognition, social skills, and executive functions. © 2013 Elsevier Inc. All rights reserved.

Loss of embryonic MET signaling alters profiles of hippocampal interneurons.

PubMed

Martins, Gabriela J; Plachez, Céline; Powell, Elizabeth M

2007-01-01

Hippocampal interneurons arise in the ventral forebrain and migrate dorsally in response to cues, including hepatocyte growth factor/scatter factor which signals via its receptor MET. Examination of the hippocampus in adult mice in which MET had been inactivated in the embryonic proliferative zones showed an increase in parvalbumin-expressing cells in the dentate gyrus, but a loss of these cells in the CA3 region. An overall loss of calretinin-expressing cells was seen throughout the hippocampus. A similar CA3 deficit of parvalbumin and calretinin cells was observed when MET was eliminated only in postmitotic cells. These data suggest that MET is required for the proper hippocampal development, and embryonic perturbations lead to long-term anatomical defects with possible learning and memory dysfunction.

Met Nuclear Localization and Signaling in Breast Cancer

DTIC Science & Technology

2006-05-01

and in germinal regions of many tissues using 4 unique antibodies . Cell fractionation reveals a 60kDa band recognized by C-terminal Met antibodies ...cascades such as Gab1 , Grb2 and PI3K, leading to proliferation, scattering, increased motility, invasion and branching morphogenesis (reviewed in (2...Identification of Met antibodies for use on tissue microarray of normal and cancerous cells, Months 12-24 Task 2. Definition of the domain

Targeting MET and EGFR crosstalk signaling in triple-negative breast cancers

PubMed Central

Essenburg, Curt J.; Turner, Lisa; Madaj, Zachary; Winn, Mary E.; Melnik, Marianne K.; Korkaya, Hasan; Maroun, Christiane R.; Christensen, James G.; Steensma, Matthew R.; Boerner, Julie L.; Graveel, Carrie R.

2016-01-01

There is a vital need for improved therapeutic strategies that are effective in both primary and metastatic triple-negative breast cancer (TNBC). Current treatment options for TNBC patients are restricted to chemotherapy; however tyrosine kinases are promising druggable targets due to their high expression in multiple TNBC subtypes. Since coexpression of receptor tyrosine kinases (RTKs) can promote signaling crosstalk and cell survival in the presence of kinase inhibitors, it is likely that multiple RTKs will need to be inhibited to enhance therapeutic benefit and prevent resistance. The MET and EGFR receptors are actionable targets due to their high expression in TNBC; however crosstalk between MET and EGFR has been implicated in therapeutic resistance to single agent use of MET or EGFR inhibitors in several cancer types. Therefore it is likely that dual inhibition of MET and EGFR is required to prevent crosstalk signaling and acquired resistance. In this study, we evaluated the heterogeneity of MET and EGFR expression and activation in primary and metastatic TNBC tumorgrafts and determined the efficacy of MET (MGCD265 or crizotinib) and/or EGFR (erlotinib) inhibition against TNBC progression. Here we demonstrate that combined MET and EGFR inhibition with either MGCD265 and erlotinib treatment or crizotinib and erlotinib treatment were highly effective at abrogating tumor growth and significantly decreased the variability in treatment response compared to monotherapy. These results advance our understanding of the RTK signaling architecture in TNBC and demonstrate that combined MET and EGFR inhibition may be a promising therapeutic strategy for TNBC patients. PMID:27655711

Alternative Fuels Data Center: Workplace Charging Success: MetLife

Science.gov Websites

people to use PEVs. " MetLife's Senior Vice President, Global Corporate Services, Joseph Sprouls vehicle (PEV) charging stations at 14 of its U.S. corporate offices as a partner in the Department of benefits of using alternative energy sources. MetLife's Senior Vice President, Global Corporate Services

19 CFR 10.133 - Conditions required to be met.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 19 Customs Duties 1 2011-04-01 2011-04-01 false Conditions required to be met. 10.133 Section 10.133 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF... Duty Dependent Upon Actual Use § 10.133 Conditions required to be met. When the tariff classification...

19 CFR 10.133 - Conditions required to be met.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 19 Customs Duties 1 2013-04-01 2013-04-01 false Conditions required to be met. 10.133 Section 10.133 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF... Duty Dependent Upon Actual Use § 10.133 Conditions required to be met. When the tariff classification...

Determining unmet, adequately met, and overly met needs for health care and services for persons living with HIV/AIDS in Mississippi.

PubMed

Krause, Denise D; May, Warren L; Butler, Kenneth R

2013-08-01

A statewide needs assessment of persons living with HIV/AIDS (PLWHA) was conducted to determine what is known about access to care, utilization of services, and perceived barriers to receiving care and services. Our objective was to determine which needs were being met or unmet among PLWHA in Mississippi to provide a better understanding of how effectively to allocate funding to provide for the needs of that group. In this cross-sectional study, a true random sample of PLWHA in Mississippi was interviewed in 2005-2006. Questions were asked to identify opinions about respondents' experiences with 23 health care services and 30 public or private assistance services. The kappa statistic was used to measure agreement between level of services needed and level of services provided. Services with the lowest kappa scores revealed which services were being either mostly unmet, or even overly met. Greatest service needs were HIV viral load test, Pap smear, CD4/T-cell count test, and medication for HIV/AIDS, which were reasonably well met. The most significantly unmet needs were dental care and dental exams, eye care and eye exams, help paying for housing, subsidized housing assistance, mental health therapy or counseling, access to emotional support groups, and job placement or employment. Overly met services included medical care at a physician's office or clinic and free condoms. This study identified needs perceived to be significantly unmet by PLWHA, as well as areas that were perceived to be adequately or overly met. This information may be used to target areas with the greatest impact for improvement and provide insight into how to effectively allocate health care resources and public/private assistance.

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

PubMed

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.

Epigenetic Upregulation of HGF and c-Met Drives Metastasis in Hepatocellular Carcinoma

PubMed Central

Ogunwobi, Olorunseun O.; Puszyk, William; Dong, Hui-Jia; Liu, Chen

2013-01-01

Hepatocyte growth factor (HGF) and its receptor, c-Met, are important regulators of growth and differentiation of healthy hepatocytes. However, upregulation of HGF and c-Met have been associated with tumor progression and metastasis in hepatocellular carcinoma (HCC). Hematogenous dissemination is the most common route for cancer metastasis, but the role of HGF and c-Met in circulating tumor cells (CTCs) is unknown. We have isolated and established a circulating tumor cell line from the peripheral blood of a mouse HCC model. Our studies show that these CTCs have increased expression of HGF and c-Met in comparison to the primary tumor cells. The CTCs display phenotypic evidence of epithelial-mesenchymal transition (EMT) and the EMT appears to be inducible by HGF. Epigenetic analysis of the c-Met promoter identified significant loss of DNA methylation in CTCs which correlated with overexpression of c-Met and increased expression of HGF. Six specific CpG sites of c-Met promoter demethylation were identified. CTCs show significantly increased tumorigenicity and metastatic potential in a novel orthotopic syngeneic model of metastatic HCC. We conclude that during hematogenous dissemination in HCC, CTCs undergo EMT under the influence of increased HGF. This process also involves up regulation of c-Met via promoter demethylation at 6 CpG sites. Consequently, targeting HGF and c-Met expression by CTCs may be a novel non-invasive approach with potential clinical applications in HCC management. PMID:23723997

Biology of MET: a double life between normal tissue repair and tumor progression

PubMed Central

2015-01-01

MNNG HOS transforming gene (MET) is a class IV receptor tyrosine kinase, expressed on the surface of epithelial cells. The interaction with the hepatocyte grow factor (HGF) induces MET dimerization and the activation of multiple intracellular pathways leading to cell proliferation, anti-apoptosis, morphogenic differentiation, motility, invasion, and angiogenesis. Knock out mice have demonstrated that MET is necessary for normal embryogenesis including the formation of striate muscles, liver and trophoblastic structures. The overexpression of MET and HGF are common in solid tumors and contribute to determine their growth. Indeed, MET has been cloned as a transforming gene from a chemically induced human osteosarcoma cell line and therefore is considered a proto-oncogene. Germline MET mutations are characteristic of hereditary papillary kidney cancers and MET amplification is observed in tumors including lung and gastric adenocarcinomas. The inhibition of MET signaling is the target for specific drugs that are raising exciting expectation for medical treatment of cancer. PMID:25992381

Rocket experiment METS Microwave Energy Transmission in Space

NASA Astrophysics Data System (ADS)

Kaya, N.; Matsumoto, H.; Akiba, R.

A METS (Microwave Energy Transmission in Space) rocket experiment is being planned by the SPS (Solar Power Satellite) Working Group at the Institute of Space and Astronautical Science (ISAS) in Japan for the forthcoming International Space Year (ISY), 1992. The METS experiment is an advanced version of our MINIX rocket experiment. This paper describes the conceptual design for the METS rocket experiment. Aims are to verify the feasibility of a newly developed microwave energy transmission system designed for use in space and to study nonlinear effects of the microwave energy beam on space plasma. A high power microwave (936 W) will be transmitted by a new phase-array antenna from a mother rocket to a separate target (daughter rocket) through the Earth's ionospheric plasma. The active phased-array system has the capability of being able to focus the microwave energy at any spatial point by individually controlling the digital phase shifters.

Rocket experiment METS - Microwave Energy Transmission in Space

NASA Astrophysics Data System (ADS)

Kaya, N.; Matsumoto, H.; Akiba, R.

A Microwave Energy Transmission in Space (METS) rocket experiment is being planned by the Solar Power Satellite Working Group at the Institute of Space and Astronautical Science in Japan for the forthcoming International Space Year, 1992. The METS experiment is an advanced version of the previous MINIX rocket experiment (Matsumoto et al., 1990). This paper describes a conceptual design of the METS rocket experiment. It aims at verifying a newly developed microwave energy transmission system for space use and to study nonlinear effects of the microwave energy beam in the space plasma environment. A high power microwave of 936 W will be transmitted by the new phased-array antenna from a mother rocket to a separated target (daughter rocket) through the ionospheric plasma. The active phased-array system has a capability of focusing the microwave energy around any spatial point by controlling the digital phase shifters individually.

Hepatocyte growth factor sensitizes brain tumors to c-MET kinase inhibition

PubMed Central

Zhang, Ying; Farenholtz, Kaitlyn E.; Yang, Yanzhi; Guessous, Fadila; diPierro, Charles G.; Calvert, Valerie S.; Deng, Jianghong; Schiff, David; Xin, Wenjun; Lee, Jae K.; Purow, Benjamin; Christensen, James; Petricoin, Emanuel; Abounader, Roger

2013-01-01

Purpose The receptor tyrosine kinase (RTK) c-MET and its ligand hepatocyte growth factor (HGF) are deregulated and promote malignancy in cancer and brain tumors. Consequently, clinically applicable c-MET inhibitors have been developed. The purpose of this study was to investigate the not well known molecular determinants that predict responsiveness to c-MET inhibitors, and to explore new strategies for improving inhibitor efficacy in brain tumors. Experimental design We investigated the molecular factors and pathway activation signatures that determine sensitivity to c-MET inhibitors in a panel of glioblastoma and medulloblastoma cells, glioblastoma stem cells (GSCs), and established cell line-derived xenografts using functional assays, reverse protein microarrays, and in vivo tumor volume measurements, but validation with animal survival analyses remains to be done. We also explored new approaches for improving the efficacy of the inhibitors in vitro and in vivo. Results We found that HGF co-expression is a key predictor of response to c-MET inhibition among the examined factors, and identified an ERK/JAK/p53 pathway activation signature that differentiates c-MET inhibition in responsive and non-responsive cells. Surprisingly, we also found that short pre-treatment of cells and tumors with exogenous HGF moderately but statistically significantly enhanced the anti-tumor effects of c-MET inhibition. We observed a similar ligand-induced sensitization effect to an EGFR small molecule kinase inhibitor. Conclusions These findings allow the identification of a subset of patients that will be responsive to c-MET inhibition, and propose ligand pre-treatment as a potential new strategy for improving the anti-cancer efficacy of RTK inhibitors. PMID:23386689

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

PubMed

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.

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

PubMed Central

2012-01-01

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. PMID:22962849

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

PubMed

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.

[Met5]Enkephalin content in brain regions of rats treated with lithium.

PubMed Central

Gillin, J C; Hong, J S; Yang, H Y; Costa, E

1978-01-01

In rats, chronic treatment with lithium elicits a dose-dependent increase in the [Met5]enkephalin content of nucleus caudatus and globus pallidus. A single injection of lithium fails to change the striatal [Met5]enkephalin content. The increase in [Met5]enkephalin caused by chronic lithium is proportional to the serum lithium level. The extent of the increase in striatal [Met5]enkephalin content levels off at a value of about 250% that of untreated rats. This increase has a time latency of 2--3 days and reaches a plateau at 5 days. The increase that was present at 5 days was no longer evident if the treatment was continued for 2 weeks. Lithium also increases striatal [Leu5]enkephalin content by an extent equal to the increase of [Met 5]enkephalin. Based on the characteristics of the lithium-induced increase in [Met6]enkephalin content, it is proposed that lithium may reduce the rate of release of [Met5]enkephalin from the small enkephalinergic neurons that are intrinsic to the striatum; this action may be related to a change in the regulation of striatal neurons. PMID:275866

Extraboard performance : TriMet case study.

DOT National Transportation Integrated Search

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...

Preproghrelin Leu72Met polymorphism is not associated with type 2 diabetes mellitus.

PubMed

Kim, Sun-Young; Jo, Dae-Sun; Hwang, Pyoung Han; Park, Ji Hyun; Park, Sung Kwang; Yi, Ho Keun; Lee, Dae-Yeol

2006-03-01

Ghrelin is a novel gut-brain peptide, which exerts somatotropic, orexigenic, and adipogenic effects. Genetic variants of ghrelin have been associated with both obesity and insulin metabolism. In this study, we determined a role of preproghrelin Leu72Met polymorphism on type 2 diabetes mellitus and its relationship to variables studied. Genotypes were assessed by polymerase chain reaction. Frequencies of the Leu72Met polymorphism were found to be 35.4% in the type 2 diabetic patients and 32.5% in the normal controls. The Leu72Met polymorphism was not associated with hypertension, macroangiopathy, retinopathy, serum cholesterol, triglyceride, blood urea nitrogen, HbA(1c), lipoprotein (a), fasting insulin, or 24-hour urinary protein levels in the type 2 diabetic group. However, the Leu72Met polymorphism was clearly associated with serum creatinine levels in the diabetic group, as the Met72 carriers exhibited lower serum creatinine levels than the Met72 noncarriers. Our data indicate that the preproghrelin Leu72Met polymorphism is not associated with type 2 diabetes mellitus. However, the Leu72Met polymorphism is associated with serum creatinine levels. These data suggest that Met72 carrier status may be a predictable marker for diabetic nephropathy or renal impairment in type 2 diabetes mellitus.

User's Guide for MetView: A Meteorological Display and Assessment Tool

DOE Office of Scientific and Technical Information (OSTI.GOV)

Glantz, Clifford S.; Pelton, Mitchell A.; Allwine, K Jerry

2000-09-27

MetView Version 2.0 is an easy-to-use model for accessing, viewing, and analyzing meteorological data. MetView provides both graphical and numerical displays of data. It can accommodate data from an extensive meteorological monitoring network that includes near-surface monitoring locations, instrumented towers, sodars, and meteorologist observations. MetView is used operationally for both routine, emergency response, and research applications at the U.S. Department of Energy's Hanford Site. At the Site's Emergency Operations Center, MetView aids in the access, visualization, and interpretation of real-time meteorological data. Historical data can also be accessed and displayed. Emergency response personnel at the Emergency Operations Center use MetViewmore » products in the formulation of protective action recommendations and other decisions. In the initial stage of an emergency, MetView can be operated using a very simple, five-step procedure. This first-responder procedure allows non-technical staff to rapidly generate meteorological products and disseminate key information. After first-responder information products are produced, the Emergency Operations Center's technical staff can conduct more sophisticated analyses using the model. This may include examining the vertical variation in winds, assessing recent changes in atmospheric conditions, evaluating atmospheric mixing rates, and forecasting changes in meteorological conditions. This user's guide provides easy-to-follow instructions for both first-responder and routine operation of the model. Examples, with explanations, are provided for each type of MetView output display. Information is provided on the naming convention, format, and contents of each type of meteorological data file used by the model area. This user's guide serves as a ready reference for experienced MetView users and a training manual for new users.« less

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

PubMed

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

2015-06-03

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.

Brain-derived neurotrophic factor Val66Met genotype modulates amygdala habituation.

PubMed

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.

Negative Suppressors of Oncogenic Activation of the Met Receptor Tyrosine Kinase

DTIC Science & Technology

2007-03-01

transfected with HA Gab1 , cells were stimulated, fixed with 3% PFA and stained with antibodies against HA (green) and endogenous Met (red). White...oncogenic activation through deregulate endocytosis. My recent work has uncovered a novel role for the Gab1 scaffold in regulating Met internalization and...I show that Gab1 localizes to CDRs and recruits the Met receptor to this plasma membrane compartment where receptors are then internalized into the

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

PubMed

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.

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

PubMed Central

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

2014-01-01

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. PMID:24930887

METs in adults while playing active video games: a metabolic chamber study.

PubMed

Miyachi, Motohiko; Yamamoto, Kenta; Ohkawara, Kazunori; Tanaka, Shigeho

2010-06-01

Active video game systems controlled through arm gestures and motions (Nintendo Wii Sports) and video games controlled through force plate (Wii Fit Plus) are becoming increasingly popular. This study was performed to determine the energy expenditure (EE) during Wii Fit Plus and Wii Sports game activities. Twelve adult men and women performed all the activities of Wii Sports (five activities: golf, bowling, tennis, baseball, and boxing) and Wii Fit Plus (63 activities classified as yoga, resistance, balance, and aerobic exercises). Each activity was continued for at least 8 min to obtain a steady-state EE. Because EE was assessed in an open-circuit indirect metabolic chamber consisting of an airtight room (20,000 or 15,000 L), subjects were freed of apparatus to collect expired gas while playing the games. MET value was calculated from resting EE and steady-state EE during activity. The mean MET values of all 68 activities were distributed over a wide range from 1.3 METs (Lotus Focus) to 5.6 METs (single-arm stand). The mean MET values in yoga, balance, resistance, and aerobic exercise of Wii Fit Plus and Wii Sports were 2.1, 2.0, 3.2, 3.4, and 3.0 METs, respectively. Forty-six activities (67%) were classified as light intensity (<3 METs), and 22 activities (33%) were classified as moderate intensity (3.0-6.0 METs). There were no vigorous-intensity activities (>6.0 METs). Time spent playing one-third of the activities supplied by motion- and gesture-controlled video games can count toward the daily amount of exercise required according to the guidelines provided by the American College of Sports Medicine and the American Heart Association, which focus on 30 min of moderate-intensity daily physical activity 5 d x wk(-1).

Recent Progress and Advances in HGF/MET-Targeted Therapeutic Agents for Cancer Treatment

PubMed Central

Zhang, Yilong; Jain, Rajul K.; Zhu, Min

2015-01-01

The hepatocyte growth factor (HGF): MET axis is a ligand-mediated receptor tyrosine kinase pathway that is involved in multiple cellular functions, including proliferation, survival, motility, and morphogenesis. Aberrancy in the HGF/MET pathway has been reported in multiple tumor types and is associated with tumor stage and prognosis. Thus, targeting the HGF/MET pathway has become a potential therapeutic strategy in oncology development in the last two decades. A number of novel therapeutic agents—either as therapeutic proteins or small molecules that target the HGF/MET pathway—have been tested in patients with different tumor types in clinical studies. In this review, recent progress in HGF/MET pathway-targeted therapy for cancer treatment, the therapeutic potential of HGF/MET-targeted agents, and challenges in the development of such agents will be discussed. PMID:28536405

Association of Catechol-O-methyltransferase polymorphism Val158Met and mammographic density: A meta-analysis.

PubMed

Kallionpää, Roope A; Uusitalo, Elina; Peltonen, Juha

2017-08-15

The Val158Met polymorphism in catechol-O-methyltransferase (COMT) enzyme reduces the methylation of catechol estrogens, which may affect mammographic density. High mammographic density is a known risk factor of breast cancer. Our aim was to perform meta-analysis of the effect of COMT Val158Met polymorphism on mammographic density. Original studies reporting data on mammographic density, stratified by the presence of COMT Val158Met polymorphism, were identified and combined using genetic models Met/Val vs. Val/Val, Met/Met vs. Val/Val, Val/Met+Met/Met vs. Val/Val (dominant model) and Met/Met vs. Val/Met+Val/Val (recessive model). Subgroup analyses by breast cancer status, menopausal status and use of hormone replacement therapy (HRT) were also performed. Eight studies were included in the meta-analysis. The overall effect in percent mammographic density was -1.41 (CI -2.86 to 0.05; P=0.06) in the recessive model. Exclusion of breast cancer patients increased the effect size to -1.93 (CI -3.49 to -0.37; P=0.02). The results suggested opposite effect of COMT Val158Met for postmenopausal users of HRT versus premenopausal women or postmenopausal non-users of HRT. COMT Val158Met polymorphism may be associated with mammographic density at least in healthy women. Menopausal status and HRT should be taken into account in future studies to avoid masking of the underlying effects. Copyright © 2017 Elsevier B.V. All rights reserved.

MET exon 14 skipping defines a unique molecular class of non-small cell lung cancer.

PubMed

Zheng, Difan; Wang, Rui; Ye, Ting; Yu, Su; Hu, Haichuan; Shen, Xuxia; Li, Yuan; Ji, Hongbin; Sun, Yihua; Chen, Haiquan

2016-07-05

Recurrent MET exon 14 splicing has been revealed in lung cancers and is a promising therapeutic target. Because we have limited knowledge about the natural history of MET mutant tumors, the current study was aiming to determine the clinical and pathological characteristics in non-small cell lung cancers (NSCLC). Twenty-three patients (1.3%) were positive for MET exon 14 skipping. Patients with MET exon 14 skipping displayed unique characteristics: female, non-smokers, earlier pathology stage and older age. MET exon 14 skipping indicated an early event as other drivers in lung cancer, while MET copy number gain was more likely a late event in lung cancer. Overall survival (OS) of patients harboring MET exon 14 skipping was longer than patients with KRAS mutation. Almost four-fifths of the lung tumors with MET exon 14 skipping had EGFR and/or HER2 gene copy number gains. EGFR inhibitor showed moderate antitumor activity in treatment of a patient harboring MET exon 14 skipping. From October 2007 to June 2013, we screened 1770 patients with NSCLC and correlated MET status with clinical pathologic characteristics and mutations in EGFR, KRAS, BRAF, HER2, and ALK. Quantitative Real-Time PCR was used to detect MET gene copy number gain. Immunohistochemistry (IHC) was also performed to screen MET exon 14 skipping. Clinicopathological characteristics and survival information were analyzed. MET exon 14 skipping was detected in 1.3% (23/1770) of the Chinese patients with NSCLC. MET exon 14 skipping defined a new molecular subset of NSCLC with identifiable clinical characteristics. The therapeutic EGFR inhibitors might be an alternative treatment for patients with MET mutant NSCLC.

The Clinical Impact of c-MET Over-Expression in Advanced Biliary Tract Cancer (BTC).

PubMed

Heo, Mi Hwa; Kim, Hee Kyung; Lee, Hansang; Kim, Kyoung-Mee; Lee, Jeeyun; Park, Se Hoon; Park, Joon Oh; Lim, Ho Yeong; Kang, Won Ki; Park, Young Suk; Kim, Seung Tae

2017-01-01

Background : c-MET is a proto-oncogene that encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF). Activation of HGF-c-MET signaling involves cell invasiveness and evokes metastasis through direct involvement of tumor angiogenesis. However, the value of c-MET overexpression is still unknown in metastatic biliary tract cancer (BTC). Methods : We analyzed the incidence and clinicopathologic characteristics of c-MET overexpression in advanced BTC. Moreover, we investigated the value of c-MET overexpression in predicting response to gemicitabine plus cisplatin (GC), a first line standard regimen, and as a prognostic marker in metastatic BTC. Results : The BTC subtype distribution (N=44) was as follows: intrahepatic cholangiocarcinoma (IHCC, n=7), extrahepatic cholangiocarcinoma (EHCC, n=25) and gallbladder cancer (GBC, n=12). Liver (52.3%) was the predominant metastatic site, followed by lymph nodes (36.4%) and bone (15.9%). Among the 44 patients analyzed for c-MET expression, 15 (34.1%) exhibited c-MET overexpression in tumor tissues. There was no significant difference in the prevalence of c-MET overexpression among primary sites in EHCC (7/25, 28.0%), IHCC (3/7, 42.9%), and GBC (5/12, 41.7%). There was also no significant correlation between specific clinicopathologic variables and c-MET expression. Comparing the tumor-response to GC according to c-MET expression (overexpression vs. non-overexpression), there was no significant difference in either RR or DCR (p=0.394 and p >0.999, respectively). The median PFS for all 44 patients was 9.00 months (95% CI, 7.5-10.5 months) and there was no significant difference for PFS between patients with c-MET overexpression and those without (p=0.917). The median OS was 14.4 months (95% CI, 11.9-16.9 months). There was no significant difference in OS between patients with c-MET overexpression compared to those without (13.7 vs. 14.4 months, respectively; p=0.708). Conclusions : c-MET overexpression was detected

Synthesis of Tc-99m labeled 1,2,3-triazole-4-yl c-met binding peptide as a potential c-met receptor kinase positive tumor imaging agent.

PubMed

Kim, Eun-Mi; Joung, Min-Hee; Lee, Chang-Moon; Jeong, Hwan-Jeong; Lim, Seok Tae; Sohn, Myung-Hee; Kim, Dong Wook

2010-07-15

The mesenchymal-epithelial transition factor (c-Met), which is related to tumor cell growth, angiogenesis and metastases, is known to be overexpressed in several tumor types. In this study, we synthesized technetium-99m labeled 1,2,3-triazole-4-yl c-Met binding peptide (cMBP) derivatives, prepared by solid phase peptide synthesis and the 'click-to-chelate' protocol for the introduction of tricarbonyl technetium-99m, as a potential c-Met receptor kinase positive tumor imaging agent, and evaluated their in vitro c-Met binding affinity, cellular uptake, and stability. The (99m)Tc labeled cMBP derivatives ([(99m)Tc(CO)(3)]12, [(99m)Tc(CO)(3)]13, and [(99m)Tc(CO)(3)]14) were prepared in 85-90% radiochemical yields. The cold surrogate cMBP derivatives, [Re(CO)(3)]12, [Re(CO)(3)]13, and [Re(CO)(3)]14, were shown to have high binding affinities (0.13 microM, 0.06 microM, and 0.16 microM, respectively) to a purified cMet/Fc chimeric recombinant protein. In addition, the in vitro cellular uptake and inhibition studies demonstrated the high specific binding of these (99m)Tc labeled cMBP derivatives ([(99m)Tc(CO)(3)]12-14) to c-Met receptor positive U87MG cells. 2010 Elsevier Ltd. All rights reserved.

Single-molecule photobleaching reveals increased MET receptor dimerization upon ligand binding in intact cells

PubMed Central

2013-01-01

Background The human receptor tyrosine kinase MET and its ligand hepatocyte growth factor/scatter factor are essential during embryonic development and play an important role during cancer metastasis and tissue regeneration. In addition, it was found that MET is also relevant for infectious diseases and is the target of different bacteria, amongst them Listeria monocytogenes that induces bacterial uptake through the surface protein internalin B. Binding of ligand to the MET receptor is proposed to lead to receptor dimerization. However, it is also discussed whether preformed MET dimers exist on the cell membrane. Results To address these issues we used single-molecule fluorescence microscopy techniques. Our photobleaching experiments show that MET exists in dimers on the membrane of cells in the absence of ligand and that the proportion of MET dimers increases significantly upon ligand binding. Conclusions Our results indicate that partially preformed MET dimers may play a role in ligand binding or MET signaling. The addition of the bacterial ligand internalin B leads to an increase of MET dimers which is in agreement with the model of ligand-induced dimerization of receptor tyrosine kinases. PMID:23731667

Involvement of lipid rafts in adhesion-induced activation of Met and EGFR.

PubMed

Lu, Ying-Che; Chen, Hong-Chen

2011-10-27

Cell adhesion has been shown to induce activation of certain growth factor receptors in a ligand-independent manner. However, the mechanism for such activation remains obscure. Human epidermal carcinoma A431 cells were used as a model to examine the mechanism for adhesion-induced activation of hepatocyte growth factor receptor Met and epidermal growth factor receptor (EGFR). The cells were suspended and replated on culture dishes under various conditions. The phosphorylation of Met at Y1234/1235 and EGFR at Y1173 were used as indicators for their activation. The distribution of the receptors and lipid rafts on the plasma membrane were visualized by confocal fluorescent microscopy and total internal reflection microscopy. We demonstrate that Met and EGFR are constitutively activated in A431 cells, which confers proliferative and invasive potentials to the cells. The ligand-independent activation of Met and EGFR in A431 cells relies on cell adhesion to a substratum, but is independent of cell spreading, extracellular matrix proteins, and substratum stiffness. This adhesion-induced activation of Met and EGFR cannot be attributed to Src activation, production of reactive oxygen species, and the integrity of the cytoskeleton. In addition, we demonstrate that Met and EGFR are independently activated upon cell adhesion. However, partial depletion of Met and EGFR prevents their activation upon cell adhesion, suggesting that overexpression of the receptors is a prerequisite for their self-activation upon cell adhesion. Although Met and EGFR are largely distributed in 0.04% Triton-insoluble fractions (i.e. raft fraction), their activated forms are detected mainly in 0.04% Triton-soluble fractions (i.e. non-raft fraction). Upon cell adhesion, lipid rafts are accumulated at the cell surface close to the cell-substratum interface, while Met and EGFR are mostly excluded from the membrane enriched by lipid rafts. Our results suggest for the first time that cell adhesion to a

Regulation of MET by FOXP2, genes implicated in higher cognitive dysfunction and autism risk.

PubMed

Mukamel, Zohar; Konopka, Genevieve; Wexler, Eric; Osborn, Gregory E; Dong, Hongmei; Bergman, Mica Y; Levitt, Pat; Geschwind, Daniel H

2011-08-10

Autism spectrum disorder (ASD) is a highly heritable, behaviorally defined, heterogeneous disorder of unknown pathogenesis. Several genetic risk genes have been identified, including the gene encoding the receptor tyrosine kinase MET, which regulates neuronal differentiation and growth. An ASD-associated polymorphism disrupts MET gene transcription, and there are reduced levels of MET protein expression in the mature temporal cortex of subjects with ASD. To address the possible neurodevelopmental contribution of MET to ASD pathogenesis, we examined the expression and transcriptional regulation of MET by a transcription factor, FOXP2, which is implicated in regulation of cognition and language, two functions altered in ASD. MET mRNA expression in the midgestation human fetal cerebral cortex is strikingly restricted, localized to portions of the temporal and occipital lobes. Within the cortical plate of the temporal lobe, the pattern of MET expression is highly complementary to the expression pattern of FOXP2, suggesting the latter may play a role in repression of gene expression. Consistent with this, MET and FOXP2 also are reciprocally expressed by differentiating normal human neuronal progenitor cells (NHNPs) in vitro, leading us to assess whether FOXP2 transcriptionally regulates MET. Indeed, FOXP2 binds directly to the 5' regulatory region of MET, and overexpression of FOXP2 results in transcriptional repression of MET. The expression of MET in restricted human neocortical regions, and its regulation in part by FOXP2, is consistent with genetic evidence for MET contributing to ASD risk.

Voice: Reflections on an Artist-Led Program at the Met

ERIC Educational Resources Information Center

Valladares, Maya

2017-01-01

This article explores an education project in which artist Fred Wilson, poets from Lincoln Center's Poet-Linc program, and the Met Museum Education Department collaborated to produce a teen-led spoken-word poetry performance in the Met's galleries. Wilson drew from his own knowledge of the collection to facilitate a group dialogue about objects…

Astronaut Alan Shepard using MET during geological training in Mexico

NASA Technical Reports Server (NTRS)

1970-01-01

Astronaut Alan B. Shepard Jr., commander of the Apollo 14 lunar landing mission, takes a piece of equipment from the Modular Equipment Transporter (MET) during geological and lunar surface simulation training training in the Pinacate volcanic area of northwestern Sonora, Mexico. The MET has been nicknamed 'Rickshaw' after its shape and method of propulsion.

The autism susceptibility gene met regulates zebrafish cerebellar development and facial motor neuron migration

PubMed Central

Elsen, Gina E.; Choi, Louis Y.; Prince, Victoria E.; Ho, Robert K.

2009-01-01

During development, Met signaling regulates a range of cellular processes including growth, differentiation, survival and migration. The Met gene encodes a tyrosine kinase receptor, which is activated by Hgf (hepatocyte growth factor) ligand. Altered regulation of human MET expression has been implicated in autism. In mouse, Met signaling has been shown to regulate cerebellum development. Since abnormalities in cerebellar structure have been reported in some autistic patients, we have used the zebrafish to address the role of Met signaling during cerebellar development and thus further our understanding of the molecular basis of autism. We find that zebrafish met is expressed in the cerebellar primordium, later localizing to the ventricular zone (VZ), with the hgf1 and hgf2 ligand genes expressed in surrounding tissues. Morpholino knockdown of either Met or its Hgf ligands leads to a significant reduction in the size of the cerebellum, primarily as a consequence of reduced proliferation. Met signaling knockdown disrupts specification of VZ-derived cell types, and also reduces granule cell numbers, due to an early effect on cerebellar proliferation and/or as an indirect consequence of loss of signals from VZ-derived cells later in development. These patterning defects preclude analysis of cerebellar neuronal migration, but we have found that Met signaling is necessary for migration of hindbrain facial motor neurons. In summary, we have described roles for Met signaling in coordinating growth and cell type specification within the developing cerebellum, and in migration of hindbrain neurons. These functions may underlie the correlation between altered MET regulation and Autism Spectrum Disorders. PMID:19732764

Inhibition of c-Met reduces lymphatic metastasis in RIP-Tag2 transgenic mice

PubMed Central

Sennino, Barbara; Ishiguro-Oonuma, Toshina; Schriver, Brian J.; Christensen, James G.; McDonald, Donald M.

2013-01-01

Inhibition of vascular endothelial growth factor (VEGF) signaling can promote lymph node metastasis in preclinical models, but the mechanism is not fully understood, and successful methods of prevention have not been found. Signaling of hepatocyte growth factor (HGF) and its receptor c-Met can promote the growth of lymphatics and metastasis of some tumors. We sought to explore the contributions of c-Met signaling to lymph node metastasis after inhibition of VEGF signaling. In particular, we examined whether c-Met is upregulated in lymphatics in or near pancreatic neuroendocrine tumors in RIP-Tag2 transgenic mice and whether lymph node metastasis can be reduced by concurrent inhibition of VEGF and c-Met signaling. Inhibition of VEGF signaling by anti-VEGF antibody or sunitinib in mice from age 14 to 17 weeks was accompanied by more intratumoral lymphatics, more tumor cells inside lymphatics, and more lymph node metastases. Under these conditions, lymphatic endothelial cells - like tumor cells - had strong immunoreactivity for c-Met and phospho-c-Met. c-Met blockade by the selective inhibitor PF-04217903 significantly reduced metastasis to local lymph nodes. Together, these results indicate that inhibition of VEGF signaling in RIP-Tag2 mice upregulates c-Met expression in lymphatic endothelial cells, increases the number of intratumoral lymphatics and number of tumor cells within lymphatics, and promotes metastasis to local lymph nodes. Prevention of lymph node metastasis by PF-04217903 in this setting implicates c-Met signaling in tumor cell spread to lymph nodes. PMID:23576559

Could the organ shortage ever be met?

PubMed

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.

AtaT blocks translation initiation by N-acetylation of the initiator tRNAfMet.

PubMed

Jurėnas, Dukas; Chatterjee, Sneha; Konijnenberg, Albert; Sobott, Frank; Droogmans, Louis; Garcia-Pino, Abel; Van Melderen, Laurence

2017-06-01

Toxin-antitoxin (TA) loci are prevalent in bacterial genomes. They are suggested to play a central role in dormancy and persister states. Under normal growth conditions, TA toxins are neutralized by their cognate antitoxins, and under stress conditions, toxins are freed and inhibit essential cellular processes using a variety of mechanisms. Here we characterize ataR-ataT, a novel TA system, from enterohemorrhagic Escherichia coli. We show that the toxin AtaT is a GNAT family enzyme that transfers an acetyl group from acetyl coenzyme A to the amine group of the methionyl aminoacyl moiety of initiator tRNA. AtaT specifically modifies Met-tRNA fMet , but no other aminoacyl-tRNAs, including the elongator Met-tRNA Met . We demonstrate that once acetylated, AcMet-tRNA fMet fails to interact with initiation factor-2 (IF2), resulting in disruption of the translation initiation complex. This work reveals a new mechanism of translation inhibition and confirms Met-tRNA fMet as a prime target to efficiently block cell growth.

Activation of the JNK pathway is essential for transformation by the Met oncogene.

PubMed

Rodrigues, G A; Park, M; Schlessinger, J

1997-05-15

The Met/Hepatocyte Growth Factor (HGF) receptor tyrosine kinase is oncogenically activated through a rearrangement that creates a hybrid gene Tpr-Met. The resultant chimeric p65(Tpr-Met) protein is constitutively phosphorylated on tyrosine residues in vivo and associates with a number of SH2-containing signaling molecules including the p85 subunit of PI-3 kinase and the Grb2 adaptor protein, which couples receptor tyrosine kinases to the Ras signaling pathway. Mutation of the binding site for Grb2 impairs the ability of Tpr-Met oncoprotein to transform fibroblasts, suggesting that the activation of the Ras/MAP kinase signaling pathway through Grb2 may be essential for cellular transformation. To test this hypothesis dominant-negative mutants of Grb2 with deletions of the SH3 domains were introduced into Tpr-Met transformed fibroblasts. Cells overexpressing the mutants were found to be morphologically reverted and exhibited reduced growth in soft agar. Surprisingly, the Grb2 mutants blocked activation of the JNK/SAPK but not MAP kinase activity induced by the Tpr-Met oncoprotein. Additionally, cells expressing dominant-negative Grb2 mutants had reduced PI-3-kinase activity and dominant-negative mutants of Rac1 blocked both Tpr-Met-induced transformation and activation of JNK. These experiments reveal a novel link between Met and the JNK pathway, which is essential for transformation by this oncogene.

Substance P-induced release of Met5-enkephalin from striatal and periaqueductal gray slices.

PubMed

Del Río, J; Naranjo, J R; Yang, H Y; Costa, E

1983-11-21

Substance P(SP), the heptapeptide SP and the stable analogue (p-Glu5-MePhe8-MeGly9) SP (DiMe-C7) induce a Ca2+-dependent release of Met5-enkephalin (MET) from slices of periaqueductal gray matter (PAG) and striatum of rats. The MET release from striatal slices is greater than that from PAG slices because of the higher MET content of striatum. Intraventricular injection of SP and of the two related peptides induce analgesia in the rat, and their analgesic potency is in line with their capacity to release MET. Other neuropeptides which possess antinociceptive activity such as bombesin, neurotensin, vasopressin and somatostatin fail to release MET from PAG slices.

The Involvement of Hepatocyte Growth Factor-MET-Matrix Metalloproteinase 1 Signaling in Bladder Cancer Invasiveness and Proliferation. Effect of the MET Inhibitor, Cabozantinib (XL184), on Bladder Cancer Cells.

PubMed

Shintani, Terumichi; Kusuhara, Yoshito; Daizumoto, Kei; Dondoo, Tsogt-Ochir; Yamamoto, Hiroki; Mori, Hidehisa; Fukawa, Tomoya; Nakatsuji, Hiroyoshi; Fukumori, Tomoharu; Takahashi, Masayuki; Kanayama, Hiroomi

2017-03-01

To clarify the invasive mechanisms of muscle-invasive bladder cancer (BCa) would be useful for the determination of appropriate treatment strategies. We previously showed that hepatocyte growth factor (HGF)-MET signaling is correlated with invasiveness of BCa cells. Here, we investigated the effects of the MET inhibitor, cabozantinib (XL184), on BCa cells. We first conducted Western blot analysis to investigate MET expression in BCa cell lines. Next, we examined the effect of cabozantinib on their proliferation and invasive abilities using MTT and Matrigel invasion assays, respectively. Invasion assays were performed using the xCELLigence system. Additionally, to investigate the biological function of HGF-MET signaling, we analyzed gene expression profiles and performed real-time polymerase chain reaction analyses of 5637 cells that were cultivated with or without HGF stimulation, with or without cabozantinib. MET was highly expressed in 4 of 5 BCa cell lines, and 5637 and T24 cells showed especially high protein expression of MET. Cabozantinib suppressed cell proliferation and invasion (cell index; mock, 1.49 vs HGF, 2.26 vs HGF + XL184, 1.47, P < .05). Gene expression profile analysis indicated that matrix metalloproteinase 1 (MMP1) was significantly elevated at the mRNA level with addition of HGF. Moreover, cabozantinib suppressed HGF-induced MMP1 expression in 5637 T24 cells. These data indicate that cabozantinib suppressed MMP1 expression by blocking HGF-MET signaling and that HGF-MET-MMP1 signaling is involved in the invasiveness and proliferation of BCa cells. These results suggest that cabozantinib might prove useful for future treatment of muscle-invasive BCa. Copyright © 2016 Elsevier Inc. All rights reserved.

Spirituelles Wohlbefinden und Coping bei Sklerodermie, Lupus erythematodes und malignem Melanom.

PubMed

Pilch, Michaela; Scharf, Sabina Nadine; Lukanz, Martin; Wutte, Nora Johanna; Fink-Puches, Regina; Glawischnig-Goschnik, Monika; Unterrainer, Human-Friedrich; Aberer, Elisabeth

2016-07-01

Religiös-spirituelles Wohlbefinden ist verbunden mit höherer Vitalität und verminderter Depressionsneigung. In unserer Studie untersuchten wir die Strategien zur Krankheitsbewältigung und die Rolle von Religiosität-Spiritualität (R-S) zur Verbesserung des subjektiven Wohlbefindens. 149 Patienten (107 Frauen), 44 mit systemischer Sklerodermie (SKL), 48 mit Lupus erythematodes (LE) und 57 mit malignem Melanom (MM), Stadium I-II, wurden mittels eines selbstentwickelten Fragebogens zum subjektiven Wohlbefinden, zu den mit der Erkrankung einhergehenden Umständen sowie mit dem Multidimensionalen Inventar (MI-RSB) zu R-S befragt. LE-Patienten sind zum Zeitpunkt der Diagnosestellung stärker belastet als SKL- und MM-Patienten. SKL- und LE-Patienten können erst nach Jahren die Erkrankung akzeptieren. Der Gesamtscore des religiös-spirituellen Befindens liegt bei LE-Patienten signifikant unter dem Wert der Normalbevölkerung. Fotosensitivität und Gelenksschmerzen sind bei LE-Patienten negativ assoziiert mit der Fähigkeit Vergeben zu können. SKL-Patienten mit Gesichtsveränderungen und Lungenbeteiligung zeigen höhere allgemeine Religiosität. MM-Patienten haben höhere Werte für transzendente Hoffnung. Vorträge über die Krankheit und psychologische Betreuung sind die wichtigsten Bedürfnisse von Patienten mit SKL, LE und MM an ihre Betreuer. Religiös-spirituelle Angebote zur Krankheitsverarbeitung scheinen derzeit eine untergeordnete Rolle zu spielen, könnten aber eine wichtige Ressource sein, der man in Zukunft mehr Aufmerksamkeit schenken sollte. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

Targeted deletion of c-Met in thymic epithelial cells leads to an autoimmune phenotype

PubMed Central

Su, Min; Hu, Rong; Song, Yinhong; Liu, Yalan; Lai, Laijun

2017-01-01

Hepatocyte growth factor (HGF) and its receptor c-Met signaling have been implicated in regulating various types of cells including epithelial cells. We have previously reported that c-Met is expressed by thymic epithelial cells (TECs), and that in vivo administration of hybrid cytokines containing IL-7 and the beta- or alpha-chain of HGF significantly increase the number of TECs. In order to study the role of c-Met signaling in TECs, we generated conditional knockout (cKO) mice in which c-Met was specifically deleted in TECs using a Foxn1-Cre transgene. We show here that c-Met deficiency in TECs results in age-progressive reduction in TEC number and reduced number of regulatory T cells. Consequently, c-Met TEC cKO mice displayed an autoimmune phenotype. Thus, c-Met signaling in TECs is important for the maintenance of TECs and immune self-tolerance. PMID:29363160

In vivo detection of c-Met expression in a rat C6 glioma model.

PubMed

Towner, R A; Smith, N; Doblas, S; Tesiram, Y; Garteiser, P; Saunders, D; Cranford, R; Silasi-Mansat, R; Herlea, O; Ivanciu, L; Wu, D; Lupu, F

2008-01-01

The tyrosine kinase receptor, c-Met, and its substrate, the hepatocyte growth factor (HGF), are implicated in the malignant progression of glioblastomas. In vivo detection of c-Met expression may be helpful in the diagnosis of malignant tumours. The C6 rat glioma model is a widely used intracranial brain tumour model used to study gliomas experimentally. We used a magnetic resonance imaging (MRI) molecular targeting agent to specifically tag the cell surface receptor, c-Met, with an anti-c-Met antibody (Ab) linked to biotinylated Gd (gadolinium)-DTPA (diethylene triamine penta acetic acid)-albumin in rat gliomas to detect overexpression of this antigen in vivo. The anti-c-Met probe (anti-c-Met-Gd-DTPA-albumin) was administered intravenously, and as determined by an increase in MRI signal intensity and a corresponding decrease in regional T(1) relaxation values, this probe was found to detect increased expression of c-Met protein levels in C6 gliomas. In addition, specificity for the binding of the anti-c-Met contrast agent was determined by using fluorescence microscopic imaging of the biotinylated portion of the targeting agent within neoplastic and 'normal'brain tissues following in vivo administration of the anti-c-Met probe. Controls with no Ab or with a normal rat IgG attached to the contrast agent component indicated no non-specific binding to glioma tissue. This is the first successful visualization of in vivo overexpression of c-Met in gliomas.

In vivo detection of c-Met expression in a rat C6 glioma model

PubMed Central

Towner, RA; Smith, N; Doblas, S; Tesiram, Y; Garteiser, P; Saunders, D; Cranford, R; Silasi-Mansat, R; Herlea, O; Ivanciu, L; Wu, D; Lupu, F

2008-01-01

Abstract The tyrosine kinase receptor, c-Met, and its substrate, the hepatocyte growth factor (HGF), are implicated in the malignant progression of glioblastomas. In vivo detection of c-Met expression may be helpful in the diagnosis of malignant tumours. The C6 rat glioma model is a widely used intracranial brain tumour model used to study gliomas experimentally. We used a magnetic resonance imaging (MRI) molecular targeting agent to specifically tag the cell surface receptor, c-Met, with an anti-c-Met antibody (Ab) linked to biotinylated Gd (gadolinium)-DTPA (diethylene triamine penta acetic acid)-albumin in rat gliomas to detect overexpression of this antigen in vivo. The anti-c-Met probe (anti-c-Met-Gd-DTPA-albumin) was administered intravenously, and as determined by an increase in MRI signal intensity and a corresponding decrease in regional T1 relaxation values, this probe was found to detect increased expression of c-Met protein levels in C6 gliomas. In addition, specificity for the binding of the anti-c-Met contrast agent was determined by using fluorescence microscopic imaging of the biotinylated portion of the targeting agent within neoplastic and ‘normal’brain tissues following in vivo administration of the anti-c-Met probe. Controls with no Ab or with a normal rat IgG attached to the contrast agent component indicated no non-specific binding to glioma tissue. This is the first successful visualization of in vivo overexpression of c-Met in gliomas. PMID:18194445

77 FR 25080 - Safety Zones; TriMet Bridge Project, Willamette River, Portland, OR

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-27

...-AA00 Safety Zones; TriMet Bridge Project, Willamette River, Portland, OR AGENCY: Coast Guard, DHS... trestles and construction cranes involved in the construction of the TriMet Bridge on the Willamette River... project. These safety zones replace the prior safety zones established for the TriMet Bridge construction...

Role and Therapeutic Targeting of the HGF/MET Pathway in Glioblastoma

PubMed Central

Cruickshanks, Nichola; Zhang, Ying; Yuan, Fang; Pahuski, Mary; Gibert, Myron; Abounader, Roger

2017-01-01

Glioblastoma (GBM) is a lethal brain tumor with dismal prognosis. Current therapeutic options, consisting of surgery, chemotherapy and radiation, have only served to marginally increase patient survival. Receptor tyrosine kinases (RTKs) are dysregulated in approximately 90% of GBM; attributed to this, research has focused on inhibiting RTKs as a novel and effective therapy for GBM. Overexpression of RTK mesenchymal epithelial transition (MET), and its ligand, hepatocyte growth factor (HGF), in GBM highlights a promising new therapeutic target. This review will discuss the role of MET in cell cycle regulation, cell proliferation, evasion of apoptosis, cell migration and invasion, angiogenesis and therapeutic resistance in GBM. It will also discuss the modes of deregulation of HGF/MET and their regulation by microRNAs. As the HGF/MET pathway is a vital regulator of multiple pro-survival pathways, efforts and strategies for its exploitation for GBM therapy are also described. PMID:28696366

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

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-25

...-AA00 Safety Zone; TriMet Bridge Project, Willamette River; Portland, OR AGENCY: Coast Guard, DHS... the TriMet Bridge on the Willamette River, in Portland, OR. This action is necessary to ensure the... Zone: TriMet Bridge Project, Willamette River; Portland, OR in the Federal Register (76 FR 86). We...

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

PubMed

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.

Preproghrelin Leu72Met polymorphism in Chinese subjects with coronary artery disease and controls.

PubMed

Tang, Na-Ping; Wang, Lian-Sheng; Yang, Li; Gu, Hai-Juan; Zhu, Huai-Jun; Zhou, Bo; Sun, Qing-Min; Cong, Ri-Hong; Wang, Bin

2008-01-01

Ghrelin, a novel endogenous ligand for the growth hormone secretagogue receptor, is considered to exert a protective effect against atherosclerosis. The Leu72Met (+408C>A) polymorphic variant of the preproghrelin, the gene for the ghrelin precursor, has been linked to obesity, diabetes and metabolic syndrome. However, it is unclear whether this polymorphism is associated with coronary artery disease (CAD). We conducted a case-control study with 317 CAD patients and 323 controls to investigate the potential association of the Leu72Met polymorphism with the occurrence of CAD and CAD-related phenotypes in Chinese population. No significant difference in the Leu72Met genotype frequency was observed between CAD patients and controls (P=NS). The Leu72Met polymorphism was not associated with hypertension, diabetes, dyslipidemia, the number of diseased vessels, plasma total cholesterol, triglyceride, high density lipoprotein cholesterol, low density lipoprotein cholesterol or fasting glucose levels in CAD patients. However, among CAD patients, those with variant genotypes (Leu72Met and Met72Met) had lower BMI (24.4+/-0.3 kg/m(2)) than Leu72Leu carriers (25.4+/-0.2 kg/m(2), adjusted P=0.033). Our data indicate that the preproghrelin Leu72Met polymorphism is not associated with CAD in Chinese population. However, the Leu72Met variant is associated with BMI among CAD patients.

Reciprocal Activating Crosstalk between c-Met and Caveolin 1 Promotes Invasive Phenotype in Hepatocellular Carcinoma

PubMed Central

Korhan, Peyda; Erdal, Esra; Kandemiş, Emine; Çokaklı, 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. PMID:25148256

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

PubMed

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.

Expression and prognostic relevance of MET and phospho-BAD in non-small cell lung cancer.

PubMed

Sun, Wenze; Ai, Ting; Gao, Ying; Zhang, Yingbing; Cui, Jie; Song, Liping

2013-01-01

MET is involved in the progression of several types of human cancers, while phospho-BAD(Ser-136) is a key molecule in apoptosis and might be regulated by MET. The aim of this study was to investigate the correlation between altered expression of MET and phospho-BAD in non-small cell lung cancer (NSCLC) and their association with clinicopathologic parameters and overall survival. MET and phospho-BAD(Ser-136) proteins were evaluated by immunohistochemical analysis in 183 paraffin-embedded specimens and were also assessed by Western blotting analysis in 12 frozen tumor tissue samples, which were representative examples of immunohistochemical staining. Positive expression of MET and phospho-BAD(Ser-136) occurred in 67.2% and 49.2% of the 183 cases of NSCLC, respectively. However, neither MET expression nor phospho-BAD(Ser-136) expression was associated with any clinicopathologic parameter. A significant correlation was found between MET and phospho-BAD(Ser-136) expression levels evaluated by immunohistochemistry (r = 0.268, P < 0.001). Overexpression of MET was significantly associated with shortened overall survival in univariate analysis (P < 0.001). Moreover, patients with a MET+/phospho-BAD(Ser-136)+ phenotype had a poorer prognosis than others (P < 0.001). Multivariate Cox proportional hazard analysis confirmed that MET expression is a prognostic factor for NSCLC. MET expression might be correlated with phospho-BAD(Ser-136) expression, and may be an adverse predictor for NSCLC. Activation of the MET/phospho-BAD(Ser-136) signaling pathway might play a role in the development and progression of NSCLC.

MET inhibition overcomes radiation resistance of glioblastoma stem-like cells.

PubMed

De Bacco, Francesca; D'Ambrosio, Antonio; Casanova, Elena; Orzan, Francesca; Neggia, Roberta; Albano, Raffaella; Verginelli, Federica; Cominelli, Manuela; Poliani, Pietro L; Luraghi, Paolo; Reato, Gigliola; Pellegatta, Serena; Finocchiaro, Gaetano; Perera, Timothy; Garibaldi, Elisabetta; Gabriele, Pietro; Comoglio, Paolo M; Boccaccio, Carla

2016-05-01

Glioblastoma (GBM) contains stem-like cells (GSCs) known to be resistant to ionizing radiation and thus responsible for therapeutic failure and rapidly lethal tumor recurrence. It is known that GSC radioresistance relies on efficient activation of the DNA damage response, but the mechanisms linking this response with the stem status are still unclear. Here, we show that the MET receptor kinase, a functional marker of GSCs, is specifically expressed in a subset of radioresistant GSCs and overexpressed in human GBM recurring after radiotherapy. We elucidate that MET promotes GSC radioresistance through a novel mechanism, relying on AKT activity and leading to (i) sustained activation of Aurora kinase A, ATM kinase, and the downstream effectors of DNA repair, and (ii) phosphorylation and cytoplasmic retention of p21, which is associated with anti-apoptotic functions. We show that MET pharmacological inhibition causes DNA damage accumulation in irradiated GSCs and their depletion in vitro and in GBMs generated by GSC xenotransplantation. Preclinical evidence is thus provided that MET inhibitors can radiosensitize tumors and convert GSC-positive selection, induced by radiotherapy, into GSC eradication. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

Modulation of the COMT Val(158)Met polymorphism on resting-state EEG power.

PubMed

Solís-Ortiz, Silvia; Pérez-Luque, Elva; Gutiérrez-Muñoz, Mayra

2015-01-01

The catechol-O-methyltransferase (COMT) Val(158)Met polymorphism impacts cortical dopamine (DA) levels and may influence cortical electrical activity in the human brain. This study investigated whether COMT genotype influences resting-state electroencephalogram (EEG) power in the frontal, parietal and midline regions in healthy volunteers. EEG recordings were conducted in the resting-state in 13 postmenopausal healthy woman carriers of the Val/Val genotype and 11 with the Met/Met genotype. The resting EEG spectral absolute power in the frontal (F3, F4, F7, F8, FC3 and FC4), parietal (CP3, CP4, P3 and P4) and midline (Fz, FCz, Cz, CPz, Pz and Oz) was analyzed during the eyes-open and eyes-closed conditions. The frequency bands considered were the delta, theta, alpha1, alpha2, beta1 and beta2. EEG data of the Val/Val and Met/Met genotypes, brain regions and conditions were analyzed using a general linear model analysis. In the individuals with the Met/Met genotype, delta activity was increased in the eyes-closed condition, theta activity was increased in the eyes-closed and in the eyes-open conditions, and alpha1 band, alpha2 band and beta1band activity was increased in the eyes-closed condition. A significant interaction between COMT genotypes and spectral bands was observed. Met homozygote individuals exhibited more delta, theta and beta1 activity than individuals with the Val/Val genotype. No significant interaction between COMT genotypes and the resting-state EEG regional power and conditions were observed for the three brain regions studied. Our findings indicate that the COMT Val(158)Met polymorphism does not directly impact resting-state EEG regional power, but instead suggest that COMT genotype can modulate resting-state EEG spectral power in postmenopausal healthy women.

Modulation of the COMT Val158Met polymorphism on resting-state EEG power

PubMed Central

Solís-Ortiz, Silvia; Pérez-Luque, Elva; Gutiérrez-Muñoz, Mayra

2015-01-01

The catechol-O-methyltransferase (COMT) Val158Met polymorphism impacts cortical dopamine (DA) levels and may influence cortical electrical activity in the human brain. This study investigated whether COMT genotype influences resting-state electroencephalogram (EEG) power in the frontal, parietal and midline regions in healthy volunteers. EEG recordings were conducted in the resting-state in 13 postmenopausal healthy woman carriers of the Val/Val genotype and 11 with the Met/Met genotype. The resting EEG spectral absolute power in the frontal (F3, F4, F7, F8, FC3 and FC4), parietal (CP3, CP4, P3 and P4) and midline (Fz, FCz, Cz, CPz, Pz and Oz) was analyzed during the eyes-open and eyes-closed conditions. The frequency bands considered were the delta, theta, alpha1, alpha2, beta1 and beta2. EEG data of the Val/Val and Met/Met genotypes, brain regions and conditions were analyzed using a general linear model analysis. In the individuals with the Met/Met genotype, delta activity was increased in the eyes-closed condition, theta activity was increased in the eyes-closed and in the eyes-open conditions, and alpha1 band, alpha2 band and beta1band activity was increased in the eyes-closed condition. A significant interaction between COMT genotypes and spectral bands was observed. Met homozygote individuals exhibited more delta, theta and beta1 activity than individuals with the Val/Val genotype. No significant interaction between COMT genotypes and the resting-state EEG regional power and conditions were observed for the three brain regions studied. Our findings indicate that the COMT Val158Met polymorphism does not directly impact resting-state EEG regional power, but instead suggest that COMT genotype can modulate resting-state EEG spectral power in postmenopausal healthy women. PMID:25883560

Designing a more efficient, effective and safe Medical Emergency Team (MET) service using data analysis

PubMed Central

Bilgrami, Irma; Bain, Christopher; Webb, Geoffrey I.; Orosz, Judit; Pilcher, David

2017-01-01

Introduction Hospitals have seen a rise in Medical Emergency Team (MET) reviews. We hypothesised that the commonest MET calls result in similar treatments. Our aim was to design a pre-emptive management algorithm that allowed direct institution of treatment to patients without having to wait for attendance of the MET team and to model its potential impact on MET call incidence and patient outcomes. Methods Data was extracted for all MET calls from the hospital database. Association rule data mining techniques were used to identify the most common combinations of MET call causes, outcomes and therapies. Results There were 13,656 MET calls during the 34-month study period in 7936 patients. The most common MET call was for hypotension [31%, (2459/7936)]. These MET calls were strongly associated with the immediate administration of intra-venous fluid (70% [1714/2459] v 13% [739/5477] p<0.001), unless the patient was located on a respiratory ward (adjusted OR 0.41 [95%CI 0.25–0.67] p<0.001), had a cardiac cause for admission (adjusted OR 0.61 [95%CI 0.50–0.75] p<0.001) or was under the care of the heart failure team (adjusted OR 0.29 [95%CI 0.19–0.42] p<0.001). Modelling the effect of a pre-emptive management algorithm for immediate fluid administration without MET activation on data from a test period of 24 months following the study period, suggested it would lead to a 68.7% (2541/3697) reduction in MET calls for hypotension and a 19.6% (2541/12938) reduction in total METs without adverse effects on patients. Conclusion Routinely collected data and analytic techniques can be used to develop a pre-emptive management algorithm to administer intravenous fluid therapy to a specific group of hypotensive patients without the need to initiate a MET call. This could both lead to earlier treatment for the patient and less total MET calls. PMID:29281665

Differential transcriptional control of the two tRNA(fMet) genes of Escherichia coli K-12.

PubMed

Nagase, T; Ishii, S; Imamoto, F

1988-07-15

The metZ gene of Escherichia coli, which encodes the tRNA(f1Met), was cloned. Using the nucleotide sequence, in vitro transcription, and S1 nuclease mapping analyses, we identified the promoter region, transcriptional start point, the two tandem tRNA(f1Met) structural genes separated by an intergenic space of 33 bp, and the two Rho-independent transcriptional termination sites, in that order. We compared the promoter region of the metZ gene with that of the metY gene, which encodes the tRNA(f2Met) and is located in the promoter-proximal portion of the nusA operon. A G + C-rich sequence (5'-GCGCATCCAC-3'), similar to the corresponding sequence of the rrn promoters that are under stringent control, was found between the Pribnow box and the transcriptional start point of the metZ promoter, but not in the metY promoter region. We therefore examined the effect of guanosine 3'-diphosphate, 5'-diphosphate (ppGpp), the chemical mediator of stringent control, and found that ppGpp inhibited the transcription of the metZ gene, but not that of the metY gene. These data suggested that the promoters for metZ and metY have different physiological functions and are regulated by different mechanisms.

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

PubMed

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.

The MetOp second generation 3MI instrument

NASA Astrophysics Data System (ADS)

Manolis, Ilias; Grabarnik, Semen; Caron, Jérôme; Bézy, Jean-Loup; Loiselet, Marc; Betto, Maurizio; Barré, Hubert; Mason, Graeme; Meynart, Roland

2013-10-01

The MetOp-SG programme is a joint Programme of EUMETSAT and ESA. ESA develops the prototype MetOp-SG satellites (including associated instruments) and procures, on behalf of EUMETSAT, the recurrent satellites (and associated instruments). Two parallel, competitive phase A/B1 studies for MetOp Second Generation (MetOp-SG) have been concluded in May 2013. The implementation phases (B2/C/D/E) are planned to start the first quarter of 2014. ESA is responsible for instrument design of six missions, namely Microwave Sounding Mission (MWS), Scatterometer mission (SCA), Radio Occultation mission (RO), Microwave Imaging mission (MWI), Ice Cloud Imager (ICI) and Multi-viewing, Multi-channel, Multi-polarisation imaging mission (3MI). The paper will present the main performances of the 3MI instrument and will highlight the performance improvements with respect to its heritage derived by the POLDER instrument, such as number of spectral channels and spectral range coverage, swath and ground spatial resolution. The engineering of some key performance requirements (multi-viewing, polarisation sensitivity, straylight etc.) will also be discussed. The results of the feasibility studies will be presented together with the programmatics for the instrument development. Several pre-development activities have been initiated to retire highest risks and to demonstrate the ultimate performances of the 3MI optics. The scope, objectives and current status of those activities will be presented. Key technologies involved in the 3MI instrument design and implementation are considered to be: the optical design featuring aspheric optics, the implementation of broadband Anti Reflection coatings featuring low polarisation and low de-phasing properties, the development and qualification of polarisers with acceptable performances as well as spectral filters with good uniformities over a large clear aperture.

Detection of MET Gene Copy Number in Cancer Samples Using the Droplet Digital PCR Method.

PubMed

Zhang, Yanni; Tang, En-Tzu; Du, Zhiqiang

2016-01-01

The analysis of MET gene copy number (CN) has been considered to be a potential biomarker to predict the response to MET-targeted therapies in various cancers. However, the current standard methods to determine MET CN are SNP 6.0 in the genomic DNA of cancer cell lines and fluorescence in situ hybridization (FISH) in tumor models, respectively, which are costly and require advanced technical skills and result in relatively subjective judgments. Therefore, we employed a novel method, droplet digital PCR (ddPCR), to determine the MET gene copy number with high accuracy and precision. The genomic DNA of cancer cell lines or tumor models were tested and compared with the MET gene CN and MET/CEN-7 ratio determined by SNP 6.0 and FISH, respectively. In cell lines, the linear association of the MET CN detected by ddPCR and SNP 6.0 is strong (Pearson correlation = 0.867). In tumor models, the MET CN detected by ddPCR was significantly different between the MET gene amplification and non-amplification groups according to FISH (mean: 15.4 vs 2.1; P = 0.044). Given that MET gene amplification is defined as MET CN >5.5 by ddPCR, the concordance rate between ddPCR and FISH was 98.0%, and Cohen's kappa coefficient was 0.760 (95% CI, 0.498-1.000; P <0.001). The results demonstrated that the ddPCR method has the potential to quantify the MET gene copy number with high precision and accuracy as compared with the results from SNP 6.0 and FISH in cancer cell lines and tumor samples, respectively.

Warmtetransport in Kleding bij Aanstraling met Warmte (Heat Transport in Clothing during Irradiation with Heat)

DTIC Science & Technology

1990-01-22

the thermal insulation of clothing . Ergonomics 2S, 1617-1632. Nielsen, B., Kasson, K. en Aschengreen, F.E. (1988). Heat balance during exercise in...the sun. Eur. J. Appl. Physiol. 58, 189-196. Nielsen, B. (1989). Solar heat load: heat balance during exercise in clothed subjects. Manuscript voor Eur...Institute for Perception, Soesterberg, The Netherlands Heat transport in clothing during irradiation vith heat A.M.J. Pieters and W.A. Lotens ABSTRACT A

Trizentrische Analyse von Kofaktoren und Komorbidität des Pyoderma gangraenosum.

PubMed

Jockenhöfer, Finja; Herberger, Katharina; Schaller, Jörg; Hohaus, Katja Christina; Stoffels-Weindorf, Maren; Ghazal, Philipp Al; Augustin, Matthias; Dissemond, Joachim

2016-10-01

Das Pyoderma gangraenosum (PG) ist eine seltene, inflammatorische destruktiv-ulzerierende neutrophile Erkrankung mit weitgehend unklarer Pathophysiologie. In dieser Studie wurden die potenziell relevanten Kofaktoren und Begleiterkrankungen von Patienten mit PG aus drei dermatologischen Wundzentren in Deutschland differenziert ausgewertet. Von den insgesamt 121 analysierten Patienten waren Frauen (66,9 %) häufiger betroffen als Männer. Das Alter der Patienten war 18-96 Jahre (Mittelwert [MW]: 59,8); die Wunden hatten eine Größe von 1-600 cm² (MW: 65,6 cm²) und waren überwiegend sehr schmerzhaft (VAS 1-10, MW: 7). Die Unterschenkel waren am häufigsten (71,9 %) betroffen. Bei 12 (9,9 %) Patienten bestanden chronisch entzündliche Darmerkrankungen (5,8 % Colitis ulcerosa; 4,1 % Morbus Crohn), bei 14,1 % der Patienten wurde eine Begleiterkrankung aus dem rheumatischen Formenkreis beschrieben. Neoplasien bestanden bei 20,6 % der Patienten, von denen 6,6 % als hämatologische und 14,1 % als solide Neoplasien klassifiziert wurden. Aus dem Kreis des metabolischen Syndroms wurde bei 69,4 % Patienten eine Adipositas, bei 57,9 % eine arterielle Hypertonie und bei 33,9 % ein Diabetes mellitus diagnostiziert. Diese Datenanalyse bestätigt Assoziationen des PG mit dem metabolischen Syndrom und mit Neoplasien, die zukünftig frühzeitig bei einer zielgerichteten Diagnostik der Patienten beachtet und behandelt werden sollten. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

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

ERIC Educational Resources Information Center

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…

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

PubMed

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.

The MetOp second generation 3MI mission

NASA Astrophysics Data System (ADS)

Manolis, Ilias; Caron, Jérôme; Grabarnik, Semen; Bézy, Jean-Loup; Betto, Maurizio; Barré, Hubert; Mason, Graeme; Meynart, Roland

2017-11-01

ESA is currently running two parallel, competitive phase A/B1 studies for MetOp Second Generation (MetOp-SG). MetOp-SG is the space segment of EUMETSAT Polar System (EPS-SG) consisting of the satellites and instruments. The Phase A/B1 studies will be completed in the first quarter of 2013. The final implementation phases (B2/C/D) are planned to start 2013. ESA is responsible for instrument design of five missions, namely Microwave Sounding Mission (MWS), Scatterometer mission (SCA), Radio Occultation mission (RO), Microwave Imaging mission (MWI), Ice Cloud Imaging (ICI) mission, and Multiviewing, Multi-channel, Multi-polarization imaging mission (3MI). This paper will present the instrument main design elements of the 3MI mission, primarily aimed at providing aerosol characterization for climate monitoring, Numerical Weather Prediction (NWP), atmospheric chemistry and air quality. The 3MI instrument is a passive radiometer measuring the polarized radiances reflected by the Earth under different viewing geometries and across several spectral bands spanning the visible and short-wave infrared spectrum. The paper will present the main performances of the instrument and will concentrate mainly on the performance improvements with respect to its heritage derived by the POLDER instrument. The engineering of some key performance requirements (multiviewing, polarization sensitivity, etc.) will also be discussed.

Targeting the MET oncogene by concomitant inhibition of receptor and ligand via an antibody-"decoy" strategy.

PubMed

Basilico, Cristina; Modica, Chiara; Maione, Federica; Vigna, Elisa; Comoglio, Paolo M

2018-04-25

MET, a master gene sustaining "invasive growth," is a relevant target for cancer precision therapy. In the vast majority of tumors, wild-type MET behaves as a "stress-response" gene and relies on the ligand (HGF) to sustain cell "scattering," invasive growth and apoptosis protection (oncogene "expedience"). In this context, concomitant targeting of MET and HGF could be crucial to reach effective inhibition. To test this hypothesis, we combined an anti-MET antibody (MvDN30) inducing "shedding" (i.e., removal of MET from the cell surface), with a "decoy" (i.e., the soluble extracellular domain of the MET receptor) endowed with HGF-sequestering ability. To avoid antibody/decoy interaction-and subsequent neutralization-we identified a single aminoacid in the extracellular domain of MET-lysine 842-that is critical for MvDN30 binding and engineered the corresponding recombinant decoyMET (K842E). DecoyMET K842E retains the ability to bind HGF with high affinity and inhibits HGF-induced MET phosphorylation. In HGF-dependent cellular models, MvDN30 antibody and decoyMET K842E used in combination cooperate in restraining invasive growth, and synergize in blocking cancer cell "scattering." The antibody and the decoy unbridle apoptosis of colon cancer stem cells grown in vitro as spheroids. In a preclinical model, built by orthotopic transplantation of a human pancreatic carcinoma in SCID mice engineered to express human HGF, concomitant treatment with antibody and decoy significantly reduces metastatic spread. The data reported indicate that vertical targeting of the MET/HGF axis results in powerful inhibition of ligand-dependent MET activation, providing proof of concept in favor of combined target therapy of MET "expedience." © 2018 UICC.

Mice with GFAP-targeted loss of neurofibromin demonstrate increased axonal MET expression with aging.

PubMed

Su, Weiping; Xing, Rubing; Guha, Abhijit; Gutmann, David H; Sherman, Larry S

2007-05-01

Neurofibromatosis 1 (NF1) is a common genetic disease that predisposes patients to peripheral nerve tumors and central nervous system (CNS) abnormalities including low-grade astrocytomas and cognitive disabilities. Using mice with glial fibrillary acidic protein (GFAP)-targeted Nf1 loss (Nf1(GFAP)CKO mice), we found that Nf1(-/-) astrocytes proliferate faster and are more invasive than wild-type astrocytes. In light of our previous finding that aberrant expression of the MET receptor tyrosine kinase contributes to the invasiveness of human NF1-associated malignant peripheral nerve sheath tumors, we sought to determine whether MET expression is aberrant in the brains of Nf1 mutant mice. We found that Nf1(-/-) astrocytes express slightly more MET than wild-type cells in vitro, but do not express elevated MET in situ. However, fiber tracts containing myelinated axons in the hippocampus, midbrain, cerebral cortex, and cerebellum express higher than normal levels of MET in older (> or =6 months) Nf1(GFAP)CKO mice. Both Nf1(GFAP)CKO and wild-type astrocytes induced MET expression in neurites of wild-type hippocampal neurons in vitro, suggesting that astrocyte-derived signals may induce MET in Nf1 mutant mice. Because the Nf1 gene product functions as a RAS GTPase, we examined MET expression in the brains of mice with GFAP-targeted constitutively active forms of RAS. MET was elevated in axonal fiber tracts in mice with active K-RAS but not H-RAS. Collectively, these data suggest that loss of Nf1 in either astrocytes or GFAP(+) neural progenitor cells results in increased axonal MET expression, which may contribute to the CNS abnormalities in children and adults with NF1. (c) 2007 Wiley-Liss, Inc.

Hepatocyte growth factor/scatter factor-MET signaling in neural crest-derived melanocyte development.

PubMed

Kos, L; Aronzon, A; Takayama, H; Maina, F; Ponzetto, C; Merlino, G; Pavan, W

1999-02-01

The mechanisms governing development of neural crest-derived melanocytes, and how alterations in these pathways lead to hypopigmentation disorders, are not completely understood. Hepatocyte growth factor/scatter factor (HGF/SF) signaling through the tyrosine-kinase receptor, MET, is capable of promoting the proliferation, increasing the motility, and maintaining high tyrosinase activity and melanin synthesis of melanocytes in vitro. In addition, transgenic mice that ubiquitously overexpress HGF/SF demonstrate hyperpigmentation in the skin and leptomenigenes and develop melanomas. To investigate whether HGF/ SF-MET signaling is involved in the development of neural crest-derived melanocytes, transgenic embryos, ubiquitously overexpressing HGF/SF, were analyzed. In HGF/SF transgenic embryos, the distribution of melanoblasts along the characteristic migratory pathway was not affected. However, additional ectopically localized melanoblasts were also observed in the dorsal root ganglia and neural tube, as early as 11.5 days post coitus (p.c.). We utilized an in vitro neural crest culture assay to further explore the role of HGF/SF-MET signaling in neural crest development. HGF/SF added to neural crest cultures increased melanoblast number, permitted differentiation into pigmented melanocytes, promoted melanoblast survival, and could replace mast-cell growth factor/Steel factor (MGF) in explant cultures. To examine whether HGF/SF-MET signaling is required for the proper development of melanocytes, embryos with a targeted Met null mutation (Met-/-) were analysed. In Met-/- embryos, melanoblast number and location were not overtly affected up to 14 days p.c. These results demonstrate that HGF/SF-MET signaling influences, but is not required for, the initial development of neural crest-derived melanocytes in vivo and in vitro.

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

PubMed Central

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

2016-01-01

People with autism spectrum disorder (ASD) 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 multi-functional 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 ASD, 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 ASD and other NDD candidates. The interactome is co-regulated 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, impacting central and peripheral phenotypes that contribute to NDD risk and clinical symptoms. PMID:27837921

Conservation and functional importance of carbon-oxygen hydrogen bonding in AdoMet-dependent methyltransferases.

PubMed

Horowitz, Scott; Dirk, Lynnette M A; Yesselman, Joseph D; Nimtz, Jennifer S; Adhikari, Upendra; Mehl, Ryan A; Scheiner, Steve; Houtz, Robert L; Al-Hashimi, Hashim M; Trievel, Raymond C

2013-10-16

S-adenosylmethionine (AdoMet)-based methylation is integral to metabolism and signaling. AdoMet-dependent methyltransferases belong to multiple distinct classes and share a catalytic mechanism that arose through convergent evolution; however, fundamental determinants underlying this shared methyl transfer mechanism remain undefined. A survey of high-resolution crystal structures reveals that unconventional carbon-oxygen (CH···O) hydrogen bonds coordinate the AdoMet methyl group in different methyltransferases irrespective of their class, active site structure, or cofactor binding conformation. Corroborating these observations, quantum chemistry calculations demonstrate that these charged interactions formed by the AdoMet sulfonium cation are stronger than typical CH···O hydrogen bonds. Biochemical and structural studies using a model lysine methyltransferase and an active site mutant that abolishes CH···O hydrogen bonding to AdoMet illustrate that these interactions are important for high-affinity AdoMet binding and transition-state stabilization. Further, crystallographic and NMR dynamics experiments of the wild-type enzyme demonstrate that the CH···O hydrogen bonds constrain the motion of the AdoMet methyl group, potentially facilitating its alignment during catalysis. Collectively, the experimental findings with the model methyltransferase and structural survey imply that methyl CH···O hydrogen bonding represents a convergent evolutionary feature of AdoMet-dependent methyltransferases, mediating a universal mechanism for methyl transfer.

Fatty Acid Synthase Activity as a Target for c-Met Driven Prostate Cancer

DTIC Science & Technology

2013-07-01

to aid future studies. Identification is a highly significant finding with regard to the potential for future therapeutic development targeted at...Met trafficking, stability, and ultimately oncogenic potential . Palmitoylation defective mutants will be used in animal models of c-Met driven tumor...growth (Aim 2). In addition, future work toward identifying the enzyme responsible for palmitoylation of c- Met will provide a new specific target

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

PubMed

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.

Clinical analysis by next-generation sequencing for NSCLC patients with MET amplification resistant to osimertinib.

PubMed

Wang, Yubo; Li, Li; Han, Rui; Jiao, Lin; Zheng, Jie; He, Yong

2018-04-01

The efficacy of osimertinib was compromised by the development of resistance mechanisms, such as MET amplification. However, cohort studies of osimertinib resistance mechanism, and the correlation of MET and progression-free survival (PFS) after osimertinib resistance have been poorly investigated. This study was carried out to study the acquired MET amplification after osimertinib resistance in advanced lung adenocarcinoma patients, and interrogate the correlation of clinical prognosis and MET amplification. We performed capture-based sequencing on longitudinal plasma and tissue samples obtained before osimertinib treatment and after resistance development from lung adenocarcinoma patients to investigate the underlying resistance mechanism. We also investigated the correlation of MET amplification and patient prognosis after osimertinib resistance using Kaplan-Meier analysis. Paired biopsies before osimertinib treatment and after the resistance development revealed underlying resistance mechanisms. In addition, a cohort of 13 patients who developed disease progression after osimertinib resistance was investigated. Patients with MET amplification after osimertinib resistance commonly had inferior median progression-free survival (mPFS) than patients without MET amplification appearance or increase (3.5 months vs. 9.9 months, p = .117). Patients in MET amplification group also displayed poor median overall survival (mOS) compared to MET amplification negative group (15.6 months vs. 30.7 months, p = .885). Furthermore, combinatorial treatment of first/third-generation EGFR-TKI and crizotinib was efficaciously administrated into two patients with newly acquired MET amplification after osimertinib resistance. Partial responses were achieved by them, both clinically and radiographically. We investigated the osimertinib resistance mechanism in a small cohort of lung adenocarcinoma patients, and demonstrated MET amplification was correlated with inferior PFS

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

PubMed

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.

Inhibition of EGFR Induces a c-MET Driven Stem Cell Population in Glioblastoma

PubMed Central

Jun, Hyun Jung; Bronson, Roderick T.; Charest, Al

2015-01-01

Glioblastoma multiforme (GBM) is the most lethal form of primary brain tumors, characterized by highly invasive and aggressive tumors that are resistant to all current therapeutic options. GBMs are highly heterogeneous in nature and contain a small but highly tumorigenic and self-renewing population of stem or initiating cells (Glioblastoma stem cells or GSCs). GSCs have been shown to contribute to tumor propagation and resistance to current therapeutic modalities. Recent studies of human GBMs have elucidated the genetic alterations common in these tumors, but much remains unknown about specific signaling pathways that regulate GSCs. Here we identify a distinct fraction of cells in a genetically engineered mouse model of EGFR-driven GBM that respond to anti-EGFR therapy by inducing high levels of c-MET expression. The MET positive cells displayed clonogenic potential and long-term self-renewal ability in vitro and are capable of differentiating into multiple lineages. The MET positive GBM cells are resistant to radiation and highly tumorigenic in vivo. Activation of MET signaling led to an increase in expression of the stemness transcriptional regulators Oct4, Nanog and Klf4. Pharmacological inhibition of MET activity in GSCs prevented the activation of Oct4, Nanog and Klf4 and potently abrogated stemness. Finally, the MET expressing cells were preferentially localized in perivascular regions of mouse tumors consistent with their function as GSCs. Together, our findings indicate that EGFR inhibition in GBM induces MET activation in GSCs, which is a functional requisite for GSCs activity and thus represents a promising therapeutic target. PMID:24115218

Receptor Tyrosine Kinase MET Interactome and Neurodevelopmental Disorder Partners at the Developing Synapse

PubMed Central

Xie, Zhihui; Li, Jing; Baker, Jonathan; Eagleson, Kathie L.; Coba, Marcelo P.; Levitt, Pat

2016-01-01

Background Atypical synapse development and plasticity are implicated in many neurodevelopmental disorders (NDDs). NDD-associated, high confidence risk genes have been identified, yet little is known about functional relationships at the level of protein-protein interactions, which are the dominant molecular bases responsible for mediating circuit development. Methods Proteomics in three independent developing neocortical synaptosomal preparations identified putative interacting proteins of the ligand-activated MET receptor tyrosine kinase, an autism risk gene that mediates synapse development. The candidates were translated into interactome networks and analyzed bioinformatically. Additionally, three independent quantitative proximity ligation assays (PLA) in cultured neurons and four independent immunoprecipitation analyses of synaptosomes validated protein interactions. Results Approximately 11% (8/72) of MET-interacting proteins, including SHANK3, SYNGAP1 and GRIN2B, are associated with NDDs. Proteins in the MET interactome were translated into a novel MET interactome network based on human protein-protein interaction databases. High confidence genes from different NDD datasets that encode synaptosomal proteins were analyzed for being enriched in MET interactome proteins. This was found for autism, but not schizophrenia, bipolar disorder, major depressive disorder or attentional deficit hyperactivity disorder. There is correlated gene expression between MET and its interactive partners in developing human temporal and visual neocortices, but not with highly expressed genes that are not in the interactome. PLA and biochemical analyses demonstrate that MET-protein partner interactions are dynamically regulated by receptor activation. Conclusions The results provide a novel molecular framework for deciphering the functional relations of key regulators of synaptogenesis that contribute to both typical cortical development and to NDDs. PMID:27086544

Macroporous hydrogel micropillars for quantifying Met kinase activity in cancer cell lysates.

PubMed

Powers, Alicia D; Liu, Bi; Lee, Andrew G; Palecek, Sean P

2012-09-07

Overactive and overexpressed kinases have been implicated in the cause and progression of many cancers. Kinase inhibitors offer a targeted approach for treating cancers associated with increased or deregulated kinase activity. Often, however, cancer cells exhibit initial resistance to these inhibitors or evolve to develop resistance during treatment. Additionally, cancers of any one tissue type are typically heterogeneous in their oncogenesis mechanisms, and thus diagnosis of a particular type of cancer does not necessarily provide insight into what kinase therapies may be effective. For example, while some lung cancer cells that overexpress the epidermal growth factor receptor (EFGR) respond to treatment with EGFR kinase inhibitors, overexpression or hyperactivity of Met kinase correlates with resistance to EGFR kinase inhibitors. Here we describe a microfluidic-based assay for quantifying Met kinase activity in cancer cell lysates with the eventual goals of predicting cancer cell responsiveness to kinase inhibitors and monitoring development of resistance to these inhibitors. In this assay, we immobilized a phosphorylation substrate for Met kinase into macroporous hydrogel micropillars. We then exposed the micropillars to a cancer cell lysate and detected substrate phosphorylation using a fluorescently conjugated antibody. This assay is able to quantify Met kinase activity in whole cell lysate from as few as 150 cancer cells. It can also detect cells expressing overactive Met kinase in a background of up to 75% non-cancerous cells. Additionally, the assay can quantify kinase inhibition by the Met-specific kinase inhibitors SU11274 and PHA665752, suggesting predictive capability for cellular response to kinase inhibitors.

(1S,2E,4S,7E,11E)-2,7,11-Cembratriene-4,6-diol semisynthetic analogs as novel c-Met inhibitors for the control of c-Met-dependent breast malignancies.

PubMed

Ebrahim, Hassan Y; Mohyeldin, Mohamed M; Hailat, Mohammad M; El Sayed, Khalid A

2016-11-15

(1S,2E,4S,6R,7E,11E)-2,7,11-Cembratriene-4,6-diol (1) and its 4-epi-analog (2) are the cembranoid precursors to several key flavor ingredients in most Nicotiana (tobacco) species. Nearly 40-60% of 1 and 2 are purposely degraded during the commercial tobacco fermentation. However, 1 and 2 display promising bioactivities, including anticancer. Breast cancer is the most diagnosed cancer in women and ranked second female disease killer. The receptor tyrosine kinase c-Met correlates with aggressiveness of certain breast cancer phenotypes and thus considered a valid therapeutic target. This study reports the discovery and optimization of the tobacco-based cembranoid 1 as a novel c-Met inhibitory scaffold using combined structure- and ligand-based approaches. 1 displayed antiproliferative, anti-migratory and anti-invasive effects against the c-Met overexpressing MDA-MB-231 breast cancer cells at moderate μM concentrations. The Z'-LYTE kinase platform and Western blot analysis identified c-Met as a potential macromolecular target. Rationally designed carbamate analogs were proposed to probe additional targeted c-Met interactions and improve the cellular potency. The 6-phenyl carbamate 3 showed enhanced c-Met inhibitory activity. Structure-activity relationships of different substituents on the 3's phenyl moiety were studied. The most active analog 20 showed potent in vitro anticancer activity against the MDA-MB-231 breast cancer cells at low μM concentrations, with minimal toxicity on the non-tumorigenic MCF-10A mammary epithelial cells. Cembranoid 20 potently inhibited the c-Met catalytic activity in Z'-LYTE kinase assay and various cellular c-Met-driven signaling pathways. Furthermore, 20 displayed a robust antitumor activity in a breast cancer xenograft athymic mouse model and thus promoted to the lead rank. Cembranoids are novel c-Met inhibitors appropriate for future use to control c-Met dependent malignancies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Preproghrelin Leu72Met polymorphism in patients with type 2 diabetes mellitus.

PubMed

Ukkola, O; Kesäniemi, Y A

2003-10-01

The association between the Leu72Met polymorphism of the preproghrelin gene and diabetic complications was examined in patients with type 2 diabetes mellitus. A total of 258 patients with type 2 diabetes mellitus and 522 control subjects were screened. Genotypes were determined by polymerase chain reaction technique. The diagnosis of coronary heart disease was based on clinical and ECG criteria. Laboratory analyses were carried out in the hospital laboratory. No differences in the genotype distributions and allele frequencies of the preproghrelin Leu72Met polymorphism were found between type 2 diabetes mellitus patients and controls. The polymorphism was not associated with macro- or micro-angiopathy or hypertension. However, Leu72Met polymorphism was associated with serum creatinine (P = 0.006) and lipoprotein(a) [Lp(a)] levels (P = 0.006) with Leu72Leu subjects showing the highest values. This association was observed only amongst diabetic group. The Leu72Met polymorphism of the preproghrelin gene was not related to cardiovascular disease in type 2 diabetes mellitus patients. Leu72Met polymorphism was, however, associated with serum creatinine and Lp(a) levels in diabetic patients. The mechanism might be associated with a possible change in ghrelin product and its somatotropic effect.

NARSTO PAC2001 CONVAIR PM OZONE MET DATA

Atmospheric Science Data Center

2018-04-09

NARSTO PAC2001 CONVAIR PM OZONE MET DATA Project Title:  NARSTO Discipline:  Tropospheric Composition Field Campaigns Aerosols ... Temperature Probe Humidity Probe Wind Sensor UV Ozone Detector Optical Counter Location:  Lower Fraser ...

Analysis and significance of c-MET expression in adenoid cystic carcinoma of the salivary gland.

PubMed

Bell, Diana; Ferrarotto, Renata; Fox, Melanie D; Roberts, Dianna; Hanna, Ehab Y; Weber, Randal S; El-Naggar, Adel K

2015-01-01

Adenoid cystic carcinoma (ACC), a rare salivary gland malignancy, is a histogenetic, morphologic, and clinical heterogeneous disease. Extensive efforts have been made to characterize molecular events associated with these tumors, including the identification of prognostic and predictive biomarkers. Increased copy number gain and amplification of c-Met, the cell surface receptor for hepatocyte growth factor, has been shown to enhance tumor growth and invasiveness and promote metastasis in certain tumor types. In this study, we evaluated the expression of c-Met by immunohistochemistry (IHC) in a large cohort of salivary gland ACCs and examined its clinicopathologic implications. Archival formalin-fixed paraffin-embedded blocks from 200 ACC patients were used in this study. Pathologic patterns and phenotypic expression of c-Met were recorded and compared with clinical factors including gender, age, disease stage at diagnosis, and clinical outcomes. Correlations between c-MET expression and clinical characteristics were assessed by Pearson's chi-square test or by the 2-tailed Fisher exact test. Curves describing overall survival were generated by Kaplan-Meier product limit method. Strong c-MET expression was seen in inner ductal and outer myoepithelial cells in 53.2% of the cases. There was no correlation between c-Met overexpression and clinicopathologic parameters or patient's overall survival ( p = .94074). In conclusion, c-MET expression is high in a significant subgroup of ACC patients. While c-MET expression is not a prognostic factor in ACC, its role as a predictive marker of benefit from MET inhibitors deserves further investigation.

The MetLife Survey of the American Teacher: Preparing Students for College and Careers

ERIC Educational Resources Information Center

MetLife, Inc., 2011

2011-01-01

"The MetLife Survey of the American Teacher: Preparing Students for College and Careers" was conducted by Harris Interactive and is the twenty-seventh in a series sponsored annually by MetLife since 1984 to give voice to those closest to the classroom. This MetLife Survey examines the priority that all students graduate from high school prepared…

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

PubMed Central

2010-01-01

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 flexible query and broad

MET Senior Projects at an Urban University.

ERIC Educational Resources Information Center

Neff, Gregory; And Others

A report describes the Purdue University Calumet Mechanical Engineering Technology (MET) program, especially the approaches used to enhance industrial involvement and take advantage of the urban setting to find real-life senior project problems. The outreach program, used by faculty to find student senior project material, is described along with…

Correlation among genetic variations of c-MET in Chinese patients with non-small cell lung cancer.

PubMed

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.

Complete or partial reduction of the Met receptor tyrosine kinase in distinct circuits differentially impacts mouse behavior.

PubMed

Thompson, Barbara L; Levitt, Pat

2015-01-01

Our laboratory discovered that the gene encoding the receptor tyrosine kinase, MET, contributes to autism risk. Expression of MET is reduced in human postmortem temporal lobe in autism and Rett Syndrome. Subsequent studies revealed a role for MET in human and mouse functional and structural cortical connectivity. To further understand the contribution of Met to brain development and its impact on behavior, we generated two conditional mouse lines in which Met is deleted from select populations of central nervous system neurons. Mice were then tested to determine the consequences of disrupting Met expression. Mating of Emx1 (cre) and Met (fx/fx) mice eliminates receptor signaling from all cells arising from the dorsal pallium. Met (fx/fx) and Nestin (cre) crosses result in receptor signaling elimination from all neural cells. Behavioral tests were performed to assess cognitive, emotional, and social impairments that are observed in multiple neurodevelopmental disorders and that are in part subserved by circuits that express Met. Met (fx/fx) /Emx1 (cre) null mice displayed significant hypoactivity in the activity chamber and in the T-maze despite superior performance on the rotarod. Additionally, these animals showed a deficit in spontaneous alternation. Surprisingly, Met (fx/fx; fx/+) /Nestin (cre) null and heterozygous mice exhibited deficits in contextual fear conditioning, and Met (fx/+) /Nestin (cre) heterozygous mice spent less time in the closed arms of the elevated plus maze. These data suggest a complex contribution of Met in the development of circuits mediating social, emotional, and cognitive behavior. The impact of disrupting developmental Met expression is dependent upon circuit-specific deletion patterns and levels of receptor activity.

The influence of COMT Val158Met genotype on the character dimension cooperativeness in healthy females

PubMed Central

Baeken, Chris; Claes, Stephan; De Raedt, Rudi

2014-01-01

Objectives Although the Val158Met catechol-O-methyltransferase (COMT) gene has been linked with the temperament dimension Novelty Seeking (NS), new insights in this polymorphism might point to a major role for character features as well. Given that individual life experiences may influence Val158 and Met158 allele carriers differently it has been suggested that the character trait cooperativeness could be implicated. Case report A homogeneous group of eighty right-handed Caucasian healthy female university students were assessed with the TCI and genotyped for the COMT Val158Met polymorphism (rs4680). Gene determination showed that eighteen were Val158 homozygotes, forty-four Val/Met158 heterozygotes, and eighteen were Met158 homozygotes. All were within the same age range and never documented to have suffered from any neuropsychiatric illness. Bonferroni corrected non-parametric analyses showed that only for the character scale cooperativeness Val158 homozygotes displayed significant higher scores when compared to Met158 homozygotes. No significant differences on cooperativeness scores were found between Val158 and Val/Met158 carriers or between Met158 and Val/Met158 carriers. No differences were observed for the COMT Val158Met polymorphism and the other temperament and character scales. Conclusions Our findings support the assumption that the Val158Met single nucleotide polymorphism (SNP) influences character traits and not only temperament. Our results add to the notion that Val158 homozygotes are considered to be helpful and empathic and it suggest that these cooperativeness character traits are related to the dopaminergic system. PMID:25161818

MET signalling in primary colon epithelial cells leads to increased transformation irrespective of aberrant Wnt signalling

PubMed Central

Boon, E M J; Kovarikova, M; Derksen, P W B; van der Neut, R

2005-01-01

It has been shown that in hereditary and most sporadic colon tumours, components of the Wnt pathway are mutated. The Wnt target MET has been implicated in the development of colon cancer. Here, we show that overexpression of wild-type or a constitutively activated form of MET in colon epithelial cells leads to increased transformation irrespective of Wnt signalling. Fetal human colon epithelial cells without aberrant Wnt signalling were transfected with wild-type or mutated MET constructs. Expression of these constructs leads to increased phosphorylation of MET and its downstream targets PKB and MAPK. Upon stimulation with HGF, the expression of E-cadherin is downregulated in wild-type MET-transfected cells, whereas cells expressing mutated MET show low E-cadherin levels independent of stimulation with ligand. This implies a higher migratory propensity of these cells. Furthermore, fetal human colon epithelial cells expressing the mutated form of MET have colony-forming capacity in soft agar, while cells expressing wild-type MET show an intermediate phenotype. Subcutaneous injection of mutated MET-transfected cells in nude mice leads to the formation of tumours within 12 days in all mice injected. At this time point, mock-transfected cells do not form tumours, while wild-type MET-transfected cells form subcutaneous tumours in one out of five mice. We thus show that MET signalling can lead to increased transformation of colon epithelial cells independent of Wnt signalling and in this way could play an essential role in the onset and progression of colorectal cancer. PMID:15785735

Hepatocyte specific deletion of c-Met leads to the development of severe non-alcoholic steatohepatitis in mice.

PubMed

Kroy, Daniela C; Schumacher, Fabienne; Ramadori, Pierluigi; Hatting, Maximilian; Bergheim, Ina; Gassler, Nikolaus; Boekschoten, Mark V; Müller, Michael; Streetz, Konrad L; Trautwein, Christian

2014-10-01

Non-alcoholic-fatty-liver disease (NAFLD) is part of the metabolic syndrome. The spectrum of NAFLD includes NASH (non-alcoholic steatohepatitis), which is characterised by progressive inflammation associated with oxidative stress and apoptosis, finally triggering liver cirrhosis and hepatocellular carcinoma. HGF (hepatocyte growth factor)/mesenchymal-epithelial transition factor (c-Met) receptor signalling is known to activate distinct intracellular pathways mediating among others anti-apoptotic properties to hepatocytes. Therefore, the aim was to characterise the role of c-Met during NASH development. Hepatocyte specific c-Met knockout mice (c-MetΔ(hepa)) using the cre-loxP system and wild type controls (c-Met(loxP/loxP)) were fed a methionine-choline deficient (MCD) diet. MCD feeding triggered massive steatosis, decreased survival and higher transaminases in c-MetΔ(hepa) livers compared to c-Met(loxP/loxP). Gene array analysis demonstrated that genes involved in fatty acid metabolism were strongly upregulated in c-MetΔ(hepa) livers correlating with higher amounts of hepatic free fatty acids. Consequently, c-MetΔ(hepa) mice showed significantly more TUNEL positive cells and more superoxide anion production than c-Met(loxPloxP) animals. Additionally, c-MetΔ(hepa) livers showed significantly larger fractions of infiltrating neutrophils, macrophages, and cytotoxic T cells. These changes correlated with an enhanced progression of liver fibrosis as evidenced by higher collagen deposition in c-MetΔ(hepa) livers. As increased apoptosis was a prominent feature in c-MetΔ(hepa) livers, we generated c-Met/Casp8Δ(hepa) double knockout mice. In these animals compared to c-MetΔ(hepa) animals the increase in apoptosis could be reverted. c-Met deletion in hepatocytes triggers NASH progression. A prominent mechanism is higher fatty acid accumulation and increased apoptosis, which in part can be reverted by blocking caspase 8. Copyright © 2014 European Association for the

Negative Suppressors of Oncogenic Activation of the Met Receptor Tyrosine Kinase

DTIC Science & Technology

2008-09-01

However, using anti-ubiquitin antibodies , we observe no increase in Met ubiquitination in Gab1 over-expressing cells when compared to vector controls...highlights an unsuspected role for Gab1 in RTK homeostasis. 11 Materials and Methods Reagents, Antibodies , Cell culture and Transfections A...its oncogenic activation through deregulate endocytosis. My recent work has uncovered a novel role for the Gab1 scaffold in regulating Met signaling

Receptor Tyrosine Kinase MET Interactome and Neurodevelopmental Disorder Partners at the Developing Synapse.

PubMed

Xie, Zhihui; Li, Jing; Baker, Jonathan; Eagleson, Kathie L; Coba, Marcelo P; Levitt, Pat

2016-12-15

Atypical synapse development and plasticity are implicated in many neurodevelopmental disorders (NDDs). NDD-associated, high-confidence risk genes have been identified, yet little is known about functional relationships at the level of protein-protein interactions, which are the dominant molecular bases responsible for mediating circuit development. Proteomics in three independent developing neocortical synaptosomal preparations identified putative interacting proteins of the ligand-activated MET receptor tyrosine kinase, an autism risk gene that mediates synapse development. The candidates were translated into interactome networks and analyzed bioinformatically. Additionally, three independent quantitative proximity ligation assays in cultured neurons and four independent immunoprecipitation analyses of synaptosomes validated protein interactions. Approximately 11% (8/72) of MET-interacting proteins, including SHANK3, SYNGAP1, and GRIN2B, are associated with NDDs. Proteins in the MET interactome were translated into a novel MET interactome network based on human protein-protein interaction databases. High-confidence genes from different NDD datasets that encode synaptosomal proteins were analyzed for being enriched in MET interactome proteins. This was found for autism but not schizophrenia, bipolar disorder, major depressive disorder, or attention-deficit/hyperactivity disorder. There is correlated gene expression between MET and its interactive partners in developing human temporal and visual neocortices but not with highly expressed genes that are not in the interactome. Proximity ligation assays and biochemical analyses demonstrate that MET-protein partner interactions are dynamically regulated by receptor activation. The results provide a novel molecular framework for deciphering the functional relations of key regulators of synaptogenesis that contribute to both typical cortical development and to NDDs. Copyright © 2016 Society of Biological Psychiatry

Non-canonical dynamic mechanisms of interaction between the p66Shc protein and Met receptor

PubMed Central

Landry, Mélissa; Pomerleau, Véronique; Saucier, Caroline

2016-01-01

Met receptor tyrosine kinase (RTK) is known to bind to the three distinct protein isoforms encoded by the ShcA (Shc) gene. Structure–function studies have unveiled critical roles for p52Shc-dependent signalling pathways in Met-regulated biological functions. The molecular basis of the interaction between the Met and p52Shc proteins is well-defined, but not for the longest protein isoform, p66Shc. In the present study, co-immunoprecipitation assays were performed in human embryonic kidney 293 (HEK293) cells, transiently co-transfected with Met and p66Shc mutants, in order to define the molecular determinants involved in mediating Met–p66Shc interaction. Our results show that p66Shc interacts constitutively with the receptor Met, and the Grb2 (growth factor receptor-bound protein-2) and Gab1 (Grb2-associated binder-1) adaptor proteins. Although its phosphotyrosine-binding domain (PTB) and Src homology 2 (SH2) domains co-ordinate p66Shc binding to non-activated Met receptor, these phosphotyrosine-binding modules, and its collagen homology domain 2 (CH2) region, exert negative constraints. In contrast, p66Shc interaction with the activated Met depends mainly on the integrity of its PTB domain, and to a lesser extent of its SH2 domain. Even though not required for the recruitment of p66Shc, tyrosine phosphorylation of p66Shc by activated Met enhances these interactions by mechanisms not reliant on the integrity of the Met multisubstrate-binding site. In turn, this increases phosphotyrosine-dependent p66Shc–Grb2–Gab1 complex formation away from the receptor, while blocking Grb2 and Gab1 recruitment to activated Met. In conclusion, we identify, for the first time, a novel non-canonical dynamic mode of interaction between Met and the p66 protein isoform of Shc and its effects on rewiring binding effector complexes according to the activation state of the receptor. PMID:27048591

Genomic profiling of a Hepatocyte growth factor-dependent signature for MET-targeted therapy in glioblastoma.

PubMed

Johnson, Jennifer; Ascierto, Maria Libera; Mittal, Sandeep; Newsome, David; Kang, Liang; Briggs, Michael; Tanner, Kirk; Marincola, Francesco M; Berens, Michael E; Vande Woude, George F; Xie, Qian

2015-09-17

Constitutive MET signaling promotes invasiveness in most primary and recurrent GBM. However, deployment of available MET-targeting agents is confounded by lack of effective biomarkers for selecting suitable patients for treatment. Because endogenous HGF overexpression often causes autocrine MET activation, and also indicates sensitivity to MET inhibitors, we investigated whether it drives the expression of distinct genes which could serve as a signature indicating vulnerability to MET-targeted therapy in GBM. Interrogation of genomic data from TCGA GBM (Student's t test, GBM patients with high and low HGF expression, p ≤ 0.00001) referenced against patient-derived xenograft (PDX) models (Student's t test, sensitive vs. insensitive models, p ≤ 0.005) was used to identify the HGF-dependent signature. Genomic analysis of GBM xenograft models using both human and mouse gene expression microarrays (Student's t test, treated vs. vehicle tumors, p ≤ 0.01) were performed to elucidate the tumor and microenvironment cross talk. A PDX model with EGFR(amp) was tested for MET activation as a mechanism of erlotinib resistance. We identified a group of 20 genes highly associated with HGF overexpression in GBM and were up- or down-regulated only in tumors sensitive to MET inhibitor. The MET inhibitors regulate tumor (human) and host (mouse) cells within the tumor via distinct molecular processes, but overall impede tumor growth by inhibiting cell cycle progression. EGFR (amp) tumors undergo erlotinib resistance responded to a combination of MET and EGFR inhibitors. Combining TCGA primary tumor datasets (human) and xenograft tumor model datasets (human tumor grown in mice) using therapeutic efficacy as an endpoint may serve as a useful approach to discover and develop molecular signatures as therapeutic biomarkers for targeted therapy. The HGF dependent signature may serve as a candidate predictive signature for patient enrollment in clinical trials using MET inhibitors

BDNF val66met Polymorphism Affects Aging of Multiple Types of Memory

PubMed Central

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 < .07) toward poorer associative 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

MetNet: Software to Build and Model the Biogenetic Lattice of Arabidopsis

DOE PAGES

Wurtele, Eve Syrkin; Li, Jie; Diao, Lixia; ...

2003-01-01

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 simplemore » 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.« less

Enhanced MET Translation and Signaling Sustains K-Ras-Driven Proliferation under Anchorage-Independent Growth Conditions.

PubMed

Fujita-Sato, Saori; Galeas, Jacqueline; Truitt, Morgan; Pitt, Cameron; Urisman, Anatoly; Bandyopadhyay, Sourav; Ruggero, Davide; McCormick, Frank

2015-07-15

Oncogenic K-Ras mutation occurs frequently in several types of cancers, including pancreatic and lung cancers. Tumors with K-Ras mutation are resistant to chemotherapeutic drugs as well as molecular targeting agents. Although numerous approaches are ongoing to find effective ways to treat these tumors, there are still no effective therapies for K-Ras mutant cancer patients. Here we report that K-Ras mutant cancers are more dependent on K-Ras in anchorage-independent culture conditions than in monolayer culture conditions. In seeking to determine mechanisms that contribute to the K-Ras dependency in anchorage-independent culture conditions, we discovered the involvement of Met in K-Ras-dependent, anchorage-independent cell growth. The Met signaling pathway is enhanced and plays an indispensable role in anchorage-independent growth even in cells in which Met is not amplified. Indeed, Met expression is elevated under anchorage-independent growth conditions and is regulated by K-Ras in a MAPK/ERK kinase (MEK)-dependent manner. Remarkably, in spite of a global downregulation of mRNA translation during anchorage-independent growth, we find that Met mRNA translation is specifically enhanced under these conditions. Importantly, ectopic expression of an active Met mutant rescues K-Ras ablation-derived growth suppression, indicating that K-Ras-mediated Met expression drives "K-Ras addiction" in anchorage-independent conditions. Our results indicate that enhanced Met expression and signaling is essential for anchorage-independent growth of K-Ras mutant cancer cells and suggests that pharmacological inhibitors of Met could be effective for K-Ras mutant tumor patients. ©2015 American Association for Cancer Research.

Enhanced MET translation and signaling sustains K-Ras driven proliferation under anchorage-independent growth conditions

PubMed Central

Fujita-Sato, Saori; Galeas, Jacqueline; Truitt, Morgan; Pitt, Cameron; Urisman, Anatoly; Bandyopadhyay, Sourav; Ruggero, Davide; McCormick, Frank

2015-01-01

Oncogenic K-Ras mutation occurs frequently in several types of cancers including pancreatic and lung cancers. Tumors with K-Ras mutation are resistant to chemotherapeutic drugs as well as molecular targeting agents. Although numerous approaches are ongoing to find effective ways to treat these tumors, there are still no effective therapies for K-Ras mutant cancer patients. Here we report that K-Ras mutant cancers are more dependent on K-Ras in anchorage independent culture conditions than in monolayer culture conditions. In seeking to determine mechanisms that contribute to the K-Ras dependency in anchorage independent culture conditions, we discovered the involvement of Met in K-Ras-dependent, anchorage independent cell growth. The Met signaling pathway is enhanced and plays an indispensable role in anchorage independent growth even in cells in which Met is not amplified. Indeed, Met expression is elevated under anchorage-independent growth conditions and is regulated by K-Ras in a MAPK/ERK kinase (MEK)-dependent manner. Remarkably, in spite of a global down-regulation of mRNA translation during anchorage independent growth, we find that Met mRNA translation is specifically enhanced under these conditions. Importantly, ectopic expression of an active Met mutant rescues K-Ras ablation-derived growth suppression, indicating that K-Ras mediated Met expression drives “K-Ras addiction” in anchorage independent conditions. Our results indicate that enhanced Met expression and signaling is essential for anchorage independent growth of K-Ras mutant cancer cells and suggests that pharmacological inhibitors of Met could be effective for K-Ras mutant tumor patients. PMID:25977330

Association between the Catechol O-Methyltransferase (COMT) Val158met Polymorphism and Different Dimensions of Impulsivity

PubMed Central

Malloy-Diniz, Leandro Fernandes; Lage, Guilherme Menezes; Campos, Simone Becho; de Paula, Jonas Jardim; de Souza Costa, Danielle; Romano-Silva, Marco Aurélio; de Miranda, Débora Marques; Correa, Humberto

2013-01-01

Background Impulsivity is a multidimensional construct which has been associated with dopaminergic neurotransmission. Nonetheless, until this moment, few studies addressed the relationship between different types of impulsivity and the single nucleotide polymorphism caused by a substitution of valine (val) with methionine (met) in the 158 codon of the Catechol-o-Methyltransferase gene (COMT-val158met). The present study aimed to investigate the association between val158met COMT polymorphism and impulsive behavior measured by two neuropsychological tests. Methodology/Principal Findings We administered two neuropsychological tests, a Continuous Performance Task and the Iowa Gambling Task were applied to 195 healthy participants to characterize their levels of motor, attentional and non-planning impulsivity. Then, subjects were grouped by genotype, and their scores on impulsivity measures were compared. There were no significant differences between group scores on attentional and motor impulsivity. Those participants who were homozygous for the met allele performed worse in the Iowa Gambling Task than val/val and val/met subjects. Conclusions/Significance Our results suggest that met allele of val158met COMT polymorphism is associated with poor performance in decision-making/cognitive impulsivity task. The results reinforce the hypothesis that val and met alleles of the val158met polymorphism show functional dissociation and are related to different prefrontal processes. PMID:24039968

Mucin glycosylating enzyme GALNT2 suppresses malignancy in gastric adenocarcinoma by reducing MET phosphorylation

PubMed Central

Liu, Shin-Yun; Shun, Chia-Tung; Hung, Kuan-Yu; Juan, Hsueh-Fen; Hsu, Chia-Lang; Huang, Min-Chuan; Lai, I-Rue

2016-01-01

Glycosylation affects malignancy in cancer. Here, we report that N- acetylgalactosaminyltransferase 2 (GALNT2), an enzyme that mediates the initial step of mucin type-O glycosylation, suppresses malignant phenotypes in gastric adenocarcinoma (GCA) by modifying MET (Hepatocyte growth factor receptor) activity. GALNT2 mRNA and protein were downregulated in GCAs, and this reduction was associated with more advanced disease stage and shorter recurrence-free survival. Suppressing GALNT2 expression in GCA cells increased cell growth, migration, and invasion in vitro, and tumor metastasis in vivo. GALNT2 knockdown enhanced phosphorylation of MET and decreased expression of the Tn antigen on MET. Inhibiting MET activity with PHA665752 decreased the malignant phenotypes caused by GALNT2 knockdown in GCA cells. Our results indicate that GALNT2 suppresses the malignant potential of GCA cells and provide novel insights into the significance of O-glycosylation in MET activity and GCA progression. PMID:26848976

Effects of the BDNF Val66Met Polymorphism on Anxiety-Like Behavior Following Nicotine Withdrawal in Mice.

PubMed

Lee, Bridgin G; Anastasia, Agustin; Hempstead, Barbara L; Lee, Francis S; Blendy, Julie A

2015-12-01

Nicotine withdrawal is characterized by both affective and cognitive symptoms. Identifying genetic polymorphisms that could affect the symptoms associated with nicotine withdrawal are important in predicting withdrawal sensitivity and identifying personalized cessation therapies. In the current study we used a mouse model of a non-synonymous single nucleotide polymorphism in the translated region of the brain-derived neurotrophic factor (BDNF) gene that substitutes a valine (Val) for a methionine (Met) amino acid (Val66Met) to examine the relationship between the Val66Met single nucleotide polymorphism and nicotine dependence. This study measured proBDNF and the BDNF prodomain levels following nicotine and nicotine withdrawal and examined a mouse model of a common polymorphism in this protein (BDNF(Met/Met)) in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test. Using the BDNF knock-in mouse containing the BDNF Val66Met polymorphism we found: (1) blunted anxiety-like behavior in BDNF(Met/Met) mice following withdrawal in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test; (2) the anxiolytic effects of chronic nicotine are absent in BDNF(Met/Met) mice; and (3) an increase in BDNF prodomain in BDNF(Met/Met) mice following nicotine withdrawal. Our study is the first to examine the effect of the BDNF Val66Met polymorphism on the affective symptoms of withdrawal from nicotine in mice. In these mice, a single-nucleotide polymorphism in the translated region of the BDNF gene can result in a blunted withdrawal, as measured by decreased anxiety-like behavior. The significant increase in the BDNF prodomain in BDNF(Met/Met) mice following nicotine cessation suggests a possible role of this ligand in the circuitry remodeling after withdrawal. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For

Methemoglobin reduction in crocodile blood: are high levels of MetHb typical of healthy reptiles?

PubMed

Gruca, M; Grigg, G C

1980-08-01

In 82 wild-caught Crocodylus porosus, levels of NADH-MetHb reductase and GSH seem adequate to maintain hemoglobin in its reduced functional state. Studies of C. porosus erythrocytes in vitro show reduction of metHb in the presence of lactate, glucose and plasma, but not pyruvate. These findings, together with recent data which show low metHb in a variety of reptiles, cast doubt on the accepted view that high levels of MetHb are typical of healthy reptiles. One explanation for the sharp contrast between earlier and more recent data could be technical. We found low metHb in Crocodylus johnstoni, Chelodina longicollis and Sphenomorphus quoyi. However, high and variable vales reminiscent of many of the earlier data were obtained by omitting final centrifugation prior to spectrophotometry. Interestingly, this step is not part of the standard clinical method but is necessary in analyses of blood with nucleated red cells. These observations suggest that high metHb may not be typical of reptiles after all.

Cathecol-O-methyl transferase Val158Met genotype is not a risk factor for conversion disorder.

PubMed

Armagan, E; Almacıoglu, M L; Yakut, T; Köse, A; Karkucak, M; Köksal, O; Görükmez, O

2013-03-19

Alterations in catechol-O-methyltransferase (COMT) activity are involved in various types of neurological disorders. We examined a possible association between the COMT Val158Met polymorphism and conversion disorder in a study of 48 patients with conversion disorder and 48 control patients. In the conversion disorder group, 31 patients were Val/Met heterozygotes, 15 patients were Val/Val homozygotes and 2 patients were Met/Met homozygotes. In the control group, 32 patients were Val/Met heterozygotes and 16 patients were Val/Val homozygotes. There was no significant difference between the groups. We conclude that the COMT Val158Met genotype is quite common in Turkey and that it is not a risk factor for conversion disorder in the Turkish population.

Operational Use of OGC Web Services at the Met Office

NASA Astrophysics Data System (ADS)

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

Regulation of HGF and c-MET Interaction in Normal Ovary and Ovarian Cancer.

PubMed

Kwon, Youngjoo; Godwin, Andrew K

2017-04-01

Binding of hepatocyte growth factor (HGF) to the c-MET receptor has mitogenic, motogenic, and morphogenic effects on cells. The versatile biological effects of HGF and c-MET interactions make them important contributors to the development of malignant tumors. We and others have demonstrated a therapeutic value in targeting the interaction of c-MET and HGF in epithelial ovarian cancer (EOC). However, both HGF and c-MET are expressed in the normal ovary as well. Therefore, it is important to understand the differences in mechanisms that control HGF signaling activation and its functional role in the normal ovary and EOC. In the normal ovary, HGF signaling may be under hormonal regulation. During ovulation, HGF-converting proteases are secreted and the subsequent activation of HGF signaling enhances the proliferation of ovarian surface epithelium in order to replenish the area damaged due to expulsion of the ovum. In contrast, EOC cells that exhibit epithelial characteristics constitutively express both c-MET and HGF-converting proteases such as urokinase-type plasminogen activator. In EOC, mechanisms to control the activation of HGF signaling are absent since HGF is provided locally from the tissue microenvironment as well as remotely throughout the body. Potential incessant HGF signaling in EOC may lead to an increase in proliferation, invasion through the stroma, and migration to other tissues of cancer cells. Therefore, targeting the interaction of c-MET and HGF would be beneficial in treating EOC.

Regulation of HGF and c-MET Interaction in Normal Ovary and Ovarian Cancer

PubMed Central

Kwon, Youngjoo; Godwin, Andrew K.

2016-01-01

Binding of hepatocyte growth factor (HGF) to the c-MET receptor has mitogenic, motogenic, and morphogenic effects on cells. The versatile biological effects of HGF and c-MET interactions make them important contributors to the development of malignant tumors. We and others have demonstrated a therapeutic value in targeting the interaction of c-MET and HGF in epithelial ovarian cancer (EOC). However, both HGF and c-MET are expressed in the normal ovary as well. Therefore, it is important to understand the differences in mechanisms that control HGF signaling activation and its functional role in the normal ovary and EOC. In the normal ovary, HGF signaling may be under hormonal regulation. During ovulation, HGF-converting proteases are secreted and the subsequent activation of HGF signaling enhances the proliferation of ovarian surface epithelium in order to replenish the area damaged due to expulsion of the ovum. In contrast, EOC cells that exhibit epithelial characteristics constitutively express both c-MET and HGF-converting proteases such as urokinase-type plasminogen activator. In EOC, mechanisms to control the activation of HGF signaling are absent since HGF is provided locally from the tissue microenvironment as well as remotely throughout the body. Potential incessant HGF signaling in EOC may lead to an increase in proliferation, invasion through the stroma, and migration to other tissues of cancer cells. Therefore, targeting the interaction of c-MET and HGF would be beneficial in treating EOC. PMID:27170665

KRC-327, a selective novel inhibitor of c-Met receptor tyrosine kinase with anticancer activity.

PubMed

Park, Byung Hee; Jung, Kyung Hee; Yun, Sun-Mi; Hong, Sang-Won; Ryu, Jae Wook; Jung, Heejung; Ha, Jae Du; Lee, Jongkook; Hong, Soon-Sun

2013-05-01

c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been reported to be involved in tumorigenesis and metastatic progression. We synthesized a novel triazolopyridazine derivative KRC-327 which selectively targets the c-Met. When we performed receptor tyrosine kinases (RTKs) array with 42 different phosphorylated-RTKs, KRC-327 strongly inhibited expression of activated c-Met in MKN-45 cancer cells. This was confirmed by immunofluorescence staining. Also, KRC-327 decreased the expression of Gab1, Akt, signal transducer and activator of transcription 3 (STAT3) and Erk, down-stream signals of c-Met. KRC-327 strongly suppressed the growth of c-Met over-expressed cancer cells (MKN-45, SNU-638, SNU-5), while not in c-Met absent cancer cell lines (MKN-1, SNU-1). Furthermore, KRC-327 effectively induced cell cycle arrest, especially G0/G1 arrest by increasing expression of p21, p27 and decreasing that of cyclin D1. In the ligand-induced functional studies, KRC-327 inhibited proliferation of HGF-stimulated BxPC-3 cells, the migration of HGF-stimulated AGS cancer cells, and suppressed colony formation in HGF-stimulated U-87MG cells. In xenograft animal models, KRC-327 significantly not only delayed tumor growth but also suppressed phosphorylation of c-Met and its signaling cascades as well as proliferation. Taken together, these results demonstrate that KRC-327 selectively targets c-Met, resulting in inhibition of cell growth and proliferation. Therefore, we suggest that KRC-327 may be a novel drug candidate with the therapeutic potential of targeting c-Met in human cancer. Crown Copyright © 2013. Published by Elsevier Ireland Ltd. All rights reserved.

Discovery of a new series of imidazo[1,2-a]pyridine compounds as selective c-Met inhibitors.

PubMed

Liu, Tong-Chao; Peng, Xia; Ma, Yu-Chi; Ji, Yin-Chun; Chen, Dan-Qi; Zheng, Ming-Yue; Zhao, Dong-Mei; Cheng, Mao-Sheng; Geng, Mei-Yu; Shen, Jing-Kang; Ai, Jing; Xiong, Bing

2016-05-01

Aberrant c-Met activation plays a critical role in cancer formation, progression and dissemination, as well as in development of resistance to anticancer drugs. Therefore, c-Met has emerged as an attractive target for cancer therapy. The aim of this study was to develop new c-Met inhibitors and elaborate the structure-activity relationships of identified inhibitors. Based on the predicted binding modes of Compounds 5 and 14 in docking studies, a new series of c-Met inhibitor-harboring 3-((1H-pyrrolo[3,2-c]pyridin-1-yl)sulfonyl)imidazo[1,2-a]pyridine scaffolds was discovered. Potent inhibitors were identified through extensive optimizations combined with enzymatic and cellular assays. A promising compound was further investigated in regard to its selectivity, its effects on c-Met signaling, cell proliferation and cell scattering in vitro. The most potent Compound 31 inhibited c-Met kinase activity with an IC50 value of 12.8 nmol/L, which was >78-fold higher than those of a panel of 16 different tyrosine kinases. Compound 31 (8, 40, 200 nmol/L) dose-dependently inhibited the phosphorylation of c-Met and its key downstream Akt and ERK signaling cascades in c-Met aberrant human EBC-1 cancer cells. In 12 human cancer cell lines harboring different background levels of c-Met expression/activation, Compound 31 potently inhibited c-Met-driven cell proliferation. Furthermore, Compound 31 dose-dependently impaired c-Met-mediated cell scattering of MDCK cells. This series of c-Met inhibitors is a promising lead for development of novel anticancer drugs.

Discovery of a new series of imidazo[1,2-a]pyridine compounds as selective c-Met inhibitors

PubMed Central

Liu, Tong-chao; Peng, Xia; Ma, Yu-chi; Ji, Yin-chun; Chen, Dan-qi; Zheng, Ming-yue; Zhao, Dong-mei; Cheng, Mao-sheng; Geng, Mei-yu; Shen, Jing-kang; Ai, Jing; Xiong, Bing

2016-01-01

Aim: Aberrant c-Met activation plays a critical role in cancer formation, progression and dissemination, as well as in development of resistance to anticancer drugs. Therefore, c-Met has emerged as an attractive target for cancer therapy. The aim of this study was to develop new c-Met inhibitors and elaborate the structure-activity relationships of identified inhibitors. Methods: Based on the predicted binding modes of Compounds 5 and 14 in docking studies, a new series of c-Met inhibitor-harboring 3-((1H-pyrrolo[3,2-c]pyridin-1-yl)sulfonyl)imidazo[1,2-a]pyridine scaffolds was discovered. Potent inhibitors were identified through extensive optimizations combined with enzymatic and cellular assays. A promising compound was further investigated in regard to its selectivity, its effects on c-Met signaling, cell proliferation and cell scattering in vitro. Results: The most potent Compound 31 inhibited c-Met kinase activity with an IC50 value of 12.8 nmol/L, which was >78-fold higher than those of a panel of 16 different tyrosine kinases. Compound 31 (8, 40, 200 nmol/L) dose-dependently inhibited the phosphorylation of c-Met and its key downstream Akt and ERK signaling cascades in c-Met aberrant human EBC-1 cancer cells. In 12 human cancer cell lines harboring different background levels of c-Met expression/activation, Compound 31 potently inhibited c-Met-driven cell proliferation. Furthermore, Compound 31 dose-dependently impaired c-Met-mediated cell scattering of MDCK cells. Conclusion: This series of c-Met inhibitors is a promising lead for development of novel anticancer drugs. PMID:27041462

Association of BDNF Val66Met polymorphism with HPA and SAM axis reactivity to psychological and physical stress.

PubMed

Tsuru, Jusen; Tanaka, Yoshihiro; Ishitobi, Yoshinobu; Maruyama, Yoshihiro; Inoue, Ayako; Kawano, Aimi; Ikeda, Rie; Ando, Tomoko; Oshita, Harumi; Aizawa, Saeko; Masuda, Koji; Higuma, Haruka; Kanehisa, Masayuki; Ninomiya, Taiga; Akiyoshi, Jotaro

2014-01-01

Decreased expression of brain-derived neurotrophic factor (BDNF) is implicated in enhanced stress responses. The BDNF Val66Met polymorphism is associated with psychological changes; for example, carriers of the Met allele exhibit increased harm avoidance as well as a higher prevalence of depression and anxiety disorder. To analyze the effects of BDNF Val66Met on stress responses, we tested 226 university students (88 women and 138 men) using a social stress procedure (Trier Social Stress Test [TSST]) and an electrical stimulation stress test. Stress indices were derived from repeated measurements of salivary α-amylase, salivary cortisol, heart rate, and psychological testing during the stress tests. All subjects were genotyped for the Val66Met polymorphism (G196A). A significant three-way interaction (time [3 levels] × BDNF [Val/Val, Val/Met, Met/Met]; P<0.05) was demonstrated that revealed different salivary cortisol responses in the TSST but not in electrical stimulation. Met/Met women had stronger cortisol responses than Val/Met and Val/Val individuals in the TSST. Met/Met men exhibited stronger salivary cortisol responses than Val/Met and Val/Val individuals in the TSST. These results indicate that a common, functionally significant polymorphism in BDNF had different effects on hypothalamic-pituitary-adrenocortical axis reactivity but not on sympathetic adrenomedullary reactivity in TSST and electrical stimulation tests.

Brain-Derived Neurotrophic Factor Val66Met Human Polymorphism Impairs the Beneficial Exercise-Induced Neurobiological Changes in Mice.

PubMed

Ieraci, Alessandro; Madaio, Alessandro I; Mallei, Alessandra; Lee, Francis S; Popoli, Maurizio

2016-12-01

Several studies have shown that exercise improves cognitive functions and emotional behaviors. Positive effects of exercise have been associated with enhanced brain plasticity, adult hippocampal neurogenesis, and increased levels of brain-derived neurotrophic factor (BDNF). However, a substantial variability of individual response to exercise has been described, which may be accounted for by individual genetic variants. Here, we have assessed whether and how the common human BDNF Val66Met polymorphism influences the neurobiological effects modulated by exercise in BDNF Val66Met knock-in male mice. Wild-type (BDNF Val/Val ) and homozygous BDNF Val66Met (BDNF Met/Met ) male mice were housed in cages equipped with or without running wheels for 4 weeks. Changes in behavioral phenotype, hippocampal adult neurogenesis, and gene expression were evaluated in exercised and sedentary control mice. We found that exercise reduced the latency to feed in the novelty suppressed feeding and the immobility time in the forced swimming test in BDNF Val/Val but not in BDNF Met/Met mice. Hippocampal neurogenesis was reduced in BDNF Met/Met mice compared with BDNF Val/Val mice. BDNF Met/Met mice had lower basal BDNF protein levels in the hippocampus, which was not recovered following exercise. Moreover, exercise-induced expression of total BDNF, BDNF splice variants 1, 2, 4, 6 and fibronectin type III domain-containing protein 5 (FNDC5) mRNA levels were absent or reduced in the dentate gyrus of BDNF Met/Met mice. Exercise failed to enhance PGC-1α and FNDC5 mRNA levels in the BDNF Met/Met muscle. Overall these results indicate that, in adult male mice, the BDNF Val66Met polymorphism impairs the beneficial behavioral and neuroplasticity effects induced by physical exercise.

BDNF val66met polymorphism affects aging of multiple types of memory.

PubMed

Kennedy, Kristen M; Reese, Elizabeth D; Horn, Marci M; Sizemore, April N; Unni, Asha K; Meerbrey, Michael E; Kalich, Allan G; Rodrigue, Karen M

2015-07-01

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×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<.07) toward poorer associative 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). This article is part of a Special Issue entitled Memory & Aging. Copyright © 2014 Elsevier B.V. All rights reserved.

The MET/AXL/FGFR Inhibitor S49076 Impairs Aurora B Activity and Improves the Antitumor Efficacy of Radiotherapy.

PubMed

Clémenson, Céline; Chargari, Cyrus; Liu, Winchygn; Mondini, Michele; Ferté, Charles; Burbridge, Mike F; Cattan, Valérie; Jacquet-Bescond, Anne; Deutsch, Eric

2017-10-01

Several therapeutic agents targeting HGF/MET signaling are under clinical development as single agents or in combination, notably with anti-EGFR therapies in non-small cell lung cancer (NSCLC). However, despite increasing data supporting a link between MET, irradiation, and cancer progression, no data regarding the combination of MET-targeting agents and radiotherapy are available from the clinic. S49076 is an oral ATP-competitive inhibitor of MET, AXL, and FGFR1-3 receptors that is currently in phase I/II clinical trials in combination with gefitinib in NSCLC patients whose tumors show resistance to EGFR inhibitors. Here, we studied the impact of S49076 on MET signaling, cell proliferation, and clonogenic survival in MET-dependent (GTL16 and U87-MG) and MET-independent (H441, H460, and A549) cells. Our data show that S49076 exerts its cytotoxic activity at low doses on MET-dependent cells through MET inhibition, whereas it inhibits growth of MET-independent cells at higher but clinically relevant doses by targeting Aurora B. Furthermore, we found that S49076 improves the antitumor efficacy of radiotherapy in both MET-dependent and MET-independent cell lines in vitro and in subcutaneous and orthotopic tumor models in vivo In conclusion, our study demonstrates that S49076 has dual antitumor activity and can be used in combination with radiotherapy for the treatment of both MET-dependent and MET-independent tumors. These results support the evaluation of combined treatment of S49076 with radiation in clinical trials without patient selection based on the tumor MET dependency status. Mol Cancer Ther; 16(10); 2107-19. ©2017 AACR . ©2017 American Association for Cancer Research.

[Interest of crizotinib in a lung cancer patient with de novo amplification of MET].

PubMed

Rabeau, A; Rouquette, I; Vantelon, J-M; Taranchon-Clermont, E; Mazières, J

2017-01-01

Targeted therapy in lung cancer changes the prognostic and treatment of patients. MET is an oncogene including exon 14 mutations and gene amplification associated with worse prognosis. We here report the case of a 47-year-old former smoker, woman, with a stage IV lung adenocarcinoma with multiple chemotherapy failure. A MET amplification was identified and the patient consequently received crizotinib. A major response was observed after eight weeks of treatment. MET amplification screening appears to be interesting with some oncogenic-addicted tumor response rate. Those patients should be enrolled in clinical trials dedicated to tumor with MET alteration. Copyright © 2016 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Evaluation of transit operations : data applications of Tri-Met's automated bus dispatching system

DOT National Transportation Integrated Search

2001-02-01

This paper presents an analysis of operating performance for Tri-Met, the transit provider for the Portland, Oregon metropolitan area. The analysis draws on data recovered by Tri-Met's automated Bus Dispatching System (BDS) and focuses on two main su...

The MetLife Survey of the American Teacher: Challenges for School Leadership

ERIC Educational Resources Information Center

MetLife, Inc., 2013

2013-01-01

"The MetLife Survey of the American Teacher: Challenges for School Leadership" (2012) was conducted by Harris Interactive and is the twenty-ninth in a series sponsored annually by MetLife since 1984 to give voice to those closest to the classroom. This report examines the views of teachers and principals on the responsibilities and challenges…

Hepatocyte Growth Factor Modulates MET Receptor Tyrosine Kinase and β-Catenin Functional Interactions to Enhance Synapse Formation

PubMed Central

Xie, Zhihui; Eagleson, Kathie L.

2016-01-01

MET, a pleiotropic receptor tyrosine kinase implicated in autism risk, influences multiple neurodevelopmental processes. There is a knowledge gap, however, in the molecular mechanism through which MET mediates developmental events related to disorder risk. In the neocortex, MET is expressed transiently during periods of peak dendritic outgrowth and synaptogenesis, with expression enriched at developing synapses, consistent with demonstrated roles in dendritic morphogenesis, modulation of spine volume, and excitatory synapse development. In a recent coimmunoprecipitation/mass spectrometry screen, β-catenin was identified as part of the MET interactome in developing neocortical synaptosomes. Here, we investigated the influence of the MET/β-catenin complex in mouse neocortical synaptogenesis. Western blot analysis confirms that MET and β-catenin coimmunoprecipitate, but N-cadherin is not associated with the MET complex. Following stimulation with hepatocyte growth factor (HGF), β-catenin is phosphorylated at tyrosine142 (Y142) and dissociates from MET, accompanied by an increase in β-catenin/N-cadherin and MET/synapsin 1 protein complexes. In neocortical neurons in vitro, proximity ligation assays confirmed the close proximity of these proteins. Moreover, in neurons transfected with synaptophysin-GFP, HGF stimulation increases the density of synaptophysin/bassoon (a presynaptic marker) and synaptophysin/PSD-95 (a postsynaptic marker) clusters. Mutation of β-catenin at Y142 disrupts the dissociation of the MET/β-catenin complex and prevents the increase in clusters in response to HGF. The data demonstrate a new mechanism for the modulation of synapse formation, whereby MET activation induces an alignment of presynaptic and postsynaptic elements that are necessary for assembly and formation of functional synapses by subsets of neocortical neurons that express MET/β-catenin complex. PMID:27595133

Liver repopulation by c-Met-positive stem/progenitor cells isolated from the developing rat liver.

PubMed

Suzuki, Atsushi; Zheng, Yun-wen; Fukao, Katashi; Nakauchi, Hiromitsu; Taniguchi, Hideki

2004-01-01

Self-renewing stem cells responsible for tissue or organ development and regeneration have been recently described. To isolate such cells using flow cytometry, it should be required to find molecules expressing on their cell surfaces. We have previously reported that, on cells fulfilling the criteria for hepatic stem cells, the hepatocyte growth factor receptor c-Met is expressed specifically in the developing mouse liver. In this study, to determine whether c-Met is an essential marker for hepatic stem cells in other animal strains, we examined the potential for in vivo liver-repopulation in sorted fetal rat-derived c-Met+ cells using the retrorsine model. Using flow cytometry and monoclonal antibodies for c-Met and leukocyte common antigen CD45, fetal rat liver cells were fractionated according to the expression of these molecules. Then, cells in each cell subpopulation were sorted and transplanted into the retrorsine-treated adult rats with two-third hepatectomy. At 9 months post transplant, frequency of liver-repopulation was examined by qualitative and quantitative analyses. When we transplanted c-Met+ CD45- sorted cells, many donor-derived cells formed colonies that included mature hepatocytes expressing albumin and containing abundant glycogen in their cytoplasm. In contrast, c-Met- cells and CD45+ cells could not repopulate damaged recipient livers. High enrichment of liver-repopulating cells was conducted by sorting of c-Met+ cells from the developing rat liver. This result suggests that c-Met/HGF interaction plays a crucial role for stem cell growth, differentiation, and self-renewal in rat liver organogenesis. Since the c-Met is also expressed in the fetal mouse-derived hepatic stem cells, this molecule could be expected to be an essential marker for such cell population in the various animal strains, including human.

Cross-activating c-Met/β1 integrin complex drives metastasis and invasive resistance in cancer

PubMed Central

Jahangiri, Arman; Nguyen, Alan; Sidorov, Maxim K.; Yagnik, Garima; Rick, Jonathan; Han, Sung Won; Chen, William; Flanigan, Patrick M.; Schneidman-Duhovny, Dina; Mascharak, Smita; De Lay, Michael; Imber, Brandon; Park, Catherine C.; Matsumoto, Kunio; Lu, Kan; Bergers, Gabriele; Sali, Andrej; Weiss, William A.

2017-01-01

The molecular underpinnings of invasion, a hallmark of cancer, have been defined in terms of individual mediators but crucial interactions between these mediators remain undefined. In xenograft models and patient specimens, we identified a c-Met/β1 integrin complex that formed during significant invasive oncologic processes: breast cancer metastases and glioblastoma invasive resistance to antiangiogenic VEGF neutralizing antibody, bevacizumab. Inducing c-Met/β1 complex formation through an engineered inducible heterodimerization system promoted features crucial to overcoming stressors during metastases or antiangiogenic therapy: migration in the primary site, survival under hypoxia, and extravasation out of circulation. c-Met/β1 complex formation was up-regulated by hypoxia, while VEGF binding VEGFR2 sequestered c-Met and β1 integrin, preventing their binding. Complex formation promoted ligand-independent receptor activation, with integrin-linked kinase phosphorylating c-Met and crystallography revealing the c-Met/β1 complex to maintain the high-affinity β1 integrin conformation. Site-directed mutagenesis verified the necessity for c-Met/β1 binding of amino acids predicted by crystallography to mediate their extracellular interaction. Far-Western blotting and sequential immunoprecipitation revealed that c-Met displaced α5 integrin from β1 integrin, creating a complex with much greater affinity for fibronectin (FN) than α5β1. Thus, tumor cells adapt to microenvironmental stressors induced by metastases or bevacizumab by coopting receptors, which normally promote both cell migration modes: chemotaxis, movement toward concentrations of environmental chemoattractants, and haptotaxis, movement controlled by the relative strengths of peripheral adhesions. Tumor cells then redirect these receptors away from their conventional binding partners, forming a powerful structural c-Met/β1 complex whose ligand-independent cross-activation and robust affinity for FN

Effects of the BDNF Val66Met polymorphism on neural responses to facial emotion.

PubMed

Mukherjee, Prerona; Whalley, Heather C; McKirdy, James W; McIntosh, Andrew M; Johnstone, Eve C; Lawrie, Stephen M; Hall, Jeremy

2011-03-31

The brain derived neurotrophic factor (BDNF) Val66Met polymorphism has been associated with affective disorders, but its role in emotion processing has not been fully established. Due to the clinically heterogeneous nature of these disorders, studying the effect of genetic variation in the BDNF gene on a common attribute such as fear processing may elucidate how the BDNF Val66Met polymorphism impacts brain function. Here we use functional magnetic resonance imaging examine the effect of the BDNF Val66Met genotype on neural activity for fear processing. Forty healthy participants performed an implicit fear task during scanning, where subjects made gender judgments from facial images with neutral or fearful emotion. Subjects were tested for facial emotion recognition post-scan. Functional connectivity was investigated using psycho-physiological interactions. Subjects were genotyped for the BDNF Val66Met polymorphism and the measures compared between genotype groups. Met carriers showed overactivation in the anterior cingulate cortex (ACC), brainstem and insula bilaterally for fear processing, along with reduced functional connectivity from the ACC to the left hippocampus, and impaired fear recognition ability. The results show that during fear processing, Met allele carriers show an increased neural response in regions previously implicated in mediating autonomic arousal. Further, the Met carriers show decreased functional connectivity with the hippocampus, which may reflect differential retrieval of emotional associations. Together, these effects show significant differences in the neural substrate for fear processing with genetic variation in BDNF. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Advanced CerMet ceramic composites for medical applications.

PubMed

Dittmer, Robert; Schaefer, Christian M; Fischer, Jean-Francois; Hausch, Ulrich; Troetzschel, Jens; Specht, Heiko

2017-11-01

Implantable active devices such as pacemakers are facing rigorous requirements. Because they reside within the body for years, materials applied in this surrounding must exhibit biocompatibility and extraordinary reliability. They also have to provide a number of functional properties. In this work we present a method that enables the realization of a highly complex profile of properties by means of a dual composite approach. Using multilayer technology, an electrical conductor is embedded into a ceramic matrix, thus, creating conductive paths that are insulated from each other. In addition to this macroscopically hybrid architecture, this approach features a second composite aspect: the conductor is not composed of a single metallic phase, but is a ceramic-metal mixture. Owing to its interpenetrating microstructure, this CerMet allows for a strong and hermetic integration of the conductor into the ceramic matrix otherwise impossible due to mismatch in thermal expansion. In fact, the CerMet ceramic composite exhibits a higher strength than the pure ceramic as revealed by a three-point bending test study. At the same time, the CerMet offers high and virtually metal-like conductor properties, enabling a down-scaling of the conductive paths to 150µm diameter and smaller. Furthermore, the described composite is biocompatible, non-magnetic, and chemically inert, which is vital for the application in active, implantable, medical devices. Beside the general fabrication route, we present the microstructural, functional, and mechanical properties of this newly developed class of dual composites. Copyright © 2017 Elsevier Ltd. All rights reserved.

Phase I dose-escalation study of the c-Met tyrosine kinase inhibitor SAR125844 in Asian patients with advanced solid tumors, including patients with MET-amplified gastric cancer.

PubMed

Shitara, Kohei; Kim, Tae Min; Yokota, Tomoya; Goto, Masahiro; Satoh, Taroh; Ahn, Jin-Hee; Kim, Hyo Song; Assadourian, Sylvie; Gomez, Corinne; Harnois, Marzia; Hamauchi, Satoshi; Kudo, Toshihiro; Doi, Toshihido; Bang, Yung-Jue

2017-10-03

SAR125844 is a potent and selective inhibitor of the c-Met kinase receptor. This was an open-label, phase I, multicenter, dose-escalation, and dose-expansion trial of SAR125844 in Asian patients with solid tumors, a subgroup of whom had gastric cancer and MET amplification (NCT01657214). SAR125844 was administered by intravenous infusion (260-570 mg/m 2 ) on days 1, 8, 15, and 22 of each 28-day cycle. Objectives were to determine the maximum tolerated dose (MTD) and to evaluate SAR125844 safety and pharmacokinetic profile. Antitumor activity was also assessed. Of 38 patients enrolled (median age 64.0 years), 22 had gastric cancer, including 14 with MET amplification. In the dose-escalation cohort ( N = 19; unselected population, including three patients with MET -amplification [two with gastric cancer and one with lung cancer]), the MTD was not reached, and the recommended dose was established at 570 mg/m 2 . Most frequent treatment-emergent adverse events (AEs) were nausea (36.8%), vomiting (34.2%), decreased appetite (28.9%), and fatigue or asthenia, constipation, and abdominal pains (each 21.1%); none appeared to be dose-dependent. Grade ≥ 3 AEs were observed in 39.5% of patients and considered drug-related in 7.9%. SAR125844 exposure increased slightly more than expected by dose proportionality; dose had no significant effect on clearance. No objective responses were observed in the dose-escalation cohort, with seven patients (three gastric cancer, two colorectal cancer, one breast cancer, and one with cancer of unknown primary origin) having stable disease. Modest antitumor activity was observed at 570 mg/m 2 in the dose-expansion cohort, comprising patients with MET -amplified tumors ( N = 19). Two gastric cancer patients had partial responses, seven patients had stable disease (six gastric cancer and one kidney cancer), and 10 patients had progressive disease. Single-agent SAR125844 administered up to 570 mg/m 2 has acceptable tolerability and modest

Discovery of imidazopyridine derivatives as novel c-Met kinase inhibitors: Synthesis, SAR study, and biological activity.

PubMed

Yang, Yifei; Zhang, Yuan; Yang, LingYun; Zhao, Leilei; Si, Lianghui; Zhang, Huibin; Liu, Qingsong; Zhou, Jinpei

2017-02-01

Receptor tyrosine kinase c-Met acts as an alternative angiogenic pathway in the process and contents of cancers. A series of imidazopyridine derivatives were designed and synthesized according to the established docking studies as possible c-Met inhibitors. Most of these imidazopyridine derivatives displayed nanomolar potency against c-Met in both biochemical enzymatic screens and cellular pharmacology studies. Especially, compound 7g exhibited the most inhibitory activity against c-Met with IC 50 of 53.4nM and 253nM in enzymatic and cellular level, respectively. Following that, the compound 7g was docked into the protein of c-Met and the structure-activity relationship was analyzed in detail. These findings indicated that the novel imidazopyridine derivative compound 7g was a potential c-Met inhibitor deserving further investigation for cancer treatment. Copyright © 2016. Published by Elsevier Inc.

MET gene copy number gain is an independent poor prognostic marker in Korean stage I lung adenocarcinomas.

PubMed

Jin, Yan; Sun, Ping-Li; Kim, Hyojin; Seo, An Na; Jheon, Sanghoon; Lee, Choon-Taek; Chung, Jin-Haeng

2014-02-01

MET gene copy number gain (CNG) and protein overexpression have been reported in lung cancer, but the clinical implications in early stage adenocarcinoma remain unclear. We investigated MET gene copy number and protein expression in 141 cases of surgically resected stage I pulmonary adenocarcinoma. MET gene CNG was determined by silver in situ hybridization, and MET protein expression was assessed by immunohistochemistry. The correlation between MET gene CNG/protein expression and clinicopathologic parameters and prognostic significance was analyzed. MET gene CNG was found in 24.1% (34 of 141) of the cases and was associated with larger tumor size, pleural invasion, and lymphatic vessel invasion. MET gene CNG was inversely correlated with the presence of lepidic subtype (r = -0.17, p = 0.045) and was not associated with EGFR, KRAS mutation, or ALK gene rearrangement. In addition, MET gene CNG was significantly associated with shorter disease-free survival (DFS) (49 vs. 75 months; p < 0.001) and shorter overall survival (OS) (65 vs. 78 months; p = 0.01). Multivariate analysis confirmed that MET gene CNG was significantly associated with poorer DFS [p < 0.001; hazard ratio (HR) 5.5; 95% confidence interval (CI) 2.2-13.9] but was not significantly associated with OS. MET overexpression was observed in 71.3% of cases (97 of 136), but it was not correlated with gene CNG. MET gene CNG is an independent poor prognostic factor in patients with stage I lung adenocarcinoma. It is associated with aggressive pathologic features and is inversely correlated with the presence of lepidic subtype.

Formation of met-cars and face-centered cubic structures. Thermodynamically or kinetically controlled

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wei, S.; Guo, B.C.; Deng, H.T.

1994-05-18

On the basis of a series of experimental studies from our laboratory, it is well established that metallocarbohedrenes, or Met-Cars for short, are a stable class of cluster materials. To account for their exceptional stability, we initially proposed a pentagonal dodecahedron structure. This cage-like structure is consistent with all the experimental findings. In general, there are two possible structures that can be developed in these metal-carbon systems, i.e., Met-Cars and cubes. Since only one structural pattern is generally observed for one particular cluster system, it has been suggested that their thermodynamical stabilities might be responsible for the selective formation ofmore » specific structures, e.g., Met-Cars or fcc structures. Herein, we present new experimental results on the system of Nb[sub m]C[sub n] under various conditions. It is shown that the experimental conditions are extremely critical for the formation of either Met-Cars or cubic structures, as predicted by Reddy and Khanma. Moreover, the new data show that the cubic structures do not develop on top of Met-Cars, but rather, they grow independently. The experiments were performed by using both time-of-flight and quadrupole mass spectrometer techniques coupled with a laser vaporization source. 23 refs., 1 fig.« less

MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib.

PubMed

Lennerz, Jochen K; Kwak, Eunice L; Ackerman, Allison; Michael, Michael; Fox, Stephen B; Bergethon, Kristin; Lauwers, Gregory Y; Christensen, James G; Wilner, Keith D; Haber, Daniel A; Salgia, Ravi; Bang, Yung-Jue; Clark, Jeffrey W; Solomon, Benjamin J; Iafrate, A John

2011-12-20

Amplification of the MET proto-oncogene in gastroesophageal cancer (GEC) may constitute a molecular marker for targeted therapy. We examined a GEC cohort with follow-up and reported the clinical response of four additional patients with MET-amplified tumors to the small molecule inhibitor crizotinib as part of an expanded phase I cohort study. From 2007 to 2009, patients with GEC were genetically screened as a consecutive series of 489 tumors (stages 0, I, and II, 39%; III, 25%; IV, 36%; n = 222 esophageal, including n = 21 squamous carcinomas). MET, EGFR, and HER2 amplification status was assessed by using fluorescence in situ hybridization. Ten (2%) of 489 patients screened harbored MET amplification; 23 (4.7%) harbored EGFR amplification; 45 (8.9%) harbored HER2 amplification; and 411 (84%) were wild type for all three genes (ie, negative). MET-amplified tumors were typically high-grade adenocarcinomas that presented at advanced stages (5%; n = 4 of 80). EGFR-amplified tumors showed the highest fraction of squamous cell carcinoma (17%; n = 4 of 23). HER2, MET, and EGFR amplification were, with one exception (MET and EGFR positive), mutually exclusive events. Survival analysis in patients with stages III and IV disease showed substantially shorter median survival in MET/EGFR-amplified groups, with a rank order for all groups by median survival (from most to least aggressive): MET (7.1 months; P < .001) less than EGFR (11.2 months; P = .16) less than HER2 (16.9 months; P = .89) when compared with the negative group (16.2 months). Two of four patients with MET-amplified tumors treated with crizotinib experienced tumor shrinkage (-30% and -16%) and experienced progression after 3.7 and 3.5 months. MET amplification defines a small and aggressive subset of GEC with indications of transient sensitivity to the targeted MET inhibitor crizotinib (PF-02341066).

Targeting MET kinase with the small-molecule inhibitor amuvatinib induces cytotoxicity in primary myeloma cells and cell lines

PubMed Central

2013-01-01

Background MET is a receptor tyrosine kinase that is activated by the ligand HGF and this pathway promotes cell survival, migration, and motility. In accordance with its oncogenic role, MET is constitutively active, mutated, or over-expressed in many cancers. Corollary to its impact, inhibition of MET kinase activity causes reduction of the downstream signaling and demise of cells. In myeloma, a B-cell plasma malignancy, MET is neither mutated nor over-expressed, however, HGF is increased in plasma or serum obtained from myeloma patients and this was associated with poor prognosis. The small-molecule, amuvatinib, inhibits MET receptor tyrosine kinase. Based on this background, we hypothesized that targeting the HGF/MET signaling pathway is a rational approach to myeloma therapy and that myeloma cells would be sensitive to amuvatinib. Methods Expression of MET and HGF mRNAs in normal versus malignant plasma cells was compared during disease progression. Cell death and growth as well as MET signaling pathway were assessed in amuvatinib treated primary myeloma cells and cell lines. Results There was a progressive increase in the transcript levels of HGF (but not MET) from normal plasma cells to refractory malignant plasma cells. Amuvatinib readily inhibited MET phosphorylation in primary CD138+ cells from myeloma patients and in concordance, increased cell death. A 48-hr amuvatinib treatment in high HGF-expressing myeloma cell line, U266, resulted in growth inhibition. Levels of cytotoxicity were time-dependent; at 24, 48, and 72 h, amuvatinib (25 μM) resulted in 28%, 40%, and 55% cell death. Consistent with these data, there was an amuvatinib-mediated decrease in MET phosphorylation in the cell line. Amuvatinib at concentrations of 5, 10, or 25 μM readily inhibited HGF-dependent MET, AKT, ERK and GSK-3-beta phosphorylation. MET-mediated effects were not observed in myeloma cell line that has low MET and/or HGF expression. Conclusions These data suggest that at

Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET

PubMed Central

Peinado, Héctor; Alečković, Maša; Lavotshkin, Simon; Matei, Irina; Costa-Silva, Bruno; Moreno-Bueno, Gema; Hergueta-Redondo, Marta; Williams, Caitlin; García-Santos, Guillermo; Nitadori-Hoshino, Ayuko; Hoffman, Caitlin; Badal, Karen; Garcia, Benjamin A.; Callahan, Margaret K.; Yuan, Jianda; Martins, Vilma R.; Skog, Johan; Kaplan, Rosandra N.; Brady, Mary S.; Wolchok, Jedd D.; Chapman, Paul B.; Kang, Yibin; Bromberg, Jacqueline; Lyden, David

2013-01-01

Tumor-derived exosomes are emerging mediators of tumorigenesis with tissue-specific addresses and messages. We explored the function of melanoma-derived exosomes in the formation of primary tumor and metastases in mouse and human subjects. Exosomes from highly metastatic melanoma increased the metastatic behavior of primary tumors by permanently “educating” bone marrow (BM) progenitors via the MET receptor. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites, and reprogrammed BM progenitors towards a c-Kit+Tie2+Met+ pro-vasculogenic phenotype. Reducing Met expression in exosomes diminished the pro-metastatic behavior of BM cells. Importantly, MET expression was elevated in circulating CD45−C-KITlow/+TIE2+ BM progenitors from metastatic melanoma subjects. RAB1a, RAB5b, RAB7, and RAB27a were highly expressed in melanoma cells and Rab27a RNA interference decreased exosome production, preventing BM education, tumor growth and metastasis. Finally, we identified an exosome-specific “melanoma signature” with prognostic and therapeutic potential, comprised of TYRP2, VLA-4, HSP70, an HSP90 isoform and the MET oncoprotein. PMID:22635005

Tumor Inhibitory Effect of IRCR201, a Novel Cross-Reactive c-Met Antibody Targeting the PSI Domain.

PubMed

Park, Hyunkyu; Kim, Donggeon; Kim, Eunmi; Sa, Jason K; Lee, Hee Won; Yu, Suji; Oh, Jiwon; Kim, Seok-Hyung; Yoon, Yeup; Nam, Do-Hyun

2017-09-13

Hepatocyte growth factor receptor (HGFR, c-Met) is an essential member of the receptor tyrosine kinase (RTK) family that is often dysregulated during tumor progression, driving a malignant phenotypic state and modulating important cellular functions including tumor growth, invasion, metastasis, and angiogenesis, providing a strong rationale for targeting HGF/c-Met signaling axis in cancer therapy. Based on its protumorigenic potentials, we developed IRCR201, a potent antagonistic antibody targeting the plexin-semaphorin-integrin (PSI) domain of c-Met, using synthetic human antibody phage libraries. We characterized and evaluated the biochemical properties and tumor inhibitory effect of IRCR201 in vitro and in vivo. IRCR201 is a novel fully-human bivalent therapeutic antibody that exhibits cross-reactivity against both human and mouse c-Met proteins with high affinity and specificity. IRCR201 displayed low agonist activity and rapidly depleted total c-Met protein via the lysosomal degradation pathway, inhibiting c-Met-dependent downstream activation and attenuating cellular proliferation in various c-Met-expressing cancer cells. In vivo tumor xenograft models also demonstrated the superior tumor inhibitory responsiveness of IRCR201. Taken together, IRCR201 provides a promising therapeutic agent for c-Met-positive cancer patients through suppressing the c-Met signaling pathway and tumor growth.

MET-2-Dependent H3K9 Methylation Suppresses Transgenerational Small RNA Inheritance.

PubMed

Lev, Itamar; Seroussi, Uri; Gingold, Hila; Bril, Roberta; Anava, Sarit; Rechavi, Oded

2017-04-24

In C. elegans, alterations to chromatin produce transgenerational effects, such as inherited increase in lifespan and gradual loss of fertility. Inheritance of histone modifications can be induced by double-stranded RNA-derived heritable small RNAs. Here, we show that the mortal germline phenotype, which is typical of met-2 mutants, defective in H3K9 methylation, depends on HRDE-1, an argonaute that carries small RNAs across generations, and is accompanied by accumulated transgenerational misexpression of heritable small RNAs. We discovered that MET-2 inhibits small RNA inheritance, and, as a consequence, induction of RNAi in met-2 mutants leads to permanent RNAi responses that do not terminate even after more than 30 generations. We found that potentiation of heritable RNAi in met-2 animals results from global hyperactivation of the small RNA inheritance machinery. Thus, changes in histone modifications can give rise to drastic transgenerational epigenetic effects, by controlling the overall potency of small RNA inheritance. Copyright © 2017 Elsevier Ltd. All rights reserved.

Acid sphingomyelinase is required for cell surface presentation of Met receptor tyrosine kinase in cancer cells

PubMed Central

Zhu, Linyu; Xiong, Xiahui; Kim, Yongsoon; Okada, Naomi; Lu, Fei; Zhang, Hui

2016-01-01

ABSTRACT Receptor tyrosine kinases (RTKs) are embedded in the lipid bilayer of the plasma membrane, but the specific roles of various lipids in cell signaling remain largely uncharacterized. We have previously found that acid sphingomyelinase (ASM; also known as SMPD1) regulates the conserved DAF-2 (the ortholog IGF-1R in mammals) RTK signaling pathway in Caenorhabditis elegans. How ASM and its catalytic products, ceramides, control RTK signaling pathways remain unclear. Here, we report that ASM regulates the homeostasis of Met, an RTK that is frequently overexpressed in various cancers. Inactivation of ASM led to a rapid loss of Met from the plasma membrane, reduced Met phosphorylation and activation, and induced Met accumulation in the trans-Golgi network (TGN). However, trafficking of integrin β3 and vesicular stomatitis virus glycoprotein (VSVG) was largely unaffected. Knockdown of syntaxin 6 (STX6) also blocked the Golgi exit of Met. Depletion of either ASM or STX6 led to aberrant trafficking of Met to lysosomes, promoting its degradation. Our studies reveal that ASM and ceramides, together with STX6 and cholesterol, constitute a new regulatory mechanism for the exit of Met from the Golgi during its biosynthetic route, which is used to rapidly replenish and regulate the plasma membrane levels of Met in various cancer cells. PMID:27802163

Preproghrelin Leu72Met polymorphism predicts a lower rate of developing renal dysfunction in type 2 diabetic nephropathy.

PubMed

Lee, Dae-Yeol; Kim, Sun-Young; Jo, Dae-Sun; Hwang, Pyoung Han; Kang, Kyung Pyo; Lee, Sik; Kim, Won; Park, Sung Kwang

2006-07-01

Ghrelin is a novel peptide hormone, which exerts somatotropic, orexigenic and adipogenic effects. Recent studies have shown that the preproghrelin Leu72Met polymorphism is associated with serum creatinine (Scr) concentration in type 2 diabetes; 72Met carriers exhibited lower Scr levels as compared with the 72Met non-carriers. We hypothesized that the preproghrelin Leu72Met polymorphism is associated with a lower rate of developing renal dysfunction in patients with type 2 diabetic nephropathy. The preproghrelin Leu72Met polymorphism was investigated using PCR techniques in 138 patients with diabetic nephropathy divided into two groups, one with normal renal function and the other with renal dysfunction. Determination of the frequency of the preproghrelin Leu72Met polymorphism was the main outcome measure. The frequency of the Leu72Met polymorphism in diabetic nephropathy was significantly lower in patients with renal dysfunction (15.9%, P < 0.01) than in patients with normal renal function (42.0%) or in the diabetes control group (40.6%). The Leu72Met polymorphism was also associated with serum total cholesterol levels in diabetic nephropathy patients with renal dysfunction; the 72Met carriers had lower total cholesterol levels than the 72Met non-carriers (P < 0.05). These data suggest that 72Met carrier status may be used as a marker predicting a lower chance of developing renal dysfunction in diabetic nephropathy.

The functional BDNF Val66Met polymorphism affects functions of pre-attentive visual sensory memory processes.

PubMed

Beste, Christian; Schneider, Daniel; Epplen, Jörg T; Arning, Larissa

2011-01-01

The brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is involved in nerve growth and survival. Especially, a single nucleotide polymorphism (SNP) in the BDNF gene, Val66Met, has gained a lot of attention, because of its effect on activity-dependent BDNF secretion and its link to impaired memory processes. We hypothesize that the BDNF Val66Met polymorphism may have modulatory effects on the visual sensory (iconic) memory performance. Two hundred and eleven healthy German students (106 female and 105 male) were included in the data analysis. Since BDNF is also discussed to be involved in the pathogenesis of depression, we additionally tested for possible interactions with depressive mood. The BDNF Val66Met polymorphism significantly influenced iconic-memory performance, with the combined Val/Met-Met/Met genotype group revealing less time stability of information stored in iconic memory than the Val/Val group. Furthermore, this stability was positively correlated with depressive mood exclusively in the Val/Val genotype group. Thus, these results show that the BDNF Val66Met polymorphism has an effect on pre-attentive visual sensory memory processes. Copyright © 2010 Elsevier Ltd. All rights reserved.

Biomarkers that currently affect clinical practice: EGFR, ALK, MET, KRAS

PubMed Central

Vincent, M.D.; Kuruvilla, M.S.; Leighl, N.B.; Kamel–Reid, S.

2012-01-01

New drugs such as pemetrexed, the epidermal growth factor receptor (egfr) tyrosine kinase inhibitors, and the Alk inhibitor crizotinib have recently enabled progress in the management of advanced non-small-cell lung cancer (nsclc). More drugs, especially Met inhibitors, will follow. However, the benefits of these agents are not uniform across the spectrum of nsclc, and optimizing their utility requires some degree of subgrouping of nsclc by the presence or absence of certain biomarkers. The biomarkers of current or imminent value are EGFR and KRAS mutational status, ALK rearrangements, and MET immunohistochemistry. As a predictor of benefit for anti-egfr monoclonal antibodies, EGFR immunohistochemistry is also of potential interest. Some of the foregoing biomarkers (EGFR, ALK, MET) are direct drivers of the malignant phenotype. As such, they are, quite rationally, the direct targets of inhibitory drugs. However, KRAS, while definitely a driver, has resisted attempts at direct pharmacologic manipulation, and its main value might lie in its role as part of an efficient testing algorithm, because KRAS mutations appear to exclude EGFR and ALK mutations. The indirect value of KRAS in determining sensitivity to other targeted agents or to pemetrexed remains controversial. The other biomarkers (EGFR, ALK, MET) may also have indirect value as predictors of sensitivity to chemotherapy in general, to pemetrexed specifically, and to radiotherapy and molecularly targeted agents. These biomarkers have all enabled the co-development of new drugs with companion diagnostics, and they illustrate the paradigm that will govern progress in oncology in the immediate future. However, in nsclc, the acquisition of sufficient biopsy material remains a stubborn obstacle to the evolution of novel targeted therapies. PMID:22787409

The COMT Val/Met polymorphism modulates effects of tDCS on response inhibition.

PubMed

Nieratschker, Vanessa; Kiefer, Christoph; Giel, Katrin; Krüger, Rejko; Plewnia, Christian

2015-01-01

Transcranial direct current stimulation (tDCS) is increasingly discussed as a new option to support the cognitive rehabilitation in neuropsychiatric disorders. However, the therapeutic impact of tDCS is limited by high inter-individual variability. Genetic factors most likely contribute to this variability by modulating the effects of tDCS. We aimed to investigate the influence of the COMT Val(108/158)Met polymorphism on cathodal tDCS effects on executive functioning. Cathodal tDCS was applied to the left dorsolateral prefrontal cortex (dlPFC) during the performance of a parametric Go/No-Go test. We demonstrate an impairing effect of cathodal tDCS to the dlPFC on response inhibition. This effect was only found in individuals homozygous for the Val-allele of the COMT Val(108/158)Met polymorphism. No effects of stimulation on executive functions in Met-allele carriers were detected. Our data indicate that i) cathodal, excitability reducing tDCS, interferes with inhibitory cognitive control, ii) the left dlPFC is critically involved in the neuronal network underlying the control of response inhibition, and iii) the COMT Val(108/158)Met polymorphism modulates the impact of cathodal tDCS on inhibitory control. Together with our previous finding that anodal tDCS selectively impairs set-shifting abilities in COMT Met/Met homozygous individuals, these results indicate that genetic factors modulate effects of tDCS on cognitive performance. Therefore, future tDCS research should account for genetic variability in the design and analysis of neurocognitive as well as therapeutic applications to reduce the variability of results and facilitate individualized neurostimulation approaches. Copyright © 2015 Elsevier Inc. All rights reserved.

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

PubMed Central

Boissinot, Marjorie; Vilaine, Mathias; Hermouet, Sylvie

2014-01-01

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). PMID:25119536

Heat Shock Protein 83 (Hsp83) Facilitates Methoprene-tolerant (Met) Nuclear Import to Modulate Juvenile Hormone Signaling*

PubMed Central

He, Qianyu; Wen, Di; Jia, Qiangqiang; Cui, Chunlai; Wang, Jian; Palli, Subba R.; Li, Sheng

2014-01-01

Juvenile hormone (JH) receptors, methoprene-tolerant (Met) and Germ-cell expressed (Gce), transduce JH signals to induce Kr-h1 expression in Drosophila. Dual luciferase assay identified a 120-bp JH response region (JHRR) in the Kr-h1α promoter. Both in vitro and in vivo experiments revealed that Met and Gce transduce JH signals to induce Kr-h1 expression through the JHRR. DNA affinity purification identified chaperone protein Hsp83 as one of the proteins bound to the JHRR in the presence of JH. Interestingly, Hsp83 physically interacts with PAS-B and basic helix-loop-helix domains of Met, and JH induces Met-Hsp83 interaction. As determined by immunohistochemistry, Met is mainly distributed in the cytoplasm of fat body cells of the larval when the JH titer is low and JH induces Met nuclear import. Hsp83 was accumulated in the cytoplasm area adjunct to the nucleus in the presence of JH and Met/Gce. Loss-of-function of Hsp83 attenuated JH binding and JH-induced nuclear import of Met, resulting in a decrease in the JHRR-driven reporter activity leading to reduction of Kr-h1 expression. These data show that Hsp83 facilitates the JH-induced nuclear import of Met that induces Kr-h1 expression through the JHRR. PMID:25122763

Energy expenditure during common sitting and standing tasks: examining the 1.5 MET definition of sedentary behaviour.

PubMed

Mansoubi, Maedeh; Pearson, Natalie; Clemes, Stacy A; Biddle, Stuart Jh; Bodicoat, Danielle H; Tolfrey, Keith; Edwardson, Charlotte L; Yates, Thomas

2015-05-29

Sedentary behavior is defined as any waking behavior characterized by an energy expenditure of 1.5 METS or less while in a sitting or reclining posture. This study examines this definition by assessing the energy cost (METs) of common sitting, standing and walking tasks. Fifty one adults spent 10 min during each activity in a variety of sitting tasks (watching TV, Playing on the Wii, Playing on the PlayStation Portable (PSP) and typing) and non-sedentary tasks (standing still, walking at 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, 1.4, and 1.6 mph). Activities were completed on the same day in a random order following an assessment of resting metabolic rate (RMR). A portable gas analyzer was used to measure oxygen uptake, and data were converted to units of energy expenditure (METs). Average of standardized MET values for screen-based sitting tasks were: 1.33 (SD: 0.24) METS (TV), 1.41 (SD: 0.28) (PSP), and 1.45 (SD: 0.32) (Typing). The more active, yet still seated, games on the Wii yielded an average of 2.06 (SD: 0.5) METS. Standing still yielded an average of 1.59 (SD: 0.37) METs. Walking MET values increased incrementally with speed from 2.17 to 2.99 (SD: 0.5 - 0.69) METs. The suggested 1.5 MET threshold for sedentary behaviors seems reasonable however some sitting based activities may be classified as non-sedentary. The effect of this on the definition of sedentary behavior and associations with metabolic health needs further investigation.

Catechol-O-Methyltransferase Val158Met Polymorphism on Striatum Structural Covariance Networks in Alzheimer's Disease.

PubMed

Chang, Chiung-Chih; Tsai, Shih-Jen; Chen, Nai-Ching; Huang, Chi-Wei; Hsu, Shih-Wei; Chang, Ya-Ting; Liu, Mu-En; Chang, Wen-Neng; Tsai, Wan-Chen; Lee, Chen-Chang

2018-06-01

The catechol-O-methyltransferase enzyme metabolizes dopamine in the prefrontal axis, and its genetic polymorphism (rs4680; Val158Met) is a known determinant of dopamine signaling. In this study, we investigated the possible structural covariance networks that may be modulated by this functional polymorphism in patients with Alzheimer's disease. Structural covariance networks were constructed by 3D T1 magnetic resonance imaging. The patients were divided into two groups: Met-carriers (n = 91) and Val-homozygotes (n = 101). Seed-based analysis was performed focusing on triple-network models and six striatal networks. Neurobehavioral scores served as the major outcome factors. The role of seed or peak cluster volumes, or a covariance strength showing Met-carriers > Val-homozygotes were tested for the effect on dopamine. Clinically, the Met-carriers had higher mental manipulation and hallucination scores than the Val-homozygotes. The volume-score correlations suggested the significance of the putaminal seed in the Met-carriers and caudate seed in the Val-homozygotes. Only the dorsal-rostral and dorsal-caudal putamen interconnected peak clusters showed covariance strength interactions (Met-carriers > Val-homozygotes), and the peak clusters also correlated with the neurobehavioral scores. Although the triple-network model is important for a diagnosis of Alzheimer's disease, our results validated the role of the dorsal-putaminal-anchored network by the catechol-O-methyltransferase Val158Met polymorphism in predicting the severity of cognitive and behavior in subjects with Alzheimer's disease.

MET network in PubMed: a text-mined network visualization and curation system.

PubMed

Dai, Hong-Jie; Su, Chu-Hsien; Lai, Po-Ting; Huang, Ming-Siang; Jonnagaddala, Jitendra; Rose Jue, Toni; Rao, Shruti; Chou, Hui-Jou; Milacic, Marija; Singh, Onkar; Syed-Abdul, Shabbir; Hsu, Wen-Lian

2016-01-01

Metastasis is the dissemination of a cancer/tumor from one organ to another, and it is the most dangerous stage during cancer progression, causing more than 90% of cancer deaths. Improving the understanding of the complicated cellular mechanisms underlying metastasis requires investigations of the signaling pathways. To this end, we developed a METastasis (MET) network visualization and curation tool to assist metastasis researchers retrieve network information of interest while browsing through the large volume of studies in PubMed. MET can recognize relations among genes, cancers, tissues and organs of metastasis mentioned in the literature through text-mining techniques, and then produce a visualization of all mined relations in a metastasis network. To facilitate the curation process, MET is developed as a browser extension that allows curators to review and edit concepts and relations related to metastasis directly in PubMed. PubMed users can also view the metastatic networks integrated from the large collection of research papers directly through MET. For the BioCreative 2015 interactive track (IAT), a curation task was proposed to curate metastatic networks among PubMed abstracts. Six curators participated in the proposed task and a post-IAT task, curating 963 unique metastatic relations from 174 PubMed abstracts using MET.Database URL: http://btm.tmu.edu.tw/metastasisway. © The Author(s) 2016. Published by Oxford University Press.

MET Amplification Identifies a Small and Aggressive Subgroup of Esophagogastric Adenocarcinoma With Evidence of Responsiveness to Crizotinib

PubMed Central

Lennerz, Jochen K.; Kwak, Eunice L.; Ackerman, Allison; Michael, Michael; Fox, Stephen B.; Bergethon, Kristin; Lauwers, Gregory Y.; Christensen, James G.; Wilner, Keith D.; Haber, Daniel A.; Salgia, Ravi; Bang, Yung-Jue; Clark, Jeffrey W.; Solomon, Benjamin J.; Iafrate, A. John

2011-01-01

Purpose Amplification of the MET proto-oncogene in gastroesophageal cancer (GEC) may constitute a molecular marker for targeted therapy. We examined a GEC cohort with follow-up and reported the clinical response of four additional patients with MET-amplified tumors to the small molecule inhibitor crizotinib as part of an expanded phase I cohort study. Patients and Methods From 2007 to 2009, patients with GEC were genetically screened as a consecutive series of 489 tumors (stages 0, I, and II, 39%; III, 25%; IV, 36%; n = 222 esophageal, including n = 21 squamous carcinomas). MET, EGFR, and HER2 amplification status was assessed by using fluorescence in situ hybridization. Results Ten (2%) of 489 patients screened harbored MET amplification; 23 (4.7%) harbored EGFR amplification; 45 (8.9%) harbored HER2 amplification; and 411 (84%) were wild type for all three genes (ie, negative). MET-amplified tumors were typically high-grade adenocarcinomas that presented at advanced stages (5%; n = 4 of 80). EGFR-amplified tumors showed the highest fraction of squamous cell carcinoma (17%; n = 4 of 23). HER2, MET, and EGFR amplification were, with one exception (MET and EGFR positive), mutually exclusive events. Survival analysis in patients with stages III and IV disease showed substantially shorter median survival in MET/EGFR-amplified groups, with a rank order for all groups by median survival (from most to least aggressive): MET (7.1 months; P < .001) less than EGFR (11.2 months; P = .16) less than HER2 (16.9 months; P = .89) when compared with the negative group (16.2 months). Two of four patients with MET-amplified tumors treated with crizotinib experienced tumor shrinkage (−30% and −16%) and experienced progression after 3.7 and 3.5 months. Conclusion MET amplification defines a small and aggressive subset of GEC with indications of transient sensitivity to the targeted MET inhibitor crizotinib (PF-02341066). PMID:22042947

Mars MetNet Precursor Mission Status

NASA Astrophysics Data System (ADS)

Harri, Ari-Matti; Aleksashkin, Sergey; Guerrero, Héctor; Schmidt, Walter; Genzer, Maria; Vazquez, Luis; Haukka, Harri

2013-04-01

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 is based on a new semi-hard landing vehicle called MetNet Lander (MNL), 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. For the precursor mission (MMPM) intended to verify the landing concept and key technology during a real Mars mission all qualification activities are completed and the payload and system flight model components are being manufactured. 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 descent phase starting shortly after separation from the spacecraft. Details of the current MMPM system and payload configuration and their performance parameters will be shown.

Study of the Met Tyrosine Kinase in the Pathogenesis of Breast Cancer.

DTIC Science & Technology

1998-10-01

cDNA clones appeared to encode for open reading frames, however, and neither clone showed any homology to the protein Gab1 , which is a signal...domain, and tissue characterization using specific antibodies , will hopefully determine whether these clones represent important c-met targets. In...Behrens J, Birchmeier W. Interaction between Gab1 and the c-met receptor tyrosine kinase is responsible for epithelial morphogenesis. Nature 1996;384:173

76 FR 25278 - Safety Zone; TriMet Bridge Project, Willamette River; Portland, OR

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-04

...-AA00 Safety Zone; TriMet Bridge Project, Willamette River; Portland, OR AGENCY: Coast Guard, DHS... safety zone during the construction of the TriMet Bridge on the Willamette River, in Portland, OR. This..., will be starting construction of the new Portland-Milwaukie Light Rail Bridge on July 1, 2011 (with in...

NARSTO PAC2001 CESSNA VOC PM OZONE MET DATA

Atmospheric Science Data Center

2018-04-09

NARSTO PAC2001 CESSNA VOC PM OZONE MET DATA Project Title:  NARSTO Discipline:  Tropospheric Composition Field Campaigns Aerosols ... Temperature Probe Humidity Probe Wind Sensor UV Ozone Detector Optical Counter GC Location:  Lower Fraser ...

BDNF Val66Met polymorphism moderates the link between child maltreatment and reappraisal ability.

PubMed

Miu, A C; Cărnuţă, M; Vulturar, R; Szekely-Copîndean, R D; Bîlc, M I; Chiş, A; Cioară, M; Fernandez, K C; Szentágotai-Tătar, A; Gross, J J

2017-04-01

Child maltreatment is associated with increased risk for virtually all common mental disorders, but it is not yet clear why. One possible mechanism is emotion regulation ability. The present study investigated for the first time the influence of a BDNF Val66Met genotype × child maltreatment interaction on emotion regulation, and compared differential susceptibility and diathesis-stress models. A sample of N = 254 healthy volunteers were genotyped for the BDNF Val66Met polymorphism and underwent an experimental assessment of reappraisal ability (i.e. the success of using reappraisal to downregulate negative affect). A self-report instrument previously validated against a clinical interview was used to investigate child maltreatment. There was a significant BDNF Val66Met genotype × child maltreatment interaction (B = -0.31, P < 0.015), with Met carriers showing both the lowest level of reappraisal ability in maltreated participants, and the highest level of reappraisal ability in non-maltreated participants. By assessing alternative models, we found that the best fitting model was in line with strong differential susceptibility. As expected, reappraisal ability was negatively correlated with depressive symptoms. Therefore, the BDNF Val66Met polymorphism moderates the link between child maltreatment and emotion regulation ability. Future studies could investigate whether improving reappraisal in maltreated BDNF Met carriers results in reduced risk for mental disorders. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

The BDNF Val66Met polymorphism regulates glucocorticoid-induced corticohippocampal remodeling and behavioral despair

PubMed Central

Notaras, M; Du, X; Gogos, J; van den Buuse, M; Hill, R A

2017-01-01

The BDNF Val66Met polymorphism has been associated with sensitivity to stress and affective disorders. We therefore sought to model the inter-causality of these relationships under controlled laboratory conditions. We subjected humanized BDNF Val66Met (hBDNFVal66Met) transgenic mice to a history of stress, modeled by chronic late-adolescent corticosterone (CORT) exposure, before evaluating affective-related behavior using the forced-swim test (FST) in adulthood. While hBDNFMet/Met mice had a depression-like phenotype in the FST irrespective of CORT, hBDNFVal/Val wildtype mice had a resilient phenotype but developed an equally robust depressive-like phenotype following CORT. A range of stress-sensitive molecules were studied across the corticohippocampal axis, and where genotype differences occurred following CORT they tended to inversely coincide with the behavior of the hBDNFVal/Val group. Notably, tyrosine hydroxylase was markedly down-regulated in the mPFC of hBDNFVal/Val mice as a result of CORT treatment, which mimicked expression levels of hBDNFMet/Met mice and the FST behavior of both groups. The expression of calretinin, PSD-95, and truncated TrkB were also concomitantly reduced in the mPFC of hBDNFVal/Val mice by CORT. This work establishes BDNFVal66Met genotype as a regulator of behavioral despair, and identifies new biological targets of BDNF genetic variation relevant to stress-inducible disorders such as depression. PMID:28926000

Val66Met polymorphism of BDNF alters prodomain structure to induce neuronal growth cone retraction.

PubMed

Anastasia, Agustin; Deinhardt, Katrin; Chao, Moses V; Will, Nathan E; Irmady, Krithi; Lee, Francis S; Hempstead, Barbara L; Bracken, Clay

2013-01-01

A common single-nucleotide polymorphism (SNP) in the human brain-derived neurotrophic factor (BDNF) gene results in a Val66Met substitution in the BDNF prodomain region. This SNP is associated with alterations in memory and with enhanced risk to develop depression and anxiety disorders in humans. Here we show that the isolated BDNF prodomain is detected in the hippocampus and that it can be secreted from neurons in an activity-dependent manner. Using nuclear magnetic resonance spectroscopy and circular dichroism, we find that the prodomain is intrinsically disordered, and the Val66Met substitution induces structural changes. Surprisingly, application of Met66 (but not Val66) BDNF prodomain induces acute growth cone retraction and a decrease in Rac activity in hippocampal neurons. Expression of p75(NTR) and differential engagement of the Met66 prodomain to the SorCS2 receptor are required for this effect. These results identify the Met66 prodomain as a new active ligand, which modulates neuronal morphology.

Val66Met Polymorphism of BDNF Alters Prodomain Structure to Induce Neuronal Growth Cone Retraction

PubMed Central

Anastasia, Agustin; Deinhardt, Katrin; Chao, Moses V.; Will, Nathan E.; Irmady, Krithi; Lee, Francis S.; Hempstead, Barbara L.; Bracken, Clay

2013-01-01

A common single-nucleotide polymorphism in the human brain-derived neurotrophic factor (BDNF) gene results in a Val66Met substitution in the BDNF prodomain region. This single-nucleotide polymorphism is associated with alterations in memory and with enhanced risk to develop depression and anxiety disorders in humans. Here we show that the isolated BDNF prodomain is detected in the hippocampus and that it can be secreted from neurons in an activity-dependent manner. Using nuclear magnetic resonance spectroscopy and circular dichroism we find that the prodomain is intrinsically disordered, and the Val66Met substitution induces structural changes. Surprisingly, application of Met66 (but not Val66) BDNF prodomain induces acute growth cone retraction and a decrease in Rac activity in hippocampal neurons. Expression of p75NTR and differential engagement of the Met66 prodomain to the SorCS2 receptor are required for this effect. These results identify the Met66 prodomain as a new active ligand which modulates neuronal morphology. PMID:24048383

Targeting c-Met in Cancer by MicroRNAs: Potential Therapeutic Applications in Hepatocellular Carcinoma.

PubMed

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.

Met receptor tyrosine kinase signals through a cortactin–Gab1 scaffold complex, to mediate invadopodia

PubMed Central

Rajadurai, Charles V.; Havrylov, Serhiy; Zaoui, Kossay; Vaillancourt, Richard; Stuible, Matthew; Naujokas, Monica; Zuo, Dongmei; Tremblay, Michel L.; Park, Morag

2012-01-01

Summary Invasive carcinoma cells form actin-rich matrix-degrading protrusions called invadopodia. These structures resemble podosomes produced by some normal cells and play a crucial role in extracellular matrix remodeling. In cancer, formation of invadopodia is strongly associated with invasive potential. Although deregulated signals from the receptor tyrosine kinase Met (also known as hepatocyte growth factor are linked to cancer metastasis and poor prognosis, its role in invadopodia formation is not known. Here we show that stimulation of breast cancer cells with the ligand for Met, hepatocyte growth factor, promotes invadopodia formation, and in aggressive gastric tumor cells where Met is amplified, invadopodia formation is dependent on Met activity. Using both GRB2-associated-binding protein 1 (Gab1)-null fibroblasts and specific knockdown of Gab1 in tumor cells we show that Met-mediated invadopodia formation and cell invasion requires the scaffold protein Gab1. By a structure–function approach, we demonstrate that two proline-rich motifs (P4/5) within Gab1 are essential for invadopodia formation. We identify the actin regulatory protein, cortactin, as a direct interaction partner for Gab1 and show that a Gab1–cortactin interaction is dependent on the SH3 domain of cortactin and the integrity of the P4/5 region of Gab1. Both cortactin and Gab1 localize to invadopodia rosettes in Met-transformed cells and the specific uncoupling of cortactin from Gab1 abrogates invadopodia biogenesis and cell invasion downstream from the Met receptor tyrosine kinase. Met localizes to invadopodia along with cortactin and promotes phosphorylation of cortactin. These findings provide insights into the molecular mechanisms of invadopodia formation and identify Gab1 as a scaffold protein involved in this process. PMID:22366451

Interacting effect of BDNF Val66Met polymorphism and stressful life events on adolescent depression.

PubMed

Chen, J; Li, X; McGue, M

2012-11-01

There is a strong etiological link between brain-derived neurotrophic factor and depression, but the neurocellular mechanisms and gene-environment interactions remain obscure. This study investigated whether one functional polymorphism in the brain-derived neurotrophic factor gene (BDNF Val66Met) modulates the influence of stressful life events on adolescent depressive symptoms. A total of 780 pairs of ethnic Han Chinese adolescent twins, 11-17 years of age, were randomly assigned to one of two subgroups (twin1 and twin2). All subjects were genotyped as Val/Val, Val/Met or Met/Met, and assessed for depressive symptoms using the Children's Depression Inventory. The level of environmental stress was estimated by the frequency of stressful life events using the Life Events Checklist. The frequency of stressful life events was significantly correlated with depressive symptoms (twin1: β = 0.21, P = 0.01; twin2: β = 0.27, P < 0.01), but there was no significant main effect of the BDNF Val66Met genotype on depressive symptoms. In both subgroups, however, the interaction between the BDNF Val66Met genotype and stressful life event frequency was significant (twin1: β = 0.19, P = 0.01; twin2: β = 0.15, P = 0.04); individuals with one or two Val alleles demonstrated a greater susceptibility to both the detrimental effects of higher stress and the beneficial effects of lower stress compared to the Met/Met genotype. These findings support the 'differential-susceptibility' hypothesis, whereby the BDNF Val allele modulates the influence of environmental stress on depression by enhancing the neuroplastic response to all life events. © 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Association between the COMT Val158Met polymorphism and fibromyalgia susceptibility and fibromyalgia impact questionnaire score: a meta-analysis.

PubMed

Lee, Young Ho; Kim, Jae-Hoon; Song, Gwan Gyu

2015-01-01

The aim of this study was to explore whether the catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with susceptibility to fibromyalgia and fibromyalgia impact questionnaire (FIQ) score in fibromyalgia patients. We conducted a meta-analysis of the associations of the COMT Val158Met polymorphism with fibromyalgia risk as well as FIQ score in fibromyalgia patients. A total of 993 fibromyalgia patients and 778 controls from 10 studies on the COMT Val158Met polymorphism and 538 fibromyalgia patients from 5 studies on the COMT Val158Met polymorphism and FIQ score were included in this meta-analysis. The meta-analysis revealed an association between fibromyalgia and the COMT Met/Met + Val/Met genotype in all study subjects (odds ratio (OR) 1.635, 95 % confidence interval (CI) 1.029-2.597, p = 0.037). However, stratification by ethnicity indicated no association between the Met/Met + Val/Met genotype and fibromyalgia in the European and Turkish populations (OR 1.202, 95 % CI 0.876-1.649, p = 0.255; OR 2.132, 95 % CI 0.764-5.949, p = 0.148, respectively). Analysis using other genetic models showed no association between the COMT Val158Met polymorphism and fibromyalgia. The meta-analysis also revealed that the FIQ score was significantly higher in individuals with the COMT Met/Met genotype than in those with the Val/Val genotype [weighted mean difference (WMD) = 14.39, 95 % CI 3.316-25.48, p = 0.011] and the Val/Met genotype (WMD = 5.108, 95 % CI 2.212-4.891, p = 0.021). This meta-analysis identified an association between fibromyalgia risk and the COMT Val158Met polymorphism as well as the FIQ score in fibromyalgia patients.

TFG-MET fusion in an infantile spindle cell sarcoma with neural features.

PubMed

Flucke, Uta; van Noesel, Max M; Wijnen, Marc; Zhang, Lei; Chen, Chun-Liang; Sung, Yun-Shao; Antonescu, Cristina R

2017-09-01

An increasing number of congenital and infantile sarcomas displaying a primitive, monomorphic spindle cell phenotype have been characterized to harbor recurrent gene fusions, including infantile fibrosarcoma and congenital spindle cell rhabdomyosarcoma. Here, we report an unusual spindle cell sarcoma presenting as a large and infiltrative pelvic soft tissue mass in a 4-month-old girl, which revealed a novel TFG-MET gene fusion by whole transcriptome RNA sequencing. The tumor resembled the morphology of an infantile fibrosarcoma with both fascicular and patternless growth, however, it expressed strong S100 protein immunoreactivity, while lacking SOX10 staining and retaining H3K27me3 expression. Although this immunoprofile suggested partial neural/neuroectodermal differentiation, overall features were unusual and did not fit into any known tumor types (cellular schwannoma, MPNST), raising the possibility of a novel pathologic entity. The TFG-MET gene fusion expands the genetic spectrum implicated in the pathogenesis of congenital spindle cell sarcomas, with yet another example of kinase oncogenic activation through chromosomal translocation. The discovery of this new fusion is significant since the resulting MET activation can potentially be inhibited by targeted therapy, as MET inhibitors are presently available in clinical trials. © 2017 Wiley Periodicals, Inc.

Chronic arsenic trioxide exposure leads to enhanced aggressiveness via Met oncogene addiction in cancer cells

PubMed Central

Kryeziu, Kushtrim; Pirker, Christine; Englinger, Bernhard; van Schoonhoven, Sushilla; Spitzwieser, Melanie; Mohr, Thomas; Körner, Wilfried; Weinmüllner, Regina; Tav, Koray; Grillari, Johannes; Cichna-Markl, Margit; Berger, Walter; Heffeter, Petra

2016-01-01

As an environmental poison, arsenic is responsible for many cancer deaths. Paradoxically, arsenic trioxide (ATO) presents also a powerful therapy used to treat refractory acute promyelocytic leukemia (APL) and is intensively investigated for treatment of other cancer types. Noteworthy, cancer therapy is frequently hampered by drug resistance, which is also often associated with enhancement of tumor aggressiveness. In this study, we analyzed ATO-selected cancer cells (A2780ATO) for the mechanisms underlying their enhanced tumorigenicity and aggressiveness. These cells were characterized by enhanced proliferation and spheroid growth as well as increased tumorigenicity of xenografts in SCID mice. Noteworthy, subsequent studies revealed that overexpression of Met receptor was the underlying oncogenic driver of these effects, as A2780ATO cells were characterized by collateral sensitivity against Met inhibitors. This finding was also confirmed by array comparative genomic hybridization (array CGH) and whole genome gene expression arrays, which revealed that Met overexpression by chronic ATO exposure was based on the transcriptional regulation via activation of AP-1. Finally, it was shown that treatment with the Met inhibitor crizotinib was also effective against A2780ATO cell xenografts in vivo, indicating that targeting of Met presents a promising strategy for the treatment of Met-overexpressing tumors after either arsenic exposure or failure to ATO treatment. PMID:27036042

Foretinib Enhances the Radiosensitivity in Esophageal Squamous Cell Carcinoma by Inhibiting Phosphorylation of c-Met

PubMed Central

Chen, Guang-Zong; Dai, Wang-Shu; Zhu, Hong-Cheng; Song, Hong-Mei; Yang, Xi; Wang, Yuan-Dong; Min, Hua; Lu, Qian; Liu, Shu; Sun, Xin-Chen; Zeng, Xiao-Ning

2017-01-01

As a crucial event involved in the metastasis and relapse of esophageal cancer, c-Met overexpression has been considered as one of the culprits responsible for the failure in patients who received radiochemotherapy. Since c-Met has been confirmed to be pivotal for cell survival, proliferation and migration, little is known about its impact on the regulation of radiosensitivity in esophageal cancer. The present study investigated the radiosensitization effects of c-Met inhibitor foretinib in ECA-109 and TE-13 cell lines. Foretinib inhibited c-Met signaling in a dose-dependent manner resulting in decreases in the cell viability of ECA-109 and TE-13. Pretreatment with foretinib synergistically prompted cell apoptosis and G2/M arrest induced by irradiation. Moreover, decreases ability of DNA damage repair was also observed. In vivo studies confirmed that the combinatorial use of foretinib with irradiation significantly diminishes tumor burden compared to either treatment alone. The present findings implied a crucial role of c-Met in the modulation of radiosensitization in esophageal cancer, and foretinib increased the radiosensitivity in ECA-109 and TE-13 cells mainly via c-Met signaling, highlighting a novel profile of foretinib as a potential radiosensitizer for the treatment of esophageal cancer. PMID:28529610

The BDNF Val66Met polymorphism impairs synaptic transmission and plasticity in the infralimbic medial prefrontal cortex

PubMed Central

Pattwell, Siobhan S.; Bath, Kevin G.; Perez-Castro, Rosalia; Lee, Francis S.; Chao, Moses V.; Ninan, Ipe

2012-01-01

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is a common human single nucleotide polymorphism (SNP) that affects the regulated release of BDNF, and has been implicated in affective disorders and cognitive dysfunction. A decreased activation of the infralimbic medial prefrontal cortex (IL-mPFC), a brain region critical for the regulation of affective behaviors, has been described in BDNFMet carriers. However, it is unclear whether and how the Val66Met polymorphism affects the IL-mPFC synapses. Here we report that spike timing-dependent plasticity (STDP) was absent in the IL-mPFC pyramidal neurons from BDNFMet/Met mice, a mouse that recapitulates the specific phenotypic properties of the human BDNF Val66Met polymorphism. Also, we observed a decrease in N-methyl-D-aspartic acid (NMDA) and γ-aminobutyric acid (GABA) receptor-mediated synaptic transmission in the pyramidal neurons of BDNFMet/Met mice. While BDNF enhanced non-NMDA receptor transmission and depressed GABA receptor transmission in the wild-type mice, both effects were absent in BDNFMet/Met mice after BDNF treatment. Indeed, exogenous BDNF reversed the deficits in STDP and NMDA receptor transmission in BDNFMet/Met neurons. BDNF-mediated selective reversal of the deficit in plasticity and NMDA receptor transmission, but its lack of effect on GABA and non-NMDA receptor transmission in BDNFMet/Met mice, suggests separate mechanisms of Val66Met polymorphism upon synaptic transmission. The effect of the Val66Met polymorphism on synaptic transmission and plasticity in the IL-mPFC represents a mechanism to account for this SNP's impact on affective disorders and cognitive dysfunction. PMID:22396415

HGF/c-Met related activation of β-catenin in hepatoblastoma

PubMed Central

2011-01-01

Background Activation of beta-catenin is a hallmark of hepatoblastoma (HB) and appears to play a crucial role in its pathogenesis. While aberrant accumulation of the beta-catenin is a common event in HB, mutations or deletions in CTNNB1 (beta-catenin gene) do not always account for the high frequency of protein expression. In this study we have investigated alternative activation of beta-catenin by HGF/c-Met signaling in a large cohort of 98 HB patients enrolled in the SIOPEL-3 clinical trial. Methods We performed immunohistochemistry, using antibodies to total beta-catenin and tyrosine654-phosphorylated beta-catenin, which is a good surrogate marker of HGF/c-Met activation. CTNNB1 mutation analysis was also carried out on all samples. We also investigated beta-catenin pathway activation in two liver cancer cell lines, HuH-6 and HuH-7. Results Aberrant beta-catenin expression was seen in the cytoplasm and/or nucleus of 87% of tumour samples. Our results also revealed a large subset of HB, 83%, with cytoplasmic expression of tyrosine654-phosphorylated beta-catenin and 30% showing additional nuclear accumulation. Sequence analysis revealed mutations in 15% of our cohort. Statistical analysis showed an association between nuclear expression of c-Met-activated beta-catenin and wild type CTNNB1 (P-value = 0.015). Analysis of total beta-catenin and Y654-beta-catenin in response to HGF activation in the cell lines, mirrors that observed in our HB tumour cohort. Results We identified a significant subset of hepatoblastoma patients for whom targeting of the c-Met pathway may be a treatment option and also demonstrate distinct mechanisms of beta-catenin activation in HB. PMID:21992464

The influence of COMT Val¹⁵⁸Met genotype on the character dimension cooperativeness in healthy females.

PubMed

Baeken, Chris; Claes, Stephan; De Raedt, Rudi

2014-07-01

Although the Val(158)Met catechol-O-methyltransferase (COMT) gene has been linked with the temperament dimension Novelty Seeking (NS), new insights in this polymorphism might point to a major role for character features as well. Given that individual life experiences may influence Val(158) and Met(158) allele carriers differently it has been suggested that the character trait cooperativeness could be implicated. A homogeneous group of eighty right-handed Caucasian healthy female university students were assessed with the TCI and genotyped for the COMT Val(158)Met polymorphism (rs4680). Gene determination showed that eighteen were Val(158) homozygotes, forty-four Val/Met(158) heterozygotes, and eighteen were Met(158) homozygotes. All were within the same age range and never documented to have suffered from any neuropsychiatric illness. Bonferroni corrected non-parametric analyses showed that only for the character scale cooperativeness Val(158) homozygotes displayed significant higher scores when compared to Met(158) homozygotes. No significant differences on cooperativeness scores were found between Val(158) and Val/Met(158) carriers or between Met(158) and Val/Met(158) carriers. No differences were observed for the COMT Val(158)Met polymorphism and the other temperament and character scales. Our findings support the assumption that the Val(158)Met single nucleotide polymorphism (SNP) influences character traits and not only temperament. Our results add to the notion that Val(158) homozygotes are considered to be helpful and empathic and it suggest that these cooperativeness character traits are related to the dopaminergic system.

Association of ghrelin Leu72Met polymorphism with type 2 diabetes mellitus in Chinese population.

PubMed

Liu, Jing; Liu, Jia; Tian, Li-min; Liu, Ju-xiang; Bing, Ya-jun; Zhang, Ji-ping; Wang, Yun-Fang; Zhang, Lu-yan

2012-08-10

Ghrelin, a novel endogenous ligand for the growth hormone secretagogue receptor, is considered to implicate the development of the type 2 diabetes mellitus (T2DM). The Leu72Met (+408C>A) polymorphism of the preproghrelin, has been linked to obesity, insulin resistance and diabetes. To investigate the distribution of ghrelin gene Leu72Met polymorphism and its association with the type 2 diabetes mellitus in Chinese population. We conducted a case-control study on 877 patients with T2DM and 864 controls, which were genotyped by the polymerase chain reaction (PCR) technique, denaturing high performance liquid chromatography (DHPLC) and DNA sequence analysis. Laboratory analyses were carried out in the hospital laboratory. No significant difference in the Leu72Met genotype distributions and allele frequency was observed between type 2 diabetes mellitus and controls (both P>0.05). The polymorphism was not associated with T2DM. However, among the T2DM group, the patients carrying Leu72Leu genotype had significantly increased levels of FPG and serum creatinine compared with variant genotypes (Leu72Met and Met72Met) (P<0.05). In the control group, the subjects with variant genotypes had significantly increased levels of FINS, HOMA-IR compared with Leu72Leu genotype (P<0.05). The Leu72Met polymorphism of the preproghrelin gene was not associated with T2DM in Chinese population. However, it may have some roles in the etiology of insulin resistance. Copyright © 2012 Elsevier B.V. All rights reserved.

Regional metabolism of Met-enkephalin and cholecystokinin on intact ratbrain slices: characterization of specific peptidases.

PubMed

Konkoy, C S; Davis, T P

1995-12-01

The metabolism of Met-enkephalin and cholecystokinin (CCK) 8-(sulfated) by intact microslices was studied in rat brain regions. Incubation of brain slices with Met-enkephalin (400 microM) resulted in a linear rate of disappearance of parent peptide and appearance of metabolic fragments whose rate of accumulation was specific to brain region. The degradative rate (pmol/min/mg of protein) of Met-enkephalin was high in caudate-putamen (5,160 +/- 120) and lower in nucleus accumbens (3,630 +/- 110) and frontal cortex (3,180 +/- 120). Inhibition of aminopeptidases decreased Met-enkephalin degradation (50-97% vs. control) in frontal cortex but was less effective in caudate-putamen (20-34%). Tyr-Gly-Gly and Phe-Met were recovered in caudate-putamen and nucleus accumbens, whereas negligible quantities of these fragments were recovered from frontal cortex. Phosphoramidon, an inhibitor of neutral endopeptidase 24.11, decreased Met-enkephalin degradation in caudate-putamen (14%) but had no effect on that in frontal cortex. A cocktail of bestatin or leuhistin (inhibitors of aminopeptidases), phosphoramidon, and captopril (an inhibitor of angiotensin converting enzyme) protected Met-enkephalin from degradation (recovery > 95%) in caudate-putamen. CCK 8-(sulfated) degradation on slices from caudate-putamen, nucleus accumbens, and frontal cortex was not altered by inhibitors of neutral endopeptidase 24.11, metalloendopeptidase 24.15, angiotensin converting enzyme, or thiol proteases. Inhibitors of either aminopeptidases or serine proteases produced small reductions (13-30%) in CCK degradation in each region. These data provide evidence for regional and structural specificity in terminating the actions of neuropeptides.

Paradoxical visuomotor adaptation to reversed visual input is predicted by BDNF Val66Met polymorphism

PubMed Central

Barton, Brian; Treister, Andrew; Humphrey, Melanie; Abedi, Garen; Cramer, Steven C.; Brewer, Alyssa A.

2014-01-01

Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the brain, influencing neural development, plasticity, and repair (Chen et al., 2004; Thoenen, 1995). The BDNF gene contains a single-nucleotide polymorphism (SNP) called Val66Met. The Met allele interferes with intracellular BDNF-trafficking, decreases activity-dependent BDNF secretion, and consequently is often associated with a shift from plasticity to stability in neural circuits (Egan et al., 2003). We investigated the behavioral consequences of the presence of the Met allele by comparing how 40 heterozygous subjects with the Val/Met genotype and 35 homozygous subjects with the Val/Val genotype performed on visuomotor tasks (reaching and navigation) under two conditions: normal vision and completely left-right reversed vision. As expected, subjects did not differ in their short-term ability to learn the tasks with normal vision (p = 0.58). Intuitively, it would be expected that homozygous Val/Val subjects with a propensity for greater BDNF-induced activity-dependent plasticity would learn new tasks more quickly than heterozygous Val/Met subjects with decreased BDNF secretion (Gilbert, Li, & Piech, 2009). However, we found the opposite here. When short-term mechanisms of visuomotor adaptation were engaged to compensate for the misalignment of visual and somatomotor information created by the left-right reversal of vision, heterozygous Val/Met subjects learned significantly more quickly than their homozygous Val/Val counterparts (p = 0.027). Our results demonstrate the paradoxical finding that the presence of the Met allele, which is thought to promote cortical stability, here improves immediate visuomotor adaptation to left–right-reversed visual input. PMID:25104829

Spark Plasma Sintering of Load-Bearing Iron-Carbon Nanotube-Tricalcium Phosphate CerMets for Orthopaedic Applications

NASA Astrophysics Data System (ADS)

Montufar, Edgar B.; Horynová, Miroslava; Casas-Luna, Mariano; Diaz-de-la-Torre, Sebastián; Celko, Ladislav; Klakurková, Lenka; Spotz, Zdenek; Diéguez-Trejo, Guillermo; Fohlerová, Zdenka; Dvorak, Karel; Zikmund, Tomáš; Kaiser, Jozef

2016-04-01

Recently, ceramic-metallic composite materials (CerMets) have been investigated for orthopaedic applications with promising results. This first generation of bio-CerMets combine the bioactivity of hydroxyapatite with the mechanical stability of titanium to fabricate bioactive, tough and biomechanically more biocompatible osteosynthetic devices. Nonetheless, these first CerMets are not biodegradable materials and a second surgery is required to remove the implant after bone healing. The present work aims to develop the next generation bio-CerMets, which are potential biodegradable materials. The process to produce the new biodegradable CerMet consisted of mixing powder of soluble and osteoconductive alpha tricalcium phosphate with biocompatible and biodegradable iron with consolidation through spark plasma sintering (SPS). The microstructure, composition and mechanical strength of the new CerMet were studied by metallography, x-ray diffraction and diametral tensile strength tests, respectively. The results show that SPS produces CerMet with higher mechanical performance (120 MPa) than the ceramic component alone (29 MPa) and similar mechanical strength to the pure metallic component (129 MPa). Nonetheless, although a short sintering time (10 min) was used, partial transformation of the alpha tricalcium phosphate into its allotropic and slightly less soluble beta phase was observed. Cell adhesion tests show that osteoblasts are able to attach to the CerMet surface, presenting spread morphology regardless of the component of the material with which they are in contact. However, the degradation process restricted to the small volume of the cell culture well quickly reduces the osteoblast viability.

MET inhibitor PHA-665752 suppresses the hepatocyte growth factor-induced cell proliferation and radioresistance in nasopharyngeal carcinoma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Tongxin; Li, Qi; Sun, Quanquan

2014-06-20

Highlights: • We demonstrated that irradiation induced MET overexpression and activation. • The aberrant MET signal mediated by HGF induced proliferation and radioresistance of NPC cells. • MET inhibitor PHA-665752 effectively suppressed HGF induced cell proliferation and radioresistance in NPC cells. • PHA-665752 suppressed the three downstream pathway of HGF/MET signal in a dose-dependent manner. - Abstract: Although ionizing radiation (IR) has provided considerable improvements in nasopharyngeal carcinoma (NPC), in subsets of patients, radioresistance is still a major problem in the treatment. In this study, we demonstrated that irradiation induced MET overexpression and activation, and the aberrant MET signal mediatedmore » by hepatocyte growth factor (HGF) induced radioresistance. We also found that MET inhibitor PHA-665752 effectively suppressed HGF induced cell proliferation and radioresistance in NPC cells. Further investigation indicated that PHA-665752 suppressed the phosphorylation of the Akt, ERK1/2, and STAT3 proteins in a dose-dependent manner. Our data indicated that the combination of IR with a MET inhibitor, such as PHA-665752, might be a promising therapeutic strategy for NPC.« less

MetLife and its corporate allies: dust diseases and the manipulation of science.

PubMed

Egilman, David S; Bird, Tess; Lee, Caroline

2013-01-01

The dust diseases silicosis and asbestosis were the first occupational diseases to have widespread impact on workers. Knowledge that asbestos and silica were hazardous to health became public long after the industry knew of the health concerns. This delay was largely influenced by the interests of Metropolitan Life Insurance Company (MetLife). To understand how MetLife influenced the science and politics of asbestos and silica exposure in the first half of the twentieth century. We examined previously secret corporate documents produced in litigation, deposition, and trial testimony, as well as published scholarship. MetLife established itself as an authority in public and industrial health in the early part of the twentieth century, gaining the trust of the public and government. They were able to use this trust and authority to avoid financial loss, including the firing of sick workers, and avoid legal liability by organizing a network of experts to testify on their behalf in silica- and asbestos-related damage suits. They further manipulated the results of scientific findings from major research institutions, delaying important knowledge about the asbestos-cancer relationship. They also influenced law and public policy through writing and implementing worker compensation laws in numerous states and concocting an arbitrary "protective" standard to monitor asbestos exposure. This standard was known by MetLife to not protect against disease. The actions of MetLife and its allies had real human and scientific consequences and an effect on the industry lasting until now.

The regulation mechanism of yitJ and metF riboswitches

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gong, Sha; Wang, Yujie; Zhang, Wenbing, E-mail: wbzhang@whu.edu.cn

2015-07-28

Riboswitches which function at the transcriptional level are sensitive to cotranscriptional folding. Based on the recently proposed theory of cotranscriptional folding, we developed a transition node approximation method to effectively decrease the conformation space of long RNA chains. Our results indicate that this approximation is reliable for calculating the cotranscriptional folding kinetics of long mRNA chains. We theoretically studied the cotranscriptional folding behavior of the yitJ and metF riboswitches in the absence/presence of S-adenosylmethionine. Although the two S-box riboswitches have similar OFF-state structures and share common features of riboswitches operated at the transcriptional level, their regulation mechanisms are different. Themore » yitJ riboswitch is regulated by a combination of thermodynamic and kinetic mechanisms, while the metF riboswitch is solely kinetically controlled. For the yitJ riboswitch, transcriptional pausing at the U-stretch directly following the terminator decreases the amount of ligand required to trigger the switch. The different regulation mechanisms and binding affinities of the two riboswitches result from the different lengths of the anti-terminator helix, which in yitJ is short and only disrupts helix P1 of the riboswitch aptamer, but in metF is long and breaks both the helices P1 and P4.« less

Distinct c-Met activation mechanisms induce cell rounding or invasion through pathways involving integrins, RhoA and HIP1.

PubMed

Mai, Anja; Muharram, Ghaffar; Barrow-McGee, Rachel; Baghirov, Habib; Rantala, Juha; Kermorgant, Stéphanie; Ivaska, Johanna

2014-05-01

Many carcinomas have acquired oncogenic mechanisms for activating c-Met, including c-Met overexpression and excessive autocrine or paracrine stimulation with hepatocyte growth factor (HGF). However, the biological outcome of c-Met activation through these distinct modes remains ambiguous. Here, we report that HGF-mediated c-Met stimulation triggers a mesenchymal-type collective cell invasion. By contrast, the overexpression of c-Met promotes cell rounding. Moreover, in a high-throughput siRNA screen that was performed using a library of siRNAs against putative regulators of integrin activity, we identified RhoA and the clathrin-adapter protein HIP1 as crucial c-Met effectors in these morphological changes. Transient RhoA activation was necessary for the HGF-induced invasion, whereas sustained RhoA activity regulated c-Met-induced cell rounding. In addition, c-Met-induced cell rounding correlated with the phosphorylation of filamin A and the downregulation of active cell-surface integrins. By contrast, a HIP1-mediated increase in β1-integrin turnover was required for the invasion triggered by HGF. Taken together, our results indicate that c-Met induces distinct cell morphology alterations depending on the stimulus that activates c-Met.

Effects of the BDNF Val66Met Polymorphism on Anxiety-Like Behavior Following Nicotine Withdrawal in Mice

PubMed Central

Lee, Bridgin G.; Anastasia, Agustin; Hempstead, Barbara L.; Lee, Francis S.

2015-01-01

Introduction: Nicotine withdrawal is characterized by both affective and cognitive symptoms. Identifying genetic polymorphisms that could affect the symptoms associated with nicotine withdrawal are important in predicting withdrawal sensitivity and identifying personalized cessation therapies. In the current study we used a mouse model of a non-synonymous single nucleotide polymorphism in the translated region of the brain-derived neurotrophic factor (BDNF) gene that substitutes a valine (Val) for a methionine (Met) amino acid (Val66Met) to examine the relationship between the Val66Met single nucleotide polymorphism and nicotine dependence. Methods: This study measured proBDNF and the BDNF prodomain levels following nicotine and nicotine withdrawal and examined a mouse model of a common polymorphism in this protein (BDNFMet/Met) in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test. Results: Using the BDNF knock-in mouse containing the BDNF Val66Met polymorphism we found: (1) blunted anxiety-like behavior in BDNFMet/Met mice following withdrawal in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test; (2) the anxiolytic effects of chronic nicotine are absent in BDNFMet/Met mice; and (3) an increase in BDNF prodomain in BDNFMet/Met mice following nicotine withdrawal. Conclusions: Our study is the first to examine the effect of the BDNF Val66Met polymorphism on the affective symptoms of withdrawal from nicotine in mice. In these mice, a single-nucleotide polymorphism in the translated region of the BDNF gene can result in a blunted withdrawal, as measured by decreased anxiety-like behavior. The significant increase in the BDNF prodomain in BDNFMet/Met mice following nicotine cessation suggests a possible role of this ligand in the circuitry remodeling after withdrawal. PMID:25744957

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

PubMed

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.

6-Phosphogluconate dehydrogenase regulates tumor cell migration in vitro by regulating receptor tyrosine kinase c-Met

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chan, Barden, E-mail: cchan@bidmc.harvard.edu; VanderLaan, Paul A.; Sukhatme, Vikas P.

2013-09-20

Highlights: •Expression of 6PGD positively correlates with advancing stage of lung carcinoma. •Knockdown of 6PGD by shRNA potently inhibits c-Met tyrosine phosphorylation. •Exogenous HGF fails to restore c-Met phosphorylation in cells with 6PGD knocked down. •6PGD knockdown results in inhibition of cell migration in vitro. •Constitutively active TPR-cMet significantly restores migration of cells without 6PGD. -- Abstract: 6-Phosphogluconate dehydrogenase (6PGD) is the third enzyme in the oxidative pentose phosphate pathway (PPP). Recently, we reported that knockdown of 6PGD inhibited lung tumor growth in vitro and in a xenograft model in mice. In this study, we continued to examine the functionalmore » role of 6PGD in cancer. We show that 6PGD expression positively correlates with advancing stage of lung carcinoma. In search of functional signals related to 6PGD, we discovered that knockdown of 6PGD significantly inhibited phosphorylation of c-Met at tyrosine residues known to be critical for activity. This downregulation of c-Met phosphorylation correlated with inhibition of cell migration in vitro. Overexpression of a constitutively active c-Met specifically rescued the migration but not proliferation phenotype of 6PGD knockdown. Therefore, 6PGD appears to be required for efficient c-Met signaling and migration of tumor cells in vitro.« less

MicroRNA-206: Effective Inhibition of Gastric Cancer Progression through the c-Met Pathway

PubMed Central

Zheng, Zhiqiang; Yan, Dongsheng; Chen, Xiaoyan; Huang, He; Chen, Ke; Li, Guangjing; Zhou, Linglin; Zheng, Dandan; Tu, LiLi; Dong, Xiang Da

2015-01-01

MicroRNAs are endogenous short chain nucleotide RNAs that regulate gene function by direct binding of target mRNAs. In this study, we investigated the effects of microRNA-206 (miR-206) on the development of gastric cancer. miR-206 was first confirmed to be downregulated in gastric cancer specimens. Conversely, upregulation of c-Met was confirmed in tissue samples of human gastric cancer, with its level inversely correlated with miR-206 expression. Introduction of miR-206 inhibited cellular proliferation by inducing G1 cell cycle arrest, as well as migration and invasion. Moreover, important proliferation and/or migration related molecules such as c-Met, CDK4, p-Rb, p-Akt and p-ERK were confirmed to be downregulated by Western blot analysis. Targeting of c-Met also directly affected AGS cell proliferation, migration and invasion. In vivo, miR-206 expressing tumor cells also displayed growth delay in comparison to unaffected tumor cells. Our results demonstrated that miR-206 suppressed c-Met expression in gastric cancer and could function as a potent tumor suppressor in c-Met overexpressing tumors. Inhibition of miR-206 function could contribute to aberrant cell proliferation and migration, leading to gastric cancer development. PMID:26186594

The MET13 Methylenetetrahydrofolate Reductase Gene Is Essential for Infection-Related Morphogenesis in the Rice Blast Fungus Magnaporthe oryzae

PubMed Central

Wang, Hong; Wang, Congcong; Li, Ya; Yue, Xiaofeng; Ma, Zhonghua; Talbot, Nicholas J.; Wang, Zhengyi

2013-01-01

Methylenetetrahydrofolate reductases (MTHFRs) play a key role in the biosynthesis of methionine in both prokaryotic and eukaryotic organisms. In this study, we report the identification of a novel T-DNA-tagged mutant WH672 in the rice blast fungus Magnaporthe oryzae, which was defective in vegetative growth, conidiation and pathogenicity. Analysis of the mutation confirmed a single T-DNA insertion upstream of MET13, which encodes a 626-amino-acid protein encoding a MTHFR. Targeted gene deletion of MET13 resulted in mutants that were non-pathogenic and significantly impaired in aerial growth and melanin pigmentation. All phenotypes associated with Δmet13 mutants could be overcome by addition of exogenous methionine. The M. oryzae genome contains a second predicted MTHFR-encoding gene, MET12. The deduced amino acid sequences of Met13 and Met12 share 32% identity. Interestingly, Δmet12 mutants produced significantly less conidia compared with the isogenic wild-type strain and grew very poorly in the absence of methionine, but were fully pathogenic. Deletion of both genes resulted in Δmet13Δmet12 mutants that showed similar phenotypes to single Δmet13 mutants. Taken together, we conclude that the MTHFR gene, MET13, is essential for infection-related morphogenesis by the rice blast fungus M. oryzae. PMID:24116181

Ex ante Implementatietoetsing van Beleid, Een Methodiek Gebaseerd op Synergie Tussen Risicomanagement en Verandermanagement (Ex Ante Test for Policy Implementation - A Method Based Upon Synergy Between Risk Management an Change Management)

DTIC Science & Technology

2006-12-01

ante implementatietoetsing van beleid Een methodiek gebaseerd op synergie tussen risicomnanagemnent en verandermanagemnent Datuni december 2006 Auteur (s...te analyseren. Het de resultaten van de interviews gebruikct bij de theorie van risicomanagement en project Verandermanagernent bij de de ontwikkehing...Opdrachtnummer Hoewel expliciet is gekeken naar voorbeelden van risico’s bij Datum december 2006 Auteur (s) PROGRAMMA PR03ECT drs. R.C.T. de Haas drs

BDNF Val66Met polymorphism modulates the effect of loneliness on white matter microstructure in young adults.

PubMed

Meng, Jie; Hao, Lei; Wei, Dongtao; Sun, Jiangzhou; Li, Yu; Qiu, Jiang

2017-12-01

Loneliness is a common experience. Susceptibility to loneliness is a stable trait and is heritable. Previous studies have suggested that loneliness may impact regional gray matter density and brain activation to social stimuli, but its relation to white matter structure and how it may interact with genetic factors remains unclear. In this study, we investigated whether and how a common polymorphism (Val66Met) in the brain-derived neurotrophic factor gene modulated the association between loneliness and white matter microstructure in 162 young adults. The tract-based spatial statistics analyses revealed that the relationships between loneliness and white matter microstructures were significantly different between Val/Met heterozygotes and Val/Val homozygotes. Specifically, loneliness was significantly correlated with reduced fractional anisotropy and increased radial diffusivity in widespread white matter fibers within Val/Met heterozygotes. It was also significantly correlated with increased radial diffusivity in Met/Met genotypes but showed no significant association with white matter measures in Val/Val genotypes. Furthermore, the associations between loneliness and fractional anisotropy (or radial diffusivity) in Val/Met heterozygotes turned out to be global effects. These results provide evidence that loneliness may interact with the BDNF Val66Met polymorphism to shape the microstructures of white matter, and the Val/Met heterozygotes may be more susceptible to social environment. Copyright © 2017 Elsevier B.V. All rights reserved.

Brain-derived neurotrophic factor Val66Met polymorphism and alcohol-related phenotypes.

PubMed

Nedic, Gordana; Perkovic, Matea Nikolac; Sviglin, Korona Nenadic; Muck-Seler, Dorotea; Borovecki, Fran; Pivac, Nela

2013-01-10

Alcoholism is a chronic psychiatric disorder affecting neural pathways that regulate motivation, stress, reward and arousal. Brain-derived neurotrophic factor (BDNF) regulates mood, response to stress and interacts with neurotransmitters and stress systems involved in reward pathways and addiction. Aim of the study was to evaluate the association between a single nucleotide polymorphism (BDNF Val66Met or rs6265) and alcohol related phenotypes in Caucasian patients. In ethnically homogenous Caucasian subjects of the Croatian origin, the BDNF Val66Met genotype distribution was determined in 549 male and 126 female patients with alcohol dependence and in 655 male and 259 female healthy non-alcoholic control subjects. Based on the structured clinical interview, additional detailed clinical interview, the Brown-Goodwin Scale, the Hamilton Rating Scale for Depression and the Clinical Global Impression scores, alcoholic patients were subdivided into those with or without comorbid depression, aggression, delirium tremens, withdrawal syndrome, early/late onset of alcohol abuse, prior suicidal attempt during lifetime, current suicidal behavior, and severity of alcohol dependence. The results showed no significant association between BDNF Val66Met variants and alcohol dependence and/or any of the alcohol related phenotypes in either Caucasian women, or men, with alcohol dependence. There are few limitations of the study. The overall study sample size was large (N=1589) but not well-powered to detect differences in BDNF Val66Met genotype distribution between studied groups. Healthy control women were older than female alcoholic patients. Only one BDNF polymorphism (rs6265) was studied. In conclusion, these data do not support the view that BDNF Val66Met polymorphism correlates with the specific alcohol related phenotypes in ethnically homogenous medication-free Caucasian subjects with alcohol dependence. Copyright © 2012 Elsevier Inc. All rights reserved.

Effects of BDNF Val66Met polymorphism on brain metabolism in Alzheimer's disease.

PubMed

Xu, Cunlu; Wang, Zhenhua; Fan, Ming; Liu, Bing; Song, Ming; Zhen, Xiantong; Jiang, Tianzi

2010-08-23

Earlier studies showed that the Val66Met polymorphisms of the brain-derived neurotrophic factor differentially affect gray matter volume and brain region activities. This study used resting positron emission tomography to investigate the relationship between the polymorphisms of Val66Met and the regional cerebral metabolic rate in the brain. We analyzed the positron emission tomography images of 215 patients from the Alzheimer's Disease Neuroimaging Initiative and found significant differences in the parahippocampal gyrus, superior temporal gyrus, prefrontal cortex, and inferior parietal lobule when comparing Met carriers with noncarriers among both the normal controls and those with mild cognitive impairment. For those with Alzheimer's disease, we also found additional differences in the bilateral insula between the carriers and noncarriers.

The roles of COMT val158met status and aviation expertise in flight simulator performance and cognitive ability.

PubMed

Kennedy, Q; Taylor, J L; Noda, A; Adamson, M; Murphy, G M; Zeitzer, J M; Yesavage, J A

2011-09-01

The polymorphic variation in the val158met position of the catechol-O-methyltransferase (COMT) gene is associated with differences in executive performance, processing speed, and attention. The purpose of this study is: (1) replicate previous COMT val158met findings on cognitive performance; (2) determine whether COMT val158met effects extend to a real-world task, aircraft navigation performance in a flight simulator; and (3) determine if aviation expertise moderates any effect of COMT val158met status on flight simulator performance. One hundred seventy two pilots aged 41-69 years, who varied in level of aviation training and experience, completed flight simulator, cognitive, and genetic assessments. Results indicate that although no COMT effect was found for an overall measure of flight performance, a positive effect of the met allele was detected for two aspects of cognitive ability: executive functioning and working memory performance. Pilots with the met/met genotype benefited more from increased levels of expertise than other participants on a traffic avoidance measure, which is a component of flight simulator performance. These preliminary results indicate that COMT val158met polymorphic variation can affect a real-world task.

The Roles of COMT val158met Status and Aviation Expertise in Flight Simulator Performance and Cognitive Ability

PubMed Central

Taylor, J. L.; Noda, A.; Adamson, M.; Murphy, G. M.; Zeitzer, J. M.; Yesavage, J. A.

2011-01-01

The polymorphic variation in the val158met position of the catechol-O-methyltransferase (COMT) gene is associated with differences in executive performance, processing speed, and attention. The purpose of this study is: (1) replicate previous COMT val158met findings on cognitive performance; (2) determine whether COMT val158met effects extend to a real-world task, aircraft navigation performance in a flight simulator; and (3) determine if aviation expertise moderates any effect of COMT val158met status on flight simulator performance. One hundred seventy two pilots aged 41–69 years, who varied in level of aviation training and experience, completed flight simulator, cognitive, and genetic assessments. Results indicate that although no COMT effect was found for an overall measure of flight performance, a positive effect of the met allele was detected for two aspects of cognitive ability: executive functioning and working memory performance. Pilots with the met/met genotype benefited more from increased levels of expertise than other participants on a traffic avoidance measure, which is a component of flight simulator performance. These preliminary results indicate that COMT val158met polymorphic variation can affect a real-world task. PMID:21193954

Preparation, crystallization and preliminary X-ray analysis of the methionine synthase (MetE) from Streptococcus mutans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fu, Tian-Min; Zhang, Xiao-Yan; Li, Lan-Fen

2006-10-01

Methionine synthase (MetE) from S. mutans was expressed, purified and crystallized. Diffraction data have been collected to 2.2 Å resolution. The Streptococcus mutans metE gene encodes methionine synthase (MetE), which catalyzes the direct transfer of a methyl group from methyltetrahydrofolate to homocysteine in the last step of methionine synthesis. metE was cloned into pET28a and the gene product was expressed at high levels in the Escherichia coli strain BL21 (DE3). MetE was purified to homogeneity using Ni{sup 2+}-chelating chromatography followed by size-exclusion chromatography. Crystals of the protein were obtained by the hanging-drop vapour-diffusion method and diffracted to 2.2 Å resolution.more » The crystal belongs to space group P2{sub 1}, with unit-cell parameters a = 52.85, b = 99.48, c = 77.88 Å, β = 94.55°.« less

Medical Emergency Team: How do we play when we stay? Characterization of MET actions at the scene.

PubMed

Silva, Raquel; Saraiva, Manuel; Cardoso, Teresa; Aragão, Irene C

2016-03-22

The creation, implementation and effectiveness of a medical emergency team (MET) in every hospital is encourage and supported by international bodies of quality certification. Issues such as what is the best composition of the team or the interventions performed by the MET at the scene and the immediate outcomes of the patients after MET intervention have not yet been sufficiently explored. The purpose of the study is to characterize MET actions at the scene and the immediate patient outcome. Retrospective cohort study, at a tertiary care, university-affiliated, 600-bed hospital, in the north of Portugal, over two years. There were 511 MET activations: 389 (76%) were for inpatients. MET activation rate was 8.6/1,000 inpatients. The main criteria for activation were airway threatening in 143 (36.8%), concern of medical staff in 121 (31.1%) and decrease in GCS > 2 in 98 (25.2%) patients; MET calls for cardiac arrest occurred in 68 patients (17.5%). The median (IQR) time the team stayed at the scene was 35 (20-50) minutes. At the scene, the most frequent actions were related to airway and ventilation, namely oxygen administration in 145 (37.3%); in circulation, fluid were administered in 158 (40.6%); overall medication was administered in 185 (47.5%) patients. End-of-life decisions were part of the MET actions in 94 (24.1%) patients. At the end of MET intervention, 73 (18.7%) patients died at the scene, 190 (60.7%) stayed on the ward and the remaining 123 patients were transferred to an increased level of care. Crude hospital mortality rate was 4.1% in the 3 years previously to MET implementation and 3.6% in the following 3 years (p < 0.001). During the study period, the rate of activation for medical inpatients was significantly higher than that for surgical inpatients. In our hospital, there is no 24/7 medical cover on the wards, with the exception of high-dependency and intensive care units; assuming that the number of unplanned admissions and chronic ill

Gab1 Is Required for Cell Cycle Transition, Cell Proliferation, and Transformation Induced by an Oncogenic Met Receptor

PubMed Central

Mood, Kathleen; Saucier, Caroline; Bong, Yong-Sik; Lee, Hyun-Shik; Park, Morag

2006-01-01

We have shown previously that either Grb2- or Shc-mediated signaling from the oncogenic Met receptor Tpr-Met is sufficient to trigger cell cycle progression in Xenopus oocytes. However, direct binding of these adaptors to Tpr-Met is dispensable, implying that another Met binding partner mediates these responses. In this study, we show that overexpression of Grb2-associated binder 1 (Gab1) promotes cell cycle progression when Tpr-Met is expressed at suboptimal levels. This response requires that Gab1 possess an intact Met-binding motif, the pleckstrin homology domain, and the binding sites for phosphatidylinositol 3-kinase and tyrosine phosphatase SHP-2, but not the Grb2 and CrkII/phospholipase Cγ binding sites. Importantly, we establish that Gab1-mediated signals are critical for cell cycle transition promoted by the oncogenic Met and fibroblast growth factor receptors, but not by progesterone, the natural inducer of cell cycle transition in Xenopus oocytes. Moreover, Gab1 is essential for Tpr-Met–mediated morphological transformation and proliferation of fibroblasts. This study provides the first evidence that Gab1 is a key binding partner of the Met receptor for induction of cell cycle progression, proliferation, and oncogenic morphological transformation. This study identifies Gab1 and its associated signaling partners as potential therapeutic targets to impair proliferation or transformation of cancer cells in human malignancies harboring a deregulated Met receptor. PMID:16775003

Cloning and characterization of the metE gene encoding S-adenosylmethionine synthetase from Bacillus subtilis.

PubMed Central

Yocum, R R; Perkins, J B; Howitt, C L; Pero, J

1996-01-01

The metE gene, encoding S-adenosylmethionine synthetase (EC 2.5.1.6) from Bacillus subtilis, was cloned in two steps by normal and inverse PCR. The DNA sequence of the metE gene contains an open reading frame which encodes a 400-amino-acid sequence that is homologous to other known S-adenosylmethionine synthetases. The cloned gene complements the metE1 mutation and integrates at or near the chromosomal site of metE1. Expression of S-adenosylmethionine synthetase is reduced by only a factor of about 2 by exogenous methioinine. Overproduction of S-adenosylmethionine synthetase from a strong constitutive promoter leads to methionine auxotrophy in B. subtilis, suggesting that S-adenosylmethionine is a corepressor of methionine biosynthesis in B. subtilis, as others have already shown for Escherichia coli. PMID:8755891

Cloning and characterization of the metE gene encoding S-adenosylmethionine synthetase from Bacillus subtilis.

PubMed

Yocum, R R; Perkins, J B; Howitt, C L; Pero, J

1996-08-01

The metE gene, encoding S-adenosylmethionine synthetase (EC 2.5.1.6) from Bacillus subtilis, was cloned in two steps by normal and inverse PCR. The DNA sequence of the metE gene contains an open reading frame which encodes a 400-amino-acid sequence that is homologous to other known S-adenosylmethionine synthetases. The cloned gene complements the metE1 mutation and integrates at or near the chromosomal site of metE1. Expression of S-adenosylmethionine synthetase is reduced by only a factor of about 2 by exogenous methioinine. Overproduction of S-adenosylmethionine synthetase from a strong constitutive promoter leads to methionine auxotrophy in B. subtilis, suggesting that S-adenosylmethionine is a corepressor of methionine biosynthesis in B. subtilis, as others have already shown for Escherichia coli.

Energy cost of physical activities in 12-y-old girls: MET values and the influence of body weight.

PubMed

Spadano, J L; Must, A; Bandini, L G; Dallal, G E; Dietz, W H

2003-12-01

Few data exist on the energy cost of specific activities in children. The influence of body weight on the energy cost of activity when expressed as metabolic equivalents (METs) has not been vigorously explored. To provide MET data on five specific activities in 12-y-old girls and to test the hypothesis that measured MET values are independent of body weight. In 17 12-y-old girls, resting metabolic rate (RMR) and the energy expended while sitting, standing, walking on a flat treadmill at 3.2 and at 4.8 km/h, and walking on a treadmill at a 10% incline at 4.8 km/h were measured using indirect calorimetry. MET values were calculated by dividing the energy expenditure of an activity by the subject's RMR. The influence of body weight was assessed using simple linear regression. The observed METs were more consistent with published values for similar activities in adults than those offered for children. Body weight was a statistically significant predictor of the MET of all three walking activities, but not the MET of sitting or standing. Body weight explained 25% of the variance in the MET value for walking at 3.2 km/h, 39% for walking at 4.8 km/h, and 63% for walking at a 10% incline at 4.8 km/h. METs for the three walking activities were not independent of body weight. The use of average MET values to estimate the energy cost of these three activities would result in an underestimation of their energy cost in heavier girls and an overestimation in lighter girls. These results suggest that the estimation of total energy expenditure from activity diary, recall, and direct observation data using average MET values may be biased by body weight.

Combination strategy targeting VEGF and HGF/c-met in human renal cell carcinoma models.

PubMed

Ciamporcero, Eric; Miles, Kiersten Marie; Adelaiye, Remi; Ramakrishnan, Swathi; Shen, Li; Ku, ShengYu; Pizzimenti, Stefania; Sennino, Barbara; Barrera, Giuseppina; Pili, Roberto

2015-01-01

Alternative pathways to the VEGF, such as hepatocyte growth factor or HGF/c-met, are emerging as key players in tumor angiogenesis and resistance to anti-VEGF therapies. The aim of this study was to assess the effects of a combination strategy targeting the VEGF and c-met pathways in clear cell renal cell carcinoma (ccRCC) models. Male SCID mice (8/group) were implanted with 786-O tumor pieces and treated with either a selective VEGF receptor tyrosine kinase inhibitor, axitinib (36 mg/kg, 2×/day); a c-met inhibitor, crizotinib (25 mg/kg, 1×/day); or combination. We further tested this drug combination in a human ccRCC patient-derived xenograft, RP-R-01, in both VEGF-targeted therapy-sensitive and -resistant models. To evaluate the resistant phenotype, we established an RP-R-01 sunitinib-resistant model by continuous sunitinib treatment (60 mg/kg, 1×/day) of RP-R-01-bearing mice. Treatment with single-agent crizotinib reduced tumor vascularization but failed to inhibit tumor growth in either model, despite also a significant increase of c-met expression and phosphorylation in the sunitinib-resistant tumors. In contrast, axitinib treatment was effective in inhibiting angiogenesis and tumor growth in both models, with its antitumor effect significantly increased by the combined treatment with crizotinib, independently from c-met expression. Combination treatment also induced prolonged survival and significant tumor growth inhibition in the 786-O human RCC model. Overall, our results support the rationale for the clinical testing of combined VEGF and HGF/c-met pathway blockade in the treatment of ccRCC, both in first- and second-line setting. ©2014 American Association for Cancer Research.

The BDNF Val66Met polymorphism affects HPA-axis reactivity to acute stress.

PubMed

Alexander, Nina; Osinsky, Roman; Schmitz, Anja; Mueller, Eva; Kuepper, Yvonne; Hennig, Juergen

2010-07-01

Growing evidence suggests that individual differences in HPA-axis reactivity to psychosocial stress are partly due to heritable influences. However, knowledge about the role of specific genetic variants remains very limited to date. Since brain-derived neurotrophic factor (BDNF) not only exhibits neurotrophic actions but is also involved in the regulation of hypothalamic neuropeptides, we investigated the role of a common functional polymorphism within the BDNF gene (BDNF Val66Met) in the context of endocrine and cardiovascular stress reactivity. Healthy male adults (N=100) were genotyped and exposed to a standardized laboratory stress task (Public Speaking). Saliva cortisol and self-reported mood levels were obtained at 6 time points prior to the stressor and during an extended recovery period. Furthermore, heart rate reactivity as an indicator of sympathetic activation was monitored continuously during the experimental procedure. We report a small, but significant effect of the BDNF Val66Met polymorphism on stress reactivity. More precisely, carriers of the met-allele showed a significantly attenuated HPA-axis and cardiovascular reactivity to the psychosocial stressor compared to subjects with the val/val genotype. Furthermore, the diminished physiological response in met-allele carriers was also attended by significantly lower self-reported ratings of perceived stress and nervousness. Our findings of a diminished endocrine and cardiovascular stress response in healthy male adults is consistent with a previously published study and adds further evidence for a crucial role of the BDNF Val66Met polymorphism in the modulation of stress reactivity. Copyright 2010. Published by Elsevier Ltd.

Distinct Recruitment and Function of Gab1 and Gab2 in Met Receptor-mediated Epithelial Morphogenesis

PubMed Central

Lock, Lisa S.; Maroun, Christiane R.; Naujokas, Monica A.; Park, Morag

2002-01-01

The Gab family of docking proteins (Gab1 and Gab2) are phosphorylated in response to various cytokines and growth factors. Gab1 acts to diversify the signal downstream from the Met receptor tyrosine kinase through the recruitment of multiple signaling proteins, and is essential for epithelial morphogenesis. To determine whether Gab1 and Gab2 are functionally redundant, we have examined the role of Gab2 in epithelial cells. Both Gab1 and Gab2 are expressed in epithelial cells and localize to cell-cell junctions. However, whereas overexpression of Gab1 promotes a morphogenic response, the overexpression of Gab2 fails to induce this response. We show that Gab2 recruitment to the Met receptor is dependent on the Grb2 adapter protein. In contrast, Gab1 recruitment to Met is both Grb2 dependent and Grb2 independent. The latter requires a novel amino acid sequence present in the Met-binding domain of Gab1 but not Gab2. Mutation of these residues in Gab1 impairs both association with the Met receptor and the ability of Gab1 to promote a morphogenic response, whereas their insertion into Gab2 increases Gab2 association with Met, but does not confer on Gab2 the ability to promote epithelial morphogenesis. We propose that the Grb2-independent recruitment of Gab proteins to Met is necessary but not sufficient to promote epithelial morphogenesis. PMID:12058075

Generation and Characterization of a Bispecific Antibody Targeting Both PD-1 and c-MET.

PubMed

Wu, Yi; Yu, Min; Sun, Zujun; Hou, Weihua; Wang, Yuxiong; Yuan, Qingyun; Mo, Wei

2018-02-08

Bispecific antibodies, BsAbs, are molecules with the ability to bind to two different epitopes on the same or different antigens. c-MET, cellular-mesenchymal to epithelial transition factor, is deregulated in many types of human malignancies. Abnormal c-MET activation in cancer correlates with poor prognosis. PD-1, programmed death-1, is an additional inhibitory receptor expressed by T cells. Blocking the interactions between PD-1 and PD-L1 has emerged as a promising immunotherapy for treating cancer. The goal of this study was to identify a novel bispecific antibody targeting both c-MET and PD-1 as an anti-cancer therapeutic candidate. The BsAb was produced using 293E expression system and purified by Protein A affinity chromatography. Then the binding specificity and affinity of the BsAb was examined by FACS and biolayer light interferometry. The ability of the BsAb to inhibit the proliferation of tuman cells was measured using the CellTiter 96 Aqueous One Solution Cell Proliferation Assay kit; the potential signaling pathway involved was identified by Western Blot. Cytokine secreted by PHA-L stimulated PBMC was measured by ELISA. Effects of BsAb on PBMC-mediated lysis of MKN45 cells was measured by LDH cytotoxicity assay. Based on the original sequences of PD-1 and c-MET mAb, a BsAb gene was designed, cloned into pCEP4 vector for expression in 293E cells. The BsAb was obtained after purification of the cell culture supernatant. It can bind to PD-1 and c-MET simultaneously, the calculated affinity was 11.5 nM for PD-1 and 9.09 nM for c-MET. The BsAb enhanced IFN-γ production over control IgG by 2-3 folds. It also inhibit the c-MET pathway activation and the proliferation of tumor cells significantly, comparable to JnJ-38877605. The BsAb showed dose-dependent cytotoxic activity against MKN45 cells. Our results indicated that a novel BsAb recognizing PD-1 and c-MET was successfully generated. It could redirect T cells to kill tumor cells, while retaining its

MET Exon 14 Skipping Mutations in Lung Adenocarcinoma: Clinicopathologic Implications and Prognostic Values.

PubMed

Lee, Geun Dong; Lee, Seung Eun; Oh, Doo-Yi; Yu, Dan-Bi; Jeong, Hae Min; Kim, Jooseok; Hong, Sungyoul; Jung, Hun Soon; Oh, Ensel; Song, Ji-Young; Lee, Mi-Sook; Kim, Mingi; Jung, Kyungsoo; Kim, Jhingook; Shin, Young Kee; Choi, Yoon-La; Kim, Hyeong Ryul

2017-08-01

Response to mesenchymal-epithelial transition (MET) inhibitors in NSCLC with mesenchymal-epithelial transition gene (MET) exon 14 skipping (METex14) has fueled molecular screening efforts and the search for optimal therapies. However, further work is needed to refine the clinicopathologic and prognostic implications of METex14 skipping. Among 795 East Asian patients who underwent a surgical procedure for NSCLC, we screened 45 patients with quintuple-negative (EGFR-negative/KRAS-negative/anaplastic lymphoma kinase gene [ALK]-negative/ROS1-negative/ret proto-oncogene [RET]-negative) lung adenocarcinomas by using reverse-transcriptase polymerase chain reaction and found 17 patients (37.8%) with METex14 skipping. We also investigated the effect of small interfering RNA (siRNA) targeting skipping junction in cells with METex14 skipping. The median age of the 17 patients was 73 years. The acinar subtype was predominant (52.9%), followed by the solid subtype (35.3%). MET immunohistochemistry demonstrated 100% sensitivity and 70.4% specificity. Multivariate analyses showed that patients with METex14 skipping had a higher recurrence rate than those with ALK fusion (versus METex14 skipping) (hazard ratio = 0.283, 95% confidence interval: 0.119-0.670) in stage I to IIIA disease; however, the differences in overall survival were not significant after adjustment for pathologic stage (p = 0.669). Meanwhile, siRNA decreased MET-driven signaling pathways in Hs746T cells, and combined treatment with siRNA and crizotinib inhibited cell proliferation in crizotinib-resistant H596 cells. The prevalence of METex14 skipping was quite high in East Asian patients without other driver mutations in lung adenocarcinomas. METex14 skipping was associated with old age, the acinar or solid histologic subtype, and high MET immunohistochemical expression. The prognosis of patients with METex14 skipping was similar to that of patients with major driver mutations. siRNA targeting the junction of

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

ERIC Educational Resources Information Center

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…

Synergistic Activation upon MET and ALK Coamplification Sustains Targeted Therapy in Sarcomatoid Carcinoma, a Deadly Subtype of Lung Cancer.

PubMed

Pelosi, Giuseppe; Gasparini, Patrizia; Conte, Davide; Fabbri, Alessandra; Perrone, Federica; Tamborini, Elena; Pupa, Serenella M; Ciravolo, Valentina; Caserini, Roberto; Rossi, Giulio; Cavazza, Alberto; Papotti, Mauro; Nakatani, Yukio; Maisonneuve, Patrick; Pastorino, Ugo; Sozzi, Gabriella

2016-05-01

Genetic alterations suitable for targeted therapy are poorly known issues in pulmonary sarcomatoid carcinoma (PSC), an uncommon and life-threatening family of non-small cell lung cancers. Ninety-eight PSCs were assessed for MNNG HOS Transforming gene (MET) and anaplastic lymphoma receptor tyrosine kinase gene (ALK) status by fluorescence in situ hybridization (FISH) and for relevant protein expression by immunohistochemical analysis, also taking advantage of phosphorylated (p-) antibodies. Moreover, levels of ALK and MET mRNA were also determined by real-time polymerase chain reaction and Western blot analysis for downstream activation pathways involving p-MET, p-protein kinase B, p-mitogen-activated protein kinase, p-SRC proto-oncogene tyrosine-protein kinase, and p-focal adhesion kinase (p-FAK). MET amplification was detected by FISH in 25 of 98 PSCs (25.6%) and ALK amplification (but not the relevant rearrangement) was found in 16 of 98 (16.3%), with all ALK-amplified tumors also showing MET amplification (p < 0.0001). Nine PSCs, however, showed MET amplification without any ALK gene alteration. ALK protein expression was always lacking, whereas MET and p-MET were confined to the relevant amplified tumors only. Increased levels of ALK and MET mRNA were detectable in tumors with no direct relationship between mRNA content, protein expression, or alterations detected by FISH. Western blot assays showed complete activation of downstream signal pathways up to p-SRC proto-oncogene tyrosine-protein kinase, and p-focal adhesion kinase recruitment in MET and ALK-coamplified tumors only, whereas isolated MET amplification, MET and ALK borderline amplification (5%-10% of tumor cells with ≥15 copies of the relevant gene), or negative tumors showing eusomy or chromosome polysomy were confined to p-mitogen-activated protein kinase, p-protein kinase B, and/or p-MET activation. Multivariate survival analysis pushed a higher percentage of MET altered cells or a higher value

Aggregation of lipid rafts activates c-met and c-Src in non-small cell lung cancer cells.

PubMed

Zeng, Juan; Zhang, Heying; Tan, Yonggang; Sun, Cheng; Liang, Yusi; Yu, Jinyang; Zou, Huawei

2018-05-30

Activation of c-Met, a receptor tyrosine kinase, induces radiation therapy resistance in non-small cell lung cancer (NSCLC). The activated residual of c-Met is located in lipid rafts (Duhon et al. Mol Carcinog 49:739-49, 2010). Therefore, we hypothesized that disturbing the integrity of lipid rafts would restrain the activation of the c-Met protein and reverse radiation resistance in NSCLC. In this study, a series of experiments was performed to test this hypothesis. NSCLC A549 and H1993 cells were incubated with methyl-β-cyclodextrin (MβCD), a lipid raft inhibitor, at different concentrations for 1 h before the cells were X-ray irradiated. The following methods were used: clonogenic (colony-forming) survival assays, flow cytometry (for cell cycle and apoptosis analyses), immunofluorescence microscopy (to show the distribution of proteins in lipid rafts), Western blotting, and biochemical lipid raft isolation (purifying lipid rafts to show the distribution of proteins in lipid rafts). Our results showed that X-ray irradiation induced the aggregation of lipid rafts in A549 cells, activated c-Met and c-Src, and induced c-Met and c-Src clustering to lipid rafts. More importantly, MβCD suppressed the proliferation of A549 and H1993 cells, and the combination of MβCD and radiation resulted in additive increases in A549 and H1993 cell apoptosis. Destroying the integrity of lipid rafts inhibited the aggregation of c-Met and c-Src to lipid rafts and reduced the expression of phosphorylated c-Met and phosphorylated c-Src in lipid rafts. X-ray irradiation induced the aggregation of lipid rafts and the clustering of c-Met and c-Src to lipid rafts through both lipid raft-dependent and lipid raft-independent mechanisms. The lipid raft-dependent activation of c-Met and its downstream pathways played an important role in the development of radiation resistance in NSCLC cells mediated by c-Met. Further studies are still required to explore the molecular mechanisms of the

CoMet: a workflow using contig coverage and composition for binning a metagenomic sample with high precision.

PubMed

Herath, Damayanthi; Tang, Sen-Lin; Tandon, Kshitij; Ackland, David; Halgamuge, Saman Kumara

2017-12-28

In metagenomics, the separation of nucleotide sequences belonging to an individual or closely matched populations is termed binning. Binning helps the evaluation of underlying microbial population structure as well as the recovery of individual genomes from a sample of uncultivable microbial organisms. Both supervised and unsupervised learning methods have been employed in binning; however, characterizing a metagenomic sample containing multiple strains remains a significant challenge. In this study, we designed and implemented a new workflow, Coverage and composition based binning of Metagenomes (CoMet), for binning contigs in a single metagenomic sample. CoMet utilizes coverage values and the compositional features of metagenomic contigs. The binning strategy in CoMet includes the initial grouping of contigs in guanine-cytosine (GC) content-coverage space and refinement of bins in tetranucleotide frequencies space in a purely unsupervised manner. With CoMet, the clustering algorithm DBSCAN is employed for binning contigs. The performances of CoMet were compared against four existing approaches for binning a single metagenomic sample, including MaxBin, Metawatt, MyCC (default) and MyCC (coverage) using multiple datasets including a sample comprised of multiple strains. Binning methods based on both compositional features and coverages of contigs had higher performances than the method which is based only on compositional features of contigs. CoMet yielded higher or comparable precision in comparison to the existing binning methods on benchmark datasets of varying complexities. MyCC (coverage) had the highest ranking score in F1-score. However, the performances of CoMet were higher than MyCC (coverage) on the dataset containing multiple strains. Furthermore, CoMet recovered contigs of more species and was 18 - 39% higher in precision than the compared existing methods in discriminating species from the sample of multiple strains. CoMet resulted in higher precision

Brain-derived neurotrophic factor Val66Met polymorphism and dexamethasone/CRH test results in depressed patients.

PubMed

Schüle, Cornelius; Zill, Peter; Baghai, Thomas C; Eser, Daniela; Zwanzger, Peter; Wenig, Nadine; Rupprecht, Rainer; Bondy, Brigitta

2006-09-01

Data suggest that both neurotrophic and hypothalamic-pituitary-adrenocortical (HPA) systems are involved in the pathophysiology of depression. The aim of the present study was to investigate whether the non-conservative brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has an impact on HPA axis activity in depressed patients. At admission, the dexamethasone/CRH (DEX/CRH) test was performed in 187 drug-free in-patients suffering from major depression or depressed state of bipolar disorder (DSM-IV criteria). Moreover, genotyping of BDNF Val66Met polymorphism was carried out using the fluorescence resonance energy transfer method (FRET). Homozygous carriers of the Met/Met genotype showed a significantly higher HPA axis activity during the DEX/CRH test than patients carrying the Val/Val or Val/Met genotype (ACTH, cortisol). Our results further contribute to the hypothesized association between HPA axis dysregulation and reduced neuroplasticity in depression and are consistent with the assumption that BDNF is a stress-responsive intercellular messenger modifying HPA axis activity.

Operational trace gas column observations from GOME-2 on MetOp

NASA Astrophysics Data System (ADS)

Valks, Pieter; Hao, Nan; Pinardi, Gaia; Hedelt, Pascal; Liu, Song; Van Roozendael, Michel; De Smedt, Isabelle; Theys, Nicolas; Koukouli, MariLiza; Balis, Dimitris

2017-04-01

This contribution focuses on the operational GOME-2 trace gas column products developed in the framework of EUMETSAT's Satellite Application Facility on Atmospheric Composition Monitoring (AC-SAF). We present an overview of the retrieval algorithms for ozone, OClO, NO2, SO2 and formaldehyde, and we show examples of various applications such as air quality and climate monitoring, using observations from the GOME-2 instruments on MetOp-A and MetOp-B. Total ozone and the minor trace gas columns from GOME-2 are retrieved with the latest version 4.8 of the GOME Data Processor (GDP), which uses an optimized Differential Optical Absorption Spectroscopy (DOAS) algorithm, with air mass factor conversions based on the LIDORT model. Improved total and tropospheric NO2 columns are retrieved in the visible wavelength region between 425 and 497 nm. SO2 emissions from volcanic and anthropogenic sources can be measured by GOME-2 using the UV wavelength region around 320 nm. For formaldehyde, an optimal DOAS fitting window around 335 nm has been determined for GOME-2. The GOME-2 trace gas columns have reached the operational EUMETSAT product status, and are available to the users in near real time (within two hours after sensing by GOME-2). The use of trace gas observations from the GOME-2 instruments on MetOp-A and MetOp-B for air quality purposed will be illustrated, e.g. for South-East Asia and Europe. Furthermore, comparisons of the GOME-2 satellite observations with ground-based measurements will be shown. Finally, the use of GOME-2 trace-gas column data in the Copernicus Atmosphere Monitoring Service (CAMS) will be presented.

A peptide representing the carboxyl-terminal tail of the met receptor inhibits kinase activity and invasive growth.

PubMed

Bardelli, A; Longati, P; Williams, T A; Benvenuti, S; Comoglio, P M

1999-10-08

Interaction of the hepatocyte growth factor (HGF) with its receptor, the Met tyrosine kinase, results in invasive growth, a genetic program essential to embryonic development and implicated in tumor metastasis. Met-mediated invasive growth requires autophosphorylation of the receptor on tyrosines located in the kinase activation loop (Tyr(1234)-Tyr(1235)) and in the carboxyl-terminal tail (Tyr(1349)-Tyr(1356)). We report that peptides derived from the Met receptor tail, but not from the activation loop, bind the receptor and inhibit the kinase activity in vitro. Cell delivery of the tail receptor peptide impairs HGF-dependent Met phosphorylation and downstream signaling. In normal and transformed epithelial cells, the tail receptor peptide inhibits HGF-mediated invasive growth, as measured by cell migration, invasiveness, and branched morphogenesis. The Met tail peptide inhibits the closely related Ron receptor but does not significantly affect the epidermal growth factor, platelet-derived growth factor, or vascular endothelial growth factor receptor activities. These experiments show that carboxyl-terminal sequences impair the catalytic properties of the Met receptor, thus suggesting that in the resting state the nonphosphorylated tail acts as an intramolecular modulator. Furthermore, they provide a strategy to selectively target the MET proto-oncogene by using small, cell-permeable, peptide derivatives.

Anti-apoptotic Role of Caspase-cleaved GAB1 Adaptor Protein in Hepatocyte Growth Factor/Scatter Factor-MET Receptor Protein Signaling*

PubMed Central

Le Goff, Arnaud; Ji, Zongling; Leclercq, Bérénice; Bourette, Roland P.; Mougel, Alexandra; Guerardel, Cateline; de Launoit, Yvan; Vicogne, Jérôme; Goormachtigh, Gautier; Fafeur, Véronique

2012-01-01

The GRB2-associated binder 1 (GAB1) docking/scaffold protein is a key mediator of the MET-tyrosine kinase receptor activated by hepatocyte growth factor/scatter factor (HGF/SF). Activated MET promotes recruitment and tyrosine phosphorylation of GAB1, which in turn recruits multiple proteins and mediates MET signaling leading to cell survival, motility, and morphogenesis. We previously reported that, without its ligand, MET is a functional caspase target during apoptosis, allowing the generation of a p40-MET fragment that amplifies apoptosis. In this study we established that GAB1 is also a functional caspase target by evidencing a caspase-cleaved p35-GAB1 fragment that contains the MET binding domain. GAB1 is cleaved by caspases before MET, and the resulting p35-GAB1 fragment is phosphorylated by MET upon HGF/SF binding and can interact with a subset of GAB1 partners, PI3K, and GRB2 but not with SHP2. This p35-GAB1 fragment favors cell survival by maintaining HGF/SF-induced MET activation of AKT and by hindering p40-MET pro-apoptotic function. These data demonstrate an anti-apoptotic role of caspase-cleaved GAB1 in HGF/SF-MET signaling. PMID:22915589

Identification of new ligands for the methionine biosynthesis transcriptional regulator (MetJ) by FAC-MS.

PubMed

Martí-Arbona, Ricardo; Teshima, Munehiro; Anderson, Penelope S; Nowak-Lovato, Kristy L; Hong-Geller, Elizabeth; Unkefer, Clifford J; Unkefer, Pat J

2012-01-01

We have developed a high-throughput approach using frontal affinity chromatography coupled to mass spectrometry (FAC-MS) for the identification and characterization of the small molecules that modulate transcriptional regulator (TR) binding to TR targets. We tested this approach using the methionine biosynthesis regulator (MetJ). We used effector mixtures containing S-adenosyl-L-methionine (SAM) and S-adenosyl derivatives as potential ligands for MetJ binding. The differences in the elution time of different compounds allowed us to rank the binding affinity of each compound. Consistent with previous results, FAC-MS showed that SAM binds to MetJ with the highest affinity. In addition, adenine and 5'-deoxy-5'-(methylthio)adenosine bind to the effector binding site on MetJ. Our experiments with MetJ demonstrate that FAC-MS is capable of screening complex mixtures of molecules and identifying high-affinity binders to TRs. In addition, FAC-MS experiments can be used to discriminate between specific and nonspecific binding of the effectors as well as to estimate the dissociation constant (K(d)) for effector-TR binding. Copyright © 2012 S. Karger AG, Basel.

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

PubMed

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

Project MET. A Trainer's Guide. Management for Effective Teaching, A Title IV-C Project.

ERIC Educational Resources Information Center

Fairfax County Public Schools, VA. Dept. of Instructional Services.

This guide provides trainers with a format and process for conducting inservice education programs for elementary school teachers on the use of the Management for Effective Teaching (MET) support kit. Project MET is a program developed to aid teachers in the Fairfax County (Virginia) public schools in implementing the school district curriculum,…

Effect of Exposure on the Mechanical Properties of Gamma MET PX

NASA Technical Reports Server (NTRS)

Draper, S. L.; Lerch, B. A.; Locci, I. E.; Shazly, M.; Prakash, V.

2004-01-01

The effect of a service environment exposure on the mechanical properties of a high Nb content TiAl alloy, Gamma MET PX , was assessed. Gamma MET PX, like other TiAl alloys, experiences a reduction of ductility following high temperature exposure. Exposure in Ar, air, and high-purity oxygen all resulted in a loss of ductility with the ductility reduction increasing with oxygen content in the exposure atmosphere. Embrittling mechanisms, including bulk microstructural changes, moisture induced environmental embrittlement, and near surface effects were investigated. The embrittlement has been shown to be a near-surface effect, most likely due to the diffusion of oxygen into the alloy.

iMet-Q: A User-Friendly Tool for Label-Free Metabolomics Quantitation Using Dynamic Peak-Width Determination

PubMed Central

Chang, Hui-Yin; Chen, Ching-Tai; Lih, T. Mamie; Lynn, Ke-Shiuan; Juo, Chiun-Gung; Hsu, Wen-Lian; Sung, Ting-Yi

2016-01-01

Efficient and accurate quantitation of metabolites from LC-MS data has become an important topic. Here we present an automated tool, called iMet-Q (intelligent Metabolomic Quantitation), for label-free metabolomics quantitation from high-throughput MS1 data. By performing peak detection and peak alignment, iMet-Q provides a summary of quantitation results and reports ion abundance at both replicate level and sample level. Furthermore, it gives the charge states and isotope ratios of detected metabolite peaks to facilitate metabolite identification. An in-house standard mixture and a public Arabidopsis metabolome data set were analyzed by iMet-Q. Three public quantitation tools, including XCMS, MetAlign, and MZmine 2, were used for performance comparison. From the mixture data set, seven standard metabolites were detected by the four quantitation tools, for which iMet-Q had a smaller quantitation error of 12% in both profile and centroid data sets. Our tool also correctly determined the charge states of seven standard metabolites. By searching the mass values for those standard metabolites against Human Metabolome Database, we obtained a total of 183 metabolite candidates. With the isotope ratios calculated by iMet-Q, 49% (89 out of 183) metabolite candidates were filtered out. From the public Arabidopsis data set reported with two internal standards and 167 elucidated metabolites, iMet-Q detected all of the peaks corresponding to the internal standards and 167 metabolites. Meanwhile, our tool had small abundance variation (≤0.19) when quantifying the two internal standards and had higher abundance correlation (≥0.92) when quantifying the 167 metabolites. iMet-Q provides user-friendly interfaces and is publicly available for download at http://ms.iis.sinica.edu.tw/comics/Software_iMet-Q.html. PMID:26784691

BDNF-Val66Met-Polymorphism Impact on Cortical Plasticity in Schizophrenia Patients: A Proof-of-Concept Study

PubMed Central

Nitsche, Michael A.; Wobrock, Thomas; Bunse, Tilmann; Rein, Bettina; Herrmann, Maximiliane; Schmitt, Andrea; Nieratschker, Vanessa; Witt, Stephanie H.; Rietschel, Marcella; Falkai, Peter; Hasan, Alkomiet

2015-01-01

Background: Brain-derived neurotrophic factor (BDNF) has been shown to be a moderator of neuroplasticity. A frequent BDNF-polymorphism (Val66Met) is associated with impairments of cortical plasticity. In patients with schizophrenia, reduced neuroplastic responses following non-invasive brain stimulation have been reported consistently. Various studies have indicated a relationship between the BDNF-Val66Met-polymorphism and motor-cortical plasticity in healthy individuals, but schizophrenia patients have yet to be investigated. The aim of this proof-of-concept study was, therefore, to test the impact of the BDNF-Val66Met-polymorphism on inhibitory and facilitatory cortical plasticity in schizophrenia patients. Methods: Cortical plasticity was investigated in 22 schizophrenia patients and 35 healthy controls using anodal and cathodal transcranial direct-current stimulation (tDCS) applied to the left primary motor cortex. Animal and human research indicates that excitability shifts following anodal and cathodal tDCS are related to molecular long-term potentiation and long-term depression. To test motor-cortical excitability before and after tDCS, well-established single- and paired-pulse transcranial magnetic stimulation protocols were applied. Results: Our analysis revealed increased glutamate-mediated intracortical facilitation in met-heterozygotes compared to val-homozygotes at baseline. Following cathodal tDCS, schizophrenia met-heterozygotes had reduced gamma-amino-butyric-acid-mediated short-interval intracortical inhibition, whereas healthy met-heterozygotes displayed the opposite effect. The BDNF-Val66Met-polymorphism did not influence single-pulse motor-evoked potential amplitudes after tDCS. Conclusions: These preliminary findings support the notion of an association of the BDNF-Val66Met-polymorphism with observable alterations in plasticity following cathodal tDCS in schizophrenia patients. This indicates a complex interaction between inhibitory

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

PubMed

Cho, Sung Ho; Kim, Jong In; Kim, Hyun Su; Park, Sung Dal; Jang, Kang Won

2017-06-01

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. 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. 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. CHIP is capable 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.

Heteronemin Is a Novel c-Met/STAT3 Inhibitor Against Advanced Prostate Cancer Cells.

PubMed

Wu, Jian-Ching; Wang, Chiang-Ting; Hung, Han-Chun; Wu, Wen-Jeng; Wu, Deng-Chyang; Chang, Min-Chi; Sung, Ping-Jyun; Chou, Yu-Wei; Wen, Zhi-Hong; Tai, Ming-Hong

2016-12-01

Prostate cancer is one of the most prevalent cancers in men worldwide. Aberrant activation of c-Met/signal transducer and activator of transcription-3 (STAT3) signaling is involved in prostate carcinogenesis, underscoring the demand for developing c-Met/STAT3-targeting drugs. Thus, we first utilized virtual screening strategy to identify STAT3-inhibiting marine compound, heteronemin, and then validated the STAT3-inhibiting function of heteronemin in prostate cancer cells. Human prostate cancer LNCaP, DU145, and PC-3 cell lines were treated with heteronemin for 24 hr, then the cell viability was evaluated by MTT assay. Flow cytometry was performed to analyze the apoptosis in heteronemin-treated cells. Western blot and quantitative real-time PCR were executed to further confirm the c-Met/STAT3 signaling inhibition by heteronemin in DU145 and PC-3 cells. In this study, we employed the virtual screening strategy to identify heteronemin, a spongean sesterterpene, as a potential STAT3 inhibitor from Taiwan marine drugs library. Application of heteronemin potently suppressed the viability and anchorage-independent growth of human prostate cancer cells. Besides, heteronemin induced apoptosis in prostate cancer cells by activation of both intrinsic (caspase-9) and extrinsic (caspase-8) apoptotic pathways. By luciferase assay and expression analysis, it was confirmed that heteronemin inhibited the phosphorylation of c-Met/src/STAT3 signaling axis, STAT3-driven luciferase activities and expression of STAT3-regulated genes including Bcl-xL, Bcl-2, and Cyclin D1. Finally, heteronemin effectively antagonized the hepatocyte growth factor (HGF)-stimulated c-Met/STAT3 activation as well as the proliferation and colonies formation in refractory prostate cancer cells. These findings suggest that heteronemin may constitute a novel c-Met/STAT3-targeting agent for prostate cancer. Prostate 76:1469-1483, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Patients' family satisfaction with needs met at the medical intensive care unit.

PubMed

Khalaila, Rabia

2013-05-01

The current study investigated the perceived importance and the perceived met needs of family members in the medical intensive care unit and assessed family members' satisfaction with needs met. Studies conducted throughout the world over the past 30 years indicate that family needs are still neglected. Unmet needs of family members of patients in the intensive care unit lead to dissatisfaction with care. A cross-sectional study. A total of 70 family members of critically ill patients were included in this study conducted in a medical intensive care unit in Israel between October 2007-September 2008, using a structured interview. Three outcomes measured by the Family Satisfaction in the Intensive Care Unit Inventory were regressed separately for baseline variables and family needs met subscales as measured by the Critical Care Family Needs Inventory. Multivariate linear regression analysis was used to detect factors that could have predicted each outcome. The results showed differences between the perceived importance and the perceived met needs of family members. Satisfaction with care was positively related to meeting all needs domains except the information need. However, satisfaction with information and decision-making was related only to meeting information and emotional support needs. Continued unmet needs of family members of intensive care unit patients have a negative impact on family satisfaction. Only sweeping changes in clinical practice will succeed in meeting the unmet needs of patients' families. © 2012 Blackwell Publishing Ltd.

Identification of Phytochemicals Targeting c-Met Kinase Domain using Consensus Docking and Molecular Dynamics Simulation Studies.

PubMed

Aliebrahimi, Shima; Montasser Kouhsari, Shideh; Ostad, Seyed Nasser; Arab, Seyed Shahriar; Karami, Leila

2018-06-01

c-Met receptor tyrosine kinase is a proto-oncogene whose aberrant activation is attributed to a lower rate of survival in most cancers. Natural product-derived inhibitors known as "fourth generation inhibitors" constitute more than 60% of anticancer drugs. Furthermore, consensus docking approach has recently been introduced to augment docking accuracy and reduce false positives during a virtual screening. In order to obtain novel small-molecule Met inhibitors, consensus docking approach was performed using Autodock Vina and Autodock 4.2 to virtual screen Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target database against active and inactive conformation of c-Met kinase domain structure. Two hit molecules that were in line with drug-likeness criteria, desired docking score, and binding pose were subjected to molecular dynamics simulations to elucidate intermolecular contacts in protein-ligand complexes. Analysis of molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area studies showed that ZINC08234189 is a plausible inhibitor for the active state of c-Met, whereas ZINC03871891 may be more effective toward active c-Met kinase domain compared to the inactive form due to higher binding energy. Our analysis showed that both the hit molecules formed hydrogen bonds with key residues of the hinge region (P1158, M1160) in the active form, which is a hallmark of kinase domain inhibitors. Considering the pivotal role of HGF/c-Met signaling in carcinogenesis, our results propose ZINC08234189 and ZINC03871891 as the therapeutic options to surmount Met-dependent cancers.

Insulin-Independent GABAA Receptor-Mediated Response in the Barrel Cortex of Mice with Impaired Met Activity

PubMed Central

Lo, Fu-Sun; Erzurumlu, Reha S.

2016-01-01

Autism spectrum disorder (ASD) is a neurodevelopmental disorder caused by genetic variants, susceptibility alleles, and environmental perturbations. The autism associated gene MET tyrosine kinase has been implicated in many behavioral domains and endophenotypes of autism, including abnormal neural signaling in human sensory cortex. We investigated somatosensory thalamocortical synaptic communication in mice deficient in Met activity in cortical excitatory neurons to gain insights into aberrant somatosensation characteristic of ASD. The ratio of excitation to inhibition is dramatically increased due to decreased postsynaptic GABAA receptor-mediated inhibition in the trigeminal thalamocortical pathway of mice lacking active Met in the cerebral cortex. Furthermore, in contrast to wild-type mice, insulin failed to increase GABAA receptor-mediated response in the barrel cortex of mice with compromised Met signaling. Thus, lacking insulin effects may be a risk factor in ASD pathogenesis. SIGNIFICANCE STATEMENT A proposed common cause of neurodevelopmental disorders is an imbalance in excitatory neural transmission, provided by the glutamatergic neurons, and the inhibitory signals from the GABAergic interneurons. Many genes associated with autism spectrum disorders impair synaptic transmission in the expected cell type. Previously, inactivation of the autism-associated Met tyrosine kinase receptor in GABAergic interneurons led to decreased inhibition. In thus report, decreased Met signaling in glutamatergic neurons had no effect on excitation, but decimated inhibition. Further experiments indicate that loss of Met activity downregulates GABAA receptors on glutamatergic neurons in an insulin independent manner. These data provide a new mechanism for the loss of inhibition and subsequent abnormal excitation/inhibition balance and potential molecular candidates for treatment or prevention. PMID:27030755

Expression of p53/HGF/c-met/STAT3 signal in fetuses with neural tube defects.

PubMed

Trovato, Maria; D'Armiento, Maria; Lavra, Luca; Ulivieri, Alessandra; Dominici, Roberto; Vitarelli, Enrica; Grosso, Maddalena; Vecchione, Raffaella; Barresi, Gaetano; Sciacchitano, Salvatore

2007-02-01

Neural tube defects (NTD) are morphogenetic alterations due to a defective closure of neural tube. Hepatocyte growth factor (HGF)/c-met system plays a role in morphogenesis of nervous system, lung, and kidney. HGF/c-met morphogenetic effects are mediated by signal transducers and activators of transcription (STAT)3 and both HGF and c-met genes are regulated from p53. The aim of our study was to analyze mRNA and protein expressions of p53, HGF, c-met, and STAT3 in fetuses with NTD. By reverse transcriptase-polymerase chain reaction and immunohistochemistry, we analyzed neural tissues from four NTD fetuses and the corresponding non-malformed lungs, kidneys and placentas. We found a reduced mRNA expression of HGF/c-met/STAT3 pathway, in the malformed nervous systems and placentas. The reduced expression of this pathway correlated with the absence of p53 in all these samples. On the contrary, detectable expression levels of p53, HGF, c-met, and STAT3 were observed in non-malformed lungs and kidneys obtained from the same fetuses. Comparable results were obtained by immunohistochemistry, with the exception of p53, which was undetected in all fetal tissues. In conclusion, in NTD fetuses, both the defective neural tube tissue and the placenta have a reduction in all components of the p53/HGF/c-met/STAT3 cascade. This raises the possibility of using the suppression of these genes for early diagnosis of NTD especially on chorionic villus sampling.

Role of BDNF val66met polymorphism on the association between physical activity and incident dementia.

PubMed

Kim, Jae-Min; Stewart, Robert; Bae, Kyung-Yeol; Kim, Sung-Wan; Yang, Su-Jin; Park, Kee-Hyung; Shin, Il-Seon; Yoon, Jin-Sang

2011-03-01

Increased physical activity may have beneficial effects on cognitive outcomes; a role of brain-derived neurotrophic factor (BDNF) has been suggested in animal models but not yet tested in humans. This study investigated modification by BDNF val66met polymorphism of the association between physical activity, incident dementia and other cognitive outcomes. Of 732 community elders, 107 had dementia at baseline, and 518 (83%) of the remainder were followed over 2.4 years. Cognitive impairment and decline were defined from Mini-Mental State Examination scores. Self-reported level of physical activity was recorded on a 4-point scale. BDNF val66met and apolipoprotein E genotypes were ascertained. Covariates included age, sex, education, depression, vascular risk factors, and instrumental activities of daily living. Baseline lower physical activity was significantly associated with incident dementia as well as with baseline dementia and cognitive impairment and incident cognitive decline. BDNF val66met polymorphism itself was not associated with any cognitive outcome. However, the strength of association between lower activity and all cognitive outcomes increased incrementally with the number of met alleles, and was strongest in those with the met/met genotype. BDNF×activity interaction terms were stronger for prospective outcomes (incident dementia, cognitive decline) compared to cross-sectional outcomes (prevalent dementia, cognitive impairment no dementia). This study supports a previously suggested neurobiological basis for the effects of physical activity on dementia involving the BDNF system since the met allele is recognised to be associated with lower activity-dependent secretion of BDNF. Copyright © 2010. Published by Elsevier Inc.

Spitznävi: unterschiedliche klinische, dermatoskopische und histopathologische Merkmale in der Kindheit.

PubMed

Dika, Emi; Neri, Iria; Fanti, Pier Alessandro; Barisani, Alessia; Ravaioli, Giulia Maria; Patrizi, Annalisa

2017-01-01

Die Charakterisierung der klinischen Merkmale und des biologischen Potenzials von Spitznävi hat in den letzten Jahrzehnten breites Interesse gefunden. Das Ziel dieser Arbeit ist die Beschreibung der klinischen und dermatoskopischen Merkmale von Spitznävi sowie des klinischen Ergebnisses nach chirurgischer Exzision von Spitznävi in drei pädiatrischen Altersgruppen. Restrospektive Studie zur Analyse von klinischen Merkmalen, videodermatoskopischen Bildern, histopathologischen Diagnosen und Behandlungsergebnissen. Der Grad der Pigmentierung wurde sowohl klinisch als auch histopathologisch beurteilt. Bei 71 Patienten wurden 72 spitzoide Neoplasien entfernt. Videodermatologische Bilder lagen für 41 Patienten vor. Das Muster der Pigmentierung korrelierte signifikant mit dem Alter der Patienten: Hyperpigmentierte Läsionen waren bei Vorschulkindern selten, bei Patienten von 7 bis 12 Jahren und ab 13 Jahren dagegen häufiger. Eine histopathologische Diagnose von atypischen Spitznävi wurde selten durchgeführt. Keiner der Patienten, bei denen ursprünglich ein atypischer Spitznävus diagnostiziert worden war, entwickelte ein Lokalrezidiv oder Metastasen während der anschließenden Nachbeobachtung. Pigmentierte Spitznävi traten im Alter ab 13 Jahren häufiger auf. Die Studie bestätigt andere Berichte über die Altersverteilung von Pigmentierungsmustern und hebt die geringe Anzahl atypischer Spitznävi bei pädiatrischen Patienten hervor sowie das Ausbleiben von Rezidiven bei der langfristigen Nachbeobachtung. © 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

MultiMetEval: Comparative and Multi-Objective Analysis of Genome-Scale Metabolic Models

PubMed Central

Gevorgyan, Albert; Kierzek, Andrzej M.; Breitling, Rainer; Takano, Eriko

2012-01-01

Comparative metabolic modelling is emerging as a novel field, supported by the development of reliable and standardized approaches for constructing genome-scale metabolic models in high throughput. New software solutions are needed to allow efficient comparative analysis of multiple models in the context of multiple cellular objectives. Here, we present the user-friendly software framework Multi-Metabolic Evaluator (MultiMetEval), built upon SurreyFBA, which allows the user to compose collections of metabolic models that together can be subjected to flux balance analysis. Additionally, MultiMetEval implements functionalities for multi-objective analysis by calculating the Pareto front between two cellular objectives. Using a previously generated dataset of 38 actinobacterial genome-scale metabolic models, we show how these approaches can lead to exciting novel insights. Firstly, after incorporating several pathways for the biosynthesis of natural products into each of these models, comparative flux balance analysis predicted that species like Streptomyces that harbour the highest diversity of secondary metabolite biosynthetic gene clusters in their genomes do not necessarily have the metabolic network topology most suitable for compound overproduction. Secondly, multi-objective analysis of biomass production and natural product biosynthesis in these actinobacteria shows that the well-studied occurrence of discrete metabolic switches during the change of cellular objectives is inherent to their metabolic network architecture. Comparative and multi-objective modelling can lead to insights that could not be obtained by normal flux balance analyses. MultiMetEval provides a powerful platform that makes these analyses straightforward for biologists. Sources and binaries of MultiMetEval are freely available from https://github.com/PiotrZakrzewski/MetEval/downloads. PMID:23272111

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

PubMed Central

Peng, Yun; Lu, Zhongming; Li, Guohui; Piechowicz, Mariel; Anderson, Miranda; Uddin, Yasin; Wu, Jie; Qiu, Shenfeng

2015-01-01

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 plays 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. PMID:26728565

Brain-Derived Neurotrophic Factor Val66Met Human Polymorphism Impairs the Beneficial Exercise-Induced Neurobiological Changes in Mice

PubMed Central

Ieraci, Alessandro; Madaio, Alessandro I; Mallei, Alessandra; Lee, Francis S; Popoli, Maurizio

2016-01-01

Several studies have shown that exercise improves cognitive functions and emotional behaviors. Positive effects of exercise have been associated with enhanced brain plasticity, adult hippocampal neurogenesis, and increased levels of brain-derived neurotrophic factor (BDNF). However, a substantial variability of individual response to exercise has been described, which may be accounted for by individual genetic variants. Here, we have assessed whether and how the common human BDNF Val66Met polymorphism influences the neurobiological effects modulated by exercise in BDNF Val66Met knock-in male mice. Wild-type (BDNFVal/Val) and homozygous BDNF Val66Met (BDNFMet/Met) male mice were housed in cages equipped with or without running wheels for 4 weeks. Changes in behavioral phenotype, hippocampal adult neurogenesis, and gene expression were evaluated in exercised and sedentary control mice. We found that exercise reduced the latency to feed in the novelty suppressed feeding and the immobility time in the forced swimming test in BDNFVal/Val but not in BDNFMet/Met mice. Hippocampal neurogenesis was reduced in BDNFMet/Met mice compared with BDNFVal/Val mice. BDNFMet/Met mice had lower basal BDNF protein levels in the hippocampus, which was not recovered following exercise. Moreover, exercise-induced expression of total BDNF, BDNF splice variants 1, 2, 4, 6 and fibronectin type III domain-containing protein 5 (FNDC5) mRNA levels were absent or reduced in the dentate gyrus of BDNFMet/Met mice. Exercise failed to enhance PGC-1α and FNDC5 mRNA levels in the BDNFMet/Met muscle. Overall these results indicate that, in adult male mice, the BDNF Val66Met polymorphism impairs the beneficial behavioral and neuroplasticity effects induced by physical exercise. PMID:27388329

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

PubMed Central

Kim, Su-A; Sung, Ki-Chul; Kim, Jang Young

2017-01-01

Background 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. Methods 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. Results 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. Conclusions 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. PMID:29261715

A sequential EMT-MET mechanism drives the differentiation of human embryonic stem cells towards hepatocytes.

PubMed

Li, Qiuhong; Hutchins, Andrew P; Chen, Yong; Li, Shengbiao; Shan, Yongli; Liao, Baojian; Zheng, Dejin; Shi, Xi; Li, Yinxiong; Chan, Wai-Yee; Pan, Guangjin; Wei, Shicheng; Shu, Xiaodong; Pei, Duanqing

2017-05-03

Reprogramming has been shown to involve EMT-MET; however, its role in cell differentiation is unclear. We report here that in vitro differentiation of hESCs to hepatic lineage undergoes a sequential EMT-MET with an obligatory intermediate mesenchymal phase. Gene expression analysis reveals that Activin A-induced formation of definitive endoderm (DE) accompanies a synchronous EMT mediated by autocrine TGFβ signalling followed by a MET process. Pharmacological inhibition of TGFβ signalling blocks the EMT as well as DE formation. We then identify SNAI1 as the key EMT transcriptional factor required for the specification of DE. Genetic ablation of SNAI1 in hESCs does not affect the maintenance of pluripotency or neural differentiation, but completely disrupts the formation of DE. These results reveal a critical mesenchymal phase during the acquisition of DE, highlighting a role for sequential EMT-METs in both differentiation and reprogramming.

Detection of Met-enkephalin and Leu-enkephalin in the posterior pituitary of the holostean fish, Amia calva.

PubMed

Dores, R M; McDonald, L K; Crim, J W

1989-01-01

Immunohistochemical analysis of the pituitary of the holostean fish, Amia calva, indicated that enkephalin-related immunoreactivity was restricted to the pars nervosa, and was not detected in other regions of the pituitary. Fractionation of acid extracts of posterior pituitaries by reverse phase HPLC followed by RIA analysis indicated the presence of immunoreactive Met-enkephalin and Leu-enkephalin. No immunoreactive forms were detected with RIAs specific for either Met-enkephalin-RF or Met-enkephalin-RGL. The molar ratio of Met- to Leu-enkephalin in this terminal field was 3:1 (n = 4). HPLC fractions were also digested with trypsin and carboxypeptidase B to test for C-terminally extended forms of Met-enkephalin. A novel modified form of Met-enkephalin was detected. Extracts of the posterior pituitary, forebrain, midbrain, hypothalamus and hindbrain were screened with RIAs specific for the Pro-dynorphin end products, alpha-neo-endorphin, dynorphin A(1-17), dynorphin A(1-8) and dynorphin B(1-13). The results of these analyses were negative. Collectively, these data suggest that a Pro-enkephalin-like molecule is present in holostean fish. The holostean enkephalin precursor contains at least Met-enkephalin and Leu-enkephalin. However, Pro-dynorphin-related end products with antigenic determinants similar to mammalian dynorphin A(1-17), dynorphin A(1-8), dynorphin B(1-13) and alpha-neo-endorphin could not be detected in the brain or pituitary of this species.

In vivo detection of c-MET expression in a rat hepatocarcinogenesis model using molecularly targeted magnetic resonance imaging.

PubMed

Towner, Rheal A; Smith, Nataliya; Tesiram, Yasvir A; Abbott, Andrew; Saunders, Debbie; Blindauer, Rebecca; Herlea, Oana; Silasi-Mansat, Robert; Lupu, Florea

2007-01-01

The multifunctional growth factor scatter factor/hepatocyte growth factor and its tyrosine kinase receptor, c-MET, have been implicated in the genesis and malignant progression of numerous human malignancies, including hepatocellular carcinomas. The incidence of hepatocellular carcinomas in the United States has increased noticeably over the past two decades and is listed as the fifth major cancer in men worldwide. In this study, we used a choline-deficient l-amino acid (CDAA)-defined rat hepatocarcinogenesis model to visualize increased in vivo expression of the c-MET antigen in neoplastic lesion formation with the use of a super paramagnetic iron oxide (SPIO)-anti-c-MET molecularly targeted magnetic resonance imaging (MRI) contrast agent. SPIO-anti-c-MET was used for the first time to detect overexpression of c-MET in neoplastic nodules and tumors within the livers of CDAA-treated rats, as determined by a decrease in MRI signal intensity and a decrease in regional T(2) values. Specificity for the binding of the molecularly targeted anti-c-MET contrast agent was determined using rat hepatoma (H4-II-E-C3) cell cultures and immunofluorescence microscopic imaging of the targeting agents within neoplastic liver tissue 1 to 2 hours following intravenous administration of SPIO-anti-c-MET and MRI investigation. This method has the ability to visualize in vivo the overexpression of c-MET at early developmental stages of tumor formation.

The association between COMT Val158Met polymorphism and migraine risk: A meta-analysis.

PubMed

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.

The Complete Loss of Tyrosine Kinase Receptors MET and RON Is a Poor Prognostic Factor in Patients with Extrahepatic Cholangiocarcinoma.

PubMed

Hayashi, Yuki; Yamaguchi, Junpei; Kokuryo, Toshio; Ebata, Tomoki; Yokoyama, Yukihiro; Igami, Tsuyoshi; Sugawara, Gen; Nagino, Masato

2016-12-01

Although the survival of patients with cholangiocarcinoma has improved, the prognosis remains unfavorable. The overexpression of mesenchymal-epithelial transition factor (MET) and recepteur d'origine nantais (RON) has been considered to be indicative of a poor prognosis in some types of cancer. On the other hand, some studies have shown that the expression of MET and RON is a favorable prognostic factor in certain types of tumors. Based on the immunohistochemical analysis of MET and RON, 290 patients who underwent resection for extrahepatic cholangiocarcinoma were divided into three groups: MET/RON-negative, -intermediate, and -positive. The associations between MET/RON expression and clinicopathological features, including prognosis, were analyzed. MET/RON-negativity was associated with nodal metastasis and advanced pathological stage. The overall 5-year survival rates were significantly lower in the MET/RON-negative and MET/RON-positive groups than in the MET/RON-intermediate group (28.3%, 32.4% and 48.5%, respectively; p=0.01). The complete loss of one or both MET and RON, as well as their overexpression, is a poor prognostic factor in patients with extrahepatic cholangiocarcinoma, probably due to the high rate of lymph-node metastasis. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

MET18 Deficiency Increases the Sensitivity of Yeast to Oxidative Stress and Shortens Replicative Lifespan by Inhibiting Catalase Activity.

PubMed

Chen, Ya-Qin; Liu, Xin-Guang; Zhao, Wei; Cui, Hongjing; Ruan, Jie; Yuan, Yuan; Tu, Zhiguang

2017-01-01

Yeast MET18 , a subunit of the cytosolic iron-sulfur (Fe/S) protein assembly (CIA) machinery which is responsible for the maturation of Fe/S proteins, has been reported to participate in the oxidative stress response. However, the underlying molecular mechanisms remain unclear. In this study, we constructed a MET18/met18Δ heterozygous mutant yeast strain and found that MET18 deficiency in yeast cells impaired oxidative stress resistance as evidenced by increased sensitivity to hydrogen peroxide (H 2 O 2 ) and cumene hydroperoxide (CHP). Mechanistically, the mRNA levels of catalase A (CTA1) and catalase T (CTT1) as well as the total catalase activity were significantly reduced in MET18 -deficient cells. In contrast, overexpression of CTT1 or CTA1 in MET18 -deficient cells significantly increased the intracellular catalase activity and enhanced the resistance ability against H 2 O 2 and CHP. In addition, MET18 deficiency diminished the replicative capacity of yeast cells as evidenced by the shortened replicative lifespan, which can be restored by CTT1 overexpression, but not by CTA1 , in the MET18 -deficient cells. These results suggest that MET18 , in a catalase-dependent manner, plays an essential role in enhancing the resistance of yeast cells to oxidative stress and increasing the replicative capacity of yeast cells.

MET18 Deficiency Increases the Sensitivity of Yeast to Oxidative Stress and Shortens Replicative Lifespan by Inhibiting Catalase Activity

PubMed Central

Zhao, Wei; Cui, Hongjing

2017-01-01

Yeast MET18, a subunit of the cytosolic iron-sulfur (Fe/S) protein assembly (CIA) machinery which is responsible for the maturation of Fe/S proteins, has been reported to participate in the oxidative stress response. However, the underlying molecular mechanisms remain unclear. In this study, we constructed a MET18/met18Δ heterozygous mutant yeast strain and found that MET18 deficiency in yeast cells impaired oxidative stress resistance as evidenced by increased sensitivity to hydrogen peroxide (H2O2) and cumene hydroperoxide (CHP). Mechanistically, the mRNA levels of catalase A (CTA1) and catalase T (CTT1) as well as the total catalase activity were significantly reduced in MET18-deficient cells. In contrast, overexpression of CTT1 or CTA1 in MET18-deficient cells significantly increased the intracellular catalase activity and enhanced the resistance ability against H2O2 and CHP. In addition, MET18 deficiency diminished the replicative capacity of yeast cells as evidenced by the shortened replicative lifespan, which can be restored by CTT1 overexpression, but not by CTA1, in the MET18-deficient cells. These results suggest that MET18, in a catalase-dependent manner, plays an essential role in enhancing the resistance of yeast cells to oxidative stress and increasing the replicative capacity of yeast cells. PMID:28828388

BDNF Val66Met is Associated with Introversion and Interacts with 5-HTTLPR to Influence Neuroticism

PubMed Central

Terracciano, Antonio; Tanaka, Toshiko; Sutin, Angelina R; Deiana, Barbara; Balaci, Lenuta; Sanna, Serena; Olla, Nazario; Maschio, Andrea; Uda, Manuela; Ferrucci, Luigi; Schlessinger, David; Costa, Paul T

2010-01-01

Brain-derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurotransmission, and has been linked to neuroticism, a major risk factor for psychiatric disorders. A recent genome-wide association (GWA) scan, however, found the BDNF Val66Met polymorphism (rs6265) associated with extraversion but not with neuroticism. In this study, we examine the links between BDNF and personality traits, assessed using the Revised NEO Personality Inventory (NEO-PI-R), in a sample from SardiNIA (n=1560) and the Baltimore Longitudinal Study of Aging (BLSA; n=1131). Consistent with GWA results, we found that BDNF Met carriers were more introverted. By contrast, in both samples and in a meta-analysis inclusive of published data (n=15251), we found no evidence for a main effect of BDNF Val66Met on neuroticism. Finally, on the basis of recent reports of an epistatic effect between BDNF and the serotonin transporter, we explored a Val66Met × 5-HTTLPR interaction in a larger SardiNIA sample (n=2333). We found that 5-HTTLPR LL carriers scored lower on neuroticism in the presence of the BDNF Val variant, but scored higher on neuroticism in the presence of the BDNF Met variant. Our findings support the association between the BDNF Met variant and introversion and suggest that BDNF interacts with the serotonin transporter gene to influence neuroticism. PMID:20042999

Genomic and Molecular Screenings Identify Different Mechanisms for Acquired Resistance to MET Inhibitors in Lung Cancer Cells.

PubMed

Gimenez-Xavier, Pol; Pros, Eva; Bonastre, Ester; Moran, Sebastian; Aza, Ana; Graña, Osvaldo; Gomez-Lopez, Gonzalo; Derdak, Sophia; Dabad, Marc; Esteve-Codina, Anna; Hernandez Mora, Jose R; Salinas-Chaparro, Diana; Esteller, Manel; Pisano, David; Sanchez-Cespedes, Montse

2017-07-01

The development of resistance to tyrosine kinase inhibitors (TKI) limits the long-term efficacy of cancer treatments involving them. We aimed to understand the mechanisms that underlie acquired resistance (AR) to MET inhibitors in lung cancer. EBC1 cells, which have MET amplification and are sensitive to TKIs against MET, were used to generate multiple clones with AR to a MET-TKI. Whole-exome sequencing, RNA sequencing, and global DNA methylation analysis were used to scrutinize the genetic and molecular characteristics of the resistant cells. AR to the MET-TKI involved changes common to all resistant cells, that is, phenotypic modifications, specific changes in gene expression, and reactivation of AKT, ERK, and mTOR. The gene expression, global DNA methylation, and mutational profiles distinguished at least two groups of resistant cells. In one of these, the cells have acquired sensitivity to erlotinib, concomitantly with mutations of the KIRREL, HDAC11, HIATL1 , and MAPK1IP1L genes, among others. In the other group, some cells have acquired inactivation of neurofibromatosis type 2 ( NF2 ) concomitantly with strong overexpression of NRG1 and a mutational profile that includes changes in LMLN and TOMM34 Multiple independent and simultaneous strategies lead to AR to the MET-TKIs in lung cancer cells. The acquired sensitivity to erlotinib supports the known crosstalk between MET and the HER family of receptors. For the first time, we show inactivation of NF2 during acquisition of resistance to MET-TKI that may explain the refractoriness to erlotinib in these cells. Mol Cancer Ther; 16(7); 1366-76. ©2017 AACR . ©2017 American Association for Cancer Research.

Preclinical Trials for Prevention of Tumor Progression of Hepatocellular Carcinoma by LZ-8 Targeting c-Met Dependent and Independent Pathways

PubMed Central

Wu, Jia-Ru; Hu, Chi-Tan; You, Ren-In; Ma, Pei-Ling; Pan, Siou-Mei; Lee, Ming-Che; Wu, Wen-Sheng

2015-01-01

Hepatocellular carcinoma (HCC) is among the most lethal cancers. Mounting studies highlighted the essential role of the HGF/c-MET axis in driving HCC tumor progression. Therefore, c-Met is a potential therapeutic target for HCC. However, several concerns remain unresolved in c-Met targeting. First, the status of active c-Met in HCC must be screened to determine patients suitable for therapy. Second, resistance and side effects have been observed frequently when using conventional c-Met inhibitors. Thus, a preclinical system for screening the status of c-Met signaling and identifying efficient and safe anti-HCC agents is urgently required. In this study, immunohistochemical staining of phosphorylated c-Met (Tyr1234) on tissue sections indicated that HCCs with positive c-Met signaling accounted for approximately 46% in 26 cases. Second, many patient-derived HCC cell lines were established and characterized according to motility and c-Met signaling status. Moreover, LZ8, a medicinal peptide purified from the herb Lingzhi, featuring immunomodulatory and anticancer properties, was capable of suppressing cell migration and slightly reducing the survival rate of both c-Met positive and negative HCCs, HCC372, and HCC329, respectively. LZ8 also suppressed the intrahepatic metastasis of HCC329 in SCID mice. On the molecular level, LZ8 suppressed the expression of c-Met and phosphorylation of c-Met, ERK and AKT in HCC372, and suppressed the phosphorylation of JNK, ERK, and AKT in HCC329. According to receptor array screening, the major receptor tyrosine kinase activated in HCC329 was found to be the epidermal growth factor receptor (EGFR). Moreover, tyrosine-phosphorylated EGFR (the active EGFR) was greatly suppressed in HCC329 by LZ8 treatment. In addition, LZ8 blocked HGF-induced cell migration and c-Met-dependent signaling in HepG2. In summary, we designed a preclinical trial using LZ8 to prevent the tumor progression of patient-derived HCCs with c-Met-positive or

Catechol-O-Methyltransferase Val158Met Polymorphism Associates with Individual Differences in Sleep Physiologic Responses to Chronic Sleep Loss

PubMed Central

Goel, Namni; Banks, Siobhan; Lin, Ling; Mignot, Emmanuel; Dinges, David F.

2011-01-01

Background The COMT Val158Met polymorphism modulates cortical dopaminergic catabolism, and predicts individual differences in prefrontal executive functioning in healthy adults and schizophrenic patients, and associates with EEG differences during sleep loss. We assessed whether the COMT Val158Met polymorphism was a novel marker in healthy adults of differential vulnerability to chronic partial sleep deprivation (PSD), a condition distinct from total sleep loss and one experienced by millions on a daily and persistent basis. Methodology/Principal Findings 20 Met/Met, 64 Val/Met, and 45 Val/Val subjects participated in a protocol of two baseline 10h time in bed (TIB) nights followed by five consecutive 4 h TIB nights. Met/Met subjects showed differentially steeper declines in non-REM EEG slow-wave energy (SWE)—the putative homeostatic marker of sleep drive—during PSD, despite comparable baseline SWE declines. Val/Val subjects showed differentially smaller increases in slow-wave sleep and smaller reductions in stage 2 sleep during PSD, and had more stage 1 sleep across nights and a shorter baseline REM sleep latency. The genotypes, however, did not differ in performance across various executive function and cognitive tasks and showed comparable increases in subjective and physiological sleepiness in response to chronic sleep loss. Met/Met genotypic and Met allelic frequencies were higher in whites than African Americans. Conclusions/Significance The COMT Val158Met polymorphism may be a genetic biomarker for predicting individual differences in sleep physiology—but not in cognitive and executive functioning—resulting from sleep loss in a healthy, racially-diverse adult population of men and women. Beyond healthy sleepers, our results may also provide insight for predicting sleep loss responses in patients with schizophrenia and other psychiatric disorders, since these groups repeatedly experience chronically-curtailed sleep and demonstrate COMT

Usos de Mets Para La Planificación, Monitoreo e Interpretación en Pastizales Áridos

USDA-ARS?s Scientific Manuscript database

Los modelos de estado y transición (METs) representan los posibles cambios en el estado ecológico de una clase específica de tierra (un sitio ecológico). Los METs permiten tener una comprensión general de los cambios en el estado ecológico y cómo gestionarlos. Pero los METs también se pueden usar di...

Global Distributions of Temperature Variances At Different Stratospheric Altitudes From Gps/met Data

NASA Astrophysics Data System (ADS)

Gavrilov, N. M.; Karpova, N. V.; Jacobi, Ch.

The GPS/MET measurements at altitudes 5 - 35 km are used to obtain global distribu- tions of small-scale temperature variances at different stratospheric altitudes. Individ- ual temperature profiles are smoothed using second order polynomial approximations in 5 - 7 km thick layers centered at 10, 20 and 30 km. Temperature inclinations from the averaged values and their variances obtained for each profile are averaged for each month of year during the GPS/MET experiment. Global distributions of temperature variances have inhomogeneous structure. Locations and latitude distributions of the maxima and minima of the variances depend on altitudes and season. One of the rea- sons for the small-scale temperature perturbations in the stratosphere could be internal gravity waves (IGWs). Some assumptions are made about peculiarities of IGW gener- ation and propagation in the tropo-stratosphere based on the results of GPS/MET data analysis.

The BDNF Val66Met polymorphism: relation to familiar risk of affective disorder, BDNF levels and salivary cortisol.

PubMed

Vinberg, Maj; Trajkovska, Viktorija; Bennike, Bente; Knorr, Ulla; Knudsen, Gitte M; Kessing, Lars V

2009-10-01

Brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis are considered to play an important role in the pathophysiology of affective disorders. The aim of the present study was to investigate whether the BDNF Val66Met polymorphism is associated with a familiar risk of affective disorder and whether these genotypes affect whole blood BDNF level and salivary cortisol. In a high-risk study, healthy monozygotic and dizygotic twins with and without a co-twin (high- and low-risk twins, respectively) history of affective disorder were identified through nationwide registers. Familiar predisposition to unipolar and bipolar disorder was not associated with any specific genotype pattern of the BDNF Val66Met polymorphism, not in this sample of 124 val/val, 58 val/met and 8 met/met individuals. However, the combination of having a high familiar risk of affective disorder and the met allele was associated with a higher whole blood BDNF (p=0.02) and a higher evening cortisol level (p=0.01), but not with awakening cortisol. Individuals at high risk of affective disorders and who are carriers of the met allele of the Val66Met polymorphism may present with an enhanced stress response. The presence of a specific genotype alone may not enhance the risk of developing an affective episode. Rather, the altered stress response may be expressed only in combination with other risk variants through interactions with the environment.

NARSTO EPA SS NEW YORK AIR CHEM PM MET DATA

Atmospheric Science Data Center

2018-04-09

NARSTO EPA SS NEW YORK AIR CHEM PM MET DATA Project Title:  NARSTO ... Nitrogen Oxides Ozone Surface Winds Air Temperature Humidity Solar Irradiance Particulate Matter ... Data Guide Documents:  New York Air Chem Guide CPM Summary Report  (PDF) Nitrate ...

Signal transduction and downregulation of C-MET in HGF stimulated low and highly metastatic human osteosarcoma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Husmann, Knut, E-mail: khusmann@research.balgrist.ch; Ducommun, Pascal; Division of Plastic Surgery and Hand Surgery, Department of Surgery, University Hospital Zurich, Zurich

2015-09-04

The poor outcome of osteosarcoma (OS), particularly in patients with metastatic disease and a five-year survival rate of only 20%, asks for more effective therapeutic strategies targeting malignancy-promoting mechanisms. Dysregulation of C-MET, its ligand hepatocyte growth factor (HGF) and the fusion oncogene product TPR-MET, first identified in human MNNG-HOS OS cells, have been described as cancer-causing factors in human cancers. Here, the expression of these molecules at the mRNA and the protein level and of HGF-stimulated signaling and downregulation of C-MET was compared in the parental low metastatic HOS and MG63 cell lines and the respective highly metastatic MNNG-HOS andmore » 143B and the MG63-M6 and MG63-M8 sublines. Interestingly, expression of TPR-MET was only observed in MNNG-HOS cells. HGF stimulated the phosphorylation of Akt and Erk1/2 in all cell lines investigated, but phospho-Stat3 remained at basal levels. Downregulation of HGF-stimulated Akt and Erk1/2 phosphorylation was much faster in the HGF expressing MG63-M8 cells than in HOS cells. Degradation of HGF-activated C-MET occurred predominantly through the proteasomal and to a lesser extent the lysosomal pathway in the cell lines investigated. Thus, HGF-stimulated Akt and Erk1/2 signaling as well as proteasomal degradation of HGF activated C-MET are potential therapeutic targets in OS. - Highlights: • Expression of TPR-MET was only observed in MNNG-HOS cells. • HGF stimulated the phosphorylation of Akt and Erk1/2 but not of Stat3 in osteosarcoma cell lines. • Degradation of HGF-activated C-MET occurred predominantly through the proteasomal pathway.« less

The clinicopathologic association of c-MET overexpression in Iranian gastric carcinomas; an immunohistochemical study of tissue microarrays.

PubMed

Sotoudeh, Kambiz; Hashemi, Forough; Madjd, Zahra; Sadeghipour, Alireza; Molanaei, Saadat; Kalantary, Elham

2012-05-28

c-MET is an oncogene protein that plays important role in gastric carcinogenesis and has been introduced as a prognostic marker and potential therapeutic target. The aim of this study was to evaluate the frequency of c-MET overexpression and its relationship with clinicopathological variables in gastric cancer of Iranian population using tissue microarray. In a cross sectional study, representative paraffin blocks of 130 patients with gastric carcinoma treated by curative gastrectomy during a 2 years period of 2008-2009 in two university hospitals in Tehran-Iran were collected in tissue microarray and c-MET expression was studied by immunohistochemical staining. Finally 124 cases were evaluated, constituted of 99 male and 25 female with the average age of 61.5 years. In 71% (88/124) of tumors, c-MET high expression was found. c-MET high expression was more associated with intestinal than diffuse tumor type (P = 0.04), deeper tumor invasion, pT3 and pT4 versus pT1 and pT2 (P = 0.014), neural invasion (P = 0.002) and advanced TNM staging, stage 3 and 4 versus stage 1 and2 (P = 0.044). The c-MET high expression was not associated with age, sex, tumor location, differentiation grade and distant metastasis, but relative associations with lymph node metastasis (P = 0.065) and vascular invasion (P = 0.078) were observed. c-MET oncogene protein was frequently overexpressed in Iranian gastric carcinomas and it was related to clinicopathological characteristics such as tumor type, depth of invasion, neural invasion and TNM staging. It can also support the idea that c-MET is a potential marker for target therapy in Iranian gastric cancer. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9744598757151429.

The BDNF Val66Met Polymorphism Influences Reading Ability and Patterns of Neural Activation in Children

PubMed Central

Jasińska, Kaja K.; Molfese, Peter J.; Kornilov, Sergey A.; Mencl, W. Einar; Frost, Stephen J.; Lee, Maria; Pugh, Kenneth R.; Grigorenko, Elena L.; Landi, Nicole

2016-01-01

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. PMID:27551971

The BDNF Val66Met Polymorphism Influences Reading Ability and Patterns of Neural Activation in Children.

PubMed

Jasińska, Kaja K; Molfese, Peter J; Kornilov, Sergey A; Mencl, W Einar; Frost, Stephen J; Lee, Maria; Pugh, Kenneth R; Grigorenko, Elena L; Landi, Nicole

2016-01-01

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.

Transition of NOAA's GPS-Met Data Acquisition and Processing System to the Commercial Sector

NASA Astrophysics Data System (ADS)

Jackson, M. E.; Holub, K.; Callahan, W.; Blatt, S.

2014-12-01

In April of 2014, NOAA/OAR/ESRL Global Systems Division (GSD) and Trimble, in collaboration with Earth Networks, Inc. (ENI) signed a Cooperative Research and Development Agreement (CRADA) to transfer the existing NOAA GPS-Met Data Acquisition and Processing System (GPS-Met DAPS) technology to a commercial Trimble/ENI partnership. NOAA's GPS-Met DAPS is currently operated in a pseudo-operational mode but has proven highly reliable and running at over 95% uptime. The DAPS uses the GAMIT software to ingest dual frequency carrier phase GPS/GNSS observations and ancillary information such as real-time satellite orbits to estimate the zenith-scaled tropospheric (ZTD) signal delays and, where surface MET data are available, retrieve integrated precipitable water vapor (PWV). The NOAA data and products are made available to end users in near real-time. The Trimble/ENI partnership will use the Trimble Pivot™ software with the Atmosphere App to calculate zenith tropospheric (ZTD), tropospheric slant delay, and integrated precipitable water vapor (PWV). Evaluation of the Trimble software is underway starting with a comparison of ZTD and PWV values determined from GPS stations located near NOAA Radiosonde Observation (Upper-Air Observation) launch sites. A success metric was established that requires Trimble's PWV estimates to match ESRL/GSD's to within 1.5 mm 95% of the time, which corresponds to a ZTD uncertainty of less than 10 mm 95% of the time. Initial results indicate that Trimble/ENI data meet and exceed the ZTD metric, but for some stations PWV estimates are out of specification. These discrepancies are primarily due to how offsets between MET and GPS stations are handled and are easily resolved. Additional test networks are proposed that include low terrain/high moisture variability stations, high terrain/low moisture variability stations, as well as high terrain/high moisture variability stations. We will present results from further testing along with a timeline

BDNFval66met affects neural activation pattern during fear conditioning and 24 h delayed fear recall.

PubMed

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.

BDNF Val66Met polymorphism, life stress and depression: A meta-analysis of gene-environment interaction.

PubMed

Zhao, Mingzhe; Chen, Lu; Yang, Jiarun; Han, Dong; Fang, Deyu; Qiu, Xiaohui; Yang, Xiuxian; Qiao, Zhengxue; Ma, Jingsong; Wang, Lin; Jiang, Shixiang; Song, Xuejia; Zhou, Jiawei; Zhang, Jian; Chen, Mingqi; Qi, Dong; Yang, Yanjie; Pan, Hui

2018-02-01

Depression is thought to be multifactorial in etiology, including genetic and environmental components. While a number of gene-environment interaction studies have been carried out, meta-analyses are scarce. The present meta-analysis aimed to quantify evidence on the interaction between brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and stress in depression. Included were 31 peer-reviewed with a pooled total of 21060 participants published before October 2016 and literature searches were conducted using PubMed, Wolters Kluwer, Web of Science, EBSCO, Elsevier Science Direct and Baidu Scholar databases. The results indicated that the Met allele of BDNF Val66Met polymorphism significantly moderated the relationship between stress and depression (Z=2.666, p = 0.003). The results of subgroup analysis concluded that stressful life events and childhood adversity separately interacted with the Met allele of BDNF Val66Met polymorphism in depression (Z = 2.552, p = 0.005; Z = 1.775, p = 0.03). The results could be affected by errors or bias in primary studies which had small sample sizes with relatively lower statistic power. We could not estimate how strong the interaction effect between gene and environment was. We found evidence that supported the hypothesis that BDNF Val66Met polymorphism moderated the relationship between stress and depression, despite the fact that many included individual studies did not show this effect. Copyright © 2017 Elsevier B.V. All rights reserved.

HDA6 directly interacts with DNA methyltransferase MET1 and maintains transposable element silencing in Arabidopsis.

PubMed

Liu, Xuncheng; Yu, Chun-Wei; Duan, Jun; Luo, Ming; Wang, Koching; Tian, Gang; Cui, Yuhai; Wu, Keqiang

2012-01-01

The molecular mechanism of how the histone deacetylase HDA6 participates in maintaining transposable element (TE) silencing in Arabidopsis (Arabidopsis thaliana) is not yet defined. In this study, we show that a subset of TEs was transcriptionally reactivated and that TE reactivation was associated with elevated histone H3 and H4 acetylation as well as increased H3K4Me3 and H3K4Me2 in hda6 mutants. Decreased DNA methylation of the TEs was also detected in hda6 mutants, suggesting that HDA6 silences the TEs by regulating histone acetylation and methylation as well as the DNA methylation status of the TEs. Similarly, transcripts of some of these TEs were also increased in the methyltransferase1 (met1) mutant, with decreased DNA methylation. Furthermore, H4 acetylation, H3K4Me3, H3K4Me2, and H3K36Me2 were enriched at the coregulated TEs in the met1 and hda6 met1 mutants. Protein-protein interaction analysis indicated that HDA6 physically interacts with MET1 in vitro and in vivo, and further deletion analysis demonstrated that the carboxyl-terminal region of HDA6 and the bromo-adjacent homology domain of MET1 were responsible for the interaction. These results suggested that HDA6 and MET1 interact directly and act together to silence TEs by modulating DNA methylation, histone acetylation, and histone methylation status.

Epigenetic regulation of HGF/Met receptor axis is critical for the outgrowth of bone metastasis from breast carcinoma.

PubMed

Bendinelli, Paola; Maroni, Paola; Matteucci, Emanuela; Desiderio, Maria Alfonsina

2017-02-02

Our translational research deals with the influence of microenvironment on the phenotype and colonization of bone metastases from breast carcinoma, and on pre-metastatic niche formation. The aim of the present study was to clarify the origin of hepatocyte growth factor (HGF), ligand of Met receptor, the control of the axis HGF/Met by DNA methylation, and its importance for the nexus supportive cells-metastatic cells and for metastasis outgrowth. In bone metastasis of the 1833-xenograft model, DNA methyltransferase blockade using the chemotherapic drug 5-aza-2'-deoxycytidine (decitabine) strongly reduced the expression of HGF/Met receptor axis and of E-cadherin, with decrease of metastasis wideness and osteolysis, prolonging mice survival. Thus, DNA methylation events acted as commanders of breast carcinoma cells metastatizing to bone influencing the epithelial phenotype. HGF emerged as a bone-marrow stimulus, and the exosomes seemed to furnish HGF to metastatic cells. In fact, decitabine treatment similarly affected some markers of these microvesicles and HGF, indicating that its supply to recipient cells was prevented. Notably, in bone metastasis the hypomethylation of HGF, Met and E-cadherin promoters did not appear responsible for their elevated expression, but we suggest the involvement of hypermethylated regulators and of Wwox oncosuppressor, the latter being affected by decitabine. Wwox expression increased under decitabine strongly localizing in nuclei of bone metastases. We hypothesize a role of Wwox in Met activity since in vitro Wwox overexpression downregulated the level of nuclear-Met protein fragment and Met stability, also under long exposure of 1833 cells to decitabine. HGF enhanced phosphoMet and the activity in nuclei, an effect partially prevented by decitabine. Altogether, the data indicated the importance to target the tumor microenvironment by blocking epigenetic mechanisms, which control critical events for colonization such as HGF/Met axis

Met-myoglobin formation, accumulation, degradation, and myoglobin oxygenation monitoring based on multiwavelength attenuance measurement in porcine meat

NASA Astrophysics Data System (ADS)

Nguyen, Thien; Phan, Kien Nguyen; Lee, Jee-Bum; Kim, Jae Gwan

2016-05-01

We propose a simple, rapid, and nondestructive method to investigate formation, accumulation, and degradation of met-myoglobin (met-Mb) and myoglobin oxygenation from the interior of porcine meat. For the experiment, color photos and attenuance spectra of porcine meat (well-bled muscle, fat, and mixed) were collected daily to perform colorimetric analysis and to obtain the differences of attenuance between 578 and 567 nm (A578-A567) and between 615 and 630 nm (A630-A615), respectively. Oxy-, deoxy-, and met-myoglobin concentration changes over storage time were also calculated using Beer-Lamberts' law with reflectance intensities at 557, 582, and 630 nm. The change of A578-A567 was well matched with the change of myoglobin oxygenation, and the change of A630-A615 corresponded well with the formation and degradation of met-Mb. In addition, attenuation differences, A578-A567 and A630-A615, were able to show the formation of met-Mb earlier than colorimetric analysis. Therefore, the attenuance differences between wavelengths can be indicators for estimating myoglobin oxygenation and met-Mb formation, accumulation, and degradation, which enable us to design a simple device to monitor myoglobin activities in porcine meat.

Photochemical cleavage of metal--carbon nanocrystals and their reconstruction into met--cars clusters

NASA Astrophysics Data System (ADS)

Pilgrim, J. S.; Duncan, M. A.

1994-10-01

Titanium and zirconium metal--carbon clusters are produced by laser vaporization in a pulsed nozzle source and detected with time-of-flight mass spectrometry. In addition to the now-familiar "met-cars" stoichiometry (M8C12), larger magic number clusters are produced with near 1:1 metal--carbon ratios. The special stoichiometries observed correspond to face-centered cubic crystal fragments, with a strong preference for fragments with symmetrical x,y,z dimensions. Mass-selected photodissociation experiments are used to investigate the structural patterns and stabilities of these systems. Photodissociation of the larger "nanocrystal" clusters leads to cleavage along crystal planes, producing smaller crystals also having highly symmetric dimensions. Photoexcitation of all these crystallites, in particular the 3 × 3 × 3 species, also leads to surface reconstruction, forming the M8C12 met-cars cluster and/or the M8C13 cluster, the latter of which is assigned to a met--cars cage with an endohedral carbon atom.

Seven Oaks Met School Builds Curriculum around Each Student

ERIC Educational Resources Information Center

Pearson, George

2009-01-01

This article features Seven Oaks School Division Met School in Winnipeg, a high school that limits class size to 15, tailors its curriculum to the needs and interests of its individual students, places students in community-based internships two days a week, and keeps the teacher--called an advisor--with the same group of students from Grade 9…

San Diego Met High School: Personalization as a Foundation

ERIC Educational Resources Information Center

Principal Leadership, 2010

2010-01-01

The mission of San Diego Met High School is to prepare students for college and the workforce through active learning, academic rigor, and community involvement in a small school setting. Because personalization is a key component of the school culture, advisories of 20-25 students work with the same teachers for all four years. Advisers, parents,…

MicroRNA-23b mediates urokinase and c-met downmodulation and a decreased migration of human hepatocellular carcinoma cells.

PubMed

Salvi, Alessandro; Sabelli, Cristiano; Moncini, Silvia; Venturin, Marco; Arici, Bruna; Riva, Paola; Portolani, Nazario; Giulini, Stefano M; De Petro, Giuseppina; Barlati, Sergio

2009-06-01

Urokinase-type plasminogen activator (uPA) and c-met play a major role in cancer invasion and metastasis. Evidence has suggested that uPA and c-met overexpression may be coordinated in human hepatocellular carcinoma (HCC). In the present study, to understand whether the expression of these genes might be coregulated by specific microRNAs (miRs) in human cells, we predicted that Homo sapiens microRNA-23b could recognize two sites in the 3'-UTR of uPA and four sites in the c-met 3'-UTR by the algorithm pictar. The miR-23b expression analysis in human tumor and normal cells revealed an inverse trend with uPA and c-met expression, indicating that uPA and c-met negative regulation might depend on miR-23b expression. Transfection of miR-23b molecules in HCC cells (SKHep1C3) led to inhibition of protein expression of the target genes and caused a decrease in cell migration and proliferation capabilities. Furthermore, anti-miR-23b transfection in human normal AB2 dermal fibroblasts upregulated the expression of endogenous uPA and c-met. Cotransfection experiments in HCC cells of the miR-23b with pGL4.71 Renilla luciferase reporter gene constructs, containing the putative uPA and c-met 3'-UTR target sites, and with the pGL3 firefly luciferase-expressing vector showed a decrease in the relative luciferase activity. This would indicate that miR-23b can recognize target sites in the 3'-UTR of uPA and of c-met mRNAs and translationally repress the expression of uPA and c-met in HCC cells. The evidence obtained shows that overexpression of miR-23b leads to uPA and c-met downregulation and to decreased migration and proliferation abilities of HCC cells.

Distinct projection targets define subpopulations of mouse brainstem vagal neurons that express the autism-associated MET receptor tyrosine kinase.

PubMed

Kamitakahara, Anna; Wu, Hsiao-Huei; Levitt, Pat

2017-12-15

Detailed anatomical tracing and mapping of the viscerotopic organization of the vagal motor nuclei has provided insight into autonomic function in health and disease. To further define specific cellular identities, we paired information based on visceral connectivity with a cell-type specific marker of a subpopulation of neurons in the dorsal motor nucleus of the vagus (DMV) and nucleus ambiguus (nAmb) that express the autism-associated MET receptor tyrosine kinase. As gastrointestinal disturbances are common in children with autism spectrum disorder (ASD), we sought to define the relationship between MET-expressing (MET+) neurons in the DMV and nAmb, and the gastrointestinal tract. Using wholemount tissue staining and clearing, or retrograde tracing in a MET EGFP transgenic mouse, we identify three novel subpopulations of EGFP+ vagal brainstem neurons: (a) EGFP+ neurons in the nAmb projecting to the esophagus or laryngeal muscles, (b) EGFP+ neurons in the medial DMV projecting to the stomach, and (b) EGFP+ neurons in the lateral DMV projecting to the cecum and/or proximal colon. Expression of the MET ligand, hepatocyte growth factor (HGF), by tissues innervated by vagal motor neurons during fetal development reveal potential sites of HGF-MET interaction. Furthermore, similar cellular expression patterns of MET in the brainstem of both the mouse and nonhuman primate suggests that MET expression at these sites is evolutionarily conserved. Together, the data suggest that MET+ neurons in the brainstem vagal motor nuclei are anatomically positioned to regulate distinct portions of the gastrointestinal tract, with implications for the pathophysiology of gastrointestinal comorbidities of ASD. © 2017 Wiley Periodicals, Inc.

Dynamic gene and protein expression patterns of the autism-associated met receptor tyrosine kinase in the developing mouse forebrain.

PubMed

Judson, Matthew C; Bergman, Mica Y; Campbell, Daniel B; Eagleson, Kathie L; Levitt, Pat

2009-04-10

The establishment of appropriate neural circuitry depends on the coordination of multiple developmental events across space and time. These events include proliferation, migration, differentiation, and survival-all of which can be mediated by hepatocyte growth factor (HGF) signaling through the Met receptor tyrosine kinase. We previously found a functional promoter variant of the MET gene to be associated with autism spectrum disorder, suggesting that forebrain circuits governing social and emotional function may be especially vulnerable to developmental disruptions in HGF/Met signaling. However, little is known about the spatiotemporal distribution of Met expression in the forebrain during the development of such circuits. To advance our understanding of the neurodevelopmental influences of Met activation, we employed complementary Western blotting, in situ hybridization, and immunohistochemistry to comprehensively map Met transcript and protein expression throughout perinatal and postnatal development of the mouse forebrain. Our studies reveal complex and dynamic spatiotemporal patterns of expression during this period. Spatially, Met transcript is localized primarily to specific populations of projection neurons within the neocortex and in structures of the limbic system, including the amygdala, hippocampus, and septum. Met protein appears to be principally located in axon tracts. Temporally, peak expression of transcript and protein occurs during the second postnatal week. This period is characterized by extensive neurite outgrowth and synaptogenesis, supporting a role for the receptor in these processes. Collectively, these data suggest that Met signaling may be necessary for the appropriate wiring of forebrain circuits, with particular relevance to the social and emotional dimensions of behavior. (c) 2009 Wiley-Liss, Inc.

AZ-2000-IECW and StaMet Black Kapton Options for Solar Probe Plus MAG Sensor MLI Kevlar/Polyimide Shells

NASA Technical Reports Server (NTRS)

Choi, Michael K.

2017-01-01

AZ-2000-IECW white paint and StaMet black Kapton have been evaluated for the Kevlar/polyimide shells that enclose the Solar Probe Plus Magnetometer (MAG) sensors and multilayer insulation. Flight qualification testing on AZ-2000-IECW painted Kevlar/polyimide laminate was completed at Goddard Space Flight Center. This paint potentially meets all the requirements. However, it has no flight heritage. StaMet is hotter in the sun, and is specular. The results of the MAG thermal balance test show StaMet meets the thermal requirement and heater power budget. The mission prefers to fly StaMet after evaluating the risks of AZ-2000-IECW flaking and glint from StaMet to the Star Trackers.

Validation of the Virtual MET as an assessment tool for executive functions.

PubMed

Rand, Debbie; Basha-Abu Rukan, Soraya; Weiss, Patrice L Tamar; Katz, Noomi

2009-08-01

The purpose of this study was to establish ecological validity and initial construct validity of a Virtual Multiple Errands Test (VMET) as an assessment tool for executive functions. It was implemented within the Virtual Mall (VMall), a novel functional video-capture virtual shopping environment. The main objectives were (1) to examine the relationships between the performance of three groups of participants in the Multiple Errands Test (MET) carried out in a real shopping mall and their performance in the VMET, (2) to assess the relationships between the MET and VMET of the post-stroke participant's level of executive functioning and independence in instrumental activities of daily living, and (3) to compare the performance of post-stroke participants to those of healthy young and older controls in both the MET and VMET. The study population included three groups; post-stroke participants (n = 9), healthy young participants (n = 20), and healthy older participants (n = 20). The VMET was able to differentiate between two age groups of healthy participants and between healthy and post-stroke participants thus demonstrating that it is sensitive to brain injury and ageing and supports construct validity between known groups. In addition, significant correlations were found between the MET and the VMET for both the post-stroke participants and older healthy participants. This provides initial support for the ecological validity of the VMET as an assessment tool of executive functions. However, further psychometric data on temporal stability are needed, namely test-retest reliability and responsiveness, before it is ready for clinical application. Further research using the VMET as an assessment tool within the VMall with larger groups and in additional populations is also recommended.

Krüppel-like factor 4 promotes c-Met amplification-mediated gefitinib resistance in non-small-cell lung cancer.

PubMed

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

2018-06-01

Gefitinib has 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. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Discovery of potent 1H-imidazo[4,5-b]pyridine-based c-Met kinase inhibitors via mechanism-directed structural optimization.

PubMed

An, Xiao-De; Liu, Hongyan; Xu, Zhong-Liang; Jin, Yi; Peng, Xia; Yao, Ying-Ming; Geng, Meiyu; Long, Ya-Qiu

2015-02-01

Starting from our previously identified novel c-Met kinase inhibitors bearing 1H-imidazo[4,5-h][1,6]naphthyridin-2(3H)-one scaffold, a global structural exploration was conducted to furnish an optimal binding motif for further development, directed by the enzyme inhibitory mechanism. First round SAR study picked two imidazonaphthyridinone frameworks with 1,8- and 3,5-disubstitution pattern as class I and class II c-Met kinase inhibitors, respectively. Further structural optimization on type II inhibitors by truncation of the imidazonaphthyridinone core and incorporation of an N-phenyl cyclopropane-1,1-dicarboxamide pharmacophore led to the discovery of novel imidazopyridine-based c-Met kinase inhibitors, displaying nanomolar enzyme inhibitory activity and improved Met kinase selectivity. More significantly, the new chemotype c-Met kinase inhibitors effectively inhibited Met phosphorylation and its downstream signaling as well as the proliferation of Met-dependent EBC-1 human lung cancer cells at submicromolar concentrations. Copyright © 2014 Elsevier Ltd. All rights reserved.

Dual targeting c-met and VEGFR2 in osteoblasts suppresses growth and osteolysis of prostate cancer bone metastasis.

PubMed

Lee, Changki; Whang, Young Mi; Campbell, Preston; Mulcrone, Patrick L; Elefteriou, Florent; Cho, Sun Wook; Park, Serk In

2018-02-01

Prostate cancer characteristically induces osteoblastic bone metastasis, for which no therapies are available. A dual kinase inhibitor of c-Met and VEGFR-2 (cabozantinib) was shown to reduce prostate cancer growth in bone, with evidence for suppressing osteoblastic activity. However, c-Met and VEGFR2 signaling in osteoblasts in the context of bone metastasis remain unclear. Here we show using cultured osteoblasts that hepatocyte growth factor (HGF) and VEGF-A increased receptor activator of NFκB ligand (RANKL) and M-CSF, two essential factors for osteoclastogenesis. Insulin-like growth factor-1 (IGF1) also increased RANKL and M-CSF via c-Met transactivation. The conditioned media from IGF1-, HGF-, or VEGFA-treated osteoblasts promoted osteoclastogenesis that was reversed by inhibiting c-Met and/or VEGFR2 in osteoblasts. In vivo experiments used cabozantinib-resistant prostate cancer cells (PC-3 and C4-2B) to test the effects of c-Met/VEGFR2 inhibition specifically in osteoblasts. Cabozantinib (60 mg/kg, 3 weeks) suppressed tumor growth in bone and reduced expression of RANKL and M-CSF and subsequent tumor-induced osteolysis. Collectively, inhibition of c-Met and VEGFR2 in osteoblasts reduced RANKL and M-CSF expression, and associated with reduction of tumor-induced osteolysis, suggesting that c-Met and VEGFR2 are promising therapeutic targets in bone metastasis. Copyright © 2017 Elsevier B.V. All rights reserved.

A novel G-quadruplex motif in the Human MET promoter region.

PubMed

Yan, Jing; Zhao, Deming; Dong, Liping; Pan, Shuang; Hao, Fengjin; Guan, Yifu

2017-12-22

It is known that the guanine-rich strands in proto-oncogene promoters can fold into G-quadruplex structures to regulate gene expression. An intramolecular parallel G-quadruplex has been identified in MET promoter. It acts as a repressor in regulating MET expression. However, the full guanine-rich region in MET promoter forms a hybrid parallel/antiparallel G-quadruplex structure under physiological conditions, which means there are some antiparallel and hybrid parallel/antiparallel G-quadruplex structures in this region. In the present study, our data indicate that g3-5 truncation adopts an intramolecular hybrid parallel/antiparallel G-quadruplex under physiological conditions in vitro The g3-5 G-quadruplex structure significantly stops polymerization by Klenow fragment in K + buffer. Furthermore, the results of circular dichroism (CD) spectra and polymerase stop assay directly demonstrate that the G-quadruplex structure in g3-5 fragment can be stabilized by the G-quadruplex ligand TMPyP4 (5,10,15,20-tetra-(N-methyl-4-pyridyl) porphine). But the dual luciferase assay indicates TMPyP4 has no effect on the formation of g3-5 G-quadruplex in HepG2 cells. The findings in the present study will enrich our understanding of the G-quadruplex formation in proto-oncogene promoters and the mechanisms of gene expression regulation. © 2017 The Author(s).

Monoclonal Antibodies against the MET/HGF Receptor and Its Ligand: Multitask Tools with Applications from Basic Research to Therapy

PubMed Central

Prat, Maria; Oltolina, Francesca; Basilico, Cristina

2014-01-01

Monoclonal antibodies can be seen as valuable tools for many aspects of basic as well as applied sciences. In the case of MET/HGFR, they allowed the identification of truncated isoforms of the receptor, as well as the dissection of different epitopes, establishing structure–function relationships. Antibodies directed against MET extracellular domain were found to be full or partial receptor agonists or antagonists. The agonists can mimic the effects of the different isoforms of the natural ligand, but with the advantage of being more stable than the latter. Thus, some agonist antibodies promote all the biological responses triggered by MET activation, including motility, proliferation, morphogenesis, and protection from apoptosis, while others can induce only a migratory response. On the other hand, antagonists can inhibit MET-driven biological functions either by competing with the ligand or by removing the receptor from the cell surface. Since MET/HGFR is often over-expressed and/or aberrantly activated in tumors, monoclonal antibodies can be used as probes for MET detection or as “bullets” to target MET-expressing tumor cells, thus pointing to their use in diagnosis and therapy. PMID:28548076

[Association of Val66Met polymorphism of brain-derived neurotrophic factor gene with cognitive impairment and clinical symptoms in first episode schizophrenia].

PubMed

Zhang, Chengcheng; Gu, Xiaochu; Wang, Qiang; Li, Mingli; Deng, Wei; Guo, Wanjun; Zhao, Liansheng; Ma, Xiaohong; Li, Tao

2017-08-10

To assess the association of cognitive impairment and clinical symptoms in first-episode schizophrenia with the Val66Met (rs6265) polymorphism of brain-derived neurotrophic factor (BDNF) gene. For 87 patients with first-episode schizophrenia and 76 healthy controls, the Val66Met polymorphism was determined with a Taqman Assay-on-Demand method. Wechsler intelligence test was carried out for all participants. Correlation of cognitive impairment with clinical severity was also analyzed. The patients were significantly lower in total IQ, verbal IQ and performance IQ compared to the controls. The lower total IQ (F=4.59, P= 0.01) and verbal IQ (F=4.44, P=0.01) were influenced by genetic factors and diagnostic interaction. The vertal IQ of Val/Val patients was significantly lower than those of Val/Met and Met/Met carriers. For the control group, the verbal IQ of Met/Met carriers was lower than that of Val/Met carriers, and the total IQ of Met/Met carriers was lower than those of Val/Met and Val/Val carriers. For the patient group, the total IQ of Val/Val carriers was negatively correlated with positive symptoms (r=-0.65, P=0.03) and thought disorders (r=-0.61, P=0.02). Cognitive impairment in first-episode schizophrenic patients is associated with the Val66Met polymorphism of the BDNF gene, and has an important clinical relevance.

Wnt Signaling Cross-Talks with JH Signaling by Suppressing Met and gce Expression

PubMed Central

Abdou, Mohamed; Peng, Cheng; Huang, Jianhua; Zyaan, Ola; Wang, Sheng; Li, Sheng; Wang, Jian

2011-01-01

Juvenile hormone (JH) plays key roles in controlling insect growth and metamorphosis. However, relatively little is known about the JH signaling pathways. Until recent years, increasing evidence has suggested that JH modulates the action of 20-hydroxyecdysone (20E) by regulating expression of broad (br), a 20E early response gene, through Met/Gce and Kr-h1. To identify other genes involved in JH signaling, we designed a novel Drosophila genetic screen to isolate mutations that derepress JH-mediated br suppression at early larval stages. We found that mutations in three Wnt signaling negative regulators in Drosophila, Axin (Axn), supernumerary limbs (slmb), and naked cuticle (nkd), caused precocious br expression, which could not be blocked by exogenous JHA. A similar phenotype was observed when armadillo (arm), the mediator of Wnt signaling, was overexpressed. qRT-PCR revealed that Met, gce and Kr-h1expression was suppressed in the Axn, slmb and nkd mutants as well as in arm gain-of-function larvae. Furthermore, ectopic expression of gce restored Kr-h1 expression but not Met expression in the arm gain-of-function larvae. Taken together, we conclude that Wnt signaling cross-talks with JH signaling by suppressing transcription of Met and gce, genes that encode for putative JH receptors. The reduced JH activity further induces down-regulation of Kr-h1expression and eventually derepresses br expression in the Drosophila early larval stages. PMID:22087234

MicroRNA-138 inhibits proliferation of cervical cancer cells by targeting c-Met.

PubMed

Li, B; Yang, X-X; Wang, D; Ji, H-K

2016-01-01

MicroRNAs (miRNAs) function as important post-transcriptional regulators involved in a wide range of biological behaviors. MicroRNA-138 (miR-138) has been shown to play a critical role in tumor pathogenesis, the present study aimed to investigate the role of miR-138 in cervical cancer. CCK-8 assay was performed to measure the viabilities of cancer cells. Quantitative real-time PCR (qRT-PCR) and western blot were used to detect the mRNA and protein expression, respectively. Moreover, the miRNA target genes were validated with luciferase activity assay. In the current study, we found that the expression of miR-138 was significantly down-regulated in cervical cancer tissues compared to the adjacent non-cancer tissues. CCK-8 assay showed that over-expression of miR-138 suppressed the proliferation of four cervical cancer cell lines including HeLa, SiHa, C33A and CaSki. By contrast, down-regulation of miR-138 promoted the growth of cervical cancer cells. In addition, increased expression of miR-138 led to a reduction in c-Met expression, whereas inhibition of miR-138 enhanced c-Met levels in cervical cancer cells. The luciferase reporter assay showed that c-Met was a direct target of miR-138 in cervical cancer cells. These findings demonstrated that miR-138 inhibited cervical cancer cells proliferation via c-Met, providing a novel target for the molecular treatment of cervical cancer.

Association between COMT Val158Met and psychiatric disorders: A comprehensive meta-analysis.

PubMed

Taylor, Steven

2018-03-01

Catechol-O-methyltransferase (COMT) Val158Met is widely regarded as potentially important for understanding the genetic etiology of many different psychiatric disorders. The present study appears to be the first comprehensive meta-analysis of COMT genetic association studies to cover all psychiatric disorders for which there were available data, published in any language, and with an emphasis on investigating disorder subtypes (defined clinically or by demographic or other variables). Studies were included if they reported one or more datasets (i.e., some studies examined more than one clinical group) in which there were sufficient information to compute effect sizes. A total of 363 datasets were included, consisting of 56,998 cases and 74,668 healthy controls from case control studies, and 2,547 trios from family based studies. Fifteen disorders were included. Attention-deficit hyperactivity disorder and panic disorder were associated with the Val allele for Caucasian samples. Substance-use disorder, defined by DSM-IV criteria, was associated with the Val allele for Asian samples. Bipolar disorder was associated with the Met allele in Asian samples. Obsessive-compulsive disorder tended to be associated with the Met allele only for males. There was suggestive evidence that the Met allele is associated with an earlier age of onset of schizophrenia. Results suggest pleiotropy and underscore the importance of examining subgroups-defined by variables such as age of onset, sex, ethnicity, and diagnostic system-rather than examining disorders as monolithic constructs. © 2017 Wiley Periodicals, Inc.

Correlation of MET gene amplification and TP53 mutation with PD-L1 expression in non-small cell lung cancer

PubMed Central

Albitar, Maher; Sudarsanam, Sucha; Ma, Wanlong; Jiang, Shiping; Chen, Wayne; Funari, Vincent; Blocker, Forrest; Agersborg, Sally

2018-01-01

Background The role of MET amplification in lung cancer, particularly in relation to checkpoint inhibition and EGFR WT, has not been fully explored. In this study, we correlated PD-L1 expression with MET amplification and EGFR, KRAS, or TP53 mutation in primary lung cancer. Methods In this retrospective study, tissue collected from 471 various tumors, including 397 lung cancers, was tested for MET amplification by FISH with a MET/centromere probe. PD-L1 expression was evaluated using clone SP142 and standard immunohistochemistry, and TP53, KRAS, and EGFR mutations were tested using next generation sequencing. Results Our results revealed that PD-L1 expression in non-small cell lung cancer is inversely correlated with EGFR mutation (P=0.0003), and positively correlated with TP53 mutation (P=0.0001) and MET amplification (P=0.004). Patients with TP53 mutations had significantly higher MET amplification (P=0.007), and were more likely (P=0.0002) to be EGFR wild type. There was no correlation between KRAS mutation and overall PD-L1 expression, but significant positive correlation between PD-L1 expression and KRAS with TP53 co-mutation (P=0.0002). A cut-off for the ratio of MET: centromere signal was determined as 1.5%, and 4% of lung cancer patients were identified as MET amplified. Conclusions This data suggests that in lung cancer both MET and TP53 play direct roles in regulating PD-L1 opposing EGFR. Moreover, KRAS and TP53 co-mutation may cooperate to drive PD-L1 expression in lung cancer. Adding MET or TP53 inhibitors to checkpoint inhibitors may be an attractive combination therapy in patients with lung cancer and MET amplification. PMID:29568386

Overexpression of c-Met in bone marrow mesenchymal stem cells improves their effectiveness in homing and repair of acute liver failure.

PubMed

Wang, Kun; Li, Yuwen; Zhu, Tiantian; Zhang, Yongting; Li, Wenting; Lin, Wenyu; Li, Jun; Zhu, Chuanlong

2017-07-05

Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) has emerged as a novel therapy for acute liver failure (ALF). However, the homing efficiency of BMSCs to the injured liver sites appears to be poor. In this study, we aimed to determine if overexpression of c-Met in BMSCs could promote the homing ability of BMSCs to rat livers affected by ALF. Overexpression of c-Met in BMSCs (c-Met-BMSCs) was attained by transfection of naive BMSCs with the lenti-c-Met-GFP. The impact of transplanted c-Met-BMSCs on both homing and repair of ALF was evaluated and compared with lenti-GFP empty vector transfected BMSCs (control BMSCs). After cells were transfected with the lenti-c-Met-GFP vector, the BMSCs displayed very high expression of c-Met protein as demonstrated by Western blot. In addition, in vitro transwell migration assays showed that the migration ability of c-Met-BMSCs was significantly increased in comparison with that of control BMSCs (P < 0.05), and was dependent on hepatocyte growth factor (HGF). Furthermore, rats with ALF that received transplanted c-Met-BMSCs showed significantly improved homing ability to the injured liver; this was accompanied by elevated survival rates and liver function in the ALF rats. Parallel pathological examination further confirmed that transplantation of c-Met-BMSCs ameliorated liver injury with reduced hepatic activity index (HAI) scores, and that the effects of c-Met-BMSCs were more profound than those of control BMSCs. Overexpression of c-Met promotes the homing of BMSCs to injured hepatic sites in a rat model of ALF, thereby improving the efficacy of BMSC therapy for ALF repair.

Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models.

PubMed

Zhao, Yingchao; Liu, Pinan; Zhang, Na; Chen, Jie; Landegger, Lukas D; Wu, Limeng; Zhao, Fu; Zhao, Yanxia; Zhang, Yanling; Zhang, Jing; Fujita, Takeshi; Stemmer-Rachamimov, Anat; Ferraro, Gino B; Liu, Hao; Muzikansky, Alona; Plotkin, Scott R; Stankovic, Konstantina M; Jain, Rakesh K; Xu, Lei

2018-02-27

Neurofibromatosis type II (NF2) is a disease that needs new solutions. Vestibular schwannoma (VS) growth causes progressive hearing loss, and the standard treatment, including surgery and radiotherapy, can further damage the nerve. There is an urgent need to identify an adjunct therapy that, by enhancing the efficacy of radiation, can help lower the radiation dose and preserve hearing. The mechanisms underlying deafness in NF2 are still unclear. One of the major limitations in studying tumor-induced hearing loss is the lack of mouse models that allow hearing testing. Here, we developed a cerebellopontine angle (CPA) schwannoma model that faithfully recapitulates the tumor-induced hearing loss. Using this model, we discovered that cMET blockade by crizotinib (CRZ) enhanced schwannoma radiosensitivity by enhancing DNA damage, and CRZ treatment combined with low-dose radiation was as effective as high-dose radiation. CRZ treatment had no adverse effect on hearing; however, it did not affect tumor-induced hearing loss, presumably because cMET blockade did not change tumor hepatocyte growth factor (HGF) levels. This cMET gene knockdown study independently confirmed the role of the cMET pathway in mediating the effect of CRZ. Furthermore, we evaluated the translational potential of cMET blockade in human schwannomas. We found that human NF2-associated and sporadic VSs showed significantly elevated HGF expression and cMET activation compared with normal nerves, which correlated with tumor growth and cyst formation. Using organoid brain slice culture, cMET blockade inhibited the growth of patient-derived schwannomas. Our findings provide the rationale and necessary data for the clinical translation of combined cMET blockade with radiation therapy in patients with NF2.

COMT met allele differentially predicts risk versus severity of aberrant eating in a large community sample.

PubMed

Donofry, Shannon D; Roecklein, Kathryn A; Wildes, Jennifer E; Miller, Megan A; Flory, Janine D; Manuck, Stephen B

2014-12-15

Prefrontal dopamine (DA) transmission participates in the reinforcement of reward-driven behaviors like eating. Because catechol-O-methyltransferase (COMT) degrades DA and is expressed in the prefrontal cortex, variation in the COMT gene may modulate eating behavior. Previous studies have shown that the met allele of the COMT val158met single nucleotide polymorphism (SNP) is associated with Bulimia Nervosa (BN). The specific aim of this study was to test whether the met allele increased risk for, and severity of, eating disorder symptomatology in community volunteers. Caucasian adults (N=1003; 51.2% female) from the University of Pittsburgh Adult Health and Behavior Project (AHAB) were genotyped and completed the Eating Disorders Inventory (EDI). Logistic and Poisson regression analyses assessed genotype-dependent presence and severity of eating disorder symptomatology. The met allele was significantly associated with the presence of symptoms on the Bulimia subscale and the severity of Body Dissatisfaction scores. All EDI subscales significantly predicted BMI. To our knowledge, these are the first data indicating that the COMT met allele increases risk for some symptoms of disordered eating, while increasing severity of others, in a community sample. These novel findings may have important implications for understanding the etiology of heterogeneous disordered eating phenotypes. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Aberrant expression of microRNAs and the miR-1/MET pathway in canine hepatocellular carcinoma.

PubMed

Lai, Y-C; Ushio, N; Rahman, M M; Katanoda, Y; Ogihara, K; Naya, Y; Moriyama, A; Iwanaga, T; Saitoh, Y; Sogawa, T; Sunaga, T; Momoi, Y; Izumi, H; Miyoshi, N; Endo, Y; Fujiki, M; Kawaguchi, H; Miura, N

2018-06-01

Canine hepatocellular carcinoma (HCC) is the most common primary hepatic tumour in dogs. MicroRNA (miRNA) dysregulation has been reported in human HCC and shown to have diagnostic and prognostic value; however, there are no data on miRNA expression in canine HCC. The aim of the present study was to investigate differentially expressed miRNAs in canine HCC. Analysis of miRNA expression in canine HCC tissues and cell lines by quantitative reverse transcription PCR showed that miR-1, miR-122, let-7a, and let-7g were downregulated, whereas miR-10b and miR-21 were upregulated in canine HCC. MET is one of the target genes of miR-1. MET was upregulated in canine HCC at the gene and protein levels, and a significant correlation between the concomitant downregulation of miR-1 and upregulation of MET was observed. Fast/intermediate-proliferating canine HCC cell lines had higher MET gene and protein expression levels than the slow-proliferating cell line. These findings suggest that miRNAs are differentially expressed in canine HCC, and that the miR-1/MET pathway may be associated with canine HCC cell proliferation. © 2018 John Wiley & Sons Ltd.

MET18 Connects the Cytosolic Iron-Sulfur Cluster Assembly Pathway to Active DNA Demethylation in Arabidopsis

PubMed Central

Tang, Kai; Zhang, Huiming; Mangrauthia, Satendra K.; Lei, Mingguang; Hsu, Chuan-Chih; Hou, Yueh-Ju; Wang, Chunguo; Li, Yan; Tao, W. Andy; Zhu, Jian-Kang

2015-01-01

DNA demethylation mediated by the DNA glycosylase ROS1 helps determine genomic DNA methylation patterns and protects active genes from being silenced. However, little is known about the mechanism of regulation of ROS1 enzymatic activity. Using a forward genetic screen, we identified an anti-silencing (ASI) factor, ASI3, the dysfunction of which causes transgene promoter hyper-methylation and silencing. Map-based cloning identified ASI3 as MET18, a component of the cytosolic iron-sulfur cluster assembly (CIA) pathway. Mutation in MET18 leads to hyper-methylation at thousands of genomic loci, the majority of which overlap with hypermethylated loci identified in ros1 and ros1dml2dml3 mutants. Affinity purification followed by mass spectrometry indicated that ROS1 physically associates with MET18 and other CIA components. Yeast two-hybrid and split luciferase assays showed that ROS1 can directly interact with MET18 and another CIA component, AE7. Site-directed mutagenesis of ROS1 indicated that the conserved iron-sulfur motif is indispensable for ROS1 enzymatic activity. Our results suggest that ROS1-mediated active DNA demethylation requires MET18-dependent transfer of the iron-sulfur cluster, highlighting an important role of the CIA pathway in epigenetic regulation. PMID:26492035

Target identification, lead optimization and antitumor evaluation of some new 1,2,4-triazines as c-Met kinase inhibitors.

PubMed

El-Wakil, Marwa H; Ashour, Hayam M; Saudi, Manal N; Hassan, Ahmed M; Labouta, Ibrahim M

2017-08-01

In silico target fishing approach using PharmMapper server identified c-Met kinase as the selective target for our previously synthesized compound NCI 748494/1. This approach was validated by in vitro kinase assay which showed that NCI 748494/1 possessed promising inhibitory activity against c-Met kinase (IC 50 =31.70μM). Assessment of ADMET profiling, drug-likeness, drug score as well as docking simulation for the binding pose of that compound in the active site of c-Met kinase domain revealed that NCI 748494/1 could be considered as a promising drug lead. Based on target identification and validation, it was observed that there is structure similarity between NCI 748494/1 and the reported type II c-Met kinase inhibitor BMS-777607. Optimization of our lead NCI 748494/1 furnished newly synthesized 1,2,4-triazine derivatives based on well-established structure-activity relationships, whereas three compounds namely; 4d, 7a and 8c displayed excellent in vitro cytotoxicity against three c-Met addicted cancer cell lines; A549 (lung adenocarcinoma), HT-29 (colon cancer) and MKN-45 (gastric carcinoma); with IC 50 values in the range 0.01-1.86µM. In vitro c-Met kinase assay showed 8c to possess the highest c-Met kinase inhibition profile (IC 50 =4.31µM). Docking of the active compounds in c-Met kinase active site revealed strong binding interactions comparable to the lead NCI 748494/1 and BMS-777607, suggesting that c-Met inhibition is very likely to be the mechanism of the antitumor effect of these derivatives. Copyright © 2017 Elsevier Inc. All rights reserved.

Histidine-rich stabilized polyplexes for cMet-directed tumor-targeted gene transfer

NASA Astrophysics Data System (ADS)

Kos, Petra; Lächelt, Ulrich; Herrmann, Annika; Mickler, Frauke Martina; Döblinger, Markus; He, Dongsheng; Krhač Levačić, Ana; Morys, Stephan; Bräuchle, Christoph; Wagner, Ernst

2015-03-01

Overexpression of the hepatocyte growth factor receptor/c-Met proto oncogene on the surface of a variety of tumor cells gives an opportunity to specifically target cancerous tissues. Herein, we report the first use of c-Met as receptor for non-viral tumor-targeted gene delivery. Sequence-defined oligomers comprising the c-Met binding peptide ligand cMBP2 for targeting, a monodisperse polyethylene glycol (PEG) for polyplex surface shielding, and various cationic (oligoethanamino) amide cores containing terminal cysteines for redox-sensitive polyplex stabilization, were assembled by solid-phase supported syntheses. The resulting oligomers exhibited a greatly enhanced cellular uptake and gene transfer over non-targeted control sequences, confirming the efficacy and target-specificity of the formed polyplexes. Implementation of endosomal escape-promoting histidines in the cationic core was required for gene expression without additional endosomolytic agent. The histidine-enriched polyplexes demonstrated stability in serum as well as receptor-specific gene transfer in vivo upon intratumoral injection. The co-formulation with an analogous PEG-free cationic oligomer led to a further compaction of pDNA polyplexes with an obvious change of shape as demonstrated by transmission electron microscopy. Such compaction was critically required for efficient intravenous gene delivery which resulted in greatly enhanced, cMBP2 ligand-dependent gene expression in the distant tumor.Overexpression of the hepatocyte growth factor receptor/c-Met proto oncogene on the surface of a variety of tumor cells gives an opportunity to specifically target cancerous tissues. Herein, we report the first use of c-Met as receptor for non-viral tumor-targeted gene delivery. Sequence-defined oligomers comprising the c-Met binding peptide ligand cMBP2 for targeting, a monodisperse polyethylene glycol (PEG) for polyplex surface shielding, and various cationic (oligoethanamino) amide cores containing

The clinicopathologic association of c-MET overexpression in Iranian gastric carcinomas; an immunohistochemical study of tissue microarrays

PubMed Central

2012-01-01

Background c-MET is an oncogene protein that plays important role in gastric carcinogenesis and has been introduced as a prognostic marker and potential therapeutic target. The aim of this study was to evaluate the frequency of c-MET overexpression and its relationship with clinicopathological variables in gastric cancer of Iranian population using tissue microarray. Methods In a cross sectional study, representative paraffin blocks of 130 patients with gastric carcinoma treated by curative gastrectomy during a 2 years period of 2008–2009 in two university hospitals in Tehran-Iran were collected in tissue microarray and c-MET expression was studied by immunohistochemical staining. Results Finally 124 cases were evaluated, constituted of 99 male and 25 female with the average age of 61.5 years. In 71% (88/124) of tumors, c-MET high expression was found. c-MET high expression was more associated with intestinal than diffuse tumor type (P = 0.04), deeper tumor invasion, pT3 and pT4 versus pT1 and pT2 (P = 0.014), neural invasion (P = 0.002) and advanced TNM staging, stage 3 and 4 versus stage 1 and2 (P = 0.044). The c-MET high expression was not associated with age, sex, tumor location, differentiation grade and distant metastasis, but relative associations with lymph node metastasis (P = 0.065) and vascular invasion (P = 0.078) were observed. Conclusions c-MET oncogene protein was frequently overexpressed in Iranian gastric carcinomas and it was related to clinicopathological characteristics such as tumor type, depth of invasion, neural invasion and TNM staging. It can also support the idea that c-MET is a potential marker for target therapy in Iranian gastric cancer. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9744598757151429 PMID:22640970

75 FR 77671 - Expansion of the Scope of NRTL Recognition of MET Laboratories, Inc.; Correction of the Scope of...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-13

... MET Laboratories, Inc., (MET) as an NRTL. MET's expansion covers the use of additional test standards... elements: (1) The type of products the NRTL may test, with each type specified by its applicable test... certification activities for test standards within the NRTL's scope; and (3) the supplemental program(s) that...

The BDNF Val66Met polymorphism and plasma brain-derived neurotrophic factor levels in Han Chinese heroin-dependent patients.

PubMed

Chen, Shiou-Lan; Lee, Sheng-Yu; Chang, Yun-Hsuan; Wang, Tzu-Yun; Chen, Shih-Heng; Chu, Chun-Hsien; Chen, Po See; Yang, Yen Kuang; Hong, Jau-Shyong; Lu, Ru-Band

2015-02-02

BDNF and its gene polymorphism may be important in synaptic plasticity and neuron survival, and may become a key target in the physiopathology of long-term heroin use. Thus, we investigated the relationships between brain-derived neurotrophic factor (BDNF) plasma concentrations and the BDNF Val66Met nucleotide polymorphism (SNP) in heroin-dependent patients. The pretreatment expression levels of plasma BDNF and the BDNF Val66Met SNP in 172 heroin-dependent patients and 102 healthy controls were checked. BDNF levels were significantly lower in patients (F = 52.28, p < 0.0001), but the distribution of the SNP was not significantly different. Nor were plasma BDNF levels significantly different between Met/Met, Met/Val, and Val/Val carriers in each group, which indicated that the BDNF Val66Met SNP did not affect plasma BDNF levels in our participants. In heroin-dependent patients, plasma BDNF levels were negatively correlated with the length of heroin dependency. Long-term (>15 years) users had significantly lower plasma BDNF levels than did short-term (<5 years) users. We conclude that plasma BDNF concentration in habitual heroin users are not affected by BDNF Val66Met gene variants, but by the length of the heroin dependency.

The BDNF Val66Met polymorphism and plasma brain-derived neurotrophic factor levels in Han Chinese heroin-dependent patients

PubMed Central

Chen, Shiou-Lan; Lee, Sheng-Yu; Chang, Yun-Hsuan; Wang, Tzu-Yun; Chen, Shih-Heng; Chu, Chun-Hsien; Chen, Po See; Yang, Yen Kuang; Hong, Jau-Shyong; Lu, Ru-Band

2015-01-01

BDNF and its gene polymorphism may be important in synaptic plasticity and neuron survival, and may become a key target in the physiopathology of long-term heroin use. Thus, we investigated the relationships between brain-derived neurotrophic factor (BDNF) plasma concentrations and the BDNF Val66Met nucleotide polymorphism (SNP) in heroin-dependent patients. The pretreatment expression levels of plasma BDNF and the BDNF Val66Met SNP in 172 heroin-dependent patients and 102 healthy controls were checked. BDNF levels were significantly lower in patients (F = 52.28, p < 0.0001), but the distribution of the SNP was not significantly different. Nor were plasma BDNF levels significantly different between Met/Met, Met/Val, and Val/Val carriers in each group, which indicated that the BDNF Val66Met SNP did not affect plasma BDNF levels in our participants. In heroin-dependent patients, plasma BDNF levels were negatively correlated with the length of heroin dependency. Long-term (>15 years) users had significantly lower plasma BDNF levels than did short-term (<5 years) users. We conclude that plasma BDNF concentration in habitual heroin users are not affected by BDNF Val66Met gene variants, but by the length of the heroin dependency. PMID:25640280

Met receptor signaling is required for sensory nerve development and HGF promotes axonal growth and survival of sensory neurons

PubMed Central

Maina, Flavio; Hilton, Mark C.; Ponzetto, Carola; Davies, Alun M.; Klein, Rüdiger

1997-01-01

The development of the nervous system is a dynamic process during which factors act in an instructive fashion to direct the differentiation and survival of neurons, and to induce axonal outgrowth, guidance to, and terminal branching within the target tissue. Here we report that mice expressing signaling mutants of the hepatocyte growth factor (HGF) receptor, the Met tyrosine kinase, show a striking reduction of sensory nerves innervating the skin of the limbs and thorax, implicating the HGF/Met system in sensory neuron development. Using in vitro assays, we find that HGF cooperates with nerve growth factor (NGF) to enhance axonal outgrowth from cultured dorsal root ganglion (DRG) neurons. HGF also enhances the neurotrophic activities of NGF in vitro, and Met receptor signaling is required for the survival of a proportion of DRG neurons in vivo. This synergism is specific for NGF but not for the related neurotrophins BDNF and NT3. By using a mild signaling mutant of Met, we have demonstrated previously that Met requires signaling via the adapter molecule Grb2 to induce proliferation of myoblasts. In contrast, the actions of HGF on sensory neurons are mediated by Met effectors distinct from Grb2. Our findings demonstrate a requirement for Met signaling in neurons during development. PMID:9407027

YKL-40/c-Met expression in rectal cancer biopsies predicts tumor regression following neoadjuvant chemoradiotherapy: a multi-institutional study.

PubMed

Senetta, Rebecca; Duregon, Eleonora; Sonetto, Cristina; Spadi, Rossella; Mistrangelo, Massimiliano; Racca, Patrizia; Chiusa, Luigi; Munoz, Fernando H; Ricardi, Umberto; Arezzo, Alberto; Cassenti, Adele; Castellano, Isabella; Papotti, Mauro; Morino, Mario; Risio, Mauro; Cassoni, Paola

2015-01-01

Neoadjuvant chemo-radiotherapy (CRT) followed by surgical resection is the standard treatment for locally advanced rectal cancer, although complete tumor pathological regression is achieved in only up to 30% of cases. A clinicopathological and molecular predictive stratification of patients with advanced rectal cancer is still lacking. Here, c-Met and YKL-40 have been studied as putative predictors of CRT response in rectal cancer, due to their reported involvement in chemoradioresistance in various solid tumors. A multicentric study was designed to assess the role of c-Met and YKL-40 expression in predicting chemoradioresistance and to correlate clinical and pathological features with CRT response. Immunohistochemistry and fluorescent in situ hybridization for c-Met were performed on 81 rectal cancer biopsies from patients with locally advanced rectal adenocarcinoma. All patients underwent standard (50.4 gy in 28 fractions + concurrent capecitabine 825 mg/m2) neoadjuvant CRT or the XELOXART protocol. CRT response was documented on surgical resection specimens and recorded as tumor regression grade (TRG) according to the Mandard criteria. A significant correlation between c-Met and YKL-40 expression was observed (R = 0.43). The expressions of c-Met and YKL-40 were both significantly associated with a lack of complete response (86% and 87% of c-Met and YKL-40 positive cases, p< 0.01 and p = 0.006, respectively). Thirty of the 32 biopsies co-expressing both markers had partial or absent tumor response (TRG 2-5), strengthening their positive predictive value (94%). The exclusive predictive role of YKL-40 and c-Met was confirmed using a multivariate analysis (p = 0.004 and p = 0.007 for YKL-40 and c-Met, respectively). TRG was the sole morphological parameter associated with poor outcome. c-Met and YKL-40 expression is a reliable predictor of partial/absent response to neoadjuvant CRT in rectal cancer. Targeted therapy protocols could take advantage of prior

GGA3 Functions as a Switch to Promote Met Receptor Recycling, Essential for Sustained ERK and Cell Migration

PubMed Central

Parachoniak, Christine Anna; Luo, Yi; Abella, Jasmine Vanessa; Keen, James H.; Park, Morag

2011-01-01

Summary Cells are dependent on correct sorting of activated receptor tyrosine kinases (RTKs) for the outcome of growth factor signaling. Upon activation, RTKs are coupled through the endocytic machinery for degradation, or recycled to the cell surface. However, the molecular mechanisms governing RTK recycling are poorly understood. Here, we show that Golgi-localized gamma-ear containing Arf-binding protein 3 (GGA3) interacts selectively with the Met/Hepatocyte Growth Factor RTK when stimulated, to sort it for recycling in association with “gyrating”-clathrin. GGA3 loss abrogates Met recycling from a Rab4 endosomal subdomain, resulting in pronounced trafficking of Met towards degradation. Decreased Met recycling attenuates ERK activation and cell migration. Met recycling, sustained ERK activation and migration require interaction of GGA3 with Arf6 and an unexpected association with the Crk adaptor. The data show that GGA3 defines an active recycling pathway and support a broader role for GGA3-mediated cargo selection in targeting receptors destined for recycling. PMID:21664574

20 CFR 416.1044 - How and when we determine whether the processing time standards are met.

Code of Federal Regulations, 2010 CFR

2010-04-01

... processing time standards are met. 416.1044 Section 416.1044 Employees' Benefits SOCIAL SECURITY... Performance Standards § 416.1044 How and when we determine whether the processing time standards are met. (a) How we determine processing times. For all initial title II cases, we calculate the mean number of...

20 CFR 404.1644 - How and when we determine whether the processing time standards are met.

Code of Federal Regulations, 2010 CFR

2010-04-01

... processing time standards are met. 404.1644 Section 404.1644 Employees' Benefits SOCIAL SECURITY... Performance Standards § 404.1644 How and when we determine whether the processing time standards are met. (a) How we determine processing times. For all initial title II cases, we calculate the mean number of...

DrugMetZ DB: an anthology of human drug metabolizing Chytochrome P450 enzymes.

PubMed

Antony, Tresa Remya Thomas; Nagarajan, Shanthi

2006-11-14

Understandings the basics of Cytochrome P450 (P450 or CYP) will help to discern drug metabolism. CYP, a super-family of heme-thiolate proteins, are found in almost all living organisms and is involved in the biotransformation of a diverse range of xenobiotics, therapeutic drugs and toxins. Here, we describe DrugMetZ DB, a database for CYP metabolizing drugs. The DB is implemented in MySQL, PHP and HTML. www.bicpu.edu.in/DrugMetZDB/

Interaction between job stress and the BDNF Val66Met polymorphism affects depressive symptoms in Chinese healthcare workers.

PubMed

He, Shu-Chang; Wu, Shuang; Wang, Chao; Du, Xiang-Dong; Yin, Guangzhong; Jia, Qiufang; Zhang, Yingyang; Wang, Li; Soares, Jair C; Zhang, Xiang Yang

2018-08-15

Chronic exposure to job-related stress can lead to depression and BDNF polymorphism may play an important role in this process. The role of the stress × BDNF Val66Met interaction in depression has been studied widely using childhood stress, but few studies have utilized chronic stress in adulthood as a moderator. This study was to examine the chronic stress × BDNF Val66Met interaction in job-related depression in the healthcare workers in a Chinese Han population, which has not been reported yet. Using a cross-sectional design, 243 doctors and nurses were recruited from a general hospital in Beijing, and were assessed for depression with Self-rating Depression Scale (SDS), and the stress using the House and Rizzo's Work Stress Scale. The BDNF Val66Met polymorphism was genotyped. There was a significant positive association between job stress and depressive scores (p < 0.001). No significant main effect of the BDNF Val66Met genotype on depressive symptoms was observed (p > 0.05). A statistically significant interaction between BDNF Val66Met and job stress on depressive symptoms was found (p < 0.05); individuals with Val/Val genotype showed a higher SDS score than Met allele carriers only in the low-stress group, without significant differences in SDS score between the BDNF Val66Met subgroups in medium- or high-stress group. Limitations include cross-sectional study design, the small sample size only in healthcare workers and only one polymorphism in BDNF gene was analyzed. Our results suggest a close relationship between job-related stress and depression, and the interaction of the BDNF Val66Met polymorphism and chronic stress in adulthood may impact the depressive symptoms. Copyright © 2018. Published by Elsevier B.V.

Met synergizes with p53 loss to induce mammary tumors that possess features of claudin-low breast cancer

PubMed Central

Knight, Jennifer F.; Lesurf, Robert; Zhao, Hong; Pinnaduwage, Dushanthi; Davis, Ryan R.; Saleh, Sadiq M. I.; Zuo, Dongmei; Naujokas, Monica A.; Chughtai, Naila; Herschkowitz, Jason I.; Prat, Aleix; Mulligan, Anna Marie; Muller, William J.; Cardiff, Robert D.; Gregg, Jeff P.; Andrulis, Irene L.; Hallett, Michael T.; Park, Morag

2013-01-01

Triple-negative breast cancer (TNBC) accounts for ∼20% of cases and contributes to basal and claudin-low molecular subclasses of the disease. TNBCs have poor prognosis, display frequent mutations in tumor suppressor gene p53 (TP53), and lack targeted therapies. The MET receptor tyrosine kinase is elevated in TNBC and transgenic Met models (Metmt) develop basal-like tumors. To investigate collaborating events in the genesis of TNBC, we generated Metmt mice with conditional loss of murine p53 (Trp53) in mammary epithelia. Somatic Trp53 loss, in combination with Metmt, significantly increased tumor penetrance over Metmt or Trp53 loss alone. Unlike Metmt tumors, which are histologically diverse and enriched in a basal-like molecular signature, the majority of Metmt tumors with Trp53 loss displayed a spindloid pathology with a distinct molecular signature that resembles the human claudin-low subtype of TNBC, including diminished claudins, an epithelial-to-mesenchymal transition signature, and decreased expression of the microRNA-200 family. Moreover, although mammary specific loss of Trp53 promotes tumors with diverse pathologies, those with spindloid pathology and claudin-low signature display genomic Met amplification. In both models, MET activity is required for maintenance of the claudin-low morphological phenotype, in which MET inhibitors restore cell-cell junctions, rescue claudin 1 expression, and abrogate growth and dissemination of cells in vivo. Among human breast cancers, elevated levels of MET and stabilized TP53, indicative of mutation, correlate with highly proliferative TNBCs of poor outcome. This work shows synergy between MET and TP53 loss for claudin-low breast cancer, identifies a restricted claudin-low gene signature, and provides a rationale for anti-MET therapies in TNBC. PMID:23509284

Anti-PSMA/CD3 Bispecific Antibody Delivery And Anti-Tumor Activity Using A Polymeric Depot Formulation.

PubMed

Leconet, Wilhem; Liu, He; Guo, Ming; Le Lamer-Déchamps, Sophie; Molinier, Charlotte; Kim, Sae; Vrlinic, Tjasa; Oster, Murielle; Liu, Fang; Navarro, Vincent; Batra, Jaspreet S; Lopez-Noriega, Adolfo; Grizot, Sylvestre; Bander, Neil H

2018-06-11

Small therapeutic proteins represent a promising novel approach to treat cancer. Nevertheless, their clinical application is often adversely impacted by their short plasma half-life. Controlled long-term delivery of small biologicals has become a challenge because of their hydrophilic properties and in some cases their limited stability. Here, an in-situ forming depot injectable polymeric system was used to deliver BiJ591, a Bispecific T-cell Engager (BiTE) targeting both prostate-specific membrane antigen (PSMA) and the CD3 T-cell receptor in prostate cancer. BiJ591 induced T-cell activation, prostate cancer directed cell lysis and tumor growth inhibition. The use of diblock and triblock biodegradable polyethylene glycol - poly(lactic acid) (PEG-PLA) copolymers solubilized in tripropionin, a small chain triglyceride, allowed maintenance of BiJ591 stability and functionality in the formed depot and controlled its release. In mice, after a single subcutaneous injection, one of the polymeric candidates, TB1/DB4, provided the most sustained release of BiJ591 for up to 21 days. Moreover, the use of BiJ591-TB1/DB4 formulation in prostate cancer xenograft models showed significant therapeutic activity in both low and high PSMA expressing tumors whereas daily intravenous administration of BiJ591 was less efficient. Collectively, the present data provide new insights into the development of controlled delivery of small therapeutic proteins in cancer. Copyright ©2018, American Association for Cancer Research.

BDNF Val66Met predicts cognitive decline in the Wisconsin Registry for Alzheimer's Prevention

PubMed Central

Boots, Elizabeth A.; Schultz, Stephanie A.; Clark, Lindsay R.; Racine, Annie M.; Darst, Burcu F.; Koscik, Rebecca L.; Carlsson, Cynthia M.; Gallagher, Catherine L.; Hogan, Kirk J.; Bendlin, Barbara B.; Asthana, Sanjay; Sager, Mark A.; Hermann, Bruce P.; Christian, Bradley T.; Dubal, Dena B.; Engelman, Corinne D.; Johnson, Sterling C.

2017-01-01

Objective: To examine the influence of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on longitudinal cognitive trajectories in a large, cognitively healthy cohort enriched for Alzheimer disease (AD) risk and to understand whether β-amyloid (Aβ) burden plays a moderating role in this relationship. Methods: One thousand twenty-three adults (baseline age 54.94 ± 6.41 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention underwent BDNF genotyping and cognitive assessment at up to 5 time points (average follow-up 6.92 ± 3.22 years). A subset (n = 140) underwent 11C-Pittsburgh compound B (PiB) scanning. Covariate-adjusted mixed-effects regression models were used to elucidate the effect of BDNF on cognitive trajectories in 4 cognitive domains, including verbal learning and memory, speed and flexibility, working memory, and immediate memory. Secondary mixed-effects regression models were conducted to examine whether Aβ burden, indexed by composite PiB load, modified any observed BDNF-related cognitive trajectories. Results: Compared to BDNF Val/Val homozygotes, Met carriers showed steeper decline in verbal learning and memory (p = 0.002) and speed and flexibility (p = 0.017). In addition, Aβ burden moderated the relationship between BDNF and verbal learning and memory such that Met carriers with greater Aβ burden showed even steeper cognitive decline (p = 0.033). Conclusions: In a middle-aged cohort with AD risk, carriage of the BDNF Met allele was associated with steeper decline in episodic memory and executive function. This decline was exacerbated by greater Aβ burden. These results suggest that the BDNF Val66Met polymorphism may play an important role in cognitive decline and could be considered as a target for novel AD therapeutics. PMID:28468845

BDNF Val66Met predicts cognitive decline in the Wisconsin Registry for Alzheimer's Prevention.

PubMed

Boots, Elizabeth A; Schultz, Stephanie A; Clark, Lindsay R; Racine, Annie M; Darst, Burcu F; Koscik, Rebecca L; Carlsson, Cynthia M; Gallagher, Catherine L; Hogan, Kirk J; Bendlin, Barbara B; Asthana, Sanjay; Sager, Mark A; Hermann, Bruce P; Christian, Bradley T; Dubal, Dena B; Engelman, Corinne D; Johnson, Sterling C; Okonkwo, Ozioma C

2017-05-30

To examine the influence of the brain-derived neurotrophic factor ( BDNF ) Val66Met polymorphism on longitudinal cognitive trajectories in a large, cognitively healthy cohort enriched for Alzheimer disease (AD) risk and to understand whether β-amyloid (Aβ) burden plays a moderating role in this relationship. One thousand twenty-three adults (baseline age 54.94 ± 6.41 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention underwent BDNF genotyping and cognitive assessment at up to 5 time points (average follow-up 6.92 ± 3.22 years). A subset (n = 140) underwent 11 C-Pittsburgh compound B (PiB) scanning. Covariate-adjusted mixed-effects regression models were used to elucidate the effect of BDNF on cognitive trajectories in 4 cognitive domains, including verbal learning and memory, speed and flexibility, working memory, and immediate memory. Secondary mixed-effects regression models were conducted to examine whether Aβ burden, indexed by composite PiB load, modified any observed BDNF -related cognitive trajectories. Compared to BDNF Val/Val homozygotes, Met carriers showed steeper decline in verbal learning and memory ( p = 0.002) and speed and flexibility ( p = 0.017). In addition, Aβ burden moderated the relationship between BDNF and verbal learning and memory such that Met carriers with greater Aβ burden showed even steeper cognitive decline ( p = 0.033). In a middle-aged cohort with AD risk, carriage of the BDNF Met allele was associated with steeper decline in episodic memory and executive function. This decline was exacerbated by greater Aβ burden. These results suggest that the BDNF Val66Met polymorphism may play an important role in cognitive decline and could be considered as a target for novel AD therapeutics. © 2017 American Academy of Neurology.

Insulin-Independent GABAA Receptor-Mediated Response in the Barrel Cortex of Mice with Impaired Met Activity.

PubMed

Lo, Fu-Sun; Erzurumlu, Reha S; Powell, Elizabeth M

2016-03-30

Autism spectrum disorder (ASD) is a neurodevelopmental disorder caused by genetic variants, susceptibility alleles, and environmental perturbations. The autism associated geneMETtyrosine kinase has been implicated in many behavioral domains and endophenotypes of autism, including abnormal neural signaling in human sensory cortex. We investigated somatosensory thalamocortical synaptic communication in mice deficient in Met activity in cortical excitatory neurons to gain insights into aberrant somatosensation characteristic of ASD. The ratio of excitation to inhibition is dramatically increased due to decreased postsynaptic GABAAreceptor-mediated inhibition in the trigeminal thalamocortical pathway of mice lacking active Met in the cerebral cortex. Furthermore, in contrast to wild-type mice, insulin failed to increase GABAAreceptor-mediated response in the barrel cortex of mice with compromised Met signaling. Thus, lacking insulin effects may be a risk factor in ASD pathogenesis. A proposed common cause of neurodevelopmental disorders is an imbalance in excitatory neural transmission, provided by the glutamatergic neurons, and the inhibitory signals from the GABAergic interneurons. Many genes associated with autism spectrum disorders impair synaptic transmission in the expected cell type. Previously, inactivation of the autism-associated Met tyrosine kinase receptor in GABAergic interneurons led to decreased inhibition. In thus report, decreased Met signaling in glutamatergic neurons had no effect on excitation, but decimated inhibition. Further experiments indicate that loss of Met activity downregulates GABAAreceptors on glutamatergic neurons in an insulin independent manner. These data provide a new mechanism for the loss of inhibition and subsequent abnormal excitation/inhibition balance and potential molecular candidates for treatment or prevention. Copyright © 2016 the authors 0270-6474/16/363691-07$15.00/0.

Analysis of EGFR, EML4-ALK, KRAS, and c-MET mutations in Chinese lung adenocarcinoma patients.

PubMed

Xia, Ning; An, Jian; Jiang, Qing-qing; Li, Min; Tan, Jun; Hu, Cheng-ping

2013-10-01

Mutation analysis of cancer driver genes is helpful for determining an optimal treatment strategy. We evaluated mutations in four driver genes, namely epidermal growth factor receptor (EGFR), Kirsten ras oncogene (KRAS), c-MET, and echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK), in Chinese lung adenocarcinoma patients from Hunan Province. We enrolled 110 lung adenocarcinoma patients in a single institution. EGFR and KRAS mutations were examined by direct sequencing, the EML4-ALK fusion gene was analyzed by fluorescence in situ hybridization, and c-MET amplification and c-Met protein expression were detected by quantitative PCR and immunohistochemistry, respectively. EGFR and KRAS mutations were observed in 52.7% (58/110) and 3.6% (4/106) of patients, respectively. c-MET amplification was detected in 5.5% (6/110) of patients. In addition, 30% (33/110) of the cases expressed c-Met protein, including all of the patients harboring c-MET amplification. Ten percent (11/110) of patients harbored the EML4-ALK fusion gene, and the frequency of ALK rearrangement was higher than that of other cohort analyses involving patients from other regions in China. Almost all of these gene mutations were exclusive except that in two female non-smoking patients, who harbored an EGFR mutation and EML4-ALK rearrangement simultaneously. In total, 70% of patients in the study harbored one of the four gene mutations. Most Chinese lung adenocarcinoma patients harbor driver gene mutations, among which ALK rearrangements were more common in Hunan patients than in previously reported populations. Future clinical trials should be conducted to determine the safety and efficacy of drug combination targeting different driver mutations.

Enhanced extinction of cocaine seeking in brain-derived neurotrophic factor Val66Met knock-in mice.

PubMed

Briand, Lisa A; Lee, Francis S; Blendy, Julie A; Pierce, R Christopher

2012-03-01

The Val66Met polymorphism in the brain-derived neurotropic factor (BDNF) gene results in alterations in fear extinction behavior in both human populations and mouse models. However, it is not clear whether this polymorphism plays a similar role in extinction of appetitive behaviors. Therefore, we examined operant learning and extinction of both food and cocaine self-administration behavior in an inbred genetic knock-in mouse strain expressing the variant Bdnf. These mice provide a unique opportunity to relate alterations in aversive and appetitive extinction learning as well as provide insight into how human genetic variation can lead to differences in behavior. BDNF(Met/Met) mice exhibited a severe deficit in operant learning as demonstrated by an inability to learn the food self-administration task. Therefore, extinction experiments were performed comparing wildtype (BDNF(Val/Val) ) animals to mice heterozygous for the Met allele (BDNF(Val/Met) ), which did not differ in food or cocaine self-administration behavior. In contrast to the deficit in fear extinction previously demonstrated in these mice, we found that BDNF(Val/Met) mice exhibited more rapid extinction of cocaine responding compared to wildtype mice. No differences were found between the genotypes in the extinction of food self-administration behavior or the reinstatement of cocaine seeking, indicating that the effect is specific to extinction of cocaine responding. These results suggest that the molecular mechanisms underlying aversive and appetitive extinction are distinct from one another and BDNF may play opposing roles in the two phenomena. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Gender effects of the COMT Val 158 Met genotype on verbal fluency in healthy adults.

PubMed

Soeiro-De-Souza, Marcio Gerhardt; Bio, Danielle Soares; David, Denise Petresco; Missio, Giovani; Lima, Bruno; Fernandes, Fernando; Machado-Vieira, Rodrigo; Moreno, Ricardo Alberto

2013-09-01

Cognitive performance in healthy individuals is associated with gender differences in specific tests; a female advantage has been demonstrated in language tests, whereas a male advantage has been demonstrated in spatial relation examinations. The prefrontal cortex (PFC) mediates important cognitive domains and is influenced by dopamine (DA) activity. The single nucleotide polymorphism (SNP) rs4680 in the catechol‑O‑methyltransferase (COMT) gene results in an amino acid substitution from valine (Val) to methionine (Met). The Met allele has been demonstrated to decrease COMT enzyme activity and improve PFC cognitive function. COMT regulates DA activity in the PFC and exhibits gender effects. The aim of the present study was to investigate the gender‑specific effects of the COMT genotype on cognition in healthy young adults. Seventy‑six healthy subjects were genotyped for COMT rs4680 and submitted to an extensive range of neuropsychological tests assessing aspects of PFC function. The COMT Met allele influenced the performance of executive function. The results revealed gender effects of the COMT rs4680 Met allele on verbal fluency, with positive effects in males and negative effects in females. This suggested that DA activity affects cognitive function in different ways, according to gender.

Cobalamin-Independent Methionine Synthase (MetE): A Face-to-Face Double Barrel that Evolved by Gene Duplication

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pejcha, Robert; Ludwig, Martha L.

2010-03-08

Cobalamin-independent methionine synthase (MetE) catalyzes the transfer of a methyl group from methyltetrahydrofolate to L-homocysteine (Hcy) without using an intermediate methyl carrier. Although MetE displays no detectable sequence homology with cobalamin-dependent methionine synthase (MetH), both enzymes require zinc for activation and binding of Hcy. Crystallographic analyses of MetE from T. maritima reveal an unusual dual-barrel structure in which the active site lies between the tops of the two ({beta}{alpha}){sub 8} barrels. The fold of the N-terminal barrel confirms that it has evolved from the C-terminal polypeptide by gene duplication; comparisons of the barrels provide an intriguing example of homologous domainmore » evolution in which binding sites are obliterated. The C-terminal barrel incorporates the zinc ion that binds and activates Hcy. The zinc-binding site in MetE is distinguished from the (Cys){sub 3}Zn site in the related enzymes, MetH and betaine-homocysteine methyltransferase, by its position in the barrel and by the metal ligands, which are histidine, cysteine, glutamate, and cysteine in the resting form of MetE. Hcy associates at the face of the metal opposite glutamate, which moves away from the zinc in the binary E {center_dot} Hcy complex. The folate substrate is not intimately associated with the N-terminal barrel; instead, elements from both barrels contribute binding determinants in a binary complex in which the folate substrate is incorrectly oriented for methyl transfer. Atypical locations of the Hcy and folate sites in the C-terminal barrel presumably permit direct interaction of the substrates in a ternary complex. Structures of the binary substrate complexes imply that rearrangement of folate, perhaps accompanied by domain rearrangement, must occur before formation of a ternary complex that is competent for methyl transfer.« less

Modification of depression by COMT val158met polymorphism in children exposed to early severe psychosocial deprivation

PubMed Central

Drury, Stacy S; Theall, Katherine P; Smyke, Anna T; Keats, Bronya JB; Egger, Helen L; Nelson, Charles A; Fox, Nathan A; Marshall, Peter J; Zeanah, Charles H

2014-01-01

Objective To examine the impact of the Catechol-O-Methyltransferase (COMT) val158met allele on depressive symptoms in young children exposed to early severe social deprivation as a result of being raised in institutions. Methods 136 children from the Bucharest Early Intervention Project (BEIP) were randomized before 31 months of age to either care as usual (CAU) in institutions or placement in newly created foster care (FCG). At 54 months of age, a psychiatric assessment using the Preschool Age Psychiatric Assessment (PAPA) was completed. DNA was collected and genotyped for the COMT val158met polymorphism. Multivariate analysis examined the relationship between COMT alleles and depressive symptoms. Results Mean level of depressive symptoms was lower among participants with the met allele compared to those with two copies of the val allele (p <0.05). Controlling for group and gender, the rate of depressive symptoms was significantly lower among participants with the met/met or the met/val genotype (adjusted relative risk (aRR) = 0.67, 95% CI = 0.45, 0.99) compared to participants with the val/val genotype, indicating an intermediate impact for heterozygotes consistent with the biological impact of this polymorphism. The impact of genotype within groups differed significantly. There was a significant protective effect of the met allele on depressive symptoms within the CAU group, however there was no relationship seen within the FCG group. Conclusions This is the first study, to our knowledge, to find evidence of a gene × environment interaction in the setting of early social deprivation. These results support the hypothesis that individual genetic differences may explain some of the variability in recovery amongst children exposed to early severe social deprivation. PMID:20403637

COMT Val(158)Met genotype determines the direction of cognitive effects produced by catechol-O-methyltransferase inhibition.

PubMed

Farrell, Sarah M; Tunbridge, Elizabeth M; Braeutigam, Sven; Harrison, Paul J

2012-03-15

Catechol-O-methyltransferase (COMT) metabolizes dopamine. The COMT Val(158)Met polymorphism influences its activity, and multiple neural correlates of this genotype on dopaminergic phenotypes, especially working memory, have been reported. COMT activity can also be regulated pharmacologically by COMT inhibitors. The inverted-U relationship between cortical dopamine signaling and working memory predicts that the effects of COMT inhibition will differ according to COMT genotype. Thirty-four COMT Met(158)Met (Met-COMT) and 33 COMT Val(158)Val (Val-COMT) men were given a single 200-mg dose of the brain-penetrant COMT inhibitor tolcapone or placebo in a randomized, double-blind, between-subjects design. They completed the N-back task of working memory and a gambling task. In the placebo group, Met-COMT subjects outperformed Val-COMT subjects on the 2- back, and they were more risk averse. Tolcapone had opposite effects in the two genotype groups: it worsened N-back performance in Met-COMT subjects but enhanced it in Val-COMT subjects. Tolcapone made Met-COMT subjects less risk averse but Val-COMT subjects more so. In both tasks, tolcapone reversed the baseline genotype differences. Depending on genotype, COMT inhibition can enhance or impair working memory and increase or decrease risky decision making. To our knowledge, the data are the clearest demonstration to date that the direction of effect of a drug can be influenced by a polymorphism in its target gene. The results support the inverted-U model of dopamine function. The findings are of translational relevance, because COMT inhibitors are used in the adjunctive treatment of Parkinson's disease and are under evaluation in schizophrenia and other disorders. Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Recent advances in the development of dual VEGFR and c-Met small molecule inhibitors as anticancer drugs.

PubMed

Zhang, Jin; Jiang, Xiangdong; Jiang, Yingnan; Guo, Mingrui; Zhang, Shouyue; Li, Jingjing; He, Jun; Liu, Jie; Wang, Jinhui; Ouyang, Liang

2016-01-27

Vascular endothelial growth factor receptor (VEGFR) is a very important receptor tyrosine kinase (RTK) that can induce angiogenesis, increase cell growth and metastasis, reduce apoptosis, alter cytoskeletal function, and affect other biologic changes. Moreover, it is identified to be deregulated in varieties of human cancers. Therefore, VEGFR turn out to be a remarkable target of significant types of anticancer drugs in clinical trials. On the other side, c-Met is the receptor of hepatocyte growth factor (HGF) and a receptor tyrosine kinase. Previous studies have shown that c-Met elicits many different signaling pathways mediating cell proliferation, migration, differentiation, and survival. Furthermore, the correlation between aberrant signaling of the HGF/c-Met pathway and aggressive tumor growth, poor prognosis in cancer patients has been established. Recent reports had shown that c-Met/HGF and VEGFR/VEGF (vascular endothelial growth factor) can act synergistically in the progression of many diseases. They were also found to be over expressed in many human cancers. Thus, in a variety of malignancies, VEGFR and c-Met receptor tyrosine kinases have acted as therapeutic targets. With the development of molecular biology techniques, further understanding of the human tumor disease pathogenesis and interrelated signaling pathways known to tumor cells, using a single target inhibitors have been difficult to achieve the desired therapeutic effect. At this point, with respect to the combination of two inhibitors, a single compound which is able to inhibit both VEGFR and c-Met may put forward the advantage of raising anticancer activity. With the strong interest in these compounds, this review represents a renewal of previous works on the development of dual VEGFR and c-Met small molecule inhibitors as novel anti-cancer agents. Newly collection derivatives have been mainly describing in their biological profiles and chemical structures. Copyright © 2015 Elsevier Masson

XRCC3 Thr241Met Polymorphism is not Associated with Lung Cancer Risk in a Romanian Population.

PubMed

Catana, Andreea; Pop, Monica; Marginean, Dragos Horea; Blaga, Ioana Cristina; Porojan, Mihai Dumitru; Popp, Radu Anghel; Pop, Ioan Victor

2016-01-01

Deoxyribonucleic Acid (DNA) repair mechanisms play a critical role in protecting the cellular genome against carcinogens. X-ray cross-complementing gene 3 (XRCC3) is involved in DNA repair and therefore certain genetic polymorphisms that occur in DNA repair genes may affect the ability to repair DNA defects and may represent a risk factor in carcinogenesis. The purpose of our study was to investigate the association between XRCC3 gene substitution of Threonine with Methionine in codon 241 of XRCC3 gene (Thr241Met) polymorphism and the risk of lung cancer, in a Romanian population. We recruited 93 healthy controls and 85 patients with lung cancer, all smokers. Thr241Met, XRCC3 gene genotyping was determined by multiplex Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). Statistical analysis (OR, recessive model), did not revealed an increased risk for lung cancer, for the variant 241Met allele and Thr241Met genotypes (p=0.138, OR=0.634, CI=0.348-1.157; p=0.023, OR=0.257, CI=0.085-6.824). Also, there were no positive statistical associations between Thr241Met polymorphism of XRCC3 gene, gender, tobacco and various histopathological tumor type of lung cancer. In conclusion, the results of the study suggest that the XRCC3 gene Thr241Met polymorphism is not associated with an increased risk for the development of lung cancer in this Romanian group.

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism affects sympathetic tone in a gender-specific way.

PubMed

Chang, Chuan-Chia; Chang, Hsin-An; Chen, Tien-Yu; Fang, Wen-Hui; Huang, San-Yuan

2014-09-01

The Val/Val genotype of the brain-derived neurotrophic factor (BDNF) polymorphism (Val66Met) has been reported to affect human anxiety-related phenotypes. Substantial research has demonstrated that anxiety is associated with sympathetic activation, while sex steroid hormones have been shown to exert differential actions in regulating BDNF expression. Thus, we examined whether the BDNF variant modulates autonomic function in a gender-dependent manner. From 708 adults initially screened for medical and psychiatric illnesses, a final cohort of 583 drug-free healthy Han Chinese (355 males, 228 females; age 34.43±8.42 years) was recruited for BDNF genotyping (Val/Val: 136, 23.3%, Val/Met: 294, 50.4%, and Met/Met: 153, 26.2%). Time- and frequency-domain analyses of heart rate variability (HRV) were used to assess autonomic outflow to the heart. Significant genotype-by-gender interaction effects were found on HRV indices. Even after adjusting for possible confounders, male participants bearing the Val/Val genotype had significant increases in low frequency (LF), LF% and LF/high frequency (HF) ratio, indicating altered sympathovagal balance with increased sympathetic modulation, compared to male Met/Met homozygotes. Females, however, showed an opposite but non-significant pattern. These results suggest that the studied BDNF polymorphism is associated with sympathetic control in a gender-specific way. The findings here support the view that male subjects with the Val/Val genotype have increased risk of anxiety by association with sympathetic activation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Learning about Teaching: Initial Findings from the Measures of Effective Teaching Project. Research Paper. MET Project

ERIC Educational Resources Information Center

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 test new approaches to measuring effective teaching. 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 that…

Preservation of General Intelligence following Traumatic Brain Injury: Contributions of the Met66 Brain-Derived Neurotrophic Factor

PubMed Central

Barbey, Aron K.; Colom, Roberto; Paul, Erick; Forbes, Chad; Krueger, Frank; Goldman, David; Grafman, Jordan

2014-01-01

Brain-derived neurotrophic factor (BDNF) promotes survival and synaptic plasticity in the human brain. The Val66Met polymorphism of the BDNF gene interferes with intracellular trafficking, packaging, and regulated secretion of this neurotrophin. The human prefrontal cortex (PFC) shows lifelong neuroplastic adaption implicating the Val66Met BDNF polymorphism in the recovery of higher-order executive functions after traumatic brain injury (TBI). In this study, we examined the effect of this BDNF polymorphism on the preservation of general intelligence following TBI. We genotyped a sample of male Vietnam combat veterans (n = 156) consisting of a frontal lobe lesion group with focal penetrating head injuries for the Val66Met BDNF polymorphism. Val/Met did not differ from Val/Val genotypes in general cognitive ability before TBI. However, we found substantial average differences between these groups in general intelligence (≈ half a standard deviation or 8 IQ points), verbal comprehension (6 IQ points), perceptual organization (6 IQ points), working memory (8 IQ points), and processing speed (8 IQ points) after TBI. These results support the conclusion that Val/Met genotypes preserve general cognitive functioning, whereas Val/Val genotypes are largely susceptible to TBI. PMID:24586380

Causality and Information Dynamics in Networked Systems with Many Agents

DTIC Science & Technology

2017-05-11

representation, the LSI filter given by A(τ) must be invertible, and a sufficient condition for this invertibility is that there is some c > 0 such that the...linear shift-invariant (LSI) filter B̃ij(z) = ∑p τ=1Bij(τ)z −τ whose coefficients are arranged into a column vector B̃ij = (Bij(1), . . . , Bij(p)). In...to the adjacency matrix of the underlying graph, so that looking “depth-wise” at location ij gives the coefficients B̃ij ∈ IRp of the LSI filter from

Incorporation of UK Met Office's radiation scheme into CPTEC's global model

NASA Astrophysics Data System (ADS)

Chagas, Júlio C. S.; Barbosa, Henrique M. J.

2009-03-01

Current parameterization of radiation in the CPTEC's (Center for Weather Forecast and Climate Studies, Cachoeira Paulista, SP, Brazil) operational AGCM has its origins in the work of Harshvardhan et al. (1987) and uses the formulation of Ramaswamy and Freidenreich (1992) for the short-wave absorption by water vapor. The UK Met Office's radiation code (Edwards and Slingo, 1996) was incorporated into CPTEC's global model, initially for short-wave only, and some impacts of that were shown by Chagas and Barbosa (2006). Current paper presents some impacts of the complete incorporation (both short-wave and long-wave) of UK Met Office's scheme. Selected results from off-line comparisons with line-by-line benchmark calculations are shown. Impacts on the AGCM's climate are assessed by comparing output of climate runs of current and modified AGCM with products from GEWEX/SRB (Surface Radiation Budget) project.

The Leu72Met polymorphism of the GHRL gene prevents the development of diabetic nephropathy in Chinese patients with type 2 diabetes mellitus.

PubMed

Zhuang, Langen; Li, Ming; Yu, Changhua; Li, Can; Zhao, Mingming; Lu, Ming; Zheng, Taishan; Zhang, Rong; Zhao, Weijing; Bao, Yuqian; Xiang, Kunsan; Jia, Weiping; Wang, Niansong; Liu, Limei

2014-02-01

The preproghrelin (GHRL) Leu72Met polymorphism (rs 696217) is associated with obesity, reduced glucose-induced insulin secretion in healthy or diabetic subjects, and reduced serum creatinine (Scr) levels in type 2 diabetes. We evaluated the association of the Leu72Met polymorphism with measures of insulin sensitivity in non-diabetic control individuals and type 2 diabetics, and whether this variation contributes to the development of diabetic nephropathy (DN) in type 2 diabetes. A case-control study was performed of 291 non-diabetic control subjects and 466 patients with type 2 diabetes, of whom 238 had DN with overt albuminuria (DN group; albuminuric excretion rate [AER] ≥ 300 mg/24 h) and 228 did not have DN, but had diabetes for more than 10 years (non-DN group). Genotyping was performed using a TaqMan PCR assay. The Leu/Leu, Leu/Met, and Met/Met genotype frequencies were significantly different between the non-DN and DN groups (p = 0.011). The frequency of the variant genotypes (Leu/Met, Met/Met) was significantly lower in the DN group than the non-DN group (23.5 vs. 36.0 %, p = 0.003). Met/Met non-diabetic control subjects had lower BMI and Scr levels and higher eGFR level than Leu/Leu or Leu/Met individuals (p < 0.05). Leu/Met and Met/Met type 2 diabetics had significantly lower AER and Scr levels and higher eGFR level than Leu/Leu type 2 diabetics (all p < 0.001). The GHRL Leu72Met polymorphism may help to maintain normal renal function and may protect against the development of DN by reducing albuminuria and improving renal function in Chinese patients with type 2 diabetes.

Genetic Correlates of Maladaptive Beliefs: COMT VAL(158)MET and Irrational Cognitions Linked Depending on Distress.

PubMed

Podina, Ioana; Popp, Radu; Pop, Ioan; David, Daniel

2015-11-01

Maladaptive/irrational beliefs are significant cognitive vulnerability mechanisms in psychopathology. They are more likely to be associated with a genetic vulnerability marker under conditions of emotional distress when irrational beliefs are more salient. Therefore, in the current study we investigated the COMT Val(158)Met gene variation in relation to irrational beliefs, assuming this relationship depended on the level of emotional distress. Two hundred and sixty-seven genotyped volunteers were assessed for core/general maladaptive beliefs, as well as trait emotional distress. We focused on context-independent measures of irrational beliefs and emotional distress in the absence of a stressor. As expected, the relationship between COMT Val(158)Met and irrational beliefs depended on the level of emotional distress (f(2)=.314). The COMT Val(158)Met-irrationality association was significant only when individuals fell in the average to above average range of emotional distress. Furthermore, within this range the Met allele seemed to relate to higher irrational beliefs. These results were significant for overall irrational beliefs and its subtypes, but not for rational beliefs, the functional counterpart of irrationality. In light of the study's limitations, the results should be considered as preliminary. If replicable, these findings have potential implications for therapygenetics, changing the view that COMT Val(158)Met might be of greater relevance when treatment modality does not rely on cognitive variables. Copyright © 2015. Published by Elsevier Ltd.

Studies of the metastable decay of met-cars. The vanadium and niobium systems

NASA Astrophysics Data System (ADS)

Purnell, J.; Wei, S.; Castleman, A. W., Jr.

1994-10-01

The decay fractions and metastable decomposition channels were measured for V(m)C(n)(+) and Nb(m)C(n)(+) clusters using a reflectron time-of-flight mass spectrometer. These measurements for the V(m)C(n)(+) clusters reveal stable (8, 12) and (8, 13) met-car species. However, under the present experimental conditions, the Nb(m)C(n)(+) clusters display dominantly cubic structures, but the decay fraction and metastable decomposition measurements also show the presence of a stable (8, 12) species in the parent cluster spectrum. This evidence indicates that cubic structures and met-cars are being formed simultaneously for the niobium system.

Activated MET acts as a salvage signal after treatment with alectinib, a selective ALK inhibitor, in ALK-positive non-small cell lung cancer.

PubMed

Kogita, Akihiro; Togashi, Yosuke; Hayashi, Hidetoshi; Banno, Eri; Terashima, Masato; De Velasco, Marco A; Sakai, Kazuko; Fujita, Yoshihiko; Tomida, Shuta; Takeyama, Yoshifumi; Okuno, Kiyotaka; Nakagawa, Kazuhiko; Nishio, Kazuto

2015-03-01

Non-small cell lung cancer (NSCLC) carrying echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements is hypersensitive to ALK inhibitors, including crizotinib and alectinib. Crizotinib was initially designed as a MET inhibitor, whereas alectinib is a selective ALK inhibitor. The MET signal, which is inhibited by crizotinib but not by alectinib, is dysregulated in many human cancers. However, the role of the MET signal in ALK-positive NSCLC remains unclear. In this study, we found that hepatocyte growth factor (HGF), ligand of MET, mediated the resistance to alectinib, but not to crizotinib, via the MET signal in ALK-positive NSCLC cell lines (H3122 and H2228 cell lines). In addition, alectinib activated the MET signal even in the absence of HGF and the inhibition of the MET signal enhanced the efficacy of alectinib. These findings suggest that activated MET acts as a salvage signal in ALK-positive NSCLC. This novel role of the MET signal in ALK-positive NSCLC may pave the way for further clinical trials examining MET inhibitors.

MAPK pathway inhibition induces MET and GAB1 levels, priming BRAF mutant melanoma for rescue by hepatocyte growth factor

PubMed Central

Caenepeel, Sean; Cooke, Keegan; Wadsworth, Sarah; Huang, Guo; Robert, Lidia; Moreno, Blanca Homet; Parisi, Giulia; Cajulis, Elaina; Kendall, Richard; Beltran, Pedro; Ribas, Antoni; Coxon, Angela; Hughes, Paul E.

2017-01-01

Therapeutic resistance is a major obstacle to achieving durable clinical responses with targeted therapies, highlighting a need to elucidate the underlying mechanisms responsible for resistance and identify strategies to overcome this challenge. An emerging body of data implicates the tyrosine kinase MET in mediating resistance to BRAF inhibitors in BRAFV600E mutant melanoma. In this study we observed a dominant role for the HGF/MET axis in mediating resistance to BRAF and MEK inhibitors in models of BRAFV600E and NRAS mutant melanoma. In addition, we showed that MAPK pathway inhibition induced rapid increases in MET and GAB1 levels, providing novel mechanistic insight into how BRAFV600E mutant melanoma is primed for HGF-mediated rescue. We also determined that tumor-derived HGF, not systemic HGF, may be required to convey resistance to BRAF inhibition in vivo and that resistance could be reversed following treatment with AMG 337, a selective MET inhibitor. In summary, these findings support the clinical evaluation of MET-directed targeted therapy to circumvent resistance to BRAF and MEK inhibitors in BRAFV600E mutant melanoma. In addition, the induction of MET following treatment with BRAF and MEK inhibitors has the potential to serve as a predictive biomarker for identifying patients best suited for MET inhibitor combination therapy. PMID:28147313

Effect of met-enkephalin on chromosomal aberrations in the lymphocytes of the peripheral blood of patients with multiple sclerosis.

PubMed

Rakanović-Todić, Maida; Burnazović-Ristić, Lejla; Ibrulj, Slavka; Mulbegović, Nedžad

2014-05-01

Endogenious opiod met-enkephalin throughout previous research manifested cytoprotective and anti-inflammatory effects. Previous research suggests that met-enkephalin has cytogenetic effects. Reducement in the frequency of structural chromosome aberrations as well as a suppressive effect on lymphocyte cell cycle is found. It also reduces apoptosis in the blood samples of the patients with immune-mediated diseases. Met-enkephalin exerts immunomodulatory properties and induces stabilization of the clinical condition in patients with multiple Sclerosis (MS). The goal of the present research was to evaluate met-enkephalin in vitro effects on the number and type of chromosome aberrations in the peripheral blood lymphocytes of patients with MS. Our research detected disappearance of ring chromosomes and chromosome fragmentations in the cultures of the peripheral blood lymphocytes treated with met-enkephalin (1.2 μg/mL). However, this research did not detect any significant effects of met-enkephalin on the reduction of structural chromosome aberrations and disappearance of dicentric chromosomes. Chromosomes with the greatest percent of inclusion in chromosome aberrations were noted as: chromosome 1, chromosome 2 and chromosome 9. Additionally, we confirmed chromosome 14 as the most frequently included in translocations. Furthermore, met-enkephalin effects on the increase of the numerical aberrations in both concentrations applied were detected. Those findings should be interpreted cautiously and more research in this field should be conducted.

The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism

PubMed Central

Klebe, Stephan; Golmard, Jean-Louis; Nalls, Michael A; Saad, Mohamad; Singleton, Andrew B; Bras, Jose M; Hardy, John; Simon-Sanchez, Javier; Heutink, Peter; Kuhlenbäumer, Gregor; Charfi, Rim; Klein, Christine; Hagenah, Johann; Gasser, Thomas; Wurster, Isabel; Lesage, Suzanne; Lorenz, Delia; Deuschl, Günther; Durif, Franck; Pollak, Pierre; Damier, Philippe; Tison, François; Durr, Alexandra; Amouyel, Philippe; Lambert, Jean-Charles; Tzourio, Christophe; Maubaret, Cécilia; Charbonnier-Beaupel, Fanny; Tahiri, Khadija; Vidailhet, Marie; Martinez, Maria; Brice, Alexis; Corvol, Jean-Christophe

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 polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD. PMID:23408064

ATM and MET kinases are synthetic lethal with non-genotoxic activation of p53

PubMed Central

Sullivan, Kelly D.; Padilla-Just, Nuria; Henry, Ryan E.; Porter, Christopher C.; Kim, Jihye; Tentler, John J.; Eckhardt, S. Gail; Tan, Aik Choon; DeGregori, James; Espinosa, Joaquín M.

2012-01-01

The p53 tumor suppressor orchestrates alternative stress responses including cell cycle arrest and apoptosis, but the mechanisms defining cell fate upon p53 activation are poorly understood. Several small molecule activators of p53 have been developed, including Nutlin-3, but their therapeutic potential is limited by the fact that they induce reversible cell cycle arrest in most cancer cell types. We report here the results of a ‘Synthetic Lethal with Nutlin-3’ genome-wide shRNA screen, which revealed that the ATM and MET kinases govern cell fate choice upon p53 activation. Genetic or pharmacological interference with ATM or MET activity converts the cellular response from cell cycle arrest into apoptosis in diverse cancer cell types without affecting expression of key p53 target genes. ATM and MET inhibitors enable Nutlin-3 to kill tumor spheroids. These results identify novel pathways controlling the cellular response to p53 activation and aid in the design of p53-based therapies. PMID:22660439

COMT Val158Met Polymorphism, Executive Dysfunction, and Sexual Risk Behavior in the Context of HIV Infection and Methamphetamine Dependence

PubMed Central

Bousman, C. A.; Cherner, M.; Atkinson, J. H.; Heaton, R. K.; Grant, I.; Everall, I. P.; HNRC Group, The

2010-01-01

Catechol-O-methyltransferease (COMT) metabolizes prefrontal cortex dopamine (DA), a neurotransmitter involved in executive behavior; the Val158Met genotype has been linked to executive dysfunction, which might increase sexual risk behaviors favoring HIV transmission. Main and interaction effects of COMT genotype and executive functioning on sexual risk behavior were examined. 192 sexually active nonmonogamous men completed a sexual behavior questionnaire, executive functioning tests, and were genotyped using blood-derived DNA. Main effects for executive dysfunction but not COMT on number of sexual partners were observed. A COMT x executive dysfunction interaction was found for number of sexual partners and insertive anal sex, significant for carriers of the Met/Met and to a lesser extent Val/Met genotypes but not Val/Val carriers. In the context of HIV and methamphetamine dependence, dopaminergic overactivity in prefrontal cortex conferred by the Met/Met genotype appears to result in a liability for executive dysfunction and potentially associated risky sexual behavior. PMID:20069120

Shp2 deletion in hepatocytes suppresses hepatocarcinogenesis driven by oncogenic β-Catenin, PIK3CA and MET.

PubMed

Liu, Jacey J; Li, Yanjie; Chen, Wendy S; Liang, Yan; Wang, Gaowei; Zong, Min; Kaneko, Kota; Xu, Ruiyun; Karin, Michael; Feng, Gen-Sheng

2018-07-01

Shp2 is an SH2-tyrosine phosphatase acting downstream of receptor tyrosine kinases (RTKs). Most recent data demonstrated a liver tumor-suppressing role for Shp2, as ablating Shp2 in hepatocytes aggravated hepatocellular carcinoma (HCC) induced by chemical carcinogens or Pten loss. We further investigated the effect of Shp2 deficiency on liver tumorigenesis driven by classical oncoproteins c-Met (receptor for HGF), β-catenin and PIK3CA. We performed hydrodynamic tail vein injection of two pairs of plasmids expressing c-Met and ΔN90-β-catenin (MET/CAT), or c-Met and PIK3CA H1047R (MET/PIK), into WT and Shp2 hep-/- mice. We compared liver tumor loads and investigated the pathogenesis and molecular mechanisms involved using multidisciplinary approaches. Despite the induction of oxidative and metabolic stresses, Shp2 deletion in hepatocytes suppressed hepatocarcinogenesis driven by overexpression of oncoproteins MET/CAT or MET/PIK. Shp2 loss inhibited proliferative signaling from c-Met, Wnt/β-catenin, Ras/Erk and PI3K/Akt pathways, but triggered cell senescence following exogenous expression of the oncogenes. Shp2, acting downstream of RTKs, is positively required for hepatocyte-intrinsic tumorigenic signaling from these oncoproteins, even if Shp2 deficiency induces a tumor-promoting hepatic microenvironment. These data suggest a new and more effective therapeutic strategy for HCCs driven by oncogenic RTKs and other upstream molecules, by inhibiting Shp2 and also suppressing any tumor-enhancing stromal factors produced because of Shp2 inhibition. Primary liver cancer is a malignant disease with poor prognosis, largely because there are limited systemic therapies available. We show here that a cytoplasmic tyrosine phosphatase Shp2 is required for liver tumorigenesis. This tumorigenesis is driven by two oncoproteins that are implicated in human liver cancer. This, together with our previous studies, uncovers the complexity of liver tumorigenesis, by elucidating the

Modulating effect of COMT Val(158)Met polymorphism on interference resolution during a working memory task.

PubMed

Jaspar, Mathieu; Dideberg, Vinciane; Bours, Vincent; Maquet, Pierre; Collette, Fabienne

2015-04-01

Genetic variability related to the catechol-O-methyltransferase (COMT) gene has received increasing attention in the last 15years, in particular as a potential modulator of the neural substrates underlying inhibitory processes and updating in working memory (WM). In an event-related functional magnetic resonance imaging (fMRI) study, we administered a modified version of the Sternberg probe recency task (Sternberg, 1966) to 43 young healthy volunteers, varying the level of interference across successive items. The task was divided into two parts (high vs. low interference) to induce either proactive or reactive control processes. The participants were separated into three groups according to their COMT Val(158)Met genotype [Val/Val (VV); Val/Met (VM); Met/Met (MM)]. The general aim of the study was to determine whether COMT polymorphism has a modulating effect on the neural substrates of interference resolution during WM processing. Results indicate that interfering trials were associated with greater involvement of frontal cortices (bilateral medial frontal gyrus, left precentral and superior frontal gyri, right inferior frontal gyrus) in VV homozygous subjects (by comparison to Met allele carriers) only in the proactive condition of the task. In addition, analysis of peristimulus haemodynamic responses (PSTH) revealed that the genotype-related difference observed in the left SFG was specifically driven by a larger increase in activity from the storage to the recognition phase of the interfering trials in VV homozygous subjects. These results confirm the impact of COMT genotype on inhibitory processes during a WM task, with an advantage for Met allele carriers. Interestingly, this impact on frontal areas is present only when the level of interference is high, and especially during the transition from storage to recognition in the left superior frontal gyrus. Copyright © 2015 Elsevier Inc. All rights reserved.

Synergistic role of Sprouty2 inactivation and c-Met up-regulation in mouse and human hepatocarcinogenesis.

PubMed

Lee, Susie A; Ladu, Sara; Evert, Matthias; Dombrowski, Frank; De Murtas, Valentina; Chen, Xin; Calvisi, Diego F

2010-08-01

Sprouty2 (Spry2), a negative feedback regulator of the Ras/mitogen-activated protein kinase (MAPK) pathway, is frequently down-regulated in human hepatocellular carcinoma (HCC). We tested the hypothesis that loss of Spry2 cooperates with unconstrained activation of the c-Met protooncogene to induce hepatocarcinogenesis via in vitro and in vivo approaches. We found coordinated down-regulation of Spry2 protein expression and activation of c-Met as well as its downstream effectors extracellular signal-regulated kinase (ERK) and v-akt murine thymoma viral oncogene homolog (AKT) in a subset of human HCC samples with poor outcome. Mechanistic studies revealed that Spry2 function is disrupted in human HCC via multiple mechanisms at both transcriptional and post-transcriptional level, including promoter hypermethylation, loss of heterozygosity, and proteosomal degradation by neural precursor cell expressed, developmentally down-regulated 4 (NEDD4). In HCC cell lines, Spry2 overexpression inhibits c-Met-induced cell proliferation as well as ERK and AKT activation, whereas loss of Spry2 potentiates c-Met signaling. Most importantly, we show that blocking Spry2 activity via a dominant negative form of Spry2 cooperates with c-Met to promote hepatocarcinogenesis in the mouse liver by sustaining proliferation and angiogenesis. The tumors exhibited high levels of activated ERK and AKT, recapitulating the subgroup of human HCC with a clinically aggressive phenotype. The occurrence of frequent genetic, epigenetic, and biochemical events leading to Spry2 inactivation provides solid evidence that Spry2 functions as a tumor suppressor gene in liver cancer. Coordinated deregulation of Spry2 and c-Met signaling may be a pivotal oncogenic mechanism responsible for unrestrained activation of ERK and AKT pathways in human hepatocarcinogenesis.

BDNF val66met modulates the association between childhood trauma, cognitive and brain abnormalities in psychoses.

PubMed

Aas, Monica; Haukvik, Unn K; Djurovic, Srdjan; Bergmann, Ørjan; Athanasiu, Lavinia; Tesli, Martin S; Hellvin, Tone; Steen, Nils Eiel; Agartz, Ingrid; Lorentzen, Steinar; Sundet, Kjetil; Andreassen, Ole A; Melle, Ingrid

2013-10-01

Brain derived neurotrophic factor (BDNF) is important for brain development and plasticity, and here we tested if the functional BDNF val66met variant modulates the association between high levels of childhood abuse, cognitive function, and brain abnormalities in psychoses. 249 patients with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder were consecutively recruited to the TOP research study (mean±age: 30.7±10.9; gender: 49% males). History of childhood trauma was obtained using the Childhood Trauma Questionnaire. Cognitive function was assessed through a standardized neuropsychological test battery. BDNF val66met was genotyped using standardized procedures. A sub-sample of n=106 Caucasians with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder (mean±age: 32.67±10.85; 49% males) had data on sMRI. Carriers of the Methionine (met) allele exposed to high level of childhood abuse demonstrated significantly poorer cognitive functioning compared to homozygotic Valine (val/val) carriers. Taking in consideration multiple testing, using a more conservative p value, this was still shown for physical abuse and emotional abuse, as well as a trend level for sexual abuse. Further, met carriers exposed to high level of childhood sexual abuse showed reduced right hippocampal volume (r(2)=0.43; p=0.008), and larger right and left lateral ventricles (r(2)=0.37; p=0.002, and r(2)=0.27; p=0.009, respectively). Our findings were independent of age, gender, diagnosis and intracranial volume. Our data demonstrate that in patients with psychoses, met carriers of the BDNF val66met with high level of childhood abuse have more cognitive and brain abnormalities than all other groups. © 2013.

MET receptor tyrosine kinase controls dendritic complexity, spine morphogenesis, and glutamatergic synapse maturation in the hippocampus.

PubMed

Qiu, Shenfeng; Lu, Zhongming; Levitt, Pat

2014-12-03

The MET receptor tyrosine kinase (RTK), implicated in risk for autism spectrum disorder (ASD) and in functional and structural circuit integrity in humans, is a temporally and spatially regulated receptor enriched in dorsal pallial-derived structures during mouse forebrain development. Here we report that loss or gain of function of MET in vitro or in vivo leads to changes, opposite in nature, in dendritic complexity, spine morphogenesis, and the timing of glutamatergic synapse maturation onto hippocampus CA1 neurons. Consistent with the morphological and biochemical changes, deletion of Met in mutant mice results in precocious maturation of excitatory synapse, as indicated by a reduction of the proportion of silent synapses, a faster GluN2A subunit switch, and an enhanced acquisition of AMPA receptors at synaptic sites. Thus, MET-mediated signaling appears to serve as a mechanism for controlling the timing of neuronal growth and functional maturation. These studies suggest that mistimed maturation of glutamatergic synapses leads to the aberrant neural circuits that may be associated with ASD risk. Copyright © 2014 the authors 0270-6474/14/3416166-14$15.00/0.

MET Receptor Tyrosine Kinase Controls Dendritic Complexity, Spine Morphogenesis, and Glutamatergic Synapse Maturation in the Hippocampus

PubMed Central

Lu, Zhongming; Levitt, Pat

2014-01-01

The MET receptor tyrosine kinase (RTK), implicated in risk for autism spectrum disorder (ASD) and in functional and structural circuit integrity in humans, is a temporally and spatially regulated receptor enriched in dorsal pallial-derived structures during mouse forebrain development. Here we report that loss or gain of function of MET in vitro or in vivo leads to changes, opposite in nature, in dendritic complexity, spine morphogenesis, and the timing of glutamatergic synapse maturation onto hippocampus CA1 neurons. Consistent with the morphological and biochemical changes, deletion of Met in mutant mice results in precocious maturation of excitatory synapse, as indicated by a reduction of the proportion of silent synapses, a faster GluN2A subunit switch, and an enhanced acquisition of AMPA receptors at synaptic sites. Thus, MET-mediated signaling appears to serve as a mechanism for controlling the timing of neuronal growth and functional maturation. These studies suggest that mistimed maturation of glutamatergic synapses leads to the aberrant neural circuits that may be associated with ASD risk. PMID:25471559

Pulmonary actions of the neurokinin1-specific agonist [Sar9,Met(O2)11]-substance P.

PubMed

Yiamouyiannis, C A; Stengel, P W; Cockerham, S L; Silbaugh, S A

1995-01-01

We examined the relationship between airway obstruction and plasma extravasation produced by the intravenous administration of the selective NK1 receptor agonist [Sar9, Met(O2)11]-substance P(SP). Conscious guinea-pigs were injected with Evans' blue dye followed by intravenous [Sar9,Met(O2)11]-SP. Animals were killed 3 min later and airway obstruction, determined via excised lung gas volumes, and plasma extravasation in the trachea, mainstem bronchi and intrapulmonary airways quantitated. Maximal plasma protein extravasation occurred at a dose about 30 times less than that required to elicit airway obstruction. Neither the neutral endopeptidase (NEP) inhibitor, thiorphan, or the angiotensin-converting enzyme (ACE) inhibitor, captopril, altered the extravasation response to [Sar9,Met(O2)11]-SP. However, thiorphan alone or combined with captopril produced a small but significant potentiation of the airway obstructive response. The marked difference between pulmonary gas trapping and Evans' blue extravasation responses suggest that [Sar9,Met(O2)11]-SP-induced airway obstruction is not secondary to increased pulmonary edema.

Sandscape - engaging people in Met Office science through sand sculpture

NASA Astrophysics Data System (ADS)

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.

Low-grade and high-grade mammary carcinomas in WAP-T transgenic mice are independent entities distinguished by Met expression.

PubMed

Otto, Benjamin; Gruner, Katharina; Heinlein, Christina; Wegwitz, Florian; Nollau, Peter; Ylstra, Bauke; Pantel, Klaus; Schumacher, Udo; Baumbusch, Lars O; Martin-Subero, José Ignacio; Siebert, Reiner; Wagener, Christoph; Streichert, Thomas; Deppert, Wolfgang; Tolstonog, Genrich V

2013-03-15

Mammary carcinomas developing in SV40 transgenic WAP-T mice arise in two distinct histological phenotypes: as differentiated low-grade and undifferentiated high-grade tumors. We integrated different types of information such as histological grading, analysis of aCGH-based gene copy number and gene expression profiling to provide a comprehensive molecular description of mammary tumors in WAP-T mice. Applying a novel procedure for the correlation of gene copy number with gene expression on a global scale, we observed in tumor samples a global coherence between genotype and transcription. This coherence can be interpreted as a matched transcriptional regulation inherited from the cells of tumor origin and determined by the activity of cancer driver genes. Despite common recurrent genomic aberrations, e.g. gain of chr. 15 in most WAP-T tumors, loss of chr. 19 frequently occurs only in low-grade tumors. These tumors show features of "basal-like" epithelial differentiation, particularly expression of keratin 14. The high-grade tumors are clearly separated from the low-grade tumors by strong expression of the Met gene and by coexpression of epithelial (e.g. keratin 18) and mesenchymal (e.g. vimentin) markers. In high-grade tumors, the expression of the nonmutated Met protein is associated with Met-locus amplification and Met activity. The role of Met as a cancer driver gene is supported by the contribution of active Met signaling to motility and growth of mammary tumor-derived cells. Finally, we discuss the independent origin of low- and high-grade tumors from distinct cells of tumor origin, possibly luminal progenitors, distinguished by Met gene expression and Met signaling. Copyright © 2012 UICC.

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

PubMed

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.

Verification of space weather forecasts at the UK Met Office

NASA Astrophysics Data System (ADS)

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.

Genetic Evidence for Function of the bHLH-PAS Protein Gce/Met As a Juvenile Hormone Receptor

PubMed Central

Jindra, Marek; Uhlirova, Mirka; Charles, Jean-Philippe; Smykal, Vlastimil; Hill, Ronald J.

2015-01-01

Juvenile hormones (JHs) play a major role in controlling development and reproduction in insects and other arthropods. Synthetic JH-mimicking compounds such as methoprene are employed as potent insecticides against significant agricultural, household and disease vector pests. However, a receptor mediating effects of JH and its insecticidal mimics has long been the subject of controversy. The bHLH-PAS protein Methoprene-tolerant (Met), along with its Drosophila melanogaster paralog germ cell-expressed (Gce), has emerged as a prime JH receptor candidate, but critical evidence that this protein must bind JH to fulfill its role in normal insect development has been missing. Here, we show that Gce binds a native D. melanogaster JH, its precursor methyl farnesoate, and some synthetic JH mimics. Conditional on this ligand binding, Gce mediates JH-dependent gene expression and the hormone's vital role during development of the fly. Any one of three different single amino acid mutations in the ligand-binding pocket that prevent binding of JH to the protein block these functions. Only transgenic Gce capable of binding JH can restore sensitivity to JH mimics in D. melanogaster Met-null mutants and rescue viability in flies lacking both Gce and Met that would otherwise die at pupation. Similarly, the absence of Gce and Met can be compensated by expression of wild-type but not mutated transgenic D. melanogaster Met protein. This genetic evidence definitively establishes Gce/Met in a JH receptor role, thus resolving a long-standing question in arthropod biology. PMID:26161662

Dual Constant Domain-Fab: A novel strategy to improve half-life and potency of a Met therapeutic antibody.

PubMed

Cignetto, Simona; Modica, Chiara; Chiriaco, Cristina; Fontani, Lara; Milla, Paola; Michieli, Paolo; Comoglio, Paolo M; Vigna, Elisa

2016-06-01

The kinase receptor encoded by the Met oncogene is a sensible target for cancer therapy. The chimeric monovalent Fab fragment of the DN30 monoclonal antibody (MvDN30) has an odd mechanism of action, based on cell surface removal of Met via activation of specific plasma membrane proteases. However, the short half-life of the Fab, due to its low molecular weight, is a severe limitation for the deployment in therapy. This issue was addressed by increasing the Fab molecular weight above the glomerular filtration threshold through the duplication of the constant domains, in tandem (DCD-1) or reciprocally swapped (DCD-2). The two newly engineered molecules showed biochemical properties comparable to the original MvDN30 in vitro, acting as full Met antagonists, impairing Met phosphorylation and activation of downstream signaling pathways. As a consequence, Met-mediated biological responses were inhibited, including anchorage-dependent and -independent cell growth. In vivo DCD-1 and DCD-2 showed a pharmacokinetic profile significantly improved over the original MvDN30, doubling the circulating half-life and reducing the clearance. In pre-clinical models of cancer, generated by injection of tumor cells or implant of patient-derived samples, systemic administration of the engineered molecules inhibited the growth of Met-addicted tumors. Copyright © 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Phase II and Biomarker Study of the Dual MET/VEGFR2 Inhibitor Foretinib in Patients With Papillary Renal Cell Carcinoma

PubMed Central

Choueiri, Toni K.; Vaishampayan, Ulka; Rosenberg, Jonathan E.; Logan, Theodore F.; Harzstark, Andrea L.; Bukowski, Ronald M.; Rini, Brian I.; Srinivas, Sandy; Stein, Mark N.; Adams, Laurel M.; Ottesen, Lone H.; Laubscher, Kevin H.; Sherman, Laurie; McDermott, David F.; Haas, Naomi B.; Flaherty, Keith T.; Ross, Robert; Eisenberg, Peter; Meltzer, Paul S.; Merino, Maria J.; Bottaro, Donald P.; Linehan, W. Marston; Srinivasan, Ramaprasad

2013-01-01

Purpose Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of foretinib in patients with PRCC. Patients and Methods Patients were enrolled onto the study in two cohorts with different dosing schedules of foretinib: cohort A, 240 mg once per day on days 1 through 5 every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR). Results Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached. The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli. Conclusion Foretinib demonstrated activity in patients with advanced PRCC with a manageable toxicity profile and a high response rate in patients with germline MET mutations. PMID:23213094

MET-activating Residues in the B-repeat of the Listeria monocytogenes Invasion Protein InlB*

PubMed Central

Bleymüller, Willem M.; Lämmermann, Nina; Ebbes, Maria; Maynard, Daniel; Geerds, Christina; Niemann, Hartmut H.

2016-01-01

The facultative intracellular pathogen Listeria monocytogenes causes listeriosis, a rare but life-threatening disease. Host cell entry begins with activation of the human receptor tyrosine kinase MET through the bacterial invasion protein InlB, which contains an internalin domain, a B-repeat, and three GW domains. The internalin domain is known to bind MET, but no interaction partner is known for the B-repeat. Adding the B-repeat to the internalin domain potentiates MET activation and is required to stimulate Madin-Darby canine kidney (MDCK) cell scatter. Therefore, it has been hypothesized that the B-repeat may bind a co-receptor on host cells. To test this hypothesis, we mutated residues that might be important for binding an interaction partner. We identified two adjacent residues in strand β2 of the β-grasp fold whose mutation abrogated induction of MDCK cell scatter. Biophysical analysis indicated that these mutations do not alter protein structure. We then tested these mutants in human HT-29 cells that, in contrast to the MDCK cells, were responsive to the internalin domain alone. These assays revealed a dominant negative effect, reducing the activity of a construct of the internalin domain and mutated B-repeat below that of the individual internalin domain. Phosphorylation assays of MET and its downstream targets AKT and ERK confirmed the dominant negative effect. Attempts to identify a host cell receptor for the B-repeat were not successful. We conclude that there is limited support for a co-receptor hypothesis and instead suggest that the B-repeat contributes to MET activation through low affinity homodimerization. PMID:27789707

COMT val108/158 met genotype affects neural but not cognitive processing in healthy individuals.

PubMed

Dennis, Nancy A; Need, Anna C; LaBar, Kevin S; Waters-Metenier, Sheena; Cirulli, Elizabeth T; Kragel, James; Goldstein, David B; Cabeza, Roberto

2010-03-01

The relationship between cognition and a functional polymorphism in the catechol-O-methlytransferase (COMT) gene, val108/158met, is one of debate in the literature. Furthermore, based on the dopaminergic differences associated with the COMT val108/158met genotype, neural differences during cognition may be present, regardless of genotypic differences in cognitive performance. To investigate these issues the current study aimed to 1) examine the effects of COMT genotype using a large sample of healthy individuals (n = 496-1218) and multiple cognitive measures, and using a subset of the sample (n = 22), 2) examine whether COMT genotype effects medial temporal lobe (MTL) and frontal activity during successful relational memory processing, and 3) investigate group differences in functional connectivity associated with successful relational memory processing. Results revealed no significant group difference in cognitive performance between COMT genotypes in any of the 19 cognitive measures. However, in the subset sample, COMT val homozygotes exhibited significantly decreased MTL and increased prefrontal activity during both successful relational encoding and retrieval, and reduced connectivity between these regions compared with met homozygotes. Taken together, the results suggest that although the COMT val108/158met genotype has no effect on cognitive behavioral measures in healthy individuals, it is associated with differences in neural process underlying cognitive output.

Variant Brain-Derived Neurotrophic Factor Val66Met Polymorphism Alters Vulnerability to Stress and Response to Antidepressants

PubMed Central

Yu, Hui; Wang, Dong-Dong; Wang, Yue; Liu, Ting; Lee, Francis S.; Chen, Zhe-Yu

2012-01-01

Brain-derived neurotrophic factor (BDNF) plays important roles in cell survival, neural plasticity, learning, and stress regulation. However, whether the recently found human BDNF Val66Met (BDNFMet) polymorphism could alter stress vulnerability remains controversial. More importantly, the molecular and structural mechanisms underlying the interaction between the BDNFMet polymorphism and stress are unclear. We found that heterozygous BDNF+/Met mice displayed hypothalamic-pituitary-adrenal axis hyperreactivity, increased depressive-like and anxiety-like behaviors, and impaired working memory compared with WT mice after 7 d restraint stress. Moreover, BDNF+/Met miceexhibited more prominent changes in BDNF levels and apical dendritic spine density in the prefrontal cortex and amygdala after stress, which correlated with the impaired working memory and elevated anxiety-like behaviors. Finally, the depressive-like behaviors in BDNF+/Met mice could be selectively rescued by acute administration of desipramine but not fluoxetine. These data indicate selective behavioral, molecular, and structural deficits resulting from the interaction between stress and the human genetic BDNFMet polymorphism. Importantly, desipramine but not fluoxetine has antidepressant effects on BDNF+/Met mice, suggesting that specific classes of antidepressant may be a more effective treatment option for depressive symptoms in humans with this genetic variant BDNF. PMID:22442074