Science.gov

Sample records for bij patienten met

  1. 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...

  2. ASI/MET

    NASA Technical Reports Server (NTRS)

    1997-01-01

    The Atmospheric Structure Instrument/Meteorology Package (ASI/MET) is the mast and windsocks at the center of this color image, taken by the Imager for Mars Pathfinder (IMP) on Sol 4. The instrument appears in two different sections due to image parallax. The ASI/MET is an engineering subsytem that acquired atmospheric data during Pathfinder's descent, and will continue to get more data through the entire landed mission. The windsocks are seen pointing almost completely up, representing little wind movement at the three locations of the windsocks. A rock at left holds a shadow of the ASI/MET, indicating the sun's position is at the rear right. Portions of a lander petal and deflated airbag are visible, in addition to several rocks of varying sizes in the distance.

    Mars Pathfinder was developed and managed by the Jet Propulsion Laboratory (JPL) for the National Aeronautics and Space Administration. JPL is an operating division of the California Institute of Technology (Caltech). The IMP was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

  3. ASI/MET Mast

    NASA Technical Reports Server (NTRS)

    1997-01-01

    The Mars Pathfinder meteorology mast casts a shadow on the lander solar array, as seen in this superpan mosaic. Looking to the southeast during the morning, the windsocks are slightly tilted, indicating the presence of a light wind from the southwest. The MET mast measured the temperature, pressure, and wind speed at the Pathfinder landing site. During the mission, the instrument returned 8.5 million individual measurements from the surface of Mars.

    Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is a division of the California Institute of Technology (Caltech). The IMP was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

  4. ASI/MET mast

    NASA Technical Reports Server (NTRS)

    1997-01-01

    The Atmospheric Structure Instrument/Meteorology Package (ASI/MET) mast is visible against a backdrop of rocky Martian terrain in this image, taken by the Imager for Mars Pathfinder (IMP). The windsocks are slightly tilted, showing some wind activity. Distortions in the background are due to parallax.

    Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

  5. MET inhibition in lung cancer

    PubMed Central

    Giaj Levra, Matteo; Novello, Silvia

    2013-01-01

    Targeted agents have completely changed cancer treatment strategy, leading it from a “one size fits all” approach to a customized therapy. In this scenario Met, a heterodimere receptor tyrosine kinase deeply involved into embryogenesis and organogenesis, has been introduced many years ago as a potential target for biological agents, becoming “druggable” only in this last period of time. Met can be altered through receptor overexpression, genomic amplification, mutations or alternative splicing, autocrine or paracrine secretion of hepatic growth factor (HGF): these dysregulations stimulate tumorigenesis (in terms of cell-cell detachment, proliferation, invasion, angiogenesis and survival) and metastatization. Met is overexpressed in lung cancer and Met gene amplification can drive the dependency of cell survival and proliferation upon the Met signaling. Both Met overexpression and amplification seem to correlate with poor prognosis. Met amplification is also described to be linked to EGFR acquired resistance. Several Met inhibitors have been tested both in preclinical and human trials, demonstrating activity in lung cancer treatment. This paper aims to summarize data on Met biological function, on its interaction with cell signaling and other pathways and to present data on those Met inhibitors currently under evaluation. PMID:25806202

  6. MET deregulation in breast cancer

    PubMed Central

    Landi, Lorenza

    2015-01-01

    Background Mesenchymal-epithelial transition (MET) is an oncogene encoding for a trans-membrane tyrosine kinase receptor activated by the hepatocyte growth factor (HGF). MET has a normal function in organ development during embryogenesis and in tissue homeostasis during adult life. Deregulation of HGF/MET signaling pathway is frequently observed in many cancer types, conferring invasive growth and tendency to progression. MET deregulation is due to gene amplification or increased copy number, gene mutation, receptor over-expression or ligand autocrine loops activation. These events lead to migration, invasion, proliferation, metastatic spread and neo-angiogenesis of cancer cells, suggesting that anti-HGF/MET agents may represent a potential antitumor strategy. In breast cancer (BC), preclinical and clinical data demonstrated the role of HGF/MET signalling pathway in carcinogenesis, disease progression and resistance features. Methods For this review article, all published data on HGF/MET in BC were collected and analyzed. Results Several evidences underline that, in early BC, MET over-expression has an independent negative prognostic significance, regardless of method used for evaluation and BC subtypes. Available data suggest that MET is a relevant target particularly in basal-like (BL) and in triple negative BC. Moreover, preclinical and retrospective data support the critical role of MET deregulation in the development of resistance to target-agents, such as anti-HER2 strategies. Conclusions MET is a promising new target in BC. Several anti-MET agents are under investigation and ongoing clinical trials will clarify its relevance in BC treatment. PMID:26366398

  7. [COPD und Klangtherapie: Pilotstudie zur Wirksamkeit einer Behandlung mit Körpertambura bei COPD-Patienten].

    PubMed

    Hartwig, Bernhard; Schmidt, Stefan; Hartwig, Isabella

    2016-01-01

    Hintergrund: Erkrankungen der Atemorgane treten mit steigendem Alter öfter auf, nehmen weltweit zu und sind häufige Ursachen für Morbidität und Mortalität. In dieser Pilotstudie wurde der Frage nachgegangen, ob eine einmalige 10-minütige Behandlung mit einer Körpertambura eine signifikante und effektive Verbesserung der Lungenfunktion von Patienten mit chronisch-obstruktiver Lungenerkrankung (COPD; GOLD-Stadium A oder B) erbringen kann. Patienten und Methoden: 54 Probanden konnten je zur Hälfte in eine Behandlungsgruppe (Körpertambura) und eine aktive Kontrollgruppe (Atemtherapie) randomisiert werden. Eine Bestimmung der Lungenfunktionsmessparameter «Einsekundenkapazität» (FEV1) und «inspiratorische Vitalkapazität» (IVC) zu den Zeitpunkten T1 (Baseline), T2 (direkt nach Behandlung) und als Follow-up etwa 3 Wochen nach T1 (T3). Ergebnisse: Die Behandlungsgruppe zeigte sich der Kontrollgruppe in beiden Werten signifikant überlegen. Die Zeit-×-Gruppe-Interaktion (Varianzanalyse) ergab p = 0,001 (FEV1) bzw. p = 0,04 (IVC). Die Behandlungsgruppe zeigte bei beiden Werten eine Verbesserung von klinischer Relevanz. Schlussfolgerung: Diese Ergebnisse zeigen, dass die Klangbehandlung mittels einer Körpertambura - neben den schulmedizinischen, leitliniengerechten Therapien - eine zusätzliche, nebenwirkungsarme, aber durchaus klinisch wirksame Option für die Behandlung von COPD-Patienten darstellen kann, um deren Lebensqualität zu stabilisieren und zu verbessern. PMID:27606616

  8. Diagnose und Therapie einer Depression im höheren Lebensalter – Einflüsse von Patienten- und Arztmerkmalen

    PubMed Central

    von dem Knesebeck, Olaf; Bönte, Markus; Siegrist, Johannes; Marceau, Lisa; Link, Carol; McKinlay, John

    2013-01-01

    Zusammenfassung Studienergebnissee aus dem englischsprachigen Raum zeigen, dass diagnostische und therapeutische Entscheidungen von Hausärzten bei der Versorgung von depressiven Patienten systematischen Einflüssen unterliegen, und dass sowohl Merkmale des Arztes als auch des Patienten unabhängig vom Krankheitsbild Einfluss auf diese Entscheidungen haben. In der vorliegenden Arbeit werden Ergebnisse einer deutschen Studie präsentiert, in der die Einflüsse von Patienten- und Arztmerkmalen auf diagnostische und therapeutische ärztliche Entscheidungen bei einer Depression untersucht wurden. Unter Anwendung eines faktoriellen Experimentaldesigns spielten professionelle Schauspieler in Videofilmen die Rolle von Patienten, die Symptome für eine depressive Erkrankung äußern. In den Videofilmen, die alle auf einem identischen Skript basieren, wurden systematisch die Patientenmerkmale Alter (55 vs. 75 Jahre), Geschlecht und sozialer Status (Hausmeister vs. Lehrer) variiert. Die randomisierte Ärztestichprobe wurde nach dem Arztgeschlecht und professioneller Erfahrung (< 5 vs. > 15 Jahre) geschichtet. Der Videofilm wurde insgesamt 128 niedergelassenen Ärzten für Allgemeinmedizin und hausärztlich tätigen Internisten in ihrer Praxis vorgespielt. Danach wurden die Ärzte zu unterschiedlichen Aspekten von Diagnose und Therapie befragt. Es wurde erhoben, ob der Arzt dem Patienten über das gezeigte Gespräch hinausgehende Fragen stellen würde, welche Diagnosen er für wahrscheinlich hält, wie sicher er sich mit seiner Diagnose ist, welche diagnostischen Tests er anordnen würde, ob er den Patienten überweisen würde oder ob er Medikamente verordnen oder ihm Empfehlungen zur Änderung seines Lebensstils geben würde. Die Ergebnisse weisen darauf hin, dass sowohl die Diagnose als auch die Therapie einer Depression durch niedergelassene Hausärzte in Deutschland nur geringfügig durch die untersuchten Merkmale der Patienten und der behandelnden Ärzte beeinflusst wird

  9. MET — EDRN Public Portal

    Cancer.gov

    From NCBI Gene: The proto-oncogene MET product is the hepatocyte growth factor receptor and encodes tyrosine-kinase activity. The primary single chain precursor protein is post-translationally cleaved to produce the alpha and beta subunits, which are disulfide linked to form the mature receptor. Various mutations in the MET gene are associated with papillary renal carcinoma. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008

  10. LCLS Heavy Met Outgassing Tests

    SciTech Connect

    Kishiyama, K. I.

    2010-12-01

    A Heavy Met that is 95% tungsten, 3% nickel and 2% iron and sintered to 100% density and is Ultra High Vacuum (UHV) compatible is proposed for use as the X-ray slit in the Front End Enclosure and the Fixed Mask for the Linac Coherent Light Source (LCLS). The Heavy Met was tested in the LLNL Vacuum Sciences and Engineering Lab (VSEL) to determine its outgassing rate and its overall compatibility with the vacuum requirements for LCLS.

  11. ASI/MET shadow & airbags

    NASA Technical Reports Server (NTRS)

    1997-01-01

    A shadow of the Atmospheric Structure Instrument/Meteorology Package (ASI/MET) has been cast on a rock at right in this image, taken by the Imager for Mars Pathfinder (IMP) on Sol 4. The instrument appears in two different sections due to image parallax. The ASI/MET is an engineering subsytem that acquired atmospheric data during Pathfinder's descent, and will continue to get more data through the entire landed mission. Portions of a lander petal and deflated airbag are visible, in addition to several rocks of varying sizes in the distance.

    Mars Pathfinder was developed and managed by the Jet Propulsion Laboratory (JPL) for the National Aeronautics and Space Administration. JPL is an operating division of the California Institute of Technology (Caltech). The IMP was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

  12. ASI/MET - 3D

    NASA Technical Reports Server (NTRS)

    1997-01-01

    The Atmospheric Structure Instrument/Meteorology Package (ASI/MET) is the mast and windsocks at the center of this color image, taken in stereo by the Imager for Mars Pathfinder (IMP) on Sol 3. The instrument appears in two different sections due to image parallax. The ASI/MET is an engineering subsytem that acquired atmospheric data during Pathfinder's descent, and will continue to get more data through the entire landed mission. The windsocks are seen pointing almost completely up, representing little wind movement at the three locations of the windsocks. A rock at left holds a shadow of the ASI/MET, indicating the sun's position is at the rear right. Portions of a lander petal and deflated airbag are visible, in addition to several rocks of varying sizes in the distance.

    Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

    Click below to see the left and right views individually. [figure removed for brevity, see original site] Left [figure removed for brevity, see original site] Right

  13. Ionospheric Profiling using GPS/MET Data

    NASA Technical Reports Server (NTRS)

    Hajj, George; Romans, Larry

    1996-01-01

    A report on ionospheric profiling using GPS and MET data is presented. A description of the GPS occultation technique, some examples of GPS/MET data products, the data processing system and a preliminary validation of ionospheric profiles is discussed.

  14. Reactions of Met-Cars

    SciTech Connect

    Castleman, A.W. Jr.; Guo, B.C.

    1993-12-31

    A new class of metal-carbon complexes, termed metallo-carbohedrenes (Met-Cars), have been discovered to form in a plasma reactor in which early transition metals are vaporized into a stream carrying small hydrocarbon molecules. The initial discovery involved the species Ti{sub 8}c{sub 12}{sup +}, while subsequent studies revealed the stability of the anon and, most importantly, the neutral species. Subsequent investigations show that similar molecules, predicted to have a pentagonal dodecahedral structure, can also be formed with vanadium, hafnium, and zirconium. In the case of the latter, more recent investigations have displaced an interesting growth pattern. In particular, pentagonal dodecahedrons with dangling carbon atoms can undergo further growth, adding at least a second and third cage. The latest results on the properties and reactivities of these new cage-like molecular clusters will be discussed.

  15. Clinical significance of MET in gastric cancer

    PubMed Central

    Inokuchi, Mikito; Otsuki, Sho; Fujimori, Yoshitaka; Sato, Yuya; Nakagawa, Masatoshi; Kojima, Kazuyuki

    2015-01-01

    Chemotherapy has become the global standard treatment for patients with metastatic or unresectable gastric cancer (GC), although outcomes remain unfavorable. Many molecular-targeted therapies inhibiting signaling pathways of various tyrosine kinase receptors have been developed, and monoclonal antibodies targeting human epidermal growth factor receptor 2 or vascular endothelial growth factor receptor 2 have become standard therapy for GC. Hepatocyte growth factor and its receptor, c-MET (MET), play key roles in tumor growth through activated signaling pathways from receptor in GC cells. Genomic amplification of MET leads to the aberrant activation found in GC tumors and is related to survival in patients with GC. This review discusses the clinical significance of MET in GC and examines MET as a potential therapeutic target in patients with GC. Preclinical studies in animal models have shown that MET antibodies or small-molecule MET inhibitors suppress tumor-cell proliferation and tumor progression in MET-amplified GC cells. These drugs are now being evaluated in clinical trials as treatments for metastatic or unresectable GC. PMID:26600931

  16. c-Met expression and MET amplification in malignant pleural mesothelioma.

    PubMed

    Bois, Melanie C; Mansfield, Aaron S; Sukov, William R; Jenkins, Sarah M; Moser, Justin C; Sattler, Christopher A; Smith, Carin Y; Molina, Julian R; Peikert, Tobias; Roden, Anja C

    2016-08-01

    c-Met is a receptor tyrosine kinase shown to be overexpressed in malignant pleural mesothelioma (MPM). Whereas MET mutations have been identified in 3%-16% of MPMs, MET amplification has recently been reported in a single epithelioid MPM. We studied c-Met expression and MET amplification in a large MPM cohort and correlated results with morphologic and clinical features. We report the first case of MET amplification in sarcomatoid MPM. MPMs from surgical pathology files (1989-2014) were reviewed. c-Met immunohistochemistry was performed. Staining intensity and distribution were multiplied (H-score). Staining localization (cytoplasmic and/or membranous) was noted. Fluorescence in situ hybridization was performed using probes for MET and centromere 7. One hundred forty-nine patients (median age, 68.0years; interquartile range, 61-75) had epithelioid (n=97), biphasic (n=18), or sarcomatoid (n=34) MPM. Median follow-up was 10.1months (range, 0.1-222.5). One hundred thirty patients died of disease; 2 were alive with disease. c-Met was expressed in 147 MPMs. c-Met staining intensity, distribution, and H-score differed among the histologic subtypes (P=.015; P=.0001, and P=.0005, respectively), but none were predictive of survival. Epithelioid subtype had greater c-Met expression. MET amplification was identified in 1 sarcomatoid MPM and MET duplication in 1 epithelioid MPM; both had poor outcomes. Chromosome 7 aneusomy was observed in 54 of 144 (37.5%) MPMs and associated with decreased overall survival in sarcomatoid MPMs (hazard ratio=2.81; 95% confidence interval, 1.21-6.51; P=.01). In conclusion, c-Met is expressed in MPM, with significant differences in expression among histologic subtypes. MET amplification is a rare event in MPM, making it an unlikely common pathogenesis for c-Met expression. PMID:27402216

  17. Mars MetNet Mission Payload Overview

    NASA Astrophysics Data System (ADS)

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

    2012-09-01

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

  18. 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.

  19. 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.

  20. MMPM - Mars MetNet Precursor Mission

    NASA Astrophysics Data System (ADS)

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

    2008-09-01

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

  1. 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.

  2. 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

  3. Mars MetNet Mission Payload Overview

    NASA Astrophysics Data System (ADS)

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

    2012-04-01

    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). The main idea behind the MetNet landing vehicles is to use a state-of-the-art 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 and more mass and volume resources are spared for the science payload. The vehicle decelerates its entry speed using the inflatable structure and final landing sequence includes a cone headed body penetrating the Martian soil. 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. The payload of the two MNL precursor models includes the following instruments: Atmospheric instruments: - Pressure device (MetBaro): mass 100g, measurement range 0..1015 hPa. - Humidity device (MetHumi): mass 15g, measurement range 0..100%RH. - Temperature sensors (MetTemp): mass 2g each, measurement range -110C..+30C. Optical devices: - Panoramic camera (PanCam): mass 100g, FOV 4 lenses mounted at 90 deg - Solar irradiance sensor (MetSIS) with optical wireless system (OWLS) for data transfer: mass 115g (MetSIS) and 7g (OWLS module), wavelength range 190..1100nm. MetSIS equipped with 28 optical detectors, two temperature sensors and two solar incidence angle detectors. - Dust sensor (DS): mass 42g, resolution: 10 particles / cm3. Composition and structure device: - Magnetometer (MOURA): mass 80g, measurement range: ±30uT. MetNet Mission payload instruments are specially designed to operate in very low power conditions. MNL flexible solar panels provides a total of

  4. Regulation of the MET oncogene: molecular mechanisms.

    PubMed

    Zhang, Jack; Babic, Andy

    2016-04-01

    TheMEToncogene is a predictive biomarker and an attractive therapeutic target for various cancers. Its expression is regulated at multiple layers via various mechanisms. It is subject to epigenetic modifications, i.e. DNA methylation and histone acetylation. Hypomethylation and acetylation of theMETgene have been associated with its high expression in some cancers. Multiple transcription factors including Sp1 and Ets-1 govern its transcription. After its transcription,METmRNA is spliced into multiple species in the nucleus before being transported to the cytoplasm where its translation is modulated by at least 30 microRNAs and translation initiation factors, e.g. eIF4E and eIF4B.METmRNA produces a single chain pro-Met protein of 170kDa which is cleaved into α and β chains. These two chains are bound together through disulfide bonds to form a heterodimer which undergoes either N-linked or O-linked glycosylation in the Golgi apparatus before it is properly localized in the membrane. Upon interactions with its ligand, i.e. hepatocyte growth factor (HGF), the activity of Met kinase is boosted through various phosphorylation mechanisms and the Met signal is relayed to downstream pathways. The phosphorylated Met is then internalized for subsequent degradation or recycle via proteasome, lysosome or endosome pathways. Moreover, the Met expression is subject to autoregulation and activation by other EGFRs and G-protein coupled receptors. Since deregulation of theMETgene leads to cancer and other pathological conditions, a better understanding of theMETregulation is critical for Met-targeted therapeutics. PMID:26905592

  5. 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.

  6. Rebound Effects Caused by Withdrawal of MET Kinase Inhibitor Are Quenched by a MET Therapeutic Antibody.

    PubMed

    Pupo, Emanuela; Ducano, Nadia; Lupo, Barbara; Vigna, Elisa; Avanzato, Daniele; Perera, Timothy; Trusolino, Livio; Lanzetti, Letizia; Comoglio, Paolo M

    2016-09-01

    MET oncogene amplification is emerging as a major mechanism of acquired resistance to EGFR-directed therapy in lung and colorectal cancers. Furthermore, MET amplification predicts responsiveness to MET inhibitors currently in clinical trials. Among the anti-MET drugs available, ATP-competitive small-molecule kinase inhibitors abrogate receptor autophosphorylation and downstream activation of ERK1/2 and AKT, resulting in cell-cycle arrest. However, this antiproliferative effect allows persistence of a pool of cancer cells that are quiescent but alive. Once the inhibition is removed, rebound activation of MET-driven cell proliferative pathways and tumor growth may occur, an adverse event observed frequently in clinical settings after drug discontinuation. Here we show that inhibitor withdrawal prompts receptor phosphorylation to levels higher than those displayed at steady-state and generates a rebound effect pushing quiescent cancer cells back into the cell cycle, both in vitro and in experimental tumor models in vivo Mechanistically, we found that inhibitor treatment blocks MET endocytosis, causing a local increase in the number of receptors at the plasma membrane. Upon inhibitor washout, the receptor is readily rephosphorylated. The initial phosphorylation is not only increased but also prolonged in duration due to downmodulation of a phosphatase-mediated MET-negative feedback loop, which accompanies receptor internalization. Notably, treatment with a MET therapeutic antibody that induces proteolytic cleavage of the receptor at the cell surface substantially prevents this rebound effect, providing a rationale to combine or alternate these mechanistically different types of MET-targeted therapy. Cancer Res; 76(17); 5019-29. ©2016 AACR. PMID:27364553

  7. 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. PMID:26201829

  8. Smart Polymeric Nanocarriers of Met-enkephalin.

    PubMed

    Szweda, Roza; Trzebicka, Barbara; Dworak, Andrzej; Otulakowski, Lukasz; Kosowski, Dominik; Hertlein, Justyna; Haladjova, Emi; Rangelov, Stanislav; Szweda, Dawid

    2016-08-01

    This study describes a novel approach to polymeric nanocarriers of the therapeutic peptide met-enkephalin based on the aggregation of thermoresponsive polymers. Thermoresponsive bioconjugate poly((di(ethylene glycol) monomethyl ether methacrylate)-ran-(oligo(ethylene glycol) monomethyl ether methacrylate) is synthesized by AGET ATRP using modified met-enkephalin as a macroinitiator. The abrupt heating of bioconjugate water solution leads to the self-assembly of bioconjugate chains and the formation of mesoglobules of controlled sizes. Mesoglobules formed by bioconjugates are stabilized by coating with cross-linked two-layer shell via nucleated radical polymerization of N-isopropylacrylamide using a degradable cross-linker. The targeting peptide RGD, containing the fluorescence marker carboxyfluorescein, is linked to a nanocarrier during the formation of the outer shell layer. In the presence of glutathione, the whole shell is completely degradable and the met-enkephalin conjugate is released. It is anticipated that precisely engineered nanoparticles protecting their cargo will emerge as the next-generation platform for cancer therapy and many other biomedical applications. PMID:27409457

  9. Truncated RAF kinases drive resistance to MET inhibition in MET-addicted cancer cells

    PubMed Central

    Petti, Consalvo; Picco, Gabriele; Martelli, Maria Luisa; Trisolini, Elena; Bucci, Enrico; Perera, Timothy; Isella, Claudio; Medico, Enzo

    2015-01-01

    Constitutively active receptor tyrosine kinases (RTKs) are known oncogenic drivers and provide valuable therapeutic targets in many cancer types. However, clinical efficacy of RTK inhibitors is limited by intrinsic and acquired resistance. To identify genes conferring resistance to inhibition of the MET RTK, we conducted a forward genetics screen in the GTL-16 gastric cancer cell line, carrying MET amplification and exquisitely sensitive to MET inhibition. Cells were transduced with three different retroviral cDNA expression libraries and selected for growth in the presence of the MET inhibitor PHA-665752. Selected cells displayed robust and reproducible enrichment of library-derived cDNAs encoding truncated forms of RAF1 and BRAF proteins, whose silencing reversed the resistant phenotype. Transduction of naïve GTL-16 cells with truncated, but not full length, RAF1 and BRAF conferred in vitro and in vivo resistance to MET inhibitors, which could be reversed by MEK inhibition. Induction of resistance by truncated RAFs was confirmed in other MET-addicted cell lines, and further extended to EGFR-addicted cells. These data show that truncated RAF1 and BRAF proteins, recently described as products of genomic rearrangements in gastric cancer and other malignancies, have the ability to render neoplastic cells resistant to RTK-targeted therapy. PMID:25473895

  10. Prognostic value of MET, cyclin D1 and MET gene copy number in non-small cell lung cancer

    PubMed Central

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

    2013-01-01

    The aim of this study was to analyze the correlation of the expression of MET and cyclin D1 and MET gene copy number in non-small cell lung cancer (NSCLC) tissues and patient clinicopathologic characteristics and survival. Sixty-one NSCLC tissue specimens were included in the study. The expression of MET and cyclin D1 was evaluated by immunohistochemistry and MET gene copy number was assessed by quantitative real-time polymerase chain reaction (Q-PCR). Positive expression of MET and cyclin D1 protein and increased MET gene copy number occurred in 59.0%, 59.0% and 18.0% of 61 NSCLC tissues, respectively. MET-positivity correlated with poor differentiation (P = 0.009). Increased MET gene copy number was significantly associated with lymph node metastasis (P = 0.004) and advanced tumor stage (P = 0.048), while the expression of cyclin D1 was not associated with any clinicopathologic parameters. There was a significant correlation between the expression of MET and MET gene copy number (P = 0.002). Additionally, the expression of cyclin D1 had a significant association with the expression of MET as well as MET gene copy number (P = 0.002 and P = 0.017, respectively). MET-positivity and increased MET gene copy number were significantly associated with poor overall survival (P = 0.003 and P < 0.001, respectively) in univariate analysis. Multivariate Cox proportional hazard analysis confirmed that the expression of MET and MET gene copy number were prognostic indicators of NSCLC (P = 0.003 and P = 0.001, respectively). The overexpression of MET and the increased MET gene copy number might be adverse prognostic factors for NSCLC patients. The activation of the MET/cyclin D1 signaling pathway may contribute to carcinogenesis and the development of NSCLC, and may represent a target for therapy. PMID:23720678

  11. ARM mobile facility surface meteorology (MET) handbook.

    SciTech Connect

    Ritsche, M. T.; Environmental Science Division

    2006-04-01

    The Atmospheric Radiation Measurement (ARM) Mobile Facility Surface Meteorology station (MET) uses mainly conventional in situ sensors to obtain 1-min statistics of surface wind speed, wind direction, air temperature, relative humidity (RH), barometric pressure, and rainrate. Additional sensors may be added to or removed from the base set of sensors depending upon the deployment location, climate regime, or programmatic needs. In addition, sensor types may change depending upon the climate regime of the deployment. These changes/additions are noted in Section 3.

  12. MET gene amplification or EGFR mutation activate MET in lung cancers untreated with EGFR tyrosine kinase inhibitors

    PubMed Central

    Kubo, Takafumi; Yamamoto, Hiromasa; Lockwood, William W.; Valencia, Ilse; Soh, Junichi; Peyton, Michael; Jida, Masaru; Otani, Hiroki; Fujii, Tetsuya; Ouchida, Mamoru; Takigawa, Nagio; Kiura, Katsuyuki; Shimizu, Kenji; Date, Hiroshi; Minna, John D.; Varella-Garcia, Marileila; Lam, Wan L.; Gazdar, Adi F.; Toyooka, Shinichi

    2009-01-01

    We analyzed MET protein and copy number in NSCLC with or without EGFR mutations untreated with EGFR tyrosine kinase inhibitors (TKIs). MET copy number was examined in 28 NSCLC and 4 human bronchial epithelial cell lines (HBEC) and 100 primary tumors using quantitative real-time PCR. Positive results were confirmed by array comparative genomic hybridization and fluorescence in-situ hybridization. Total and phospho-MET protein expression was determined in 24 NSCLC and 2 HBEC cell lines using Western blot. EGFR mutations were examined for exon 19 deletions, T790M, and L858R. Knockdown of EGFR with siRNA was performed to examine the relation between EGFR and MET activation. High-level MET amplification was observed in 3 of 28 NSCLC cell lines and in 2 of 100 primary lung tumors that had not been treated with EGFR-TKIs. MET protein was highly expressed and phosphorylated in all the 3 cell lines with high MET amplification. In contrast, 6 NSCLC cell lines showed phospho-MET among 21 NSCLC cell lines without MET amplification (p = 0.042). Furthermore, those 6 cell lines harboring phospho-MET expression without MET amplification were all EGFR mutant (p = 0.0039). siRNA-mediated knockdown of EGFR abolished phospho-MET expression in examined 3 EGFR mutant cell lines of which MET gene copy number was not amplified. By contrast, phospho-MET expression in 2 cell lines with amplified MET gene was not down-regulated by knockdown of EGFR. Our results indicated that MET amplification was present in untreated NSCLC and EGFR mutation or MET amplification activated MET protein in NSCLC. PMID:19117057

  13. 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.

  14. Gastrointestinal malignancies harbor actionable MET exon 14 deletions

    PubMed Central

    Hong, Mineui; Kim, Sun Young; Jang, Jiryeon; Ahn, Soomin; Kang, So Young; Lee, Sujin; Kim, Seung Tae; Kim, Bogyou; Choi, Jaehyun; Kim, Kyung-Ah; Lee, Jiyun; Park, Charny; Park, Se Hoon; Park, Joon Oh; Lim, Ho Yeong; Kang, Won Ki; Park, Keunchil; Park, Young Suk; Kim, Kyoung-Mee

    2015-01-01

    Recently, MET exon 14 deletion (METex14del) has been postulated to be one potential mechanism for MET protein overexpression. We screened for the presence of METex14del transcript by multiplexed fusion transcript analysis using nCounter assay followed by confirmation with quantitative reverse transcription PCR with correlation to MET protein expression by immunohistochemistry (IHC) and MET amplification by fluorescence in situ hybridization (FISH). We extracted RNAs from 230 patients enrolled onto the prospective molecular profiling clinical trial (NEXT-1) (NCT02141152) between November 2013 and August 2014. Thirteen METex14del cases were identified including 3 gastric cancer, 4 colon cancer, 5 non-small cell lung cancer, and one adenocarcinoma of unknown primary. Of these 13 METex14del cases, 11 were MET IHC 3+ and 2 were 2+. Only one out of the 13 METex14del cases was MET amplified (MET/CEP ratio > 2.0). Growths of two (gastric, colon) METex14del+ patient tumor derived cell lines were profoundly inhibited by both MET tyrosine kinase inhibitors and a monoclonal antibody targeting MET. In conclusion, METex14del is a unique molecular aberration present in gastrointestinal (GI) malignancies corresponding with overexpression of MET protein but rarely with MET amplification. Substantial growth inhibition of METex14del+ patient tumor derived cell lines by several MET targeting drugs strongly suggests METex14del is a potential actionable driver mutation in GI malignancies. PMID:26375439

  15. 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... Duty Dependent Upon Actual Use § 10.133 Conditions required to be met. When the tariff classification of any article is controlled by its actual use in the United States, three conditions must be met...

  16. 19 CFR 10.133 - Conditions required to be met.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 19 Customs Duties 1 2014-04-01 2014-04-01 false Conditions required to be met. 10.133 Section 10... Duty Dependent Upon Actual Use § 10.133 Conditions required to be met. When the tariff classification of any article is controlled by its actual use in the United States, three conditions must be met...

  17. 19 CFR 10.133 - Conditions required to be met.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 19 Customs Duties 1 2012-04-01 2012-04-01 false Conditions required to be met. 10.133 Section 10... Duty Dependent Upon Actual Use § 10.133 Conditions required to be met. When the tariff classification of any article is controlled by its actual use in the United States, three conditions must be met...

  18. 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... Duty Dependent Upon Actual Use § 10.133 Conditions required to be met. When the tariff classification of any article is controlled by its actual use in the United States, three conditions must be met...

  19. 19 CFR 10.133 - Conditions required to be met.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 19 Customs Duties 1 2010-04-01 2010-04-01 false Conditions required to be met. 10.133 Section 10... Duty Dependent Upon Actual Use § 10.133 Conditions required to be met. When the tariff classification of any article is controlled by its actual use in the United States, three conditions must be met...

  20. Tidal analysis of Met rocket wind data

    NASA Technical Reports Server (NTRS)

    Bedinger, J. F.; Constantinides, E.

    1976-01-01

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

  1. Depleting MET-Expressing Tumor Cells by ADCC Provides a Therapeutic Advantage over Inhibiting HGF/MET Signaling.

    PubMed

    Hultberg, Anna; Morello, Virginia; Huyghe, Leander; De Jonge, Natalie; Blanchetot, Christophe; Hanssens, Valérie; De Boeck, Gitte; Silence, Karen; Festjens, Els; Heukers, Raimond; Roux, Benjamin; Lamballe, Fabienne; Ginestier, Christophe; Charafe-Jauffret, Emmanuelle; Maina, Flavio; Brouckaert, Peter; Saunders, Michael; Thibault, Alain; Dreier, Torsten; de Haard, Hans; Michieli, Paolo

    2015-08-15

    Hepatocyte growth factor (HGF) and its receptor MET represent validated targets for cancer therapy. However, HGF/MET inhibitors being explored as cancer therapeutics exhibit cytostatic activity rather than cytotoxic activity, which would be more desired. In this study, we engineered an antagonistic anti-MET antibody that, in addition to blocking HGF/MET signaling, also kills MET-overexpressing cancer cells by antibody-dependent cellular cytotoxicity (ADCC). As a control reagent, we engineered the same antibody in an ADCC-inactive form that is similarly capable of blocking HGF/MET activity, but in the absence of any effector function. In comparing these two antibodies in multiple mouse models of cancer, including HGF-dependent and -independent tumor xenografts, we determined that the ADCC-enhanced antibody was more efficacious than the ADCC-inactive antibody. In orthotopic mammary carcinoma models, ADCC enhancement was crucial to deplete circulating tumor cells and to suppress metastases. Prompted by these results, we optimized the ADCC-enhanced molecule for clinical development, generating an antibody (ARGX-111) with improved pharmacologic properties. ARGX-111 competed with HGF for MET binding, inhibiting ligand-dependent MET activity, downregulated cell surface expression of MET, curbing HGF-independent MET activity, and engaged natural killer cells to kill MET-expressing cancer cells, displaying MET-specific cytotoxic activity. ADCC assays confirmed the cytotoxic effects of ARGX-111 in multiple human cancer cell lines and patient-derived primary tumor specimens, including MET-expressing cancer stem-like cells. Together, our results show how ADCC provides a therapeutic advantage over conventional HGF/MET signaling blockade and generates proof-of-concept for ARGX-111 clinical testing in MET-positive oncologic malignancies. PMID:26141862

  2. Accelerometer Output and MET Values of Common Physical Activities

    PubMed Central

    Kozey, Sarah L.; Lyden, Kate; Howe, Cheryl A.; Staudenmayer, John W.; Freedson, Patty S.

    2010-01-01

    Purpose This paper 1) provides the calibration procedures and methods for metabolic and activity monitor data collection, 2) compares measured MET values to the MET values from the Compendium of Physical Activities, and 3) examines the relationship between accelerometer output and METs for a range of physical activities Methods Participants (n=277) completed 11 activities for seven minutes each from a menu of 23 physical activities. Oxygen consumption (VO2) was measured using a portable metabolic system and an accelerometer was worn. MET values were defined as follows; measuredMETs (VO2/measured RMR) and standardMETs (VO2/3.5ml·kg·min−1). For the total sample and by sub-group (age [young <40y], sex and BMI [normal-weight <25 kg·m2]), measuredMETs and standardMETs were compared to the Compendium, using 95% confidence intervals to determine statistical significance (α=0.05). Average count·min−1 for each activity and the linear association between count·min−1 and METs are presented. Results Compendium METs were different than measured METs for 17/21 activities (81%). The number of activities different than the Compendium were similar between sub-groups or when standard METs were used. The average counts for the activities ranged from 11 counts·min−1(dishes) to 7490 counts·min−1 (2.23m·s−1, 3%) The r2 between counts and METs was 0.65. Conclusions This study provides valuable information about data collection, metabolic responses, and accelerometer output for common physical activities in a diverse participant sample. The Compendium should be updated with additional empirical data and linear regression models are inappropriate for accurately predicting METs from accelerometer output. PMID:20142781

  3. 3D RoboMET Characterization

    SciTech Connect

    Madison, Jonathan D.; Susan, Donald F.; Kilgo, Alice C.

    2015-10-01

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

  4. MET Inhibition in Clear Cell Renal Cell Carcinoma

    PubMed Central

    Xie, Zuoquan; Lee, Young H.; Boeke, Marta; Jilaveanu, Lucia B.; Liu, Zongzhi; Bottaro, Donald P.; Kluger, Harriet M.; Shuch, Brian

    2016-01-01

    Background: Clear cell renal cell carcinoma (ccRCC) is the most lethal form of kidney cancer. Small molecule VEGFR inhibitors are widely used but are not curative and various resistance mechanisms such as activation of the MET pathway have been described. Dual MET/VEGFR2 inhibitors have recently shown clinical benefit but limited preclinical data evaluates their effects in ccRCC. Methods: An interrogation of the Cancer Genome Atlas (TCGA) dataset was performed to evaluate oncogenic alterations in the MET/VEGFR2 pathway. We evaluated the in vitro effects of Cabozantinib, a dual MET/VEGFR2 inhibitor, using a panel of ccRCC cell lines. Drug effects of cell viability and proliferation, migration, cell scatter, anchorage independent growth, and downstream MET/VEGFR2 signaling pathways were assessed. Results: Twelve percent of TCGA cases had possible MET/HGF oncogenic alterations with co-occurrence noted (p<0.001). MET/HGF altered cases had worse overall survival (p=0.044). Cabozantinib was a potent inhibitor of MET and VEGFR2 in vitro in our cell line panel. PI3K, MAPK and mTOR pathways were also suppressed by cabozantinib, however the effects on cell viability in vitro were modest. At nanomolar concentrations of cabozantinib, HGF-stimulated migration, invasion, cellular scattering and soft agar colony formation were inhibited. Conclusions: We provide further preclinical rationale for dual MET/VEGFR2 inhibition in ccRCC. While the MET pathway is implicated in VEGFR resistance, dual inhibitors may have direct anti-tumor effects in a patient subset with evidence of MET pathway involvement. Cabozantinib is a potent dual MET/VEGFR2 inhibitor, significantly inhibits cell migration and invasion in vitro and likely has anti-angiogenic effects similar to other VEGFR tyrosine kinase inhibitors. Future work involving in vivo models will be useful to better define mechanisms of potential anti-tumor activity. PMID:27390595

  5. Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia.

    PubMed

    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

    2015-12-01

    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 (MET(Δ14)) 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 MET(Δ14) 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

  6. Mars MetNet Mission Pressure and Humidity Devices

    NASA Astrophysics Data System (ADS)

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

    2012-09-01

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

  7. Structure of the fMet-tRNAfMet-binding domain of B.stearothermophilus initiation factor IF2

    PubMed Central

    Meunier, Sylvie; Spurio, Roberto; Czisch, Michael; Wechselberger, Rainer; Guenneugues, Marc; Gualerzi, Claudio O.; Boelens, Rolf

    2000-01-01

    The three-dimensional structure of the fMet-tRNAfMet -binding domain of translation initiation factor IF2 from Bacillus stearothermophilus has been determined by heteronuclear NMR spectroscopy. Its structure consists of six antiparallel β-strands, connected via loops, and forms a closed β-barrel similar to domain II of elongation factors EF-Tu and EF-G, despite low sequence homology. Two structures of the ternary complexes of the EF-Tu⋅aminoacyl-tRNA⋅ GDP analogue have been reported and were used to propose and discuss the possible fMet-tRNAfMet-binding site of IF2. PMID:10775275

  8. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping

    PubMed Central

    Paik, Paul K.; Drilon, Alexander; Fan, Pang-Dian; Yu, Helena; Rekhtman, Natasha; Ginsberg, Michelle S.; Borsu, Laetitia; Schultz, Nikolaus; Berger, Michael F.; Rudin, Charles M.; Ladanyi, Marc

    2015-01-01

    Mutations in the MET exon 14 RNA splice acceptor and donor sites, which lead to exon skipping, deletion of the juxtamembrane domain containing the Cbl E3-ubiquitin ligase binding site, and decreased turnover of the resultant aberrant MET protein, were previously reported to be oncogenic in preclinical models. We now report responses to the MET inhibitors crizotinib and cabozantinib in four patients with stage IV lung adenocarcinomas harboring mutations leading to MET exon 14 skipping, highlighting a new therapeutic strategy for the 4% of lung adenocarcinoma patients whose tumors harbor this previously underappreciated genetic alteration. PMID:25971939

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

    PubMed Central

    Shuch, Brian; Falbo, Ryan; Parisi, Fabio; Adeniran, Adebowale; Kluger, Yuval; Kluger, Harriet M.; Jilaveanu, Lucia B.

    2015-01-01

    Aims. Inhibitors of the MET pathway hold promise in the treatment for metastatic kidney cancer. Assessment of predictive biomarkers may be necessary for appropriate patient selection. Understanding MET expression in metastases and the correlation to the primary site is important, as distant tissue is not always available. Methods and Results. MET immunofluorescence was performed using automated quantitative analysis and a tissue microarray containing matched nephrectomy and distant metastatic sites from 34 patients with clear cell renal cell carcinoma. Correlations between MET expressions in matched primary and metastatic sites and the extent of heterogeneity were calculated. The mean expression of MET was not significantly different between primary tumors when compared to metastases (P = 0.1). MET expression weakly correlated between primary and matched metastatic sites (R = 0.5) and a number of cases exhibited very high levels of discordance between these tumors. Heterogeneity within nephrectomy specimens compared to the paired metastatic tissues was not significantly different (P = 0.39). Conclusions. We found that MET expression is not significantly different in primary tumors than metastatic sites and only weakly correlates between matched sites. Moderate concordance of MET expression and significant expression heterogeneity may be a barrier to the development of predictive biomarkers using MET targeting agents. PMID:26448928

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

    PubMed Central

    Piater, Birgit; Doerner, Achim; Guenther, Ralf; Kolmar, Harald; Hock, Bjoern

    2015-01-01

    The human receptor tyrosine kinase c-Met plays an important role in the control of critical cellular processes. Since c-Met is frequently over expressed or deregulated in human malignancies, blocking its activation is of special interest for therapy. In normal conditions, the c-Met receptor is activated by its bivalent ligand hepatocyte growth factor (HGF). Also bivalent antibodies can activate the receptor by cross linking, limiting therapeutic applications. We report the generation of the RNA aptamer CLN64 containing 2’-fluoro pyrimidine modifications by systematic evolution of ligands by exponential enrichment (SELEX). CLN64 and a previously described single-stranded DNA (ssDNA) aptamer CLN3 exhibited high specificities and affinities to recombinant and cellular expressed c-Met. Both aptamers effectively inhibited HGF-dependent c-Met activation, signaling and cell migration. We showed that these aptamers did not induce c-Met activation, revealing an advantage over bivalent therapeutic molecules. Both aptamers were shown to bind overlapping epitopes but only CLN3 competed with HGF binding to cMet. In addition to their therapeutic and diagnostic potential, CLN3 and CLN64 aptamers exhibit valuable tools to further understand the structural and functional basis for c-Met activation or inhibition by synthetic ligands and their interplay with HGF binding. PMID:26658271

  11. 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…

  12. Targeting the HGF/MET signalling pathway in cancer therapy

    PubMed Central

    Cecchi, Fabiola; Rabe, Daniel C.; Bottaro, Donald P.

    2012-01-01

    Introduction Under normal conditions, hepatocyte growth factor (HGF)-induced activation of its cell surface receptor, the Met tyrosine kinase (TK), is tightly regulated by paracrine ligand delivery, ligand activation at the target cell surface, and ligand activated receptor internalization and degradation. Despite these controls, HGF/Met signaling contributes to oncogenesis and tumor progression in several cancers and promotes aggressive cellular invasiveness that is strongly linked to tumor metastasis. Area covered The prevalence of HGF/Met pathway activation in human malignancies has driven rapid growth in cancer drug development programs. The authors review Met structure and function, the basic properties of HGF/Met pathway antagonists now in preclinical and clinical development, as well as the latest clinical trial results. Expert opinion Clinical trials with HGF/Met pathway antagonists show that as a class these agents are well tolerated. Although widespread efficacy was not seen in several completed phase 2 studies, promising results have been reported in lung, gastric, prostate and papillary renal cancer patients treated with these agents. The main challenges facing the effective use of HGF/Met-targeted antagonists for cancer treatment are optimal patient selection, diagnostic and pharmacodynamic biomarker development, and the identification and testing of optimal therapy combinations. The wealth of basic information, analytical reagents and model systems available concerning HGF/Met oncogenic signaling will continue to be invaluable in meeting these challenges and moving expeditiously toward more effective disease control. PMID:22530990

  13. 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.

  14. Solving CASMI 2013 with MetFrag, MetFusion and MOLGEN-MS/MS

    PubMed Central

    Schymanski, Emma L.; Gerlich, Michael; Ruttkies, Christoph; Neumann, Steffen

    2014-01-01

    The second Critical Assessment of Small Molecule Identification (CASMI) contest took place in 2013. A joint team from the Swiss Federal Institute of Aquatic Science and Technology (Eawag) and Leibniz Institute of Plant Biochemistry (IPB) participated in CASMI 2013 with an automatic workflow-style entry. MOLGEN-MS/MS was used for Category 1, molecular formula calculation, restricted by the information given for each challenge. MetFrag and MetFusion were used for Category 2, structure identification, retrieving candidates from the compound databases KEGG, PubChem and ChemSpider and joining these lists pre-submission. The results from Category 1 were used to guide whether formula or exact mass searches were performed for Category 2. The Category 2 results were impressive considering the database size and automated regime used, although these could not compete with the manual approach of the contest winner. The Category 1 results were affected by large m/z and ppm values in the challenge data, where strategies beyond pure enumeration from other participants were more successful. However, the combination used for the CASMI 2013 entries was extremely useful for developing decision-making criteria for automatic, high throughput general unknown (non-target) identification and for future contests. PMID:26819879

  15. Funktionelle Elektrostimulation Paraplegischer Patienten

    PubMed Central

    2014-01-01

    Functional Electrical Stimulation on Paraplegic Patients. We report on clinical and physiological effects of 8 months Functional Electrical Stimulation (FES) of quadriceps femoris muscle on 16 paraplegic patients. Each patient had muscle biopsies, CT-muscle diameter measurements, knee extension strength testing carried out before and after 8 months FES training. Skin perfusion was documented through infrared telethermography and xenon clearance, muscle perfusion was recorded through thallium scintigraphy. After 8 months FES training baseline skin perfusion showed 86 % increase, muscle perfusion was augmented by 87 %. Muscle fiber diameters showed an average increase of 59 % after 8 months FES training. Muscles in patients with spastic paresis as well as in patients with denervation showed an increase in aerob and anaerob muscle enzymes up to the normal range. Even without axonal neurotropic substances FES was able to demonstrate fiberhypertrophy, enzyme adaptation and intracellular structural benefits in denervated muscles. The increment in muscle area as visible on CT-scans of quadriceps femoris was 30 % in spastic paraplegia and 10 % in denervated patients respectively. FES induced changes were less in areas not directly underneath the surface electrodes. We strongly recommend the use of Kern’s current for FES in denervated muscles to induce tetanic muscle contractions as we formed a very critical opinion of conventional exponential current. In patients with conus-cauda-lesions FES must be integrated into modern rehabilitation to prevent extreme muscle degeneration and decubital ulcers. Using FES we are able to improve metabolism and induce positive trophic changes in our patients lower extremities. In spastic paraplegics the functions „rising and walking“ achieved through FES are much better training than FES ergometers. Larger muscle masses are activated and an increased heart rate is measured, therefore the impact on cardiovascular fitness and metabolism is much greater. This effectively addresses and prevents all problems which result from inactivity in paraplegic patients. PMID:26913132

  16. Artificial human Met agonists based on macrocycle scaffolds

    PubMed Central

    Ito, Kenichiro; Sakai, Katsuya; Suzuki, Yoshinori; Ozawa, Naoya; Hatta, Tomohisa; Natsume, Tohru; Matsumoto, Kunio; Suga, Hiroaki

    2015-01-01

    Hepatocyte growth factor (HGF) receptor, also known as Met, is a member of the receptor tyrosine kinase family. The Met–HGF interaction regulates various signalling pathways involving downstream kinases, such as Akt and Erk. Met activation is implicated in wound healing of tissues via multiple biological responses triggered by the above-mentioned signalling cascade. Here we report the development of artificial Met-activating dimeric macrocycles. We identify Met-binding monomeric macrocyclic peptides by means of the RaPID (random non-standard peptide integrated discovery) system, and dimerize the respective monomers through rational design. These dimeric macrocycles specifically and strongly activate Met signalling pathways through receptor dimerization and induce various HGF-like cellular responses, such as branching morphogenesis, in human cells. This work suggests our approach for generating dimeric macrocycles as non-protein ligands for cell surface receptors can be useful for developing potential therapeutics with a broad range of potential applications. PMID:25758345

  17. 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

  18. FOXC2 promotes colorectal cancer metastasis by directly targeting MET.

    PubMed

    Cui, Y-M; Jiao, H-L; Ye, Y-P; Chen, C-M; Wang, J-X; Tang, N; Li, T-T; Lin, J; Qi, L; Wu, P; Wang, S-Y; He, M-R; Liang, L; Bian, X-W; Liao, W-T; Ding, Y-Q

    2015-08-13

    Metastasis is the major cause of death in colorectal cancer (CRC). Although multiple genes have been identified to be responsible for the development of CRC, the molecular changes that enable CRC cells to undergo early local invasion and to form distant metastatic colonies still remain largely unknown. Herein, we investigated the role of Forkhead box protein C2 (FOXC2) and explored the underlying mechanisms in invasion and metastasis of CRC. We show that both high FOXC2 expression and nuclear localization of FOXC2 are significantly correlated with advanced TNM (T=primary tumor; N=regional lymph nodes; M=distant metastasis) stages. FOXC2 enhanced the invasive abilities of CRC cells in vitro and promoted local invasion and distant metastasis in an orthotopic mouse metastatic model of CRC. Microarray analysis revealed that overexpression of FOXC2 increased the proto-oncogene MET tyrosine kinase expression and activated the hepatocyte growth factor (HGF)-MET signaling pathway. Furthermore, luciferase reporter assays and chromatin immunoprecipitation assays revealed that FOXC2 directly associated with MET promoter to increase the transcriptional activity of MET. Inhibition of MET attenuates the invasive phenotype and metastatic potential of FOXC2-overexpressing CRC cells, indicating that MET is a major mediator of FOXC2-promoted metastasis. In addition, FOXC2 expression was positively correlated with MET expression in CRC tissue samples. Our findings suggest that FOXC2 has a crucial role in CRC metastasis by regulating HGF-MET signaling via inducing MET expression, highlighting FOXC2 as a potential therapeutic target for preventing or reducing metastasis in CRC. PMID:25381815

  19. Targeting the oncogenic Met receptor by antibodies and gene therapy.

    PubMed

    Vigna, E; Comoglio, P M

    2015-04-01

    The receptor for hepatocyte growth factor (HGF), a tyrosine kinase encoded by the Met oncogene, has a crucial role in cancer growth, invasion and metastasis. It is a validated therapeutic target for 'personalized' treatment of a number of malignancies. Therapeutic tools prompting selective, robust and highly effective Met inhibition potentially represent a major step in the battle against cancer. Antibodies targeting either Met or its ligand HGF, although challenging, demonstrate to be endowed with promising features. Here we briefly review and discuss the state of the art in the field. PMID:24882574

  20. 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

  1. Oxidation of Met(144) and Met(145) in Calmodulin Blocks Calmodulin Dependent Activation of the Plasma Membrane Ca-ATPase.

    SciTech Connect

    Bartlett, Ryan K.; Urbauer, Ramona J.; Anbanandam, A; Smallwood, Heather S.; Urbauer, Jeffrey L.; Squier, Thomas C.

    2003-04-15

    Methionine oxidation in calmodulin (CaM) isolated from senescent brain results in an inability to fully activate the plasma membrane (PM) Ca-ATPase which may contribute to observed increases in cytosolic calcium levels under conditions of oxidative stress and biological aging. To identify the functional importance of the oxidation of Met-144 and Met-145 near the carboxyl-terminus of CaM, we have used site-directed mutagenesis to substitute leucines for methionines at other positions in CaM, permitting the site-specific oxidation of Met-144 and Met-145. Prior to the oxidation, the CaM-dependent activation of the PM-CA-ATPase by these CaM mutants is similar to that of wild-type CaM. Likewise, oxidation of individual methionines has a minimal effect on the CaM concentration necessary for half-maximal activation of the PM-Ca-ATPase. These results are consistent with previous suggestions that no single methionine within CaM is essential for activation of the PM-CA-ATPase. Oxidation of either Met-144 or Met-145 or all nine methionines in CaM results in an equivalent inhibition of the PM-Ca-ATPase, resulting in a 50-60% reduction in the level of enzyme activation. Oxidation of Met-144 is largely responsible for the decreased extent of enzyme activation, suggesting that this site is critical in modulating the sensitivity of CaM to oxidant-induced loss-of-function. These results are discussed in terms of a possible functional role for Met-144 and Met-145 in CaM as redox sensors that function to modulate calcium homeostasis and energy metabolism in response to conditions of oxidative stress.

  2. Regular Expression-Based Learning for METs Value Extraction.

    PubMed

    Redd, Douglas; Kuang, Jinqiu; Mohanty, April; Bray, Bruce E; Zeng-Treitler, Qing

    2016-01-01

    Functional status as measured by exercise capacity is an important clinical variable in the care of patients with cardiovascular diseases. Exercise capacity is commonly reported in terms of Metabolic Equivalents (METs). In the medical records, METs can often be found in a variety of clinical notes. To extract METs values, we adapted a machine-learning algorithm called REDEx to automatically generate regular expressions. Trained and tested on a set of 2701 manually annotated text snippets (i.e. short pieces of text), the regular expressions were able to achieve good accuracy and F-measure of 0.89 and 0.86. This extraction tool will allow us to process the notes of millions of cardiovascular patients and extract METs value for use by researchers and clinicians. PMID:27570673

  3. Regular Expression-Based Learning for METs Value Extraction

    PubMed Central

    Redd, Douglas; Kuang, Jinqiu; Mohanty, April; Bray, Bruce E.; Zeng-Treitler, Qing

    2016-01-01

    Functional status as measured by exercise capacity is an important clinical variable in the care of patients with cardiovascular diseases. Exercise capacity is commonly reported in terms of Metabolic Equivalents (METs). In the medical records, METs can often be found in a variety of clinical notes. To extract METs values, we adapted a machine-learning algorithm called REDEx to automatically generate regular expressions. Trained and tested on a set of 2701 manually annotated text snippets (i.e. short pieces of text), the regular expressions were able to achieve good accuracy and F-measure of 0.89 and 0.86. This extraction tool will allow us to process the notes of millions of cardiovascular patients and extract METs value for use by researchers and clinicians. PMID:27570673

  4. 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.

  5. Decreased Expression of Met During Differentiation in Rat Lung

    PubMed Central

    Kato, T.; Oka, K.; Nakamura, T.; Ito, A.

    2016-01-01

    Organ-specific stem cells play key roles in maintaining the epithelial cell layers of lung. Bronchioalveolar stem cells (BASCs) are distal lung epithelial stem cells of adult mice. Alveolar type 2 (AT2) cells have important functions and serve as progenitor cells of alveolar type 1 (AT1) cells to repair the epithelium when they are injured. Hepatocyte growth factor (HGF) elicits mitogenic, morphogenic, and anti-apoptotic effects on lung epithelial cells through tyrosine phosphorylation of Met receptor, and thus is recognized as a pulmotrophic factor. To understand which cells HGF targets in lung, we identified the cells expressing Met by immunofluorescence assay. Met was strongly expressed in BASCs, which expressed an AT2 cell marker, pro-SP-C, and a club cell marker, CCSP. In alveoli, we found higher expression of Met in primary AT2 than in AT1 cells, which was confirmed using primary AT2 cells. We further examined the mitogenic activity of HGF in AT2-cell-derived alveolar-like cysts (ALCs) in 3D culture. Multicellular ALCs expressed Met, and HGF enhanced the ALC production. Taking these findings together, BASCs could also be an important target for HGF, and HGF-Met signaling could function more potent on cells that have greater multipotency in adult lung. PMID:26972715

  6. The role of the HGF/Met axis in mesothelioma.

    PubMed

    Thayaparan, Thivyan; Spicer, James F; Maher, John

    2016-04-15

    Malignant mesothelioma is an asbestos-related cancer that occurs most commonly in the pleural space and is incurable. Increasing evidence suggests that aberrant receptor tyrosine kinase (RTK)-directed signalling plays a key role in the pathogenesis of this cancer. In the majority of mesotheliomas, up-regulated expression or signalling by Met, the receptor for hepatocyte growth factor (HGF) can be demonstrated. Following binding of ligand, Met relays signals that promote cell survival, proliferation, movement, invasiveness, branching morphogenesis and angiogenesis. Here we describe the HGF/Met axis and review the mechanisms that lead to the aberrant activation of this signalling system in mesothelioma. We also describe the cross-talk that occurs between HGF/Met and a number of other receptors, ligands and co-receptor systems. The prevalent occurrence of HGF/Met dysregulation in patients with mesothelioma sets the scene for the investigation of pharmaceutical inhibitors of this axis. In light of the inter-relationship between HGF/Met and other ligand receptor, combinatorial targeting strategies may provide opportunities for therapeutic advancement in this challenging tumour. PMID:27068941

  7. 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

  8. Structure of the fMet-tRNA(fMet)-binding domain of B. stearothermophilus initiation factor IF2.

    PubMed

    Meunier, S; Spurio, R; Czisch, M; Wechselberger, R; Guenneugues, M; Gualerzi, C O; Boelens, R

    2000-04-17

    The three-dimensional structure of the fMet-tRNA(fMet) -binding domain of translation initiation factor IF2 from Bacillus stearothermophilus has been determined by heteronuclear NMR spectroscopy. Its structure consists of six antiparallel beta-strands, connected via loops, and forms a closed beta-barrel similar to domain II of elongation factors EF-Tu and EF-G, despite low sequence homology. Two structures of the ternary complexes of the EF-Tu small middle dotaminoacyl-tRNA small middle dot GDP analogue have been reported and were used to propose and discuss the possible fMet-tRNA(fMet)-binding site of IF2. PMID:10775275

  9. Expressions and clinical significances of c-MET, p-MET and E2f-1 in human gastric carcinoma

    PubMed Central

    2014-01-01

    Background To investigate on the expressions and the clinical significances of hepatocyte growth factor receptor (c-MET), phosphorylated c-MET (p-MET) and e2f-1 transcription factor in primary lesion of gastric adenocarcinoma (GC). Method Tissue samples from the primary lesion of GC in patients who accepted D2/D3 radical gastrectomy with R0/R1 resection were stained by immunohistochemistry of c-MET, p-MET, e2f-1 and Ki-67. The univariate and the multivariate analyses involving in clinicopathological parameters and prognostic factors were evaluated. Results The positivity rates for c-MET (66.12%, 80 cases/121 cases), p-MET (59.50%, 72 cases/121 cases), e2f-1 (38.84%, 47 cases/121 cases) and Ki-67 (72.73%, 88 cases/121 cases) in primary lesion of GC was significantly higher than that in non-cancerous tissue at 5 cm places far from the margin of primary lesion (P < 0.05, respectively). The deeper tumor invasion, the severer lymph node metastasis, the later stage of TNM and the higher expression of Ki-67 was respectively an independent risk factor for the higher expression of c-MET or p-MET, but the younger age and the shorter survival time was an independent risk factor for the higher expression of e2f-1 respectively. Survival analysis showed that the worse prognosis could be observed in the patients with the combination of both c-MET-positive and e2f-1-negative (P = 0.038) or both p-MET-positive and e2f-1-negative (P = 0.042). Cox analysis demonstrated that the severer lymphatic node metastasis and the higher positivity rate of c-MET, p-MET or e2f-1 were an independent prognosis factor respectively. The higher expression of e2f-1 was identified in patients with Stage I-II, which correlated with a shorter survival time. Survival analysis also revealed that the prognosis of patients with positive expression of e2f-1 at Stage I-II was significantly worse than that in patients with negative expression of e2f-1 (χ2 = 13.437, P = 0.001). However, in

  10. MET Gene Amplification and MET Receptor Activation Are Not Sufficient to Predict Efficacy of Combined MET and EGFR Inhibitors in EGFR TKI-Resistant NSCLC Cells.

    PubMed

    Presutti, Dario; Santini, Simonetta; Cardinali, Beatrice; Papoff, Giuliana; Lalli, Cristiana; Samperna, Simone; Fustaino, Valentina; Giannini, Giuseppe; Ruberti, Giovina

    2015-01-01

    Epidermal growth factor receptor (EGFR), member of the human epidermal growth factor receptor (HER) family, plays a critical role in regulating multiple cellular processes including proliferation, differentiation, cell migration and cell survival. Deregulation of the EGFR signaling has been found to be associated with the development of a variety of human malignancies including lung, breast, and ovarian cancers, making inhibition of EGFR the most promising molecular targeted therapy developed in the past decade against cancer. Human non small cell lung cancers (NSCLC) with activating mutations in the EGFR gene frequently experience significant tumor regression when treated with EGFR tyrosine kinase inhibitors (TKIs), although acquired resistance invariably develops. Resistance to TKI treatments has been associated to secondary mutations in the EGFR gene or to activation of additional bypass signaling pathways including the ones mediated by receptor tyrosine kinases, Fas receptor and NF-kB. In more than 30-40% of cases, however, the mechanisms underpinning drug-resistance are still unknown. The establishment of cellular and mouse models can facilitate the unveiling of mechanisms leading to drug-resistance and the development or validation of novel therapeutic strategies aimed at overcoming resistance and enhancing outcomes in NSCLC patients. Here we describe the establishment and characterization of EGFR TKI-resistant NSCLC cell lines and a pilot study on the effects of a combined MET and EGFR inhibitors treatment. The characterization of the erlotinib-resistant cell lines confirmed the association of EGFR TKI resistance with loss of EGFR gene amplification and/or AXL overexpression and/or MET gene amplification and MET receptor activation. These cellular models can be instrumental to further investigate the signaling pathways associated to EGFR TKI-resistance. Finally the drugs combination pilot study shows that MET gene amplification and MET receptor activation

  11. MET Gene Amplification and MET Receptor Activation Are Not Sufficient to Predict Efficacy of Combined MET and EGFR Inhibitors in EGFR TKI-Resistant NSCLC Cells

    PubMed Central

    Presutti, Dario; Santini, Simonetta; Cardinali, Beatrice; Papoff, Giuliana; Lalli, Cristiana; Samperna, Simone; Fustaino, Valentina; Giannini, Giuseppe; Ruberti, Giovina

    2015-01-01

    Epidermal growth factor receptor (EGFR), member of the human epidermal growth factor receptor (HER) family, plays a critical role in regulating multiple cellular processes including proliferation, differentiation, cell migration and cell survival. Deregulation of the EGFR signaling has been found to be associated with the development of a variety of human malignancies including lung, breast, and ovarian cancers, making inhibition of EGFR the most promising molecular targeted therapy developed in the past decade against cancer. Human non small cell lung cancers (NSCLC) with activating mutations in the EGFR gene frequently experience significant tumor regression when treated with EGFR tyrosine kinase inhibitors (TKIs), although acquired resistance invariably develops. Resistance to TKI treatments has been associated to secondary mutations in the EGFR gene or to activation of additional bypass signaling pathways including the ones mediated by receptor tyrosine kinases, Fas receptor and NF-kB. In more than 30–40% of cases, however, the mechanisms underpinning drug-resistance are still unknown. The establishment of cellular and mouse models can facilitate the unveiling of mechanisms leading to drug-resistance and the development or validation of novel therapeutic strategies aimed at overcoming resistance and enhancing outcomes in NSCLC patients. Here we describe the establishment and characterization of EGFR TKI-resistant NSCLC cell lines and a pilot study on the effects of a combined MET and EGFR inhibitors treatment. The characterization of the erlotinib-resistant cell lines confirmed the association of EGFR TKI resistance with loss of EGFR gene amplification and/or AXL overexpression and/or MET gene amplification and MET receptor activation. These cellular models can be instrumental to further investigate the signaling pathways associated to EGFR TKI-resistance. Finally the drugs combination pilot study shows that MET gene amplification and MET receptor activation

  12. c-Met as a Target for Personalized Therapy

    PubMed Central

    Garajová, Ingrid; Giovannetti, Elisa; Biasco, Guido; Peters, Godefridus J.

    2015-01-01

    MET and its ligand HGF are involved in many biological processes, both physiological and pathological, making this signaling pathway an attractive therapeutic target in oncology. Downstream signaling effects are transmitted via mitogen-activated protein kinase (MAPK), PI3K (phosphoinositide 3-kinase protein kinase B)/AKT, signal transducer and activator of transcription proteins (STAT), and nuclear factor-κB. The final output of the terminal effector components of these pathways is activation of cytoplasmic and nuclear processes leading to increases in cell proliferation, survival, mobilization and invasive capacity. In addition to its role as an oncogenic driver, increasing evidence implicates MET as a common mechanism of resistance to targeted therapies including EGFR and VEGFR inhibitors. In the present review, we summarize the current knowledge on the role of the HGF-MET signaling pathway in cancer and its therapeutic targeting (HGF activation inhibitors, HGF inhibitors, MET antagonists and selective/nonselective MET kinase inhibitors). Recent advances in understanding the role of this pathway in the resistance to current anticancer strategies used in lung, kidney and pancreatic cancer are discussed. PMID:26628860

  13. 21 CFR 111.73 - What is your responsibility for determining whether established specifications are met?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... whether established specifications are met? 111.73 Section 111.73 Food and Drugs FOOD AND DRUG... determining whether established specifications are met? You must determine whether the specifications you establish under § 111.70 are met....

  14. 21 CFR 111.73 - What is your responsibility for determining whether established specifications are met?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... whether established specifications are met? 111.73 Section 111.73 Food and Drugs FOOD AND DRUG... determining whether established specifications are met? You must determine whether the specifications you establish under § 111.70 are met....

  15. 21 CFR 111.73 - What is your responsibility for determining whether established specifications are met?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... whether established specifications are met? 111.73 Section 111.73 Food and Drugs FOOD AND DRUG... determining whether established specifications are met? You must determine whether the specifications you establish under § 111.70 are met....

  16. 21 CFR 111.73 - What is your responsibility for determining whether established specifications are met?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... whether established specifications are met? 111.73 Section 111.73 Food and Drugs FOOD AND DRUG... determining whether established specifications are met? You must determine whether the specifications you establish under § 111.70 are met....

  17. 21 CFR 111.73 - What is your responsibility for determining whether established specifications are met?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... whether established specifications are met? 111.73 Section 111.73 Food and Drugs FOOD AND DRUG... determining whether established specifications are met? You must determine whether the specifications you establish under § 111.70 are met....

  18. BacMet: antibacterial biocide and metal resistance genes database

    PubMed Central

    Pal, Chandan; Bengtsson-Palme, Johan; Rensing, Christopher; Kristiansson, Erik; Larsson, D. G. Joakim

    2014-01-01

    Antibiotic resistance has become a major human health concern due to widespread use, misuse and overuse of antibiotics. In addition to antibiotics, antibacterial biocides and metals can contribute to the development and maintenance of antibiotic resistance in bacterial communities through co-selection. Information on metal and biocide resistance genes, including their sequences and molecular functions, is, however, scattered. Here, we introduce BacMet (http://bacmet.biomedicine.gu.se)—a manually curated database of antibacterial biocide- and metal-resistance genes based on an in-depth review of the scientific literature. The BacMet database contains 470 experimentally verified resistance genes. In addition, the database also contains 25 477 potential resistance genes collected from public sequence repositories. All resistance genes in the BacMet database have been organized according to their molecular function and induced resistance phenotype. PMID:24304895

  19. Remembering the early days of the Met Lab

    SciTech Connect

    Katz, J.J.

    1990-01-01

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

  20. MET-targeted therapy for gastric cancer: the importance of a biomarker-based strategy.

    PubMed

    Kawakami, Hisato; Okamoto, Isamu

    2016-07-01

    The MET protooncogene encodes the receptor tyrosine kinase c-MET (MET). Aberrant activation of MET signaling occurs in a subset of advanced malignancies, including gastric cancer, and promotes tumor cell growth, survival, migration, and invasion as well as tumor angiogenesis, suggesting its potential importance as a therapeutic target. MET can be activated by two distinct pathways that are dependent on or independent of its ligand, hepatocyte growth factor (HGF), with the latter pathway having been attributed mostly to MET amplification in gastric cancer. Preclinical evidence has suggested that interruption of the HGF-MET axis either with antibodies to HGF or with MET tyrosine kinase inhibitors (TKIs) has antitumor effects in gastric cancer cells. Overexpression of MET occurs frequently in gastric cancer and has been proposed as a potential predictive biomarker for anti-MET therapy. However, several factors can trigger such MET upregulation in a manner independent of HGF, suggesting that gastric tumors with MET overexpression are not necessarily MET driven. On the other hand, gastric cancer cells with MET amplification are dependent on MET signaling for their survival and are thus vulnerable to MET TKI treatment. Given the low prevalence of MET amplification in gastric cancer (approximately 8 %), testing for this genetic change would substantially narrow the target population but it might constitute a better biomarker than MET overexpression for MET TKI therapy. We compare aberrant MET signaling dependent on the HGF-MET axis or on MET amplification as well as address clinical issues and challenges associated with the identification of appropriate biomarkers for MET-driven tumors. PMID:26690587

  1. Cetuximab-induced MET activation acts as a novel resistance mechanism in colon cancer cells.

    PubMed

    Song, Na; Liu, Shizhou; Zhang, Jingdong; Liu, Jing; Xu, Ling; Liu, Yunpeng; Qu, Xiujuan

    2014-01-01

    Aberrant MET expression and hepatocyte growth factor (HGF) signaling are implicated in promoting resistance to targeted agents; however, the induced MET activation by epidermal growth factor receptor (EGFR) inhibitors mediating resistance to targeted therapy remains elusive. In this study, we identified that cetuximab-induced MET activation contributed to cetuximab resistance in Caco-2 colon cancer cells. MET inhibition or knockdown sensitized Caco-2 cells to cetuximab-mediated growth inhibition. Additionally, SRC activation promoted cetuximab resistance by interacting with MET. Pretreatment with SRC inhibitors abolished cetuximab-mediated MET activation and rendered Caco-2 cells sensitive to cetuximab. Notably, cetuximab induced MET/SRC/EGFR complex formation. MET inhibitor or SRC inhibitor suppressed phosphorylation of MET and SRC in the complex, and MET inhibitor singly led to disruption of complex formation. These results implicate alternative targeting of MET or SRC as rational strategies for reversing cetuximab resistance in colon cancer. PMID:24714091

  2. NARSTO EPA SS ST LOUIS AIR CHEM PM MET DATA

    Atmospheric Science Data Center

    2014-05-07

    NARSTO EPA SS ST LOUIS AIR CHEM PM MET DATA Project Title:  NARSTO ... Amount Surface Pressure Solar Radiation Surface Air Temperature Particulates Trace Metals Order Data:  ... Data Guide Documents:  St Louis Air Chem Guide St Louis Final Report  (PDF) St Louis QA ...

  3. NARSTO EPA SS NEW YORK AIR CHEM PM MET DATA

    Atmospheric Science Data Center

    2014-04-25

    NARSTO EPA SS NEW YORK AIR CHEM PM MET DATA Project Title:  NARSTO ... Thermooptical Transmission Location:  New York Spatial Resolution:  Point Measurements ...   Order Data Guide Documents:  New York Air Chem Guide CPM Summary Report  (PDF) ...

  4. The MET Project: The Wrong 45 Million Dollar Question

    ERIC Educational Resources Information Center

    Gabriel, Rachael; Allington, Richard

    2012-01-01

    In 2009, the Bill and Melinda Gates Foundation funded the investigation of a $45 million question: How can we identify and develop effective teaching? Now that the findings from their Measures of Effective Teaching (MET) project have been released, it's clear they asked a simpler question, namely, What other measures match up well with value-added…

  5. 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…

  6. Radical AdoMet enzymes in complex metal cluster biosynthesis.

    PubMed

    Duffus, Benjamin R; Hamilton, Trinity L; Shepard, Eric M; Boyd, Eric S; Peters, John W; Broderick, Joan B

    2012-11-01

    Radical S-adenosylmethionine (AdoMet) enzymes comprise a large superfamily of proteins that engage in a diverse series of biochemical transformations through generation of the highly reactive 5'-deoxyadenosyl radical intermediate. Recent advances into the biosynthesis of unique iron-sulfur (FeS)-containing cofactors such as the H-cluster in [FeFe]-hydrogenase, the FeMo-co in nitrogenase, as well as the iron-guanylylpyridinol (FeGP) cofactor in [Fe]-hydrogenase have implicated new roles for radical AdoMet enzymes in the biosynthesis of complex inorganic cofactors. Radical AdoMet enzymes in conjunction with scaffold proteins engage in modifying ubiquitous FeS precursors into unique clusters, through novel amino acid decomposition and sulfur insertion reactions. The ability of radical AdoMet enzymes to modify common metal centers to unusual metal cofactors may provide important clues into the stepwise evolution of these and other complex bioinorganic catalysts. This article is part of a Special Issue entitled: Radical SAM enzymes and Radical Enzymology. PMID:22269887

  7. The Marshall Engineering Thermosphere (MET) Model. Volume 1; Technical Description

    NASA Technical Reports Server (NTRS)

    Smith, R. E.

    1998-01-01

    Volume 1 presents a technical description of the Marshall Engineering Thermosphere (MET) model atmosphere and a summary of its historical development. Various programs developed to augment the original capability of the model are discussed in detail. The report also describes each of the individual subroutines developed to enhance the model. Computer codes for these subroutines are contained in four appendices.

  8. 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,…

  9. NARSTO PAC2001 CESSNA VOC PM OZONE MET DATA

    Atmospheric Science Data Center

    2014-04-25

    NARSTO PAC2001 CESSNA VOC PM OZONE MET DATA Project Title:  NARSTO Discipline:  ... Temperature Probe Humidity Probe Wind Sensor UV Ozone Detector Optical Counter GC Location:  Lower Fraser ... Air Temperature Humidity Upper Level Winds Ozone Aerosol Particle Properties Volatile Organic Compounds ...

  10. NARSTO PAC2001 CONVAIR PM OZONE MET DATA

    Atmospheric Science Data Center

    2014-04-25

    NARSTO PAC2001 CONVAIR PM OZONE MET DATA Project Title:  NARSTO Discipline:  ... Temperature Probe Humidity Probe Wind Sensor UV Ozone Detector Optical Counter Location:  Lower Fraser ... Air Temperature Humidity Upper Level Winds Ozone Aerosol Particle Properties Order Data:  ASDC Order ...

  11. Altered white matter architecture in BDNF met carriers.

    PubMed

    Ziegler, Erik; Foret, Ariane; Mascetti, Laura; Muto, Vincenzo; Le Bourdiec-Shaffii, Anahita; Stender, Johan; Balteau, Evelyne; Dideberg, Vinciane; Bours, Vincent; Maquet, Pierre; Phillips, Christophe

    2013-01-01

    Brain-derived neurotrophic factor (BDNF) modulates the pruning of synaptically silent axonal arbors. The Met allele of the BDNF gene is associated with a reduction in the neurotrophin's activity-dependent release. We used diffusion-weighted imaging to construct structural brain networks for 36 healthy subjects with known BDNF genotypes. Through permutation testing we discovered clear differences in connection strength between subjects carrying the Met allele and those homozygotic for the Val allele. We trained a Gaussian process classifier capable of identifying the subjects' allelic group with 86% accuracy and high predictive value. In Met carriers structural connectivity was greatly increased throughout the forebrain, particularly in connections corresponding to the anterior and superior corona radiata as well as corticothalamic and corticospinal projections from the sensorimotor, premotor, and prefrontal portions of the internal capsule. Interhemispheric connectivity was also increased via the corpus callosum and anterior commissure, and extremely high connectivity values were found between inferior medial frontal polar regions via the anterior forceps. We propose that the decreased availability of BDNF leads to deficits in axonal maintenance in carriers of the Met allele, and that this produces mesoscale changes in white matter architecture. PMID:23935975

  12. Lessons Learned: The MetLife Foundation Awards

    ERIC Educational Resources Information Center

    Kazis, Richard; Haynes, Leslie; Liebowitz, Martin

    2002-01-01

    This past year, Jobs for the Future studied strategies that community colleges are using to improve the quality and effectiveness of their services to low-income youth and adults. Much of this research was conducted for the MetLife Foundation Community College Excellence Awards Initiative. Across the country, in urban, rural, and suburban…

  13. In Vitro and In Vivo Activity of AMG 337, a Potent and Selective MET Kinase Inhibitor, in MET-Dependent Cancer Models.

    PubMed

    Hughes, Paul E; Rex, Karen; Caenepeel, Sean; Yang, Yajing; Zhang, Yihong; Broome, Martin A; Kha, Hue T; Burgess, Teresa L; Amore, Benny; Kaplan-Lefko, Paula J; Moriguchi, Jodi; Werner, Jonathan; Damore, Michael A; Baker, Daniel; Choquette, Deborah M; Harmange, Jean-Christophe; Radinsky, Robert; Kendall, Richard; Dussault, Isabelle; Coxon, Angela

    2016-07-01

    The MET receptor tyrosine kinase is involved in cell growth, survival, and invasion. Clinical studies with small molecule MET inhibitors have shown the role of biomarkers in identifying patients most likely to benefit from MET-targeted therapy. AMG 337 is an oral, small molecule, ATP-competitive, highly selective inhibitor of the MET receptor. Herein, we describe AMG 337 preclinical activity and mechanism of action in MET-dependent tumor models. These studies suggest MET is the only therapeutic target for AMG 337. In an unbiased tumor cell line proliferation screen (260 cell lines), a closely related analogue of AMG 337, Compound 5, exhibited activity in 2 of 260 cell lines; both were MET-amplified. Additional studies examining the effects of AMG 337 on the proliferation of a limited panel of cell lines with varying MET copy numbers revealed that high-level focal MET amplification (>12 copies) was required to confer MET oncogene addiction and AMG 337 sensitivity. One MET-amplified cell line, H1573 (>12 copies), was AMG 337 insensitive, possibly because of a downstream G12A KRAS mutation. Mechanism-of-action studies in sensitive MET-amplified cell lines demonstrated that AMG 337 inhibited MET and adaptor protein Gab-1 phosphorylation, subsequently blocking the downstream PI3K and MAPK pathways. AMG 337 exhibited potency in pharmacodynamic assays evaluating MET signaling in tumor xenograft models; >90% inhibition of Gab-1 phosphorylation was observed at 0.75 mg/kg. These findings describe the preclinical activity and mechanism of action of AMG 337 in MET-dependent tumor models and indicate its potential as a novel therapeutic for the treatment of MET-dependent tumors. Mol Cancer Ther; 15(7); 1568-79. ©2016 AACR. PMID:27196782

  14. 76 FR 401 - MetLife Insurance Company of Connecticut, et al.

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-04

    ..., Branch Chief, Office of Insurance Products, Division of Investment Management, at (202) 551-6795... COMMISSION MetLife Insurance Company of Connecticut, et al. December 28, 2010. AGENCY: Securities and...: MetLife Insurance Company of Connecticut (``MetLife of CT''), MetLife of CT Separate Account...

  15. Testing ATLAS Z+MET excess with LHC Run 2

    NASA Astrophysics Data System (ADS)

    Lu, Xiaochuan; Shirai, Satoshi; Terada, Takahiro

    2016-05-01

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

  16. 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

  17. Preliminary Results from the Mars Pathfinder ASI/MET Experiment

    NASA Technical Reports Server (NTRS)

    Haberle, R. M.; Schofield, J. T.; Crisp, D.; Barnes, J. R.; Magalhaes, J. A.; Murphy, J. R.; Seiff, A.; Wilson, G.; Larsen, S.; Young, Richard E. (Technical Monitor)

    1997-01-01

    Mars Pathfinder successfully landed in the Ares Vallis flood plain (19.3 N, 33.6 W) on July 4, 1997. The spacecraft carried a suite of instruments to record the structure of the atmosphere during the entry, descent, and landing as well as for monitoring meteorological phenomenon while on the surface. Collectively, these instruments are known as the ASI/MET experiment (Atmospheric Structure Investigation/Meteorology). In this paper we present preliminary results from the ASI/MET experiment. As of this writing, the spacecraft is healthy and continues to take daily meteorological measurements. We expect this will continue for almost one more earth year. Additional information is contained in the original extended abstract.

  18. Remote Sensing of Volcanic ASH at the Met Office

    NASA Astrophysics Data System (ADS)

    Marenco, F.; Kent, J.; Adam, M.; Buxmann, J.; Francis, P.; Haywood, J.

    2016-06-01

    The eruption of Eyjafjallajökull in 2010 has triggered the rapid development of volcanic ash remote sensing activities at the Met Office. Volcanic ash qualitative and quantitative mapping have been achieved using lidar on board the Facility for Airborne Atmospheric Measurements (FAAM) research aircraft, and using improved satellite retrieval algorithms. After the eruption, a new aircraft facility, the Met Office Civil Contingencies Aircraft (MOCCA), has been set up to enable a rapid response, and a network of ground-based remote sensing sites with lidars and sunphotometers is currently being developed. Thanks to these efforts, the United Kingdom (UK) will be much better equipped to deal with such a crisis, should it happen in the future.

  19. The MET receptor tyrosine kinase in invasion and metastasis.

    PubMed

    Benvenuti, Silvia; Comoglio, Paolo M

    2007-11-01

    Various cytokines and soluble growth factors upon interaction with their membrane receptors are responsible for inducing cellular proliferation, differentiation, movement, and protection from anoikis (a planned suicide activated by normal cells in absence of attachment to neighboring cells or extracellular matrix (EMC)). Among those soluble factors a major position is exerted by hepatocyte growth factor (HGF) together with its receptor MET and macrophage-stimulating protein (MSP) in cooperation with its receptor RON. PMID:17607709

  20. 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

  1. Astronaut Alan Shepard walks toward MET during first EVA

    NASA Technical Reports Server (NTRS)

    1971-01-01

    Astronaut Alan B. Shepard Jr., foreground, Apollo 14 commander, walks toward the Modularized Equipment Transporter (MET), out of view at right, during the first Apollo 14 extravehicular activity (EVA-1). An EVA checklist is attached to Shepard's left wrist. Astronaut Edgar D. Mitchell, lunar module pilot, is in the background working at a subpackage of the Apollo Lunar Surface Experiments Package (ALSEP). The cylindrical keg-like object directly under Mitchell's extended left hand is the Passive Seismic Experiment (PSE).

  2. HGF/Met and FOXM1 Form a Positive Feedback Loop and Render Pancreatic Cancer Cells Resistance to Met Inhibition and Aggressive Phenotypes

    PubMed Central

    Cui, Jiujie; Xia, Tian; Xie, Dacheng; Gao, Yong; Jia, Zhiliang; Wei, Daoyan; Wang, Liang; Huang, Suyun; Quan, Ming; Xie, Keping

    2015-01-01

    Purpose Hepatocyte growth factor (HGF)/Met signaling plays critical roles in pancreatic ductal adenocarcinoma (PDA) development and progression and is considered a potential therapeutic target for this disease. However, the mechanism of aberrant activation of HGF/Met signaling and resistance to Met inhibition in PDA remains unclear. Experimental Design The mechanistic role of cross-talk between Forkhead box M1 (FOXM1) and HGF/Met signaling in promotion of PDA growth and resistance to Met inhibition was examined using cell culture, molecular biology and mouse models; and the relevance of our experimental and mechanistic findings were validated using human PDA tissues. Results Met was markedly overexpressed in both PDA cell lines and pancreatic tumor specimens, and the expression of Met correlated directly with that of FOXM1 in human tumor specimens. Mechanistically, FOXM1 bound to the promoter region of the Met gene and transcriptionally increased the expression of Met. Increased expression of FOXM1 enhanced the activation of HGF/Met signaling and its downstream pathways, including RAS/extracellular signal-regulated kinase 1/2, phosphoinositide 3-kinase/AKT, and signal transducer and activator of transcription 3. Furthermore, activation of HGF/Met signaling increased the expression and transcriptional activity of FOXM1, and the cross-talk between FOXM1 and HGF/Met signaling promoted PDA growth and resistance to Met inhibition. Conclusions Collectively, our findings identified a positive feedback loop formed by FOXM1 and HGF/Met and revealed that this loop is a potentially effective therapeutic target for PDA. PMID:26876216

  3. Absolute Quantitation of Met Using Mass Spectrometry for Clinical Application: Assay Precision, Stability, and Correlation with MET Gene Amplification in FFPE Tumor Tissue

    PubMed Central

    Catenacci, Daniel V. T.; Liao, Wei-Li; Thyparambil, Sheeno; Henderson, Les; Xu, Peng; Zhao, Lei; Rambo, Brittany; Hart, John; Xiao, Shu-Yuan; Bengali, Kathleen; Uzzell, Jamar; Darfler, Marlene; Krizman, David B.; Cecchi, Fabiola; Bottaro, Donald P.; Karrison, Theodore; Veenstra, Timothy D.; Hembrough, Todd; Burrows, Jon

    2014-01-01

    Background Overexpression of Met tyrosine kinase receptor is associated with poor prognosis. Overexpression, and particularly MET amplification, are predictive of response to Met-specific therapy in preclinical models. Immunohistochemistry (IHC) of formalin-fixed paraffin-embedded (FFPE) tissues is currently used to select for ‘high Met’ expressing tumors for Met inhibitor trials. IHC suffers from antibody non-specificity, lack of quantitative resolution, and, when quantifying multiple proteins, inefficient use of scarce tissue. Methods After describing the development of the Liquid-Tissue-Selected Reaction Monitoring-mass spectrometry (LT-SRM-MS) Met assay, we evaluated the expression level of Met in 130 FFPE gastroesophageal cancer (GEC) tissues. We assessed the correlation of SRM Met expression to IHC and mean MET gene copy number (GCN)/nucleus or MET/CEP7 ratio by fluorescence in situ hybridization (FISH). Results Proteomic mapping of recombinant Met identified 418TEFTTALQR426 as the optimal SRM peptide. Limits of detection (LOD) and quantitation (LOQ) for this peptide were 150 and 200 amol/µg tumor protein, respectively. The assay demonstrated excellent precision and temporal stability of measurements in serial sections analyzed one year apart. Expression levels of 130 GEC tissues ranged (<150 amol/µg to 4669.5 amol/µg. High correlation was observed between SRM Met expression and both MET GCN and MET/CEP7 ratio as determined by FISH (n = 30; R2 = 0.898). IHC did not correlate well with SRM (n = 44; R2 = 0.537) nor FISH GCN (n = 31; R2 = 0.509). A Met SRM level of ≥1500 amol/µg was 100% sensitive (95% CI 0.69–1) and 100% specific (95% CI 0.92–1) for MET amplification. Conclusions The Met SRM assay measured the absolute Met levels in clinical tissues with high precision. Compared to IHC, SRM provided a quantitative and linear measurement of Met expression, reliably distinguishing between non-amplified and amplified MET

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

    SciTech Connect

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

    2012-11-15

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

  5. MET17 and Hydrogen Sulfide Formation in Saccharomyces cerevisiae

    PubMed Central

    Spiropoulos, Apostolos; Bisson, Linda F.

    2000-01-01

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

  6. Materials Evaluation Test Series (METS) 04, 05, and 06

    SciTech Connect

    Zalk, D; Ingram, C; Simmons, L; Arganbright, R; Lyle, J; Wong, K

    2006-03-23

    The purpose of this work is to examine the environmental, safety, health and operational aspects of detonating a confined explosive test apparatus that has been designed to maximize the dynamics of impact on beryllium metal components for Contained Firing Facility (CFF) applications. A combination of experimental collection and evaluation methods were designed and implemented to provide an evaluation of immediately postdetonation by-products reflecting a potential worst-case scenario beryllium aerosolization explosive event. The collective Material Evaluation Test Series (METS) 04 - 06 provided explosive devices designed to scale for the dedicated METS firing tank that would provide a post-detonation internal environment comparable to the CFF. The experimental results provided appropriate information to develop operational parameters to be considered for conducting full-scale beryllium-containing experimental tests with similar designs within CFF and B801A. These operational procedures include the inclusion of chelating agents in pre-shot CFF cardboard containers with a minimum of 600 gallons content, an extended time period post-test before purging the CFF chamber, and an adaptation of approaches toward applications of the scrubber and HEPA systems during the post-shot sequence for an integrated environmental, safety, and health approach. In addition, re-entry and film retrieval procedures will be adapted, in line with abatement techniques for cleaning the chamber, that will be required for work inside a CFF that will contain an elevated concentration of spherical and highly aerosolizable beryllium particulate.

  7. MicroRNA and MET in lung cancer

    PubMed Central

    2015-01-01

    MicroRNAs (miRNAs) are a class of small non-protein coding RNAs that modulate important cellular functions via their post-transcriptional regulation of messenger RNAs (mRNAs). Recent evidences from multiple tumor types and model systems implicate miRNA dysregulation as a common mechanism of tumorigenesis, cancer progression and resistance to therapy. Several miRNAs are dysregulated in cancers and a single miRNA can have multiple targets involved in different oncogenic pathways. MET, the tyrosine kinase receptor for hepatocyte growth factor (HGF), has a central role in lung cancer development and in acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors; it has been predicted and shown to be the target gene of multiple miRNAs, which play a crucial role in controlling its activity in a stimulatory or inhibitory sense. In this review we will focus on the most important and recent studies about the role of miRNAs in the control of MET expression, reporting also the progress made using miRNAs for therapy of lung cancer. PMID:25992367

  8. Computational study of Met-Car analogue heterofullerenes

    NASA Astrophysics Data System (ADS)

    Domingos, H. S.

    2006-06-01

    Structural, chemical and electronic properties of a number of Met-Car analogue heterofullerenes were investigated using a combination of ab initio and semi-empirical quantum mechanical calculations.Met-Car clusters of known structure and chemistry were studied together with some new hypothetical configurations. In particular, the stability of clusters of the form Y8C12 (Y = Al, S, Si, Ti, As, Bi, Sb, P, N, B, Sn, Sc, Cr, V), XY7C12 (X, Y = B, N, Si) and Y8Z12 (Y, Z = N, B, Si) were investigated based on computed binding energies, Mulliken charges, bond orders and ionization potentials. The results indicate that some novel clusters are due for observation. Clusters of this type are known to form the building blocks of new polymerized solids and may exhibit some novel dielectric, magnetic and superconducting properties. Isomers of D3d symmetry, which are possible global energy minima for Cr, V and Sc carbide clusters, were also identified.

  9. MetOp/HIRS pre-launch characterization data reanalysis

    NASA Astrophysics Data System (ADS)

    Chang, Tiejun; Cao, Changyong

    2011-09-01

    Instrument self-emission and nonlinear response play important roles in satellite thermal infrared radiometers, and can affect the accuracy of Earth scene radiance retrieval if uncorrected. This paper presents a simplified self-emission model for infrared radiometers and analyzes the interrelationships between the instrument selfemission, detector nonlinearity, and calibration intercept and slope variations using MetOp-A/HIRS prelaunch characterization data. HIRS is a traditional cross-track line scanning radiometer in the infrared and visible spectrum, including 12 long wave infrared channels (669-1529cm-1), 7 short wave infrared channels (2188- 2657cm-1), and 1 visible channel, with beamsplitters and a rotating filter wheel assembly consisting of 20 spectral filters separates individual channels. The warm filters and other in-path components generate selfemission which becomes the majority of the total radiance falling on the detector. The pre-launch TV data allow us to evaluate the self-emission using the simplified model. It was found that the self-emission contributions at the detectors are in the range of 95% to 97%. The self-emission fluctuates with the instrument temperature and causes the variation in instrument response, including the variations of intercept and the instrument gain. The quantification of these variations provides guideline for on-orbit calibration algorithm improvement. The selfemission model is improved and its impact on MetOp-A/HIRS on-orbit calibration and Earth scene retrieval are also assessed.

  10. 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

  11. GOME-2 total ozone columns from MetOp-A/MetOp-B and assimilation in the MACC system

    NASA Astrophysics Data System (ADS)

    Hao, N.; Koukouli, M. E.; Inness, A.; Valks, P.; Loyola, D. G.; Zimmer, W.; Balis, D. S.; Zyrichidou, I.; Van Roozendael, M.; Lerot, C.; Spurr, R. J. D.

    2014-03-01

    The two Global Ozone Monitoring Instrument (GOME-2) sensors operated in tandem are flying onboard EUMETSAT's MetOp-A and MetOp-B satellites, launched in October 2006 and September 2012 respectively. This paper presents the operational GOME-2/MetOp-A (GOME-2A) and GOME-2/MetOp-B (GOME-2B) total ozone products provided by the EUMETSAT Satellite Application Facility on Ozone and Atmospheric Chemistry Monitoring (O3M-SAF). These products are generated using the latest version of the GOME Data Processor (GDP version 4.7). The enhancements in GDP 4.7, including the application of Brion-Daumont-Malicet ozone absorption cross-sections, are presented here. On a global scale, GOME-2B has the same high accuracy as the corresponding GOME-2A products. There is an excellent agreement between the ozone total columns from the two sensors, with GOME-2B values slightly lower with a mean difference of only 0.55 ± 0.29%. First global validation results for 6 months of GOME-2B total ozone using ground-based measurements show that on average the GOME-2B total ozone data obtained with GDP 4.7 slightly overestimate Dobson observations by about 2.0 ± 1.0% and Brewer observations by about 1.0 ± 0.8%. It is concluded that the total ozone columns (TOCs) provided by GOME-2A and GOME-2B are consistent and may be used simultaneously without introducing trends or other systematic effects. GOME-2A total ozone data have been used operationally in the Copernicus atmospheric service project MACC-II (Monitoring Atmospheric Composition and Climate - Interim Implementation) near-real-time (NRT) system since October 2013. The magnitude of the bias correction needed for assimilating GOME-2A ozone is reduced (to about -6 DU in the global mean) when the GOME-2 ozone retrieval algorithm changed to GDP 4.7.

  12. GOME-2 total ozone columns from MetOp-A/MetOp-B and assimilation in the MACC system

    NASA Astrophysics Data System (ADS)

    Hao, N.; Koukouli, M. E.; Inness, A.; Valks, P.; Loyola, D. G.; Zimmer, W.; Balis, D. S.; Zyrichidou, I.; Van Roozendael, M.; Lerot, C.; Spurr, R. J. D.

    2014-09-01

    The two Global Ozone Monitoring Instrument (GOME-2) sensors operated in tandem are flying onboard EUMETSAT's (European Organisation for the Exploitation of Meteorological Satellites) MetOp-A and MetOp-B satellites, launched in October 2006 and September 2012 respectively. This paper presents the operational GOME-2/MetOp-A (GOME-2A) and GOME-2/MetOp-B (GOME-2B) total ozone products provided by the EUMETSAT Satellite Application Facility on Ozone and Atmospheric Chemistry Monitoring (O3M-SAF). These products are generated using the latest version of the GOME Data Processor (GDP version 4.7). The enhancements in GDP 4.7, including the application of Brion-Daumont-Malicet ozone absorption cross sections, are presented here. On a global scale, GOME-2B has the same high accuracy as the corresponding GOME-2A products. There is an excellent agreement between the ozone total columns from the two sensors, with GOME-2B values slightly lower with a mean difference of only 0.55±0.29%. First global validation results for 6 months of GOME-2B total ozone using ground-based measurements show that on average the GOME-2B total ozone data obtained with GDP 4.7 are slightly higher than, both, Dobson observations by about 2.0±1.0% and Brewer observations by about 1.0±0.8%. It is concluded that the total ozone columns (TOCs) provided by GOME-2A and GOME-2B are consistent and may be used simultaneously without introducing systematic effects, which has been illustrated for the Antarctic ozone hole on 18 October 2013. GOME-2A total ozone data have been used operationally in the Copernicus atmospheric service project MACC-II (Monitoring Atmospheric Composition and Climate - Interim Implementation) near-real-time (NRT) system since October 2013. The magnitude of the bias correction needed for assimilating GOME-2A ozone is reduced (to about -6 DU in the global mean) when the GOME-2 ozone retrieval algorithm changed to GDP 4.7.

  13. 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. PMID:26923413

  14. Design, synthesis and structure-activity relationships of novel biarylamine-based Met kinase inhibitors

    SciTech Connect

    Williams, David K; Chen, Xiao-Tao; Tarby, Christine; Kaltenbach, Robert; Cai, Zhen-Wei; Tokarski, John S; An, Yongmi; Sack, John S; Wautlet, Barri; Gullo-Brown, Johnni; Henley, Benjamin J; Jeyaseelan, Robert; Kellar, Kristen; Manne, Veeraswamy; Trainor, George L; Lombardo, Louis J; Fargnoli, Joseph; Borzilleri, Robert M

    2010-09-03

    Biarylamine-based inhibitors of Met kinase have been identified. Lead compounds demonstrate nanomolar potency in Met kinase biochemical assays and significant activity in the Met-driven GTL-16 human gastric carcinoma cell line. X-ray crystallography revealed that these compounds adopt a bioactive conformation, in the kinase domain, consistent with that previously seen with 2-pyridone-based Met kinase inhibitors. Compound 9b demonstrated potent in vivo antitumor activity in the GTL-16 human tumor xenograft model.

  15. The MetLife Survey of the American Teacher: Collaborating for Student Success

    ERIC Educational Resources Information Center

    MetLife, Inc., 2010

    2010-01-01

    "The MetLife Survey of the American Teacher: Collaborating for Student Success (2009)" was conducted by Harris Interactive and is twenty-sixth in a series sponsored by MetLife since 1984 to give voice to those closest to the classroom. This "MetLife Survey" examines the views of teachers, principals and students about respective roles and…

  16. 29 CFR 779.227 - Conditions which must be met for exception.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 3 2010-07-01 2010-07-01 false Conditions which must be met for exception. 779.227 Section... met for exception. This exception, in accordance with its specific terms, will apply to exclude an establishment from enterprise coverage only if the following conditions are met: (a) The establishment must be...

  17. 29 CFR 779.510 - Conditions that must be met for section 13(b)(11) exemption.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 3 2011-07-01 2011-07-01 false Conditions that must be met for section 13(b)(11) exemption... met for section 13(b)(11) exemption. In order that an employee be exempt from the overtime provisions... under section 7(a) of the Act. If all the preceding conditions are not met the exemption is inapplicable....

  18. 29 CFR 779.227 - Conditions which must be met for exception.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 3 2012-07-01 2012-07-01 false Conditions which must be met for exception. 779.227 Section... met for exception. This exception, in accordance with its specific terms, will apply to exclude an establishment from enterprise coverage only if the following conditions are met: (a) The establishment must be...

  19. 29 CFR 779.510 - Conditions that must be met for section 13(b)(11) exemption.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 3 2010-07-01 2010-07-01 false Conditions that must be met for section 13(b)(11) exemption... met for section 13(b)(11) exemption. In order that an employee be exempt from the overtime provisions... under section 7(a) of the Act. If all the preceding conditions are not met the exemption is inapplicable....

  20. 43 CFR 1810.2 - Communications by mail; when mailing requirements are met.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... requirements are met. 1810.2 Section 1810.2 Public Lands: Interior Regulations Relating to Public Lands... GENERAL GUIDANCE General Rules § 1810.2 Communications by mail; when mailing requirements are met. (a... requirement for mailing is met when the communication, addressed to the addressee at his last address...

  1. 29 CFR 779.227 - Conditions which must be met for exception.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 3 2013-07-01 2013-07-01 false Conditions which must be met for exception. 779.227 Section... met for exception. This exception, in accordance with its specific terms, will apply to exclude an establishment from enterprise coverage only if the following conditions are met: (a) The establishment must be...

  2. 34 CFR 648.70 - What conditions must be met by a fellow?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 34 Education 3 2013-07-01 2013-07-01 false What conditions must be met by a fellow? 648.70 Section 648.70 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF... Must Be Met by a Fellow After an Award? § 648.70 What conditions must be met by a fellow? To...

  3. 34 CFR 648.70 - What conditions must be met by a fellow?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 34 Education 3 2014-07-01 2014-07-01 false What conditions must be met by a fellow? 648.70 Section 648.70 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF... Must Be Met by a Fellow After an Award? § 648.70 What conditions must be met by a fellow? To...

  4. 34 CFR 650.34 - What conditions must be met by fellows?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 3 2010-07-01 2010-07-01 false What conditions must be met by fellows? 650.34 Section... POSTSECONDARY EDUCATION, DEPARTMENT OF EDUCATION JACOB K. JAVITS FELLOWSHIP PROGRAM What Conditions Must be Met By Fellows? § 650.34 What conditions must be met by fellows? In order to continue to receive...

  5. 43 CFR 1810.2 - Communications by mail; when mailing requirements are met.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... requirements are met. 1810.2 Section 1810.2 Public Lands: Interior Regulations Relating to Public Lands... GENERAL GUIDANCE General Rules § 1810.2 Communications by mail; when mailing requirements are met. (a... requirement for mailing is met when the communication, addressed to the addressee at his last address...

  6. 34 CFR 272.40 - What conditions must be met by a recipient of a grant?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... with appropriate SEAs funded under 34 CFR part 271. As part of this coordination, the recipient shall... 34 Education 1 2012-07-01 2012-07-01 false What conditions must be met by a recipient of a grant... Conditions Must Be Met by a Recipient of a Grant? § 272.40 What conditions must be met by a recipient of...

  7. 34 CFR 648.70 - What conditions must be met by a fellow?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 3 2010-07-01 2010-07-01 false What conditions must be met by a fellow? 648.70 Section 648.70 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF... Must Be Met by a Fellow After an Award? § 648.70 What conditions must be met by a fellow? To...

  8. 29 CFR 779.510 - Conditions that must be met for section 13(b)(11) exemption.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 3 2013-07-01 2013-07-01 false Conditions that must be met for section 13(b)(11) exemption... met for section 13(b)(11) exemption. In order that an employee be exempt from the overtime provisions... under section 7(a) of the Act. If all the preceding conditions are not met the exemption is inapplicable....

  9. 29 CFR 779.510 - Conditions that must be met for section 13(b)(11) exemption.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 3 2014-07-01 2014-07-01 false Conditions that must be met for section 13(b)(11) exemption... met for section 13(b)(11) exemption. In order that an employee be exempt from the overtime provisions... under section 7(a) of the Act. If all the preceding conditions are not met the exemption is inapplicable....

  10. 43 CFR 1810.2 - Communications by mail; when mailing requirements are met.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... requirements are met. 1810.2 Section 1810.2 Public Lands: Interior Regulations Relating to Public Lands... GENERAL GUIDANCE General Rules § 1810.2 Communications by mail; when mailing requirements are met. (a... requirement for mailing is met when the communication, addressed to the addressee at his last address...

  11. 34 CFR 650.34 - What conditions must be met by fellows?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 34 Education 3 2014-07-01 2014-07-01 false What conditions must be met by fellows? 650.34 Section... POSTSECONDARY EDUCATION, DEPARTMENT OF EDUCATION JACOB K. JAVITS FELLOWSHIP PROGRAM What Conditions Must be Met By Fellows? § 650.34 What conditions must be met by fellows? In order to continue to receive...

  12. 34 CFR 650.34 - What conditions must be met by fellows?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 34 Education 3 2011-07-01 2011-07-01 false What conditions must be met by fellows? 650.34 Section... POSTSECONDARY EDUCATION, DEPARTMENT OF EDUCATION JACOB K. JAVITS FELLOWSHIP PROGRAM What Conditions Must be Met By Fellows? § 650.34 What conditions must be met by fellows? In order to continue to receive...

  13. 34 CFR 272.40 - What conditions must be met by a recipient of a grant?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... with appropriate SEAs funded under 34 CFR part 271. As part of this coordination, the recipient shall... 34 Education 1 2011-07-01 2011-07-01 false What conditions must be met by a recipient of a grant... Conditions Must Be Met by a Recipient of a Grant? § 272.40 What conditions must be met by a recipient of...

  14. 34 CFR 650.34 - What conditions must be met by fellows?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 34 Education 3 2012-07-01 2012-07-01 false What conditions must be met by fellows? 650.34 Section... POSTSECONDARY EDUCATION, DEPARTMENT OF EDUCATION JACOB K. JAVITS FELLOWSHIP PROGRAM What Conditions Must be Met By Fellows? § 650.34 What conditions must be met by fellows? In order to continue to receive...

  15. 34 CFR 650.34 - What conditions must be met by fellows?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 34 Education 3 2013-07-01 2013-07-01 false What conditions must be met by fellows? 650.34 Section... POSTSECONDARY EDUCATION, DEPARTMENT OF EDUCATION JACOB K. JAVITS FELLOWSHIP PROGRAM What Conditions Must be Met By Fellows? § 650.34 What conditions must be met by fellows? In order to continue to receive...

  16. 34 CFR 272.40 - What conditions must be met by a recipient of a grant?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... with appropriate SEAs funded under 34 CFR part 271. As part of this coordination, the recipient shall... 34 Education 1 2013-07-01 2013-07-01 false What conditions must be met by a recipient of a grant... Conditions Must Be Met by a Recipient of a Grant? § 272.40 What conditions must be met by a recipient of...

  17. 29 CFR 779.227 - Conditions which must be met for exception.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 3 2014-07-01 2014-07-01 false Conditions which must be met for exception. 779.227 Section... met for exception. This exception, in accordance with its specific terms, will apply to exclude an establishment from enterprise coverage only if the following conditions are met: (a) The establishment must be...

  18. 34 CFR 648.70 - What conditions must be met by a fellow?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 34 Education 3 2011-07-01 2011-07-01 false What conditions must be met by a fellow? 648.70 Section 648.70 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF... Must Be Met by a Fellow After an Award? § 648.70 What conditions must be met by a fellow? To...

  19. 34 CFR 272.40 - What conditions must be met by a recipient of a grant?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... with appropriate SEAs funded under 34 CFR part 271. As part of this coordination, the recipient shall... 34 Education 1 2014-07-01 2014-07-01 false What conditions must be met by a recipient of a grant... Conditions Must Be Met by a Recipient of a Grant? § 272.40 What conditions must be met by a recipient of...

  20. 29 CFR 779.510 - Conditions that must be met for section 13(b)(11) exemption.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 3 2012-07-01 2012-07-01 false Conditions that must be met for section 13(b)(11) exemption... met for section 13(b)(11) exemption. In order that an employee be exempt from the overtime provisions... under section 7(a) of the Act. If all the preceding conditions are not met the exemption is inapplicable....

  1. 29 CFR 779.227 - Conditions which must be met for exception.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 3 2011-07-01 2011-07-01 false Conditions which must be met for exception. 779.227 Section... met for exception. This exception, in accordance with its specific terms, will apply to exclude an establishment from enterprise coverage only if the following conditions are met: (a) The establishment must be...

  2. 43 CFR 1810.2 - Communications by mail; when mailing requirements are met.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... requirements are met. 1810.2 Section 1810.2 Public Lands: Interior Regulations Relating to Public Lands... GENERAL GUIDANCE General Rules § 1810.2 Communications by mail; when mailing requirements are met. (a... requirement for mailing is met when the communication, addressed to the addressee at his last address...

  3. 34 CFR 648.70 - What conditions must be met by a fellow?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 34 Education 3 2012-07-01 2012-07-01 false What conditions must be met by a fellow? 648.70 Section 648.70 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF... Must Be Met by a Fellow After an Award? § 648.70 What conditions must be met by a fellow? To...

  4. 34 CFR 272.40 - What conditions must be met by a recipient of a grant?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... with appropriate SEAs funded under 34 CFR part 271. As part of this coordination, the recipient shall... 34 Education 1 2010-07-01 2010-07-01 false What conditions must be met by a recipient of a grant... Conditions Must Be Met by a Recipient of a Grant? § 272.40 What conditions must be met by a recipient of...

  5. Effects of Wearing Compression Stockings on the Physical Performance of T2DM Men with MetS.

    PubMed

    Brinkmann, C; Hermann, R; Rühl, E; Kerzel, H; Reinhardt, L; Grau, M; Latsch, J; Kohl-Bareis, M; Bloch, W; Brixius, K

    2016-05-01

    Metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) are associated with macro- and microcirculatory complications that reduce physical performance. Wearing compression garments to potentially optimize hemodynamics has been discussed. This study investigates the effects of wearing compression stockings on physical performance-related variables in type 2 diabetic men with metabolic syndrome (n=9, 57±12 years, BMI: 36±4 kg/m(2)). Participants served as their own controls in a randomized 3*3 crossover study wearing below-knee stockings with either compression (24 or 30 mmHg ankle pressure) or no compression. Venous pooling and lower limb oxygenation profiles were determined with near-infrared spectroscopy and arterial oxygen saturation was determined using a pulse oxymeter. Measurements were performed in the supine lying position, during standing, following 10 tiptoe exercises and after submaximal intensity cycling. In addition, lactate and erythrocyte deformability were analyzed in capillary blood pre- and post-exercise. Erythrocyte deformability was analyzed using a laser-assisted optical rotational red cell analyzer. No significant differences in any variables when wearing different compression or regular stockings were evident at any point of measurement. This study did not reveal any beneficial effects of wearing compression stockings at rest and during acute bouts of moderately intense exercise in this particular patient group. PMID:26859644

  6. The new Met Office strategy for seasonal forecasts

    NASA Astrophysics Data System (ADS)

    Hewson, T. D.

    2012-04-01

    In October 2011 the Met Office began issuing a new-format UK seasonal forecast, called "The 3-month Outlook". Government interest in a UK-relevant product had been heightened by infrastructure issues arising during the severe cold of previous winters. At the same time there was evidence that the Met Office's "GLOSEA4" long range forecasting system exhibited some hindcast skill for the UK, that was comparable to its hindcast skill for the larger (and therefore less useful) 'northern Europe' region. Also, the NAO- and AO- signals prevailing in the previous two winters had been highlighted by the GLOSEA4 model well in advance. This presentation will initially give a brief overview of GLOSEA4, describing key features such as evolving sea-ice, a well-resolved stratosphere, and the perturbation strategy. Skill measures will be shown, along with forecasts for the last 3 winters. The new structure 3-month outlook will then be described and presented. Previously, our seasonal forecasts had been based on a tercile approach. The new format outlook aims to substantially improve upon this by illustrating graphically, and with text, the full range of possible outcomes, and by placing those outcomes in the context of climatology. In one key component the forecast pdfs (probability density functions) are displayed alongside climatological pdfs. To generate the forecast pdf we take the bias-corrected GLOSEA4 output (42 members), and then incorporate, via expert team, all other relevant information. Firstly model forecasts from other centres are examined. Then external 'forcing factors', such as solar, and the state of the land-ocean-ice system, are referenced, assessing how well the models represent their influence, and bringing in statistical relationships where appropriate. The expert team thereby decides upon any changes to the GLOSEA4 data, employing an interactive tool to shift, expand or contract the forecast pdfs accordingly. The full modification process will be illustrated

  7. A novel antagonist anti-cMet antibody with antitumor activities targeting both ligand-dependent and ligand-independent c-Met receptors.

    PubMed

    Gonzalez, Alexandra; Broussas, Matthieu; Beau-Larvor, Charlotte; Haeuw, Jean-François; Boute, Nicolas; Robert, Alain; Champion, Thierry; Beck, Alain; Bailly, Christian; Corvaïa, Nathalie; Goetsch, Liliane

    2016-10-15

    c-Met is a prototypic member of a sub-family of RTKs. Inappropriate c-Met activation plays a crucial role in tumor formation, proliferation and metastasis. Using a key c-Met dimerization assay, a set of 12 murine whole IgG1 monoclonal antibodies was selected and a lead candidate, m224G11, was humanized by CDR-grafting and engineered to generate a divalent full antagonist humanized IgG1 antibody, hz224G11. Neither m224G11 nor hz224G11 bind to the murine c-Met receptor. Their antitumor activity was investigated in vitro in a set of experiments consistent with the reported pleiotropic effects mediated by c-Met and, in vivo, using several human tumor xenograft models. Both m224G11 and hz224G11 exhibited nanomolar affinities for the receptor and inhibited HGF binding, c-Met phosphorylation, and receptor dimerization in a similar fashion, resulting in a profound inhibition of all c-Met functions in vitro. These effects were presumably responsible for the inhibition of c-Met's major functions including cell proliferation, migration, invasion scattering, morphogenesis and angiogenesis. In addition to these in vitro properties, hz224G11 dramatically inhibits the growth of autocrine, partially autophosphorylated and c-Met amplified cell lines in vivo. Pharmacological studies performed on Hs746T gastric cancer xenografts demonstrate that hz224G11 strongly downregulates c-Met expression and phosphorylation. It also decreases the tumor mitotic index (Ki67) and induces apoptosis. Taken together, the in vitro and in vivo data suggest that hz224G11 is a promising candidate for the treatment of tumors. This antibody, now known as ABT-700 and currently in Phase I clinical trials, may provide a novel therapeutic approach to c-Met-expressing cancers. PMID:27144973

  8. Cytotoxic activity of Tivantinib (ARQ 197) is not due solely to MET inhibition

    PubMed Central

    Katayama, Ryohei; Aoyama, Aki; Yamori, Takao; Qi, Jie; Oh-hara, Tomoko; Song, Youngchul; Engelman, Jeffrey A.; Fujita, Naoya

    2013-01-01

    The receptor tyrosine kinase c-MET is the high-affinity receptor for the hepatocyte growth factor (HGF). The HGF/c-MET axis is often dysregulated in tumors. c-MET activation can be caused by MET gene amplification, activating mutations, and auto- or paracrine mechanisms. Thus, c-MET inhibitors are under development as anti-cancer drugs. Tivantinib (ARQ 197) was reported as a small molecule c-MET inhibitor and early clinical studies suggest anti-tumor activity. To assess if the anti-tumor activity of tivantinib was due to inhibition of c-MET, we compared the activity of tivantinib to other c-MET inhibitors in both c-MET addicted and non-addicted cancer cells. As expected, other c-MET inhibitors, crizotinib and PHA-665752, suppressed the growth of c-MET addicted cancers, but not the growth of cancers that are not addicted to c-MET. In contrast, tivantinib inhibited cell viability with similar potency in both c-MET addicted and non-addicted cells. These results suggest that tivantinib exhibits its antitumor activity in a manner independent of c-MET status. Tivantinib treatment induced a G2/M cell cycle arrest in EBC1 cells similarly to vincristine treatment, whereas PHA-665752 or crizotinib treatment markedly induced G0/G1 cell cycle arrest. To identify the additional molecular target of tivantinib, we performed COMPARE analysis, an in silico screening of a database of drug sensitivities across 39 cancer cell lines (JFCR39), and identified microtubule as a target of tivantinib. Tivantinib treated cells demonstrated typical microtubule disruption similar to vincristine and inhibited microtubule assembly in vitro. These results suggest that tivantinib inhibits microtubule polymerization in addition to inhibiting c-MET. PMID:23598276

  9. Aerosol impacts in the Met Office global NWP model

    NASA Astrophysics Data System (ADS)

    Mulcahy, Jane P.; Brooks, Malcolm E.; Milton, Sean F.

    2010-05-01

    An accurate representation of the direct and indirect effect of aerosols is of growing concern for global numerical weather prediction (NWP). Increased scattering and absorption of incoming shortwave (SW) and outgoing longwave radiation (OLR) fields due to the presence of aerosol layers in the atmosphere modifies the atmospheric heating profile and can affect large-scale circulation patterns. The current representation of aerosols in the global NWP configuration of the Met Office Unified ModelTM (MetUM) is based on a simple aerosol climatology (Cusack et al., 1998). Profiles of water soluble dust, soot, oceanic and stratospheric sulphate aerosols are described separately for land and ocean surfaces and are distributed over the boundary layer, free troposphere and stratosphere (sulphates only). While this improved the reflected SW radiative bias at the top-of-atmosphere (TOA), there is evidence that the climatology is too absorbing leading to a temperature bias in the lower troposphere of approximately 0.5 K/day. Furthermore, the omission of the scattering and absorption properties of mineral dust and biomass burning aerosol particles in particular, is believed to be the principal cause of significant model biases (in the region of 50-56 W m-2) in both the model OLR at the TOA (Haywood et al., 2005) and the surface SW radiation fields (Milton et al., 2008). One of the objectives of the Global Aerosols (G-AER) component of the MACC (Monitoring Atmospheric Composition and Climate) project is to evaluate the impact of an improved aerosol representation on the performance of global NWP models. In a stepwise approach of increasing the aerosol complexity in the MetUM, the Cusack climatology is being replaced by the CLASSIC (Coupled Large-scale Aerosol Simulator for Studies in Climate) aerosol scheme, developed for the HadGEM (Hadley Centre Global Environmental Model) climate model. CLASSIC includes representations of external mixtures of sulphate, black carbon, organic

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

    SciTech Connect

    Lee, R.H.

    1995-12-31

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

  11. Airbag and ASI/MET instrument in 360-degree panorama

    NASA Technical Reports Server (NTRS)

    1997-01-01

    This view from the lander was imaged by the Imager for Mars Pathfinder (IMP) as part of a 360-degree color panorama, taken over sols 8, 9 and 10. A deflated airbag is at the bottom of the image. At the extreme right, the Atmospheric Structure Instrument and Meteorology package (ASI/MET)mast, with its three windsocks, is visible.are at the bottom right of the image.

    Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

  12. MetNH3: Metrology for ammonia in ambient air

    NASA Astrophysics Data System (ADS)

    Braban, Christine; Twigg, Marsailidh; Tang, Sim; Leuenberger, Daiana; Ferracci, Valerio; Martin, Nick; Pascale, Celine; Hieta, Tuomas; Pogany, Andrea; Persijn, Stefan; van Wijk, Janneke; Gerwig, Holger; Wirtze, Klaus; Tiebe, Carlo; Balslev-Harder, David; Niederhausen, Bernhardt

    2015-04-01

    Measuring ammonia in ambient air is a sensitive and priority issue due to its harmful effects on human health and ecosystems. The European Directive 2001/81/EC on 'National Emission Ceilings for Certain Atmospheric Pollutants (NEC)' regulates ammonia emissions in the member states. However, there is a lack of regulation to ensure reliable ammonia measurements namely in applicable analytical technology, maximum allowed uncertainty, quality assurance and quality control (QC/QA) procedures as well as in the infrastructure to attain metrological traceability. Validated ammonia measurement data of high quality from air monitoring networks are vitally important for identifying changes due to implementations of environment policies, for understanding where the uncertainties in current emission inventories are derived from and for providing independent verification of atmospheric model predictions. The new EURAMET project MetNH3 aims to develop improved reference gas mixtures by static and dynamic gravimetric generation methods, develop and characterise laser based optical spectrometric standards and establish the transfer from high-accuracy standards to field applicable methods. MetNH3started in June 2014 and in this presentation the first results from the metrological characterisation of a commercially available cavity ring-down spectrometer (CRDS) will be discussed. Also first tests and results from a new design, Controlled Atmosphere Test Facility (CATFAC), which is to be characterised and used to validate the performance of diffusive samplers, denuders and on-line instruments, will be reported. CAFTEC can be used to control test parameters such as ammonia concentration, relative humidity and wind speed. Outline plans for international laboratory and field intercomparisons in 2016 will be presented.

  13. Statin action favors normalization of the plasma lipidome in the atherogenic mixed dyslipidemia of MetS: potential relevance to statin-associated dysglycemia.

    PubMed

    Meikle, Peter J; Wong, Gerard; Tan, Ricardo; Giral, Philippe; Robillard, Paul; Orsoni, Alexina; Hounslow, Neil; Magliano, Dianna J; Shaw, Jonathan E; Curran, Joanne E; Blangero, John; Kingwell, Bronwyn A; Chapman, M John

    2015-12-01

    The impact of statin treatment on the abnormal plasma lipidome of mixed dyslipidemic patients with metabolic syndrome (MetS), a group at increased risk of developing diabetes, was evaluated. Insulin-resistant hypertriglyceridemic hypertensive obese males (n = 12) displaying MetS were treated with pitavastatin (4 mg/day) for 180 days; healthy normolipidemic age-matched nonobese males (n = 12) acted as controls. Statin treatment substantially normalized triglyceride (-41%), remnant cholesterol (-55%), and LDL-cholesterol (-39%), with minor effect on HDL-cholesterol (+4%). Lipidomic analysis, normalized to nonHDL-cholesterol in order to probe statin-induced differences in molecular composition independently of reduction in plasma cholesterol, revealed increment in 132 of 138 lipid species that were subnormal at baseline and significantly shifted toward the control group on statin treatment. Increment in alkyl- and alkenylphospholipids (plasmalogens) was prominent, and consistent with significant statin-induced increase in plasma polyunsaturated fatty acid levels. Comparison of the statin-mediated lipidomic changes in MetS with the abnormal plasma lipidomic profile characteristic of prediabetes and T2D in the Australian Diabetes, Obesity, and Lifestyle Study and San Antonio Family Heart Study cohorts by hypergeometric analysis revealed a significant shift toward the lipid profile of controls, indicative of a marked trend toward a normolipidemic phenotype. Pitavastatin attenuated the abnormal plasma lipidome of MetS patients typical of prediabetes and T2D. PMID:26486974

  14. PEA3 transcription factors are downstream effectors of Met signaling involved in migration and invasiveness of Met-addicted tumor cells.

    PubMed

    Kherrouche, Zoulika; Monte, Didier; Werkmeister, Elisabeth; Stoven, Luc; De Launoit, Yvan; Cortot, Alexis B; Tulasne, David; Chotteau-Lelievre, Anne

    2015-11-01

    Various solid tumors including lung or gastric carcinomas display aberrant activation of the Met receptor which correlates with aggressive phenotypes and poor prognosis. Although downstream signaling of Met is well described, its integration at the transcriptional level is poorly understood. We demonstrate here that in cancer cells harboring met gene amplification, inhibition of Met activity with tyrosine kinase inhibitors or specific siRNA drastically decreased expression of ETV1, ETV4 and ETV5, three transcription factors constituting the PEA3 subgroup of the ETS family, while expression of the other members of the family were less or not affected. Similar link between Met activity and PEA3 factors expression was found in lung cancer cells displaying resistance to EGFR targeted therapy involving met gene amplification. Using silencing experiments, we demonstrate that the PEA3 factors are required for efficient migration and invasion mediated by Met, while other biological responses such as proliferation or unanchored growth remain unaffected. PEA3 overexpression or silencing revealed that they participated in the regulation of the MMP2 target gene involved in extracellular matrix remodeling. Our results demonstrated that PEA3-subgroup transcription factors are key players of the Met signaling integration involved in regulation of migration and invasiveness. PMID:26238631

  15. Emerging molecular targets in oncology: clinical potential of MET/hepatocyte growth-factor inhibitors

    PubMed Central

    Smyth, Elizabeth C; Sclafani, Francesco; Cunningham, David

    2014-01-01

    The MET/hepatocyte growth-factor (HGF) signaling pathway plays a key role in the processes of embryogenesis, wound healing, and organ regeneration. Aberrant activation of MET/HGF occurs through multiple mechanisms including gene amplification, mutation, protein overexpression, and abnormal gene splicing interrupting autocrine and paracrine regulatory feedback mechanisms. In many cancers including non-small-cell lung cancer, colorectal, gastric, renal, and hepatocellular cancer, dysregulation of MET may lead to a more aggressive cancer phenotype and may be a negative prognostic indicator. Successful therapeutic targeting of the MET/HGF pathway has been achieved using monoclonal antibodies against the MET receptor and its ligand HGF in addition to MET-specific and multitargeted small-molecule tyrosine-kinase inhibitors with several drugs in late-phase clinical trials including onartuzumab, rilotumumab, tivantinib, and cabozantinib. MET frequently interacts with other key oncogenic tyrosine kinases including epidermal growth-factor receptor (EGFR) and HER-3 and these interactions may be responsible for resistance to anti-EGFR therapies. Similarly, resistance to MET inhibition may be mediated through EGFR activation, or alternatively by increasing levels of MET amplification or acquisition of novel “gatekeeper” mutations. In order to optimize development of effective inhibitors of the MET/HGF pathway clinical trials must be enriched for patients with demonstrable MET-pathway dysregulation for which robustly standardized and validated assays are required. PMID:24959087

  16. PAX3 and ETS1 synergistically activate MET expression in melanoma cells

    PubMed Central

    Kubic, Jennifer D.; Little, Elizabeth C.; Lui, Jason W.; Iizuka, Takumi; Lang, Deborah

    2014-01-01

    Melanoma is a highly aggressive disease that is difficult to treat due to rapid tumor growth, apoptotic resistance, and high metastatic potential. The MET tyrosine kinase receptor promotes many of these cellular processes, and while MET is often overexpressed in melanoma, the mechanism driving this overexpression is unknown. Since the MET gene is rarely mutated or amplified in melanoma, MET overexpression may be driven by to increased activation through promoter elements. In this report, we find that transcription factors PAX3 and ETS1 directly interact to synergistically activate MET expression. Inhibition of PAX3 and ETS1 expression in melanoma cells leads to a significant reduction of MET receptor levels. The 300 bp 5′ proximal MET promoter contains a PAX3 response element and two ETS1 consensus motifs. While ETS1 can moderately activate both of these sites without cofactors, robust MET promoter activation of the first site is PAX-dependent and requires the presence of PAX3, while the second site is PAX-independent. The induction of MET by ETS1 via this second site is enhanced by HGF-dependent ETS1 activation, thereby MET indirectly promotes its own expression. We further find that expression of a dominant negative ETS1 reduces the ability of melanoma cells to grow both in culture and in vivo. Thus, we discover a pathway where ETS1 advances melanoma through the expression of MET via PAX-dependent and independent mechanisms. PMID:25531327

  17. Prognostic and predictive value of MET deregulation in non-small cell lung cancer

    PubMed Central

    Toschi, Luca; Gianoncelli, Letizia; Baretti, Marina; Santoro, Armando

    2015-01-01

    Recent progress in cancer biology has led to the discovery of increasing number of oncogene alterations that have dramatically changed the paradigm of lung cancer treatment. MET is a tyrosine kinase receptor for the hepatocyte growth factor (HGF) that is deregulated in several malignancies, including non-small cell lung cancer (NSCLC). Abnormal MET-HGF signaling pathway activation can occur via different mechanisms, including HGF and/or MET overexpression, MET gene amplification, mutations or rearrangements. MET protein overexpression and increased MET gene number have been identified as poor prognostic factors in several series of surgically resected NSCLC making this receptor an attractive target for cancer treatment. Several clinical trials have recently evaluated the activity of a variety of anti-MET strategies in NSCLC patients with or without molecular selection with a variable degree of success, underscoring the need of establishing the best predictive biomarker for the identification of responding patients. PMID:25992382

  18. Antitumor activity of SNX-2112, a synthetic heat shock protein-90 inhibitor, in MET-amplified tumor cells with or without resistance to selective MET inhibition

    PubMed Central

    Bachleitner-Hofmann, Thomas; Sun, Mark Y.; Chen, Chin-Tung; Liska, David; Zeng, Zhaoshi; Viale, Agnes; Olshen, Adam B.; Mittlboeck, Martina; Christensen, James G.; Rosen, Neal; Solit, David B.; Weiser, Martin R.

    2012-01-01

    Purpose Heat shock protein-90 (HSP-90), a molecular chaperone required by numerous oncogenic kinases (e.g. HER-2, EGFR, Raf-1, v-Src, AKT) for conformational stability, has attracted wide interest as a novel target for cancer therapy. HSP-90 inhibition induces degradation of HSP-90 client proteins, leading to a combinatorial inhibition of multiple oncogenic signaling pathways with consecutive growth arrest and apoptosis. MET, a tyrosine kinase which is constitutively active in tumor cells with MET oncogene amplification, has recently been identified as another HSP-90 client. Experimental Design Aim of our study was to assess the efficacy of SNX-2112, a synthetic HSP-90 inhibitor, in 3 different MET-amplified tumor cell lines (GTL-16, MKN-45 and EBC-1) as well as PR-GTL-16 cells, a GTL-16 subline selected for resistance to the highly selective MET kinase inhibitor PHA-665752. Results In all cell lines, SNX-2112 led to degradation of MET, HER-2, EGFR and AKT as well as abrogation of Ras/Raf/MEK/MAPK and PI3K/AKT signaling, followed by complete cell cycle arrest. SNX-5542, an orally bioavailable prodrug of SNX-2112, displayed significant antitumor efficacy in vivo in nude mice bearing MET-amplified tumor xenografts. Importantly, HSP-90 inhibition maintained its antitumor efficacy in PR-GTL-16 cells both in vitro and in vivo, suggesting that HSP-90 inhibition could be a particularly valuable strategy in MET-amplified tumors which have acquired resistance to MET kinase inhibition. Conclusions Our study provides evidence for the efficacy of HSP-90 inhibition in MET-amplified cancer cells, particularly when MET kinase inhibitor resistance has emerged. PMID:21208906

  19. Total column water vapour measurements from GOME-2 MetOp-A and MetOp-B

    NASA Astrophysics Data System (ADS)

    Grossi, M.; Valks, P.; Loyola, D.; Aberle, B.; Slijkhuis, S.; Wagner, T.; Beirle, S.; Lang, R.

    2015-03-01

    Knowledge of the total column water vapour (TCWV) global distribution is fundamental for climate analysis and weather monitoring. In this work, we present the retrieval algorithm used to derive the operational TCWV from the GOME-2 sensors aboard EUMETSAT's MetOp-A and MetOp-B satellites and perform an extensive inter-comparison in order to evaluate their consistency and temporal stability. For the analysis, the GOME-2 data sets are generated by DLR in the framework of the EUMETSAT O3M-SAF project using the GOME Data Processor (GDP) version 4.7. The retrieval algorithm is based on a classical Differential Optical Absorption Spectroscopy (DOAS) method and combines a H2O and O2 retrieval for the computation of the trace gas vertical column density. We introduce a further enhancement in the quality of the H2O total column by optimizing the cloud screening and developing an empirical correction in order to eliminate the instrument scan angle dependencies. The overall consistency between measurements from the newer GOME-2 instrument on board of the MetOp-B platform and the GOME-2/MetOp-A data is evaluated in the overlap period (December 2012-June 2014). Furthermore, we compare GOME-2 results with independent TCWV data from the ECMWF ERA-Interim reanalysis, with SSMIS satellite measurements during the full period January 2007-June 2014 and against the combined SSM/I + MERIS satellite data set developed in the framework of the ESA DUE GlobVapour project (January 2007-December 2008). Global mean biases as small as ±0.035 g cm-2 are found between GOME-2A and all other data sets. The combined SSM/I-MERIS sample and the ECMWF ERA-Interim data set are typically drier than the GOME-2 retrievals, while on average GOME-2 data overestimate the SSMIS measurements by only 0.006 g cm-2. However, the size of these biases is seasonally dependent. Monthly average differences can be as large as 0.1 g cm-2, based on the analysis against SSMIS measurements, which include only data over

  20. MetPetDB: New Directions for Metamorphic Studies

    NASA Astrophysics Data System (ADS)

    Spear, F. S.; Adali, S.; Szymanski, B. K.; Hallett, B. K.; Waters, A. J.; Linder, Z. J.; Fyffe, M. E.; Goldfarb, D.; Barlett, K.

    2008-12-01

    It is estimated that less than 1% of the data collected on metamorphic rocks is published, and MetPetDB (database for metamorphic geochemistry) is being developed and populated to preserve these data and to foster new and innovative directions for scientific research and education. The data model is based on a sample of metamorphic rock and includes information about location, rock type, mineral assemblage, fabric, plus images of all types and mineral composition data. Mineral analyses are linked to locations on appropriate images so the spatial integrity of the data is preserved. Tools will be available for mineral recalculation, plotting, and thermobarometric applications. Derivative data such as peak P-T conditions, metamorphic P-T path, and cooling rate will also be stored. The database will be searchable based on any number of data fields, permitting rapid location of samples that can be used to test hypotheses and discover new relationships. For example: A student is designing a thesis project and MetPetDB will be a first resource to determine the types of rocks present in a region, the work that has been done on them, and links to the published findings. The Fe/Mg zoning in migmatitic garnets has been used to infer cooling rates. What is the range of cooling rates recorded by migmatitic garnets, and is there a correlation between peak metamorphic temperature and cooling rate? Is it possible that melting triggers rapid thrusting that causes the rapid cooling? A search on: rock type = migmatite plus Fe and Mg X-ray maps of garnet would reveal all samples that could be used in this study. A new geobarometer based on a specific mineral assemblage is proposed that permits pressures to be estimated to within 50 MPa. A search of the database for all samples with this assemblage plus analyses of the necessary minerals would provide a set of samples to which this new barometer can be applied. Recalculating pressures and temperatures for an entire region using new

  1. M-COPA, a Golgi Disruptor, Inhibits Cell Surface Expression of MET Protein and Exhibits Antitumor Activity against MET-Addicted Gastric Cancers.

    PubMed

    Ohashi, Yoshimi; Okamura, Mutsumi; Hirosawa, Asaka; Tamaki, Naomi; Akatsuka, Akinobu; Wu, Kuo-Ming; Choi, Hyeong-Wook; Yoshimatsu, Kentaro; Shiina, Isamu; Yamori, Takao; Dan, Shingo

    2016-07-01

    The Golgi apparatus is responsible for transporting, processing, and sorting numerous proteins in the cell, including cell surface-expressed receptor tyrosine kinases (RTK). The small-molecule compound M-COPA [2-methylcoprophilinamide (AMF-26)] disrupts the Golgi apparatus by inhibiting the activation of Arf1, resulting in suppression of tumor growth. Here, we report an evaluation of M-COPA activity against RTK-addicted cancers, focusing specifically on human gastric cancer (GC) cells with or without MET amplification. As expected, the MET-addicted cell line MKN45 exhibited a better response to M-COPA than cell lines without MET amplification. Upon M-COPA treatment, cell surface expression of MET was downregulated with a concurrent accumulation of its precursor form. M-COPA also reduced levels of the phosphorylated form of MET along with the downstream signaling molecules Akt and S6. Similar results were obtained in additional GC cell lines with amplification of MET or the FGF receptor FGFR2 MKN45 murine xenograft experiments demonstrated the antitumor activity of M-COPA in vivo Taken together, our results offer an initial preclinical proof of concept for the use of M-COPA as a candidate treatment option for MET-addicted GC, with broader implications for targeting the Golgi apparatus as a novel cancer therapeutic approach. Cancer Res; 76(13); 3895-903. ©2016 AACR. PMID:27197184

  2. Overexpression of FGFR2 contributes to inherent resistance to MET inhibitors in MET-amplified patient-derived gastric cancer xenografts

    PubMed Central

    LIU, KAI; SONG, XILIN; ZHU, MEIRONG; MA, HENG

    2015-01-01

    Gastric cancer is one of the most malignant diseases and one of the leading causes of cancer-associated mortality worldwide. Although advances have been made in surgical techniques, perioperative management and the combined use of surgery with chemotherapy and/or radiotherapy, patients with advanced stage gastric cancer continue to face poor outcomes. Furthermore, it was reported that MET gene amplification and overexpression predicted the sensitivity to MET inhibitors in gastric cancer. However, the identification of drug-resistant tumors has encouraged the pre-emptive elucidation of the possible mechanisms of clinical resistance. The current study assessed a number of patient-derived gastric cancer models with MET amplification and overexpression, including CNGAS028. The tumor tissues were subjected to microarray analysis (using single nucleotide polymorphism 6.0 and human genome U133 arrays) followed by western blotting. The results demonstrated that CNGAS028 xenograft tumors did not respond to treatment with a selective MET inhibitor. Additional analysis indicated that FGFR2 overexpression contributed to the resistance to MET inhibitors. Furthermore, treatment with a combination of fibroblast growth factor receptor 2 and MET inhibitors inhibited the growth of CNGAS028 xenograft tumors in vivo. In conclusion, the current results aid in understanding the mechanism of inherent resistance to selective MET inhibitors as well as provide important information for patient selection and clinical treatment strategies. PMID:26622787

  3. Off Target Effects of c-MET Inhibitors on Thyroid Cancer Cells

    PubMed Central

    Zhou, Yan; Zhao, Conghui; Gery, Sigal; Braunstein, Glenn D.; Okamoto, Ryoko; Alvarez, Rocio; Miles, Steven A.; Doan, Ngan B.; Said, Jonathan W.; Gu, Jiang; Koeffler, H. Phillip

    2013-01-01

    Aberrantly activated c-MET signaling occurs in several cancers, promoting the development of c-MET inhibitors. In this study, we found that eight of 8 thyroid cancer cell lines (including six anaplastic thyroid cell lines) have prominent expression of c-MET protein. Fifty percent of the thyroid cancer cell lines (four of 8) were growth-inhibited by two small molecule c-MET inhibitors (Tivantinib and Crizotinib), associated with apoptosis and G2/M cell cycle arrest. However, Crizotinib did not inhibit 50% proliferation of thyroid cancer cells (SW1736 and TL3) at a concentration at which the drug completely inhibited ligand-stimulated c-MET phosphorylation. On the other hand, Tivantinib was less potent than Crizotinib at inhibiting c-MET phosphorylation, but was more potent than Crizotinib at decreasing cell growth. Suppressing c-MET protein expression and phosphorylation using siRNA targeting c-MET did not induce cell cycle arrest and apoptosis. Taken together, Tivantinib and Crizotinib have off target(s) activity, contributing to their anti-tumor activity. In vivo study showed that Crizotinib markedly inhibited the growth of thyroid cancer cells (SW1736) in immunodeficient mice. In summary, c-MET inhibitors (Tivantinib and Crizotinib) suppress the growth of aggressive thyroid cancer cells, and this potential therapeutic benefit results from their non-MET-targeting effects. PMID:24170771

  4. Live cell imaging shows hepatocyte growth factor-induced Met dimerization.

    PubMed

    Koschut, David; Richert, Ludovic; Pace, Giuseppina; Niemann, Hartmut H; Mély, Yves; Orian-Rousseau, Véronique

    2016-07-01

    The canonical model of receptor tyrosine kinase (RTK) activation assumes that ligand-induced dimerization of inactive receptor monomers is a prerequisite for autophosphorylation. For several RTK families, recent results of fluorescence microscopy provided evidence for preformed receptor dimers that may or may not require ligand binding for kinase activity. Here we report, for the first time, the application of advanced quantitative fluorescence microscopy techniques to study changes in the oligomerization state of the RTK Met in response to stimulation by its endogenous ligand hepatocyte growth factor (HGF). We used inducible C-terminal fusions between Met and enhanced green fluorescent protein (EGFP) or red fluorescent protein (RFP) in combination with fluorescence resonance energy transfer (FRET)-based fluorescence-lifetime imaging microscopy (FLIM) and fluorescence correlation spectroscopy (FCS). A small fraction of HGF-independent Met dimers appeared to be present in cells even at low receptor density. At high receptor density, both the fraction of Met dimers and the level of Met autophosphorylation increased in the absence of HGF. Stimulation with HGF at low receptor density significantly increased the fraction of Met dimers on live cells. We found no indications of Met oligomers larger than dimers. Our findings thus confirm a model of Met activation through HGF-induced dimerization and at the same time they support previous reports of Met dimers in unstimulated cells. The tools established in this work will be useful to further characterize the mechanism of Met activation and to define the contribution of co-receptors. PMID:27094128

  5. Mechanistic Support for Combined MET and AR Blockade in Castration-Resistant Prostate Cancer12

    PubMed Central

    Qiao, Yuanyuan; Feng, Felix Y.; Wang, Yugang; Cao, Xuhong; Han, Sumin; Wilder-Romans, Kari; Navone, Nora M.; Logothetis, Christopher; Taichman, Russell S.; Keller, Evan T.; Palapattu, Ganesh S.; Alva, Ajjai S.; Smith, David C.; Tomlins, Scott A.; Chinnaiyan, Arul M.; Morgan, Todd M.

    2016-01-01

    A recent phase III trial of the MET kinase inhibitor cabozantinib in men with castration-resistant prostate cancer (CRPC) failed to meet its primary survival end point; however, most men with CRPC have intact androgen receptor (AR) signaling. As previous work supports negative regulation of MET by AR signaling, we hypothesized that intact AR signaling may have limited the efficacy of cabozantinib in some of these patients. To assess the role of AR signaling on MET inhibition, we first performed an in silico analysis of human CRPC tissue samples stratified by AR signaling status (+ or −), which identified MET expression as markedly increased in AR− samples. In vitro, AR signaling inhibition in AR+ CRPC models increased MET expression and resulted in susceptibility to ligand (HGF) activation. Likewise, MET inhibition was only effective in blocking cancer phenotypes in cells with MET overexpression. Using multiple AR+ CRPC in vitro and in vivo models, we showed that combined cabozantinib and enzalutamide (AR antagonist) treatment was more efficacious than either inhibitor alone. These data provide a compelling rationale to combine AR and MET inhibition in CRPC and may explain the negative results of the phase III cabozantinib study in CRPC. Similarly, the expression of MET in AR− disease, whether due to AR inhibition or loss of AR signaling, suggests potential utility for MET inhibition in select patients with AR therapy resistance and in AR− prostate cancer. PMID:26806347

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

    PubMed Central

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

    2016-01-01

    Objective 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. Patients and Methods 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. Results 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. Conclusion 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. PMID:27300295

  7. 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

  8. Increasing sulphite formation in Saccharomyces cerevisiae by overexpression of MET14 and SSU1.

    PubMed

    Donalies, Ute E B; Stahl, Ulf

    2002-04-01

    Saccharomyces cerevisiae produces sulphite as an intermediate product during the assimilatory reduction of sulphate to sulphide. Three genes, MET3, MET14 and MET16, are essential for this reduction. We investigated the level of transcription of these genes in strains of S. cerevisiae with high, medium and low sulphite formation. The level of MET14- and MET16-mRNA varied with sulphite production, whereas the level of MET3-mRNA was very weak in almost all strains. We also analysed the effect of overexpression of MET14 and MET16 on sulphite formation. Two strains with low sulphite production were transformed with high-copy plasmids containing either or both MET14 and MET16. The overexpression of these two genes leads to a two- to three-fold sulphite formation. In addition, inactivation of MET10, encoding a subunit of the sulphite reductase, also leads to a distinct increase in sulphite formation; however, the cells became methionine auxotroph. The overexpression of SSU1, a gene encoding a putative sulphite pump, yields a slight increase in sulphite accumulation, whereas overexpression of SSU1, together with MET14, increases sulphite formation up to 10-fold. Furthermore, sulphite formation strongly depends on growth conditions, e.g. yeast transformants growing in wort produce much higher amounts of sulphite when compared to growth in minimal media. The addition of glucose can also increase the sulphite formation in strains overexpressing MET14 and/or SSU1 under oxygen-limiting conditions, while the addition of glucose has no significant effect under aerobic conditions. PMID:11921096

  9. MET is required for the recruitment of anti-tumoural neutrophils

    PubMed Central

    Finisguerra, Veronica; Di Conza, Giusy; Di Matteo, Mario; Serneels, Jens; Costa, Sandra; Thompson, A.A. Roger; Wauters, Els; Walmsley, Sarah; Prenen, Hans; Granot, Zvi; Casazza, Andrea; Mazzone, Massimiliano

    2015-01-01

    Mutations or amplification of the MET proto-oncogene are involved in the pathogenesis of several tumours1-4, which rely on the constitutive engagement of this pathway for their growth and survival1,5. However, MET is expressed not only by cancer cells but also by tumour-associated stromal cells although its precise role in this compartment is not well characterized6-11. Here, we show that MET is required for neutrophil chemoattraction and cytotoxicity in response to its ligand HGF. Met deletion in neutrophils enhances tumour growth and metastasis. This phenotype correlates with reduced neutrophil infiltration to both primary tumour and metastatic site. Similarly, Met is necessary for neutrophil transudation during colitis, skin rash or peritonitis. Mechanistically, Met is induced by tumour-derived TNF-α or other inflammatory stimuli in both mouse and human neutrophils. This induction is instrumental for neutrophil transmigration across an activated endothelium and iNOS production upon HGF stimulation. Consequently, HGF/MET-dependent nitric oxide release by neutrophils promotes cancer cell killing, which abates tumour growth and metastasis. Following systemic administration of a MET kinase inhibitor, we prove that the therapeutic benefit of MET targeting in cancer cells is partly countered by the pro-tumoural effect rising from MET blockade in neutrophils. Our work identifies an unprecedented role of MET in neutrophils, suggests a potential “Achilles’ heel” of MET-targeted therapies in cancer, and supports the rationale for evaluating anti-MET drugs in certain inflammatory diseases. PMID:25985180

  10. Effects of met-enkephalin on the mechanical activity and distribution of met-enkephalin-like immunoreactivity in the cat small intestine.

    PubMed

    Radomirov, R; Venkova, K; Davidoff, M; Pencheva, N

    1990-01-01

    Naloxone-dependent effects of Met-enkephalin (10(-8) M) on the spontaneous and electrically induced mechanical activities were studied in longitudinal and circular preparations isolated from the cat duodenum, jejunum and ileum. Met-Enkephalin changed the spontaneous activity of all preparations tested with the exception of the circular preparations from the ileum. Met-Enkephalin-induced responses of the longitudinal preparations from the ileum were abolished by treatment with tetrodotoxin (10(-7) M), while the responses of both longitudinal and circular preparations from the duodenum and jejunum were only partially depressed, being resistant to tetrodotoxin components. The latter were most pronounced in the duodenum. The neurogenic electrically induced (0.5 msec, 5 Hz, 150 pulses) responses of all the preparations consisted mainly of contractile components which were significantly and naloxone-dependently reduced by Met-enkephalin (10(-8) M). The contractile components of the responses, which were reduced by Met-enkephalin, were entirely abolished by atropine (3 x 10(-6) M). Both Met-enkephalin and atropine inhibitory effects on the neurogenic responses were more pronounced in the ileum. Met-Enkephalin was found in nerve fibers of the myenteric plexus distributed mainly among the circular muscle. Single immunoreactive nerve fibers were observed in the longitudinal muscle layer of the duodenum but not in the jejunum and ileum. The distribution of Met-enkephalin-like immunoreactivity along the small intestine did not show significant differences among the three intestinal regions tested. The results obtained suggest that Met-enkephalin can modulate the mechanical activity of the cat small intestine, inhibiting cholinergic transmission and/or activating smooth muscle opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2199944

  11. Contrail Cirrus Parameterization in the UK Met Office Climate Model

    NASA Astrophysics Data System (ADS)

    Rap, A.; Forster, P.; Dobbie, S.

    2011-12-01

    Air travel and its associated emissions are growing faster than other sectors and they are predicted to contribute a significant warming of climate over the coming century. According to current best estimates, the largest single radiative forcing component associated with aviation is due to aviation-induced cloudiness (AIC), which includes contrail cirrus and changes in the natural cirrus caused by air traffic. However, there is still a high level of uncertainty associated with these, and limited estimates for the forcing of the total effect of aviation induced cloudiness exist. This study, as part of the Contrails Spreading into Cirrus (COSIC) project, aimed to build a physically based parameterization of contrails spreading into cirrus within the UK Met Office Unified Model (UM) and thus to give an independent estimate of the climate impact of AIC. In-situ observations of contrails properties and their spreading have been performed during a series of flights with the UK Facility for Airborne Atmospheric Measurements (FAAM) BAe-146 aircraft. These observations were used in the development of the parameterization, which simulates contrail formation and ageing interactively with the natural cirrus module within the UM. Based on this new parameterisation, estimates of global contrail cirrus coverage, optical depth, and radiative forcing are given, investigating also the contrail effect on the natural cirrus cloud and contrail saturation regional effects of future air traffic growth.

  12. HGF-independent Potentiation of EGFR Action by c-Met

    PubMed Central

    Dulak, Austin M.; Gubish, Christopher T.; Stabile, Laura P.; Henry, Cassandra; Siegfried, Jill M.

    2011-01-01

    The c-Met receptor is a potential therapeutic target for non-small cell lung cancer (NSCLC). Signaling interactions between c-Met and the mutant Epidermal Growth Factor Receptor (EGFR) have been studied extensively, but signaling intermediates and biological consequences of lateral signaling to c-Met in EGFR wild-type tumors is minimally understood. Our observations indicate that delayed c-Met activation in NSCLC cell lines is initiated by wild-type EGFR, the receptor most often found in NSCLC tumors. EGFR ligands induce accumulation of activated c-Met which begins at 8 h continues for 48 h. This effect is accompanied by an increase in c-Met expression and phosphorylation of critical c-Met tyrosine residues without activation of MAPK or Akt. Gene transcription is required for delayed c-Met activation; however, phosphorylation of c-Met by EGFR occurs without production of HGF or another secreted factor, supporting a ligand-independent mechanism. Lateral signaling is blocked by two selective c-Met tyrosine kinase inhibitors (TKIs), PF2341066 and SU11274, or with gefitinib, an EGFR TKI, suggesting kinase activity of both receptors is required for this effect. Prolonged c-Src phosphorylation is observed, and c-Src pathway is essential for EGFR to c-Met communication. Pre-treatment with pan-SFK inhibitors, PP2 and dasatinib, abolishes delayed c-Met phosphorylation. A c-Src dominant-negative construct reduces EGF-induced c-Met phosphorylation compared to control, further, confirming a c-Src requirement. Inhibition of c-Met with PF2341066 and siRNA decreases EGF-induced phenotypes of invasion by ~86% and motility by ~81%, suggesting that a novel form of c-Met activation is utilized by EGFR to maximize these biological effects. Combined targeting of c-Met and EGFR leads to increased xenograft anti-tumor activity, demonstrating that inhibition of downstream and lateral signaling from the EGFR-c-Src-c-Met axis might be effective in treatment of NSCLC. PMID:21423210

  13. Cloning and characterization of the Pichia pastoris MET2 gene as a selectable marker.

    PubMed

    Thor, Der; Xiong, See; Orazem, Claire C; Kwan, An-Chun; Cregg, James M; Lin-Cereghino, Joan; Lin-Cereghino, Geoff P

    2005-07-01

    We describe the isolation and characterization of a new biosynthetic gene, MET2, from the methylotrophic yeast Pichia pastoris. The predicted product of PpMET2 is significantly similar to its Saccharomyces cerevisiae counterpart, ScMET2, which encodes homoserine-O-transacetylase. The ScMET2 was able to complement the P. pastoris met2 strain; however, the converse was not true. Expression vectors based on PpMET2 for the intracellular and secreted production of foreign proteins and corresponding auxotrophic strains were constructed and tested for use in heterologous expression. The expression vectors and corresponding strains provide greater flexibility when using P. pastoris for recombinant protein expression. PMID:15996626

  14. Transgenic expression in the liver of truncated Met blocks apoptosis and permits immortalization of hepatocytes.

    PubMed Central

    Amicone, L; Spagnoli, F M; Späth, G; Giordano, S; Tommasini, C; Bernardini, S; De Luca, V; Della Rocca, C; Weiss, M C; Comoglio, P M; Tripodi, M

    1997-01-01

    Hepatocyte growth factor induces proliferation, motility and differentiation of epithelial cells through the tyrosine kinase receptor encoded by the MET protooncogene. The cytoplasmic portion of Met (referred to as cyto-Met) is activated but only weakly transforming. In order to determine the effect of activated Met on hepatocytes, we have targeted truncated Met expression to the liver by incorporating the cDNA into a vector carrying the entire human alpha-1-antitrypsin transcriptional unit. Transgenic expression in the liver of truncated human Met, containing the regulatory and the catalytic cytoplasmic domains, renders hepatocytes constitutively resistant to apoptosis and reproducibly permits immortalization. The emerging stable cell lines are not transformed and maintain a highly differentiated phenotype judged by the retention of epithelial cell polarity and the expression of hepatocyte-enriched transcription factors as well as hepatic products. PMID:9034332

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

    PubMed Central

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

    2016-01-01

    Purpose 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. Methods 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. Results 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). Conclusions 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. PMID:26765781

  16. Improvement and Refinement of the GPS/MET Data Analysis Algorithm

    NASA Technical Reports Server (NTRS)

    Herman, Benjamin M.

    2003-01-01

    The GPS/MET project was a satellite-to-satellite active microwave atmospheric limb sounder using the Global Positioning System transmitters as signal sources. Despite its remarkable success, GPS/MET could not independently sense atmospheric water vapor and ozone. Additionally the GPS/MET data retrieval algorithm needs to be further improved and refined to enhance the retrieval accuracies in the lower tropospheric region and the upper stratospheric region. The objectives of this proposal were to address these 3 problem areas.

  17. Fusion Welding of AerMet 100 Alloy

    SciTech Connect

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

    1999-08-01

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

  18. Are older patients’ cardiac rehabilitation needs being met?

    PubMed Central

    Tolmie, Elizabeth P; Lindsay, Grace M; Kelly, Tim; Tolson, Debbie; Baxter, Susan; Belcher, Philip R

    2009-01-01

    Aims. The primary aim of this study was to examine the needs of older people in relation to cardiac rehabilitation and to determine if these were currently being met. A secondary aim was to compare illness representations, quality of life and anxiety and depression in groups with different levels of attendance at a cardiac rehabilitation programme. Background. Coronary heart disease accounted for over seven million cardiovascular deaths globally in 2001. Associated deaths increase with age and are highest in those older than 65. Effective cardiac rehabilitation can assist independent function and maintain health but programme uptake rates are low. We have, therefore, focussed specifically on the older patient to determine reasons for the low uptake. Design. Mixed methods. Methods. A purposive sample of 31 older men and women (≥65 years) completed three questionnaires to determine illness representations, quality of life and anxiety and depression. They then underwent a brief clinical assessment and participated in a face-to-face audio-taped interview. Results. Quantitative: Older adults, who did not attend a cardiac rehabilitation programme, had significantly poorer personal control and depression scores (p < 0·01) and lower quality of life scores than those who had attended. Few achieved recommended risk factor reduction targets. Qualitative: The three main themes identified as reflecting the views and experiences of and attendance at the cardiac rehabilitation programme were: ‘The sensible thing to do’, ‘Assessing the impact’ and ‘Nothing to gain’. Conclusions. Irrespective of level of attendance, cardiac rehabilitation programmes are not meeting the needs of many older people either in terms of risk factor reduction or programme uptake. More appropriate programmes are needed. Relevance to clinical practice. Cardiac rehabilitation nurses are ideally placed to identify the rehabilitation needs of older people. Identifying these from the older

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

    PubMed Central

    Lee, Young H.; Apolo, Andrea B.; Agarwal, Piyush K.; Bottaro, Donald P.

    2014-01-01

    There is mounting evidence of oncogenic hepatocyte growth factor (HGF)/Met signaling in urothelial carcinoma (UC) of the bladder. The effects of three kinase inhibitors, cabozantinib, crizotinib and EMD1214063, on HGF-driven signaling and cell growth, invasion and tumorigenicity were analyzed in cultured UC cell lines. SW780 xenograft growth in SCID and human HGF knock-in SCID (hHGF/SCID) mice treated with cabozantinib or vehicle, as well as tumor levels of Met and pMet, were also determined. Met content was robust in most UC-derived cell lines. Basal pMet content and effector activation state in quiescent cells were low, but significantly enhanced by added HGF, as were cell invasion, proliferation and anchorage independent growth. These HGF-driven effects were reversed by Met inhibitor treatment. Tumor xenograft growth was significantly higher in hHGF/SCID mice vs. SCID mice and significantly inhibited by cabozantinib, as was tumor phospho-Met content. These studies indicate the prevalence and functionality of the HGF/Met signaling pathway in UC cells, suggest that paracrine HGF may contribute to UC tumor growth and progression, and that support further preclinical investigation of Met inhibitors for the treatment of UC is warranted. PMID:25534569

  20. Role of Methoprene-Tolerant (Met) in Adult Morphogenesis and in Adult Ecdysis of Blattella germanica

    PubMed Central

    Lozano, Jesus; Belles, Xavier

    2014-01-01

    Juvenile Hormone (JH) represses metamorphosis of young instars in insects. One of the main players in hormonal signalling is Methoprene-tolerant (Met), which plays the role of JH receptor. Using the Polyneopteran insect Blattella germanica as the model and RNAi for transcript depletion, we have confirmed that Met transduces the antimetamorphic signal of JH in young nymphs and plays a role in the last nymphal instar moult in this species. Previously, the function of Met as the JH receptor had been demonstrated in the Eumetabola clade, with experiments in Holometabola (in the beetle Tribolium castaneum) and in their sister group Paraneoptera (in the bug Pyrrhocoris apterus). Our result shows that the function of Met as JH receptor is also conserved in the more basal Polyneoptera. The function of Met as JH transducer might thus predate the evolutionary innovation of metamorphosis. Moreover, expression of Met was also found in last nymphal instar of B. germanica, when JH is absent. Depletion of Met in this stage provoked deficiencies in wing growth and ecdysis problems in the imaginal moult. Down-regulation of the ecdysone-inducible gene E75A and Insulin-Like-Peptide 1 in these Met-depleted specimens suggest that Met is involved in the ecdysone and insulin signalling pathways in last nymphal instar, when JH is virtually absent. PMID:25072526

  1. Role of Methoprene-tolerant (Met) in adult morphogenesis and in adult ecdysis of Blattella germanica.

    PubMed

    Lozano, Jesus; Belles, Xavier

    2014-01-01

    Juvenile Hormone (JH) represses metamorphosis of young instars in insects. One of the main players in hormonal signalling is Methoprene-tolerant (Met), which plays the role of JH receptor. Using the Polyneopteran insect Blattella germanica as the model and RNAi for transcript depletion, we have confirmed that Met transduces the antimetamorphic signal of JH in young nymphs and plays a role in the last nymphal instar moult in this species. Previously, the function of Met as the JH receptor had been demonstrated in the Eumetabola clade, with experiments in Holometabola (in the beetle Tribolium castaneum) and in their sister group Paraneoptera (in the bug Pyrrhocoris apterus). Our result shows that the function of Met as JH receptor is also conserved in the more basal Polyneoptera. The function of Met as JH transducer might thus predate the evolutionary innovation of metamorphosis. Moreover, expression of Met was also found in last nymphal instar of B. germanica, when JH is absent. Depletion of Met in this stage provoked deficiencies in wing growth and ecdysis problems in the imaginal moult. Down-regulation of the ecdysone-inducible gene E75A and Insulin-Like-Peptide 1 in these Met-depleted specimens suggest that Met is involved in the ecdysone and insulin signalling pathways in last nymphal instar, when JH is virtually absent. PMID:25072526

  2. Pyridazinone derivatives displaying highly potent and selective inhibitory activities against c-Met tyrosine kinase.

    PubMed

    Liu, Yang; Jin, Shiyu; Peng, Xia; Lu, Dong; Zeng, Limin; Sun, Yiming; Ai, Jing; Geng, Meiyu; Hu, Youhong

    2016-01-27

    Over activation of c-Met tyrosine kinase is known to promote tumorigenesis and metastasis, as well as to cause therapeutic resistance. Herein we describe the design, synthesis and biological activities of novel, ATP-competitive, c-Met tyrosine kinase inhibitors that are members of the 6-aryl-2-(3-(heteroarylamino)benzyl)pyridazinone family. A structure-activity relationship (SAR) study of these substances led to identification of pyridazinone 19 as a highly selective and potent c-Met tyrosine inhibitor, which displays favorable pharmacokinetic properties in mice and significant antitumor activity against a c-Met driven EBC-1 tumor xenograft. PMID:26698536

  3. Petrography of Lunar Meteorite MET 01210, A New Basaltic Regolith Breccia

    NASA Technical Reports Server (NTRS)

    Zeigler, R. A.; Korotev, R. L.; Jolliff, B. L.; Haskin, L. A.

    2005-01-01

    Lunar meteorite MET 01210 (hereafter referred to as MET) is a 22.8 g breccia collected during the 2001 field season in the Meteorite Hills, Antarctica. Although initially classified as an anorthositic breccia, MET is a regolith breccia composed predominantly of very-low-Ti (VLT) basaltic material. Four other brecciated lunar meteorites (NWA 773, QUE 94281, EET 87/96, Yamato 79/98) with a significant VLT basaltic component have been identified. We present here the petrography and bulk major element composition of MET and compare it to previously studied basaltic lunar meteorite breccias.

  4. 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. PMID:24930887

  5. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma.

    PubMed

    Zhou, L; Liu, X-D; Sun, M; Zhang, X; German, P; Bai, S; Ding, Z; Tannir, N; Wood, C G; Matin, S F; Karam, J A; Tamboli, P; Sircar, K; Rao, P; Rankin, E B; Laird, D A; Hoang, A G; Walker, C L; Giaccia, A J; Jonasch, E

    2016-05-01

    Antiangiogenic therapy resistance occurs frequently in patients with metastatic renal cell carcinoma (RCC). The purpose of this study was to understand the mechanism of resistance to sunitinib, an antiangiogenic small molecule, and to exploit this mechanism therapeutically. We hypothesized that sunitinib-induced upregulation of the prometastatic MET and AXL receptors is associated with resistance to sunitinib and with more aggressive tumor behavior. In the present study, tissue microarrays containing sunitinib-treated and untreated RCC tissues were stained with MET and AXL antibodies. The low malignant RCC cell line 786-O was chronically treated with sunitinib and assayed for AXL, MET, epithelial-mesenchymal transition (EMT) protein expression and activation. Co-culture experiments were used to examine the effect of sunitinib pretreatment on endothelial cell growth. The effects of AXL and MET were evaluated in various cell-based models by short hairpin RNA or inhibition by cabozantinib, the multi-tyrosine kinases inhibitor that targets vascular endothelial growth factor receptor, MET and AXL. Xenograft mouse models tested the ability of cabozantinib to rescue sunitinib resistance. We demonstrated that increased AXL and MET expression was associated with inferior clinical outcome in patients. Chronic sunitinib treatment of RCC cell lines activated both AXL and MET, induced EMT-associated gene expression changes, including upregulation of Snail and β-catenin, and increased cell migration and invasion. Pretreatment with sunitinib enhanced angiogenesis in 786-0/human umbilical vein endothelial cell co-culture models. The suppression of AXL or MET expression and the inhibition of AXL and MET activation using cabozantinib both impaired chronic sunitinib treatment-induced prometastatic behavior in cell culture and rescued acquired resistance to sunitinib in xenograft models. In summary, chronic sunitinib treatment induces the activation of AXL and MET signaling and

  6. Association of Brain-Derived Neurotrophic Factor Gene Val66Met Polymorphism with Primary Dysmenorrhea

    PubMed Central

    Chen, Li-Fen; Shen, Horng-Der; Chao, Hsiang-Tai; Lin, Ming-Wei; Hsieh, Jen-Chuen

    2014-01-01

    Primary dysmenorrhea (PDM), the most prevalent menstrual cycle-related problem in women of reproductive age, is associated with negative moods. Whether the menstrual pain and negative moods have a genetic basis remains unknown. Brain-derived neurotrophic factor (BDNF) plays a key role in the production of central sensitization and contributes to chronic pain conditions. BDNF has also been implicated in stress-related mood disorders. We screened and genotyped the BDNF Val66Met polymorphism (rs6265) in 99 Taiwanese (Asian) PDMs (20–30 years old) and 101 age-matched healthy female controls. We found that there was a significantly higher frequency of the Met allele of the BDNF Val66Met polymorphism in the PDM group. Furthermore, BDNF Met/Met homozygosity had a significantly stronger association with PDM compared with Val carrier status. Subsequent behavioral/hormonal assessments of sub-groups (PDMs = 78, controls = 81; eligible for longitudinal multimodal neuroimaging battery studies) revealed that the BDNF Met/Met homozygous PDMs exhibited a higher menstrual pain score (sensory dimension) and a more anxious mood than the Val carrier PDMs during the menstrual phase. Although preliminary, our study suggests that the BDNF Val66Met polymorphism is associated with PDM in Taiwanese (Asian) people, and BDNF Met/Met homozygosity may be associated with an increased risk of PDM. Our data also suggest the BDNF Val66Met polymorphism as a possible regulator of menstrual pain and pain-related emotions in PDM. Absence of thermal hypersensitivity may connote an ethnic attribution. The presentation of our findings calls for further genetic and neuroscientific investigations of PDM. PMID:25383981

  7. Structural basis for DNA recognition by the transcription regulator MetR.

    PubMed

    Punekar, Avinash S; Porter, Jonathan; Carr, Stephen B; Phillips, Simon E V

    2016-06-01

    MetR, a LysR-type transcriptional regulator (LTTR), has been extensively studied owing to its role in the control of methionine biosynthesis in proteobacteria. A MetR homodimer binds to a 24-base-pair operator region of the met genes and specifically recognizes the interrupted palindromic sequence 5'-TGAA-N5-TTCA-3'. Mechanistic details underlying the interaction of MetR with its target DNA at the molecular level remain unknown. In this work, the crystal structure of the DNA-binding domain (DBD) of MetR was determined at 2.16 Å resolution. MetR-DBD adopts a winged-helix-turn-helix (wHTH) motif and shares significant fold similarity with the DBD of the LTTR protein BenM. Furthermore, a data-driven macromolecular-docking strategy was used to model the structure of MetR-DBD bound to DNA, which revealed that a bent conformation of DNA is required for the recognition helix α3 and the wing loop of the wHTH motif to interact with the major and minor grooves, respectively. Comparison of the MetR-DBD-DNA complex with the crystal structures of other LTTR-DBD-DNA complexes revealed residues that may confer operator-sequence binding specificity for MetR. Taken together, the results show that MetR-DBD uses a combination of direct base-specific interactions and indirect shape recognition of the promoter to regulate the transcription of met genes. PMID:27303893

  8. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma

    PubMed Central

    Zhou, Lijun; Liu, Xian-De; Sun, Mianen; Zhang, Xuesong; German, Peter; Bai, Shanshan; Ding, Zhiyong; Tannir, Nizar; Wood, Christopher G; Matin, Surena F; Karam, Jose A; Tamboli, Pheroze; Sircar, Kanishka; Rao, Priya; Rankin, Erinn B.; Laird, Douglas A; Hoang, Anh G; Walker, Cheryl L; Giaccia, Amato J; Jonasch, Eric

    2016-01-01

    Antiangiogenic therapy resistance occurs frequently in patients with metastatic renal cell carcinoma (RCC). The purpose of this study was to understand the mechanism of resistance to sunitinib, an antiangiogenic small molecule, and to exploit this mechanism therapeutically. We hypothesized that sunitinib-induced upregulation of the prometastatic MET and AXL receptors is associated with resistance to sunitinib and with more aggressive tumor behavior. In the present study, tissue microarrays containing sunitinib treated and untreated RCC tissues were stained with MET and AXL antibodies. The low malignant RCC cell line, 786-O, was chronically treated with sunitinib, and assayed for AXL, MET, epithelial mesenchymal transition (EMT) protein expression and activation. Co-culture experiments were used to examine the effect of sunitinib pretreatment on endothelial cell growth. The effects of AXL and MET were evaluated in various cell-based models by shRNA or inhibition by cabozantinib, the multi-tyrosine kinases inhibitor that targets VEGFR, MET and AXL. Xenograft mouse models tested the ability of cabozantinib to rescue sunitinib resistance. We demonstrated that increased AXL and MET expression was associated with inferior clinical outcome in patients. Chronic sunitinib treatment of RCC cell lines activated both AXL and MET, induced EMT associated gene expression changes including upregulation of Snail and β-catenin, and increased cell migration and invasion. Pretreatment with sunitinib enhanced angiogenesis in 786-0/HUVEC co-culture models. The suppression of AXL or MET expression, and the inhibition of AXL and MET activation using cabozantinib both impaired chronic sunitinib treatment-induced prometastatic behavior in cell culture, and rescued acquired resistance to sunitinib in xenograft models. In summary, chronic sunitinib treatment induces the activation of AXL and MET signaling and promotes pro-metastatic behavior and angiogenesis. The inhibition of AXL and MET

  9. Alteration of the Centromedial Amygdala Glutamatergic Synapses by the BDNF Val66Met Polymorphism.

    PubMed

    Galvin, Christopher; Lee, Francis S; Ninan, Ipe

    2015-08-01

    Fear expression is mediated by an activation of the centromedial amygdala (CEm), the major output nucleus of the amygdaloid complex. Consistently, fear extinction is associated with an increased synaptic inhibition as well as a suppression of the excitability of the CEm neurons. However, little is known about the role of CEm glutamatergic synapses in fear regulation and anxiety-like behaviors. The BDNF Val66Met, a single-nucleotide polymorphism in the human BDNF gene, impairs fear extinction and leads to anxiety-like symptoms. To determine whether the BDNF Val66Met polymorphism affects the CEm excitatory synapses, we examined basal glutamatergic synaptic transmission and plasticity in the CEm neurons of BDNF Val66Met knock-in (BDNF(Met/Met)) mice. The BDNF Val66Met single-nucleotide polymorphism exerted an opposite effect on non-NMDA and NMDA receptor transmission with a potentiation of the former and a suppression of the latter. In addition, the decay time of NMDA currents was decreased in BDNF(Met/Met) mice, suggesting a modification of NMDA receptor subunit composition. Unlike the wild-type mice that exhibited a potentiation of non-NMDA receptor transmission following fear conditioning and a depotentiation upon fear extinction, BDNF(Met/Met) mice failed to show this experience-dependent synaptic plasticity in the CEm neurons. Our results suggest that the elevated non-NMDA receptor transmission, the suppression of NMDA receptor transmission, and an impairment of synaptic plasticity in the CEm neurons might contribute to the fear extinction deficit and increased anxiety-like symptoms in BDNF Val66Met carriers. PMID:25786582

  10. Mulstiscale Stochastic Generator of Multivariate Met-Ocean Time Series

    NASA Astrophysics Data System (ADS)

    Guanche, Yanira; Mínguez, Roberto; Méndez, Fernando J.

    2013-04-01

    The design of maritime structures requires information on sea state conditions that influence its behavior during its life cycle. In the last decades, there has been a increasing development of sea databases (buoys, reanalysis, satellite) that allow an accurate description of the marine climate and its interaction with a given structure in terms of functionality and stability. However, these databases have a limited timelength, and its appliance entails an associated uncertainty. To avoid this limitation, engineers try to sample synthetically generated time series, statistically consistent, which allow the simulation of longer time periods. The present work proposes a hybrid methodology to deal with this issue. It is based in the combination of clustering algorithms (k-means) and an autoregressive logistic regression model (logit). Since the marine climate is directly related to the atmospheric conditions at a synoptic scale, the proposed methodology takes both systems into account; generating simultaneously circulation patterns (weather types) time series and the sea state time series related. The generation of these time series can be summarized in three steps: (1) By applying the clustering technique k-means the atmospheric conditions are classified into a representative number of synoptical patterns (2) Taking into account different covariates involved (such as seasonality, interannual variability, trends or autoregressive term) the autoregressive logistic model is adjusted (3) Once the model is able to simulate weather types time series the last step is to generate multivariate hourly metocean parameters related to these weather types. This is done by an autoregressive model (ARMA) for each variable, including cross-correlation between them. To show the goodness of the proposed method the following data has been used: Sea Level Pressure (SLP) databases from NCEP-NCAR and Global Ocean Wave (GOW) reanalysis from IH Cantabria. The synthetical met-ocean hourly

  11. ASI/MET Within Color-Enhanced Panorama

    NASA Technical Reports Server (NTRS)

    1997-01-01

    This is a sub-section of the 'geometrically improved, color enhanced' version of the 360-degree panorama heretofore known as the 'Gallery Pan', the first contiguous, uniform panorama taken by the Imager for Mars Pathfinder (IMP) over the course of Sols 8, 9, and 10. Different regions were imaged at different times over the three Martian days to acquire consistent lighting and shadow conditions for all areas of the panorama.

    The IMP is a stereo imaging system that, in its fully deployed configuration, stands 1.8 meters above the Martian surface, and has a resolution of two millimeters at a range of two meters. In this geometrically improved version of the panorama, distortion due to a 2.5 degree tilt in the IMP camera mast has been removed, effectively flattening the horizon.

    The IMP has color capability provided by 24 selectable filters -- twelve filters per 'eye'. Its red, green, and blue filters were used to take this image. The color was digitally balanced according to the color transmittance capability of a high-resolution TV at the Jet Propulsion Laboratory (JPL), and is dependent on that device. In this color enhanced version of the panorama, detail in surface features are brought out via changes to saturation and intensity, holding the original hue constant. A threshold was applied to avoid changes to the sky.

    At the bottom of the image, two of the Lander petals are visible. At the extreme right of the image, the Atmospheric Structure Instrument and Meteorology package (ASI/MET) mast, with its three windsocks, is visible.

    Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is a division of the California Institute of Technology (Caltech). The IMP was developed by the University of Arizona Lunar and Planetary Laboratory under contract

  12. A human anti-c-Met Fab fragment conjugated with doxorubicin as targeted chemotherapy for hepatocellular carcinoma.

    PubMed

    Chen, Ximin; Ding, Guipeng; Gao, Qihe; Sun, Jian; Zhang, Qianqian; Du, Lijian; Qiu, Zhenning; Wang, Changjun; Zheng, Feng; Sun, Bowang; Ni, Jian; Feng, Zhenqing; Zhu, Jin

    2013-01-01

    c-Met is over-expressed in hepatocellular carcinoma(HCC) but is absent or expressed at low levels in normal tissues. Therefore we generated a novel conjugate of a human anti-c-Met Fab fragment (MetFab) with doxorubicin (DOX) and assessed whether it had targeted antitumor activity against HCC and reduced the side-effects of DOX. The MetFab was screened from human phage library, conjugated with DOX via chemical synthesis, and the conjugation MetFab-DOX was confirmed by HPLC. The drug release patterns, the binding efficacy, and cellular distribution of MetFab-DOX were assessed. MetFab-DOX was stable at pH7.2 PBS while release doxorubicin quickly at pH4.0, the binding efficacy of MetFab-DOX was similarly as MetFab, and the cellular distribution of the MetFab-DOX is distinct from free DOX. The cytotoxicity of MetFab-DOX was analyzed by the MTT method and the nude mouse HCC model. The MetFab-DOX demonstrated cytotoxic effects on c-Met expressing-tumor cells, but not on the cells without c-Met expression. MetFab-DOX exerted anti-tumor effect and significantly reduced the side effect of free DOX in mice model. Furthermore, the localization of conjugate was confirmed by immunofluorescence staining of tumor tissue sections and optical tumor imaging, respectively, and the tissue-distribution of drug was compared between free DOX and MetFab-DOX treatment by spectrofluorometer. MetFab-DOX can localize to the tumor tissue, and the concentration of doxorubicin in the tumor was higher after MetFab-DOX administration than after DOX administration. In summary, MetFab-DOX can target c-Met expressing HCC cells effectively and have obvious antitumor activity with decreased side-effects in preclinical models of HCC. PMID:23675455

  13. Future Plans for MetNet Lander Mars Missions

    NASA Astrophysics Data System (ADS)

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

    2012-04-01

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

  14. Future Plans for MetNet Lander Mars Missions

    NASA Astrophysics Data System (ADS)

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

    2012-04-01

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

  15. 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…

  16. Constitutive activation of MET signaling impairs myogenic differentiation of rhabdomyosarcoma and promotes its development and progression

    PubMed Central

    Szewczyk, Barbara; Adamus, Tomasz; Lukasiewicz, Ewa; Miekus, Katarzyna; Majka, Marcin

    2015-01-01

    Rhabdomyosarcoma (RMS) is a soft tissue sarcoma, which may originate from impaired differentiation of mesenchymal stem cells (MSC). Expression of MET receptor is elevated in alveolar RMS subtype (ARMS) which is associated with worse prognosis, compared to embryonal RMS (ERMS). Forced differentiation of ARMS cells diminishes MET level and, as shown previously, MET silencing induces differentiation of ARMS. In ERMS cells introduction of TPR-MET oncogene leads to an uncontrolled overstimulation of the MET receptor downstream signaling pathways. In vivo, tumors formed by those cells in NOD-SCID mice display inhibited differentiation, enhanced proliferation, diminished apoptosis and increased infiltration of neutrophils. Consequently, tumors grow significantly faster and they display enhanced ability to metastasize to lungs and to vascularize due to elevated VEGF, MMP9 and miR-378 expression. In vitro, TPR-MET ERMS cells display enhanced migration, chemotaxis and invasion toward HGF and SDF-1. Introduction of TPR-MET into MSC increases survival and may induce expression of early myogenic factors depending on the genetic background, and it blocks terminal differentiation of skeletal myoblasts. To conclude, our results suggest that activation of MET signaling may cause defects in myogenic differentiation leading to rhabdomyosarcoma development and progression. PMID:26384300

  17. Constitutive activation of MET signaling impairs myogenic differentiation of rhabdomyosarcoma and promotes its development and progression.

    PubMed

    Skrzypek, Klaudia; Kusienicka, Anna; Szewczyk, Barbara; Adamus, Tomasz; Lukasiewicz, Ewa; Miekus, Katarzyna; Majka, Marcin

    2015-10-13

    Rhabdomyosarcoma (RMS) is a soft tissue sarcoma, which may originate from impaired differentiation of mesenchymal stem cells (MSC). Expression of MET receptor is elevated in alveolar RMS subtype (ARMS) which is associated with worse prognosis, compared to embryonal RMS (ERMS). Forced differentiation of ARMS cells diminishes MET level and, as shown previously, MET silencing induces differentiation of ARMS. In ERMS cells introduction of TPR-MET oncogene leads to an uncontrolled overstimulation of the MET receptor downstream signaling pathways. In vivo, tumors formed by those cells in NOD-SCID mice display inhibited differentiation, enhanced proliferation, diminished apoptosis and increased infiltration of neutrophils. Consequently, tumors grow significantly faster and they display enhanced ability to metastasize to lungs and to vascularize due to elevated VEGF, MMP9 and miR-378 expression. In vitro, TPR-MET ERMS cells display enhanced migration, chemotaxis and invasion toward HGF and SDF-1. Introduction of TPR-MET into MSC increases survival and may induce expression of early myogenic factors depending on the genetic background, and it blocks terminal differentiation of skeletal myoblasts. To conclude, our results suggest that activation of MET signaling may cause defects in myogenic differentiation leading to rhabdomyosarcoma development and progression. PMID:26384300

  18. Piperlongumine and its analogs down-regulate expression of c-Met in renal cell carcinoma.

    PubMed

    Golovine, Konstantin; Makhov, Peter; Naito, Sei; Raiyani, Henish; Tomaszewski, Jeffrey; Mehrazin, Reza; Tulin, Alexei; Kutikov, Alexander; Uzzo, Robert G; Kolenko, Vladimir M

    2015-01-01

    The c-Met protein, a transmembrane receptor tyrosine kinase, is the product of a proto-oncogene. Its only known ligand, hepatocyte growth factor (HGF), regulates cell growth, motility, migration, invasion, proliferation, and angiogenesis. The aberrant expression of c-Met is often associated with poor prognosis in multiple cancers, including renal cell carcinoma (RCC). Silencing or inactivation of c-Met leads to decreased viability of cancer cells, thereby making ablation of c-Met signaling an attractive concept for developing novel strategies for the treatment of renal tumors. Naturally-occurring products or substances are the most consistent source of drug development. As such, we investigated the functional impact of piperlongumine (PL), a naturally occurring alkaloid present in the Long pepper (Piper longum) on c-Met expression in RCC cells and demonstrated that PL and its analogs rapidly reduce c-Met protein and RNA levels in RCC cells via ROS-dependent mechanism. PL-mediated c-Met depletion coincided with the inhibition of downstream c-Met signaling; namely Erk/MAPK, STAT3, NF-κB and Akt/mTOR. As such, PL and PL analogs hold promise as potential therapeutic agents for the treatment of metastatic RCC and the prevention of postoperative RCC recurrence. PMID:25801713

  19. MET Is Required for the Maximal Action of 20-Hydroxyecdysone during Bombyx Metamorphosis

    PubMed Central

    Guo, Enen; He, Qianyu; Liu, Shumin; Tian, Ling; Sheng, Zhentao; Peng, Qin; Guan, Jingmin; Shi, Mingan; Li, Kang; Gilbert, Lawrence I.; Wang, Jian; Cao, Yang; Li, Sheng

    2012-01-01

    Little is known about how the putative juvenile hormone (JH) receptor, the bHLH-PAS transcription factor MET, is involved in 20-hydroxyecdysone (20E; the molting hormone) action. Here we report that two MET proteins found in the silkworm, Bombyx mori, participate in 20E signal transduction. Met is 20E responsive and its expression peaks during molting and pupation, when the 20E titer is high. As found with results from RNAi knockdown of EcR-USP (the ecdysone receptor genes), RNAi knockdown of Met at the early wandering stage disrupts the 20E-triggered transcriptional cascade, preventing tissue remodeling (including autophagy, apoptosis and destruction of larval tissues and generation of adult structures) and causing lethality during the larval-pupal transition. MET physically interacts with EcR-USP. Moreover, MET, EcR-USP and the 20E-response element (EcRE) form a protein-DNA complex, implying that MET might modulate 20E-induced gene transcription by interacting with EcR-USP. In conclusion, the 20E induction of MET is required for the maximal action of 20E during Bombyx metamorphosis. PMID:23300902

  20. Piperlongumine and its analogs down-regulate expression of c-Met in renal cell carcinoma

    PubMed Central

    Golovine, Konstantin; Makhov, Peter; Naito, Sei; Raiyani, Henish; Tomaszewski, Jeffrey; Mehrazin, Reza; Tulin, Alexei; Kutikov, Alexander; Uzzo, Robert G; Kolenko, Vladimir M

    2015-01-01

    The c-Met protein, a transmembrane receptor tyrosine kinase, is the product of a proto-oncogene. Its only known ligand, hepatocyte growth factor (HGF), regulates cell growth, motility, migration, invasion, proliferation, and angiogenesis. The aberrant expression of c-Met is often associated with poor prognosis in multiple cancers, including renal cell carcinoma (RCC). Silencing or inactivation of c-Met leads to decreased viability of cancer cells, thereby making ablation of c-Met signaling an attractive concept for developing novel strategies for the treatment of renal tumors. Naturally-occurring products or substances are the most consistent source of drug development. As such, we investigated the functional impact of piperlongumine (PL), a naturally occurring alkaloid present in the Long pepper (Piper longum) on c-Met expression in RCC cells and demonstrated that PL and its analogs rapidly reduce c-Met protein and RNA levels in RCC cells via ROS-dependent mechanism. PL-mediated c-Met depletion coincided with the inhibition of downstream c-Met signaling; namely Erk/MAPK, STAT3, NF-κB and Akt/mTOR. As such, PL and PL analogs hold promise as potential therapeutic agents for the treatment of metastatic RCC and the prevention of postoperative RCC recurrence. PMID:25801713

  1. 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…

  2. 42 CFR 59.5 - What requirements must be met by a family planning project?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

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

  3. COMT Val158Met Genotype as a Risk Factor for Problem Behaviors in Youth

    ERIC Educational Resources Information Center

    Albaugh, Matthew D.; Harder, Valerie S.; Althoff, Robert R.; Rettew, David C.; Ehli, Erik A.; Lengyel-Nelson, Timea; Davies, Gareth E.; Ayer, Lynsay; Sulman, Julie; Stanger, Catherine; Hudziak, James J.

    2010-01-01

    Objective: To test the association between the catechol-O-methyltransferase (COMT) Val158Met polymorphism and both aggressive behavior and attention problems in youth. We hypothesized that youth carrying a Met allele would have greater average aggressive behavior scores, and that youth exhibiting Val-homozygosity would have greater average…

  4. Conservation and Functional Importance of Carbon-Oxygen Hydrogen Bonding in AdoMet-Dependent Methyltransferases

    SciTech Connect

    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.

    2013-09-06

    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.

  5. Hepatocyte Growth Factor/cMET Pathway Activation Enhances Cancer Hallmarks in Adrenocortical Carcinoma.

    PubMed

    Phan, Liem M; Fuentes-Mattei, Enrique; Wu, Weixin; Velazquez-Torres, Guermarie; Sircar, Kanishka; Wood, Christopher G; Hai, Tao; Jimenez, Camilo; Cote, Gilbert J; Ozsari, Levent; Hofmann, Marie-Claude; Zheng, Siyuan; Verhaak, Roeland; Pagliaro, Lance; Cortez, Maria Angelica; Lee, Mong-Hong; Yeung, Sai-Ching J; Habra, Mouhammed Amir

    2015-10-01

    Adrenocortical carcinoma is a rare malignancy with poor prognosis and limited response to chemotherapy. Hepatocyte growth factor (HGF) and its receptor cMET augment cancer growth and resistance to chemotherapy, but their role in adrenocortical carcinoma has not been examined. In this study, we investigated the association between HGF/cMET expression and cancer hallmarks of adrenocortical carcinoma. Transcriptomic and immunohistochemical analyses indicated that increased HGF/cMET expression in human adrenocortical carcinoma samples was positively associated with cancer-related biologic processes, including proliferation and angiogenesis, and negatively correlated with apoptosis. Accordingly, treatment of adrenocortical carcinoma cells with exogenous HGF resulted in increased cell proliferation in vitro and in vivo while short hairpin RNA-mediated knockdown or pharmacologic inhibition of cMET suppressed cell proliferation and tumor growth. Moreover, exposure of cells to mitotane, cisplatin, or radiation rapidly induced pro-cMET expression and was associated with an enrichment of genes (e.g., CYP450 family) related to therapy resistance, further implicating cMET in the anticancer drug response. Together, these data suggest an important role for HGF/cMET signaling in adrenocortical carcinoma growth and resistance to commonly used treatments. Targeting cMET, alone or in combination with other drugs, could provide a breakthrough in the management of this aggressive cancer. PMID:26282167

  6. 76 FR 25278 - Safety Zone; TriMet Bridge Project, Willamette River; Portland, OR

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-04

    ... SECURITY Coast Guard 33 CFR Part 165 RIN 1625-AA00 Safety Zone; TriMet Bridge Project, Willamette River... is proposing the establishment of a safety zone during the construction of the TriMet Bridge on the..., 2008, issue of the Federal Register (73 FR 3316). Public Meeting We do not now plan to hold a...

  7. Abl Kinases Regulate HGF/Met Signaling Required for Epithelial Cell Scattering, Tubulogenesis and Motility

    PubMed Central

    Li, Ran; Knight, Jennifer F.; Park, Morag; Pendergast, Ann Marie

    2015-01-01

    Tight regulation of receptor tyrosine kinases (RTKs) is crucial for normal development and homeostasis. Dysregulation of RTKs signaling is associated with diverse pathological conditions including cancer. The Met RTK is the receptor for hepatocyte growth factor (HGF) and is dysregulated in numerous human tumors. Here we show that Abl family of non-receptor tyrosine kinases, comprised of Abl (ABL1) and Arg (ABL2), are activated downstream of the Met receptor, and that inhibition of Abl kinases dramatically suppresses HGF-induced cell scattering and tubulogenesis. We uncover a critical role for Abl kinases in the regulation of HGF/Met-dependent RhoA activation and RhoA-mediated actomyosin contractility and actin cytoskeleton remodeling in epithelial cells. Moreover, treatment of breast cancer cells with Abl inhibitors markedly decreases Met-driven cell migration and invasion. Notably, expression of a transforming mutant of the Met receptor in the mouse mammary epithelium results in hyper-activation of both Abl and Arg kinases. Together these data demonstrate that Abl kinases link Met activation to Rho signaling and Abl kinases are required for Met-dependent cell scattering, tubulogenesis, migration, and invasion. Thus, inhibition of Abl kinases might be exploited for the treatment of cancers driven by hyperactivation of HGF/Met signaling. PMID:25946048

  8. Targeting the MET Pathway in Gastric and Oesophageal Cancers: Refining the Optimal Approach.

    PubMed

    Lee, J; Tran, P; Klempner, S J

    2016-08-01

    Gastric and oesophageal cancers are a major cause of global cancer-related morbidity and mortality. Improvements in treatment for locoregional and metastatic gastric and oesophageal cancer have been incremental and the overall prognosis remains poor. Increasingly, molecular classification has identified recurrent, therapeutically relevant, somatic alterations in gastroesophageal malignancies. However, other than ERBB2 amplification, molecularly directed therapies have not translated to improved survival. Amplification of the receptor tyrosine kinase MET is found in about 5% of gastroesophageal cancers and represents an oncogenic driver and therapeutic target. Small series have shown activity of MET-directed tyrosine kinase inhibitors, but the clinical benefit of anti-MET antibodies has been disappointing. Here we discuss the MET pathway in gastroesophageal cancers, the clinical data for MET small molecule tyrosine kinase inhibitors, anti-MET antibodies and future clinical directions for targeting MET in gastric and oesophageal cancers. To our knowledge, this is the most comprehensive review of the clinical experience with MET-directed therapies in gastric and oesophageal cancers. PMID:26880063

  9. 8 CFR 273.4 - Demonstration by carrier that screening requirements were met.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 8 Aliens and Nationality 1 2013-01-01 2013-01-01 false Demonstration by carrier that screening requirements were met. 273.4 Section 273.4 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION... UNDER SECTION 273 OF THE ACT § 273.4 Demonstration by carrier that screening requirements were met....

  10. 20 CFR 10.205 - What conditions must be met to receive COP?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 20 Employees' Benefits 1 2014-04-01 2012-04-01 true What conditions must be met to receive COP? 10.205 Section 10.205 Employees' Benefits OFFICE OF WORKERS' COMPENSATION PROGRAMS, DEPARTMENT OF LABOR..., AS AMENDED Continuation of Pay Eligibility for Cop § 10.205 What conditions must be met to...

  11. 42 CFR 51a.6 - What confidentiality requirements must be met?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false What confidentiality requirements must be met? 51a.6 Section 51a.6 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS PROJECT GRANTS FOR MATERNAL AND CHILD HEALTH § 51a.6 What confidentiality requirements must be met?...

  12. 34 CFR 692.101 - What requirements must be met by a State partnership?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 34 Education 4 2013-07-01 2013-07-01 false What requirements must be met by a State partnership? 692.101 Section 692.101 Education Regulations of the Offices of the Department of Education (Continued...? § 692.101 What requirements must be met by a State partnership? (a) State. A State that is receiving...

  13. 34 CFR 692.101 - What requirements must be met by a State partnership?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 34 Education 4 2014-07-01 2014-07-01 false What requirements must be met by a State partnership? 692.101 Section 692.101 Education Regulations of the Offices of the Department of Education (Continued...? § 692.101 What requirements must be met by a State partnership? (a) State. A State that is receiving...

  14. 21 CFR 111.77 - What must you do if established specifications are not met?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 2 2012-04-01 2012-04-01 false What must you do if established specifications are not met? 111.77 Section 111.77 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... Production and Process Control System § 111.77 What must you do if established specifications are not met?...

  15. 42 CFR 51a.6 - What confidentiality requirements must be met?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false What confidentiality requirements must be met? 51a.6 Section 51a.6 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS PROJECT GRANTS FOR MATERNAL AND CHILD HEALTH § 51a.6 What confidentiality requirements must be met?...

  16. 43 CFR 3284.3 - What happens if the minimum initial unit obligations are not met?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 43 Public Lands: Interior 2 2014-10-01 2014-10-01 false What happens if the minimum initial unit obligations are not met? 3284.3 Section 3284.3 Public Lands: Interior Regulations Relating to Public Lands... not met? (a) If the unit operator does not drill a well designed to produce or utilize...

  17. 34 CFR 692.101 - What requirements must be met by a State partnership?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 34 Education 4 2012-07-01 2012-07-01 false What requirements must be met by a State partnership? 692.101 Section 692.101 Education Regulations of the Offices of the Department of Education (Continued...? § 692.101 What requirements must be met by a State partnership? (a) State. A State that is receiving...

  18. 34 CFR 692.101 - What requirements must be met by a State partnership?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 3 2010-07-01 2010-07-01 false What requirements must be met by a State partnership? 692.101 Section 692.101 Education Regulations of the Offices of the Department of Education (Continued... What requirements must be met by a State partnership? (a) State. A State that is receiving an...

  19. 34 CFR 692.101 - What requirements must be met by a State partnership?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 34 Education 4 2011-07-01 2011-07-01 false What requirements must be met by a State partnership? 692.101 Section 692.101 Education Regulations of the Offices of the Department of Education (Continued...? § 692.101 What requirements must be met by a State partnership? (a) State. A State that is receiving...

  20. 20 CFR 10.205 - What conditions must be met to receive COP?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 20 Employees' Benefits 1 2010-04-01 2010-04-01 false What conditions must be met to receive COP? 10.205 Section 10.205 Employees' Benefits OFFICE OF WORKERS' COMPENSATION PROGRAMS, DEPARTMENT OF...' COMPENSATION ACT, AS AMENDED Continuation of Pay Eligibility for Cop § 10.205 What conditions must be met...

  1. 34 CFR 692.21 - What requirements must be met by a State program?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 34 Education 4 2011-07-01 2011-07-01 false What requirements must be met by a State program? 692.21 Section 692.21 Education Regulations of the Offices of the Department of Education (Continued... Participate in the Leap Program? § 692.21 What requirements must be met by a State program? To receive...

  2. 34 CFR 692.21 - What requirements must be met by a State program?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 34 Education 4 2012-07-01 2012-07-01 false What requirements must be met by a State program? 692.21 Section 692.21 Education Regulations of the Offices of the Department of Education (Continued... Participate in the Leap Program? § 692.21 What requirements must be met by a State program? To receive...

  3. 43 CFR 3284.3 - What happens if the minimum initial unit obligations are not met?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 43 Public Lands: Interior 2 2012-10-01 2012-10-01 false What happens if the minimum initial unit obligations are not met? 3284.3 Section 3284.3 Public Lands: Interior Regulations Relating to Public Lands... not met? (a) If the unit operator does not drill a well designed to produce or utilize...

  4. 8 CFR 273.4 - Demonstration by carrier that screening requirements were met.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 8 Aliens and Nationality 1 2012-01-01 2012-01-01 false Demonstration by carrier that screening requirements were met. 273.4 Section 273.4 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION... UNDER SECTION 273 OF THE ACT § 273.4 Demonstration by carrier that screening requirements were met....

  5. 34 CFR 692.21 - What requirements must be met by a State program?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 34 Education 4 2013-07-01 2013-07-01 false What requirements must be met by a State program? 692.21 Section 692.21 Education Regulations of the Offices of the Department of Education (Continued... Participate in the Leap Program? § 692.21 What requirements must be met by a State program? To receive...

  6. "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…

  7. 42 CFR 51a.6 - What confidentiality requirements must be met?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false What confidentiality requirements must be met? 51a.6 Section 51a.6 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS PROJECT GRANTS FOR MATERNAL AND CHILD HEALTH § 51a.6 What confidentiality requirements must be met?...

  8. 42 CFR 423.2470 - Remittance to CMS if the applicable MLR requirement is not met.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 3 2014-10-01 2014-10-01 false Remittance to CMS if the applicable MLR requirement is not met. 423.2470 Section 423.2470 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES... applicable MLR requirement is not met. (a) General requirement. For each contract year, a Part D sponsor...

  9. 42 CFR 422.2470 - Remittance to CMS if the applicable MLR requirement is not met.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 3 2014-10-01 2014-10-01 false Remittance to CMS if the applicable MLR requirement is not met. 422.2470 Section 422.2470 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES... not met. (a) General requirement. For each contract year, an MA organization must provide a...

  10. 43 CFR 3284.3 - What happens if the minimum initial unit obligations are not met?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 43 Public Lands: Interior 2 2011-10-01 2011-10-01 false What happens if the minimum initial unit obligations are not met? 3284.3 Section 3284.3 Public Lands: Interior Regulations Relating to Public Lands... not met? (a) If the unit operator does not drill a well designed to produce or utilize...

  11. 8 CFR 273.4 - Demonstration by carrier that screening requirements were met.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 8 Aliens and Nationality 1 2014-01-01 2014-01-01 false Demonstration by carrier that screening requirements were met. 273.4 Section 273.4 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION... UNDER SECTION 273 OF THE ACT § 273.4 Demonstration by carrier that screening requirements were met....

  12. 20 CFR 10.205 - What conditions must be met to receive COP?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 20 Employees' Benefits 1 2013-04-01 2012-04-01 true What conditions must be met to receive COP? 10.205 Section 10.205 Employees' Benefits OFFICE OF WORKERS' COMPENSATION PROGRAMS, DEPARTMENT OF LABOR..., AS AMENDED Continuation of Pay Eligibility for Cop § 10.205 What conditions must be met to...

  13. 8 CFR 273.4 - Demonstration by carrier that screening requirements were met.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 8 Aliens and Nationality 1 2011-01-01 2011-01-01 false Demonstration by carrier that screening requirements were met. 273.4 Section 273.4 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION... UNDER SECTION 273 OF THE ACT § 273.4 Demonstration by carrier that screening requirements were met....

  14. 42 CFR 423.2470 - Remittance to CMS if the applicable MLR requirement is not met.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 3 2013-10-01 2013-10-01 false Remittance to CMS if the applicable MLR requirement is not met. 423.2470 Section 423.2470 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES... applicable MLR requirement is not met. (a) General requirement. For each contract year, a Part D sponsor...

  15. 42 CFR 422.2470 - Remittance to CMS if the applicable MLR requirement is not met.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 3 2013-10-01 2013-10-01 false Remittance to CMS if the applicable MLR requirement is not met. 422.2470 Section 422.2470 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES... not met. (a) General requirement. For each contract year, an MA organization must provide a...

  16. 21 CFR 111.77 - What must you do if established specifications are not met?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 2 2011-04-01 2011-04-01 false What must you do if established specifications are not met? 111.77 Section 111.77 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... Production and Process Control System § 111.77 What must you do if established specifications are not met?...

  17. 21 CFR 111.77 - What must you do if established specifications are not met?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 2 2010-04-01 2010-04-01 false What must you do if established specifications are not met? 111.77 Section 111.77 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... Production and Process Control System § 111.77 What must you do if established specifications are not met?...

  18. 42 CFR 51a.6 - What confidentiality requirements must be met?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false What confidentiality requirements must be met? 51a.6 Section 51a.6 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS PROJECT GRANTS FOR MATERNAL AND CHILD HEALTH § 51a.6 What confidentiality requirements must be met?...

  19. 21 CFR 111.77 - What must you do if established specifications are not met?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 2 2013-04-01 2013-04-01 false What must you do if established specifications are not met? 111.77 Section 111.77 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... Production and Process Control System § 111.77 What must you do if established specifications are not met?...

  20. 42 CFR 51a.6 - What confidentiality requirements must be met?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false What confidentiality requirements must be met? 51a.6 Section 51a.6 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS PROJECT GRANTS FOR MATERNAL AND CHILD HEALTH § 51a.6 What confidentiality requirements must be met?...

  1. 34 CFR 692.21 - What requirements must be met by a State program?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 34 Education 4 2014-07-01 2014-07-01 false What requirements must be met by a State program? 692.21 Section 692.21 Education Regulations of the Offices of the Department of Education (Continued... Participate in the Leap Program? § 692.21 What requirements must be met by a State program? To receive...

  2. 20 CFR 10.205 - What conditions must be met to receive COP?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 20 Employees' Benefits 1 2012-04-01 2012-04-01 false What conditions must be met to receive COP? 10.205 Section 10.205 Employees' Benefits OFFICE OF WORKERS' COMPENSATION PROGRAMS, DEPARTMENT OF...' COMPENSATION ACT, AS AMENDED Continuation of Pay Eligibility for Cop § 10.205 What conditions must be met...

  3. 43 CFR 3284.3 - What happens if the minimum initial unit obligations are not met?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 43 Public Lands: Interior 2 2013-10-01 2013-10-01 false What happens if the minimum initial unit obligations are not met? 3284.3 Section 3284.3 Public Lands: Interior Regulations Relating to Public Lands... not met? (a) If the unit operator does not drill a well designed to produce or utilize...

  4. 20 CFR 10.205 - What conditions must be met to receive COP?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 20 Employees' Benefits 1 2011-04-01 2011-04-01 false What conditions must be met to receive COP? 10.205 Section 10.205 Employees' Benefits OFFICE OF WORKERS' COMPENSATION PROGRAMS, DEPARTMENT OF...' COMPENSATION ACT, AS AMENDED Continuation of Pay Eligibility for Cop § 10.205 What conditions must be met...

  5. The MetLife Survey of the American Teacher: Listening to Teachers in Rural Schools

    ERIC Educational Resources Information Center

    MetLife, Inc., 2013

    2013-01-01

    MetLife has sponsored and Harris Interactive has conducted the annual MetLife Survey of the American Teacher series since 1984 to share the voices of teachers with educators, policymakers and the public. The series examines significant changes and trends over time, highlights important current issues, and explores topics relevant to the future of…

  6. 21 CFR 111.77 - What must you do if established specifications are not met?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 2 2014-04-01 2014-04-01 false What must you do if established specifications are not met? 111.77 Section 111.77 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... Production and Process Control System § 111.77 What must you do if established specifications are not met?...

  7. MET Exon 14 Alterations in Lung Cancer: Exon Skipping Extends Half-Life.

    PubMed

    Drilon, Alexander

    2016-06-15

    MET exon 14 alterations are a diverse group of mutations, many of which disrupt splice acceptor or donor sites leading to exon 14 skipping, impaired receptor degradation, and oncogenic transformation. These alterations are clinically targetable with MET-directed therapy. Clin Cancer Res; 22(12); 2832-4. ©2016 AACRSee related article by Tong et al., p. 3048. PMID:27009743

  8. 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…

  9. The HGF receptor/Met tyrosine kinase is a key regulator of dendritic cell migration in skin immunity.

    PubMed

    Baek, Jea-Hyun; Birchmeier, Carmen; Zenke, Martin; Hieronymus, Thomas

    2012-08-15

    The Met tyrosine kinase has a pivotal role in embryonic development and tissue regeneration, and deregulated Met signaling contributes to tumorigenesis. After binding of its cognate ligand hepatocyte growth factor, Met signaling confers mitogenic, morphogenic, and motogenic activity to various cells. Met expression in the hematopoietic compartment is limited to progenitor cells and their Ag-presenting progeny, including dendritic cells (DCs). In this study, we demonstrate that Met signaling in skin-resident DCs is essential for their emigration toward draining lymph nodes upon inflammation-induced activation. By using a conditional Met-deficient mouse model (Met(flox/flox)), we show that Met acts on the initial step of DC release from skin tissue. Met-deficient DCs fail to reach skin-draining lymph nodes upon activation while exhibiting an activated phenotype. Contact hypersensitivity reactions in response to various contact allergens is strongly impaired in Met-deficient mice. Inhibition of Met signaling by single-dose epicutaneous administration of the Met kinase-specific inhibitor SU11274 also suppressed contact hypersensitivity in wild-type mice. Additionally, we found that Met signaling regulates matrix metalloproteinase MMP2 and MMP9 activity, which is important for DC migration through extracellular matrix. These data unveil Met signaling in DCs as a critical determinant for the maintenance of normal immune function and suggest Met as a potential target for treatment of autoimmune skin diseases. PMID:22802413

  10. Dimerization mediated through a leucine zipper activates the oncogenic potential of the met receptor tyrosine kinase.

    PubMed Central

    Rodrigues, G A; Park, M

    1993-01-01

    Oncogenic activation of the met (hepatocyte growth factor/scatter factor) receptor tyrosine kinase involves a genomic rearrangement that generates a hybrid protein containing tpr-encoded sequences at its amino terminus fused directly to the met-encoded receptor kinase domain. Deletion of Tpr sequences abolishes the transforming ability of this protein, implicating this region in oncogenic activation. We demonstrate, by site-directed mutagenesis and coimmunoprecipitation experiments, that a leucine zipper motif within Tpr mediates dimerization of the tpr-met product and is essential for the transforming activity of the met oncogene. By analogy with ligand-stimulated activation of receptor tyrosine kinases, we propose that constitutive dimerization mediated by a leucine zipper motif within Tpr is responsible for oncogenic activation of the Met kinase. The possibility that this mechanism of activation represents a paradigm for a class of receptor tyrosine kinase oncogenes activated by DNA rearrangement is discussed. Images PMID:8413267

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

    SciTech Connect

    Stiene-Martin, A.; Hauser, K.F. )

    1990-01-01

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

  12. Structure of Met-enkephalin in explicit aqueous solution using replica exchange molecular dynamics.

    PubMed

    Sanbonmatsu, K Y; García, A E

    2002-02-01

    Replica exchange molecular dynamics (MD) simulations of Met-enkephalin in explicit solvent reveal helical and nonhelical structures. Four predominant structures of Met-enkephalin are sampled with comparable probabilities (two helical and two nonhelical). The energy barriers between these configurations are low, suggesting that Met-enkephalin switches easily between configurations. This is consistent with the requirement that Met-enkephalin be sufficiently flexible to bind to several different receptors. Replica exchange simulations of 32 ns are shown to sample approximately five times more configurational space than constant temperature MD simulations of the same duration. The energy landscape for the replica exchange simulation is presented. A detailed study of replica trajectories demonstrates that the significant increases in temperature provided by the replica exchange technique enable transitions from nonhelical to helical structures that would otherwise be prevented by kinetic trapping. Met-enkephalin (Type Entrez Proteins; Value A61445; Service Entrez Proteins). PMID:11807951

  13. 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

  14. Expression of HGF and c-Met Proteins in Human Keratoconus Corneas

    PubMed Central

    You, Jingjing; Wen, Li; Roufas, Athena; Hodge, Chris; Sutton, Gerard; Madigan, Michele C.

    2015-01-01

    Keratoconus (KC) is a progressive degenerative inflammatory-related disease of the human cornea leading to decreased visual function. The pathogenesis of KC remains to be understood. Recent genetic studies indicate that gene variants of an inflammation-related molecule, hepatocyte growth factor (HGF), are associated with an increased susceptibility for developing KC. However HGF protein expression in KC has not been explored. In this initial study, we investigated late-stage KC and control corneas for the expression of HGF and its receptor mesenchymal-epithelial transition factor (c-Met/Met). KC buttons (~8 mm diameter) (n = 10) and whole control corneas (n = 6) were fixed in 10% formalin or 2% paraformaldehyde, paraffin embedded and sectioned. Sections were immunolabelled with HGF and c-Met antibodies, visualised using immunofluorescence, and examined with scanning laser confocal microscopy. Semiquantitative grading was used to compare HGF and c-Met immunostaining in KC and control corneas. Overall, KC corneas showed increased HGF and c-Met immunostaining compared to controls. KC corneal epithelium displayed heterogeneous moderate-to-strong immunoreactivity for HGF and c-Met, particularly in the basal epithelium adjacent to the cone area. Taken together with the recent genetic studies, our results further support a possible role for HGF/c-Met in the pathogenesis of KC. PMID:26697215

  15. Mitochondrial-Targeting MET Kinase Inhibitor Kills Erlotinib-Resistant Lung Cancer Cells.

    PubMed

    Yang, Tianming; Ng, Wai Har; Chen, Huan; Chomchopbun, Kamon; Huynh, The Hung; Go, Mei Lin; Kon, Oi Lian

    2016-08-11

    Lung cancer cells harboring activating EGFR mutations acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) by activating several bypass mechanisms, including MET amplification and overexpression. We show that a significant proportion of activated MET protein in EGFR TKI-resistant HCC827 lung cancer cells resides within the mitochondria. Targeting the total complement of MET in the plasma membrane and mitochondria should render these cells more susceptible to cell death and hence provide a means of circumventing drug resistance. Herein, the mitochondrial targeting triphenylphosphonium (TPP) moiety was introduced to the selective MET kinase inhibitor PHA665752. The resulting TPP analogue rapidly localized to the mitochondria of MET-overexpressing erlotinib-resistant HCC827 cells, partially suppressed the phosphorylation (Y1234/Y1235) of MET in the mitochondrial inner membrane and was as cytotoxic and apoptogenic as the parent compound. These findings provide support for the targeting of mitochondrial MET with a TPP-TKI conjugate as a means of restoring responsiveness to chemotherapy. PMID:27563407

  16. Catechol-O-Methyltransferase val158met Polymorphism Predicts Placebo Effect in Irritable Bowel Syndrome

    PubMed Central

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

    2012-01-01

    Identifying patients who are potential placebo responders has major implications for clinical practice and trial design. Catechol-O-methyltransferase (COMT), an important enzyme in dopamine catabolism plays a key role in processes associated with the placebo effect such as reward, pain, memory and learning. We hypothesized that the COMT functional val158met polymorphism, was a predictor of placebo effects and tested our hypothesis in a subset of 104 patients from a previously reported randomized controlled trial in irritable bowel syndrome (IBS). The three treatment arms from this study were: no-treatment (“waitlist”), placebo treatment alone (“limited”) and, placebo treatment “augmented” with a supportive patient-health care provider interaction. The primary outcome measure was change from baseline in IBS-Symptom Severity Scale (IBS-SSS) after three weeks of treatment. In a regression model, the number of methionine alleles in COMT val158met was linearly related to placebo response as measured by changes in IBS-SSS (p = .035). The strongest placebo response occurred in met/met homozygotes treated in the augmented placebo arm. A smaller met/met associated effect was observed with limited placebo treatment and there was no effect in the waitlist control. These data support our hypothesis that the COMT val158met polymorphism is a potential biomarker of placebo response. PMID:23110189

  17. Pharmacological inhibition of KIT activates MET signaling in gastrointestinal stromal tumors

    PubMed Central

    Cohen, Noah A.; Zeng, Shan; Seifert, Adrian M.; Kim, Teresa S.; Sorenson, Eric C.; Greer, Jonathan B.; Beckman, Michael J.; Santamaria-Barria, Juan A.; Crawley, Megan H.; Green, Benjamin L.; Rossi, Ferdinand; Besmer, Peter; Antonescu, Cristina R.; DeMatteo, Ronald P.

    2015-01-01

    Gastrointestinal stromal tumors (GIST) are the most common adult sarcomas and the oncogenic driver is usually a KIT or PDGFRA mutation. While GIST are often initially sensitive to imatinib or other tyrosine kinase inhibitors, resistance generally develops necessitating backup strategies for therapy. In this study, we determined that a subset of human GIST specimens that acquired imatinib resistance acquired expression of activated forms of the MET oncogene. MET activation also developed after imatinib therapy in a mouse model of GIST (KitV558del/+ mice), where it was associated with increased tumor hypoxia. MET activation also occurred in imatinib-sensitive human GIST cell lines after imatinib treatment in vitro. MET inhibition by crizotinib or RNA interference was cytotoxic to an imatinib-resistant human GIST cell population. Moreover, combining crizotinib and imatinib was more effective than imatinib alone in imatinib-sensitive GIST models. Lastly, cabozantinib, a dual MET and KIT small molecule inhibitor, was markedly more effective than imatinib in multiple preclinical models of imatinib-sensitive and imatinib-resistant GIST. Collectively, our findings showed that activation of compensatory MET signaling by KIT inhibition may contribute to tumor resistance. Furthermore, our work offered a preclinical proof of concept for MET inhibition by cabozantinib as an effective strategy for GIST treatment. PMID:25836719

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

    PubMed

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

    2012-01-01

    Identifying patients who are potential placebo responders has major implications for clinical practice and trial design. Catechol-O-methyltransferase (COMT), an important enzyme in dopamine catabolism plays a key role in processes associated with the placebo effect such as reward, pain, memory and learning. We hypothesized that the COMT functional val158met polymorphism, was a predictor of placebo effects and tested our hypothesis in a subset of 104 patients from a previously reported randomized controlled trial in irritable bowel syndrome (IBS). The three treatment arms from this study were: no-treatment ("waitlist"), placebo treatment alone ("limited") and, placebo treatment "augmented" with a supportive patient-health care provider interaction. The primary outcome measure was change from baseline in IBS-Symptom Severity Scale (IBS-SSS) after three weeks of treatment. In a regression model, the number of methionine alleles in COMT val158met was linearly related to placebo response as measured by changes in IBS-SSS (p = .035). The strongest placebo response occurred in met/met homozygotes treated in the augmented placebo arm. A smaller met/met associated effect was observed with limited placebo treatment and there was no effect in the waitlist control. These data support our hypothesis that the COMT val158met polymorphism is a potential biomarker of placebo response. PMID:23110189

  19. MiR-34c suppresses tumor growth and metastasis in nasopharyngeal carcinoma by targeting MET

    PubMed Central

    Li, Y-Q; Ren, X-Y; He, Q-M; Xu, Y-F; Tang, X-R; Sun, Y; Zeng, M-S; Kang, T-B; Liu, N; Ma, J

    2015-01-01

    Our previous microarray analysis indicated that miR-34c was downregulated in nasopharyngeal carcinoma (NPC). However, little is known about the function and molecular mechanism of miR-34c in NPC. In this study, miR-34c was found to be significantly downregulated in NPC cell lines and clinical tissues. Ectopic expression of miR-34c suppressed NPC cell viability, colony formation, anchorage-independent growth, cell migration and invasion in vitro, and inhibited xenograft tumor growth and lung metastasis in vivo. MET proto-oncogene (MET) was identified as a direct target of miR-34c using luciferase reporter assays, quantitative RT-PCR, western blotting and immunofluorescent staining. Overexpression of miR-34c markedly reduced MET expression at both the mRNA and protein levels. Knockdown of MET suppressed NPC cell proliferation, migration and invasion, whereas the restoration of MET rescued the suppressive effects of miR-34c. The demethylation agent 5-aza-2′-deoxycytidine (DAC) restored the expression of miR-34c in NPC cell lines. The promoter region of miR-34c was hypermethylated in NPC cells. In conclusion, miR-34c suppresses tumor growth and metastasis in NPC by targeting MET. The newly identified miR-34c/MET pathway provides further insights into the development and progression of NPC, and may represent a novel therapeutic target for NPC treatment. PMID:25611392

  20. Four individually druggable MET hotspots mediate HGF-driven tumor progression

    PubMed Central

    Basilico, Cristina; Hultberg, Anna; Blanchetot, Christophe; de Jonge, Natalie; Festjens, Els; Hanssens, Valérie; Osepa, Sjudry-Ilona; De Boeck, Gitte; Mira, Alessia; Cazzanti, Manuela; Morello, Virginia; Dreier, Torsten; Saunders, Michael; de Haard, Hans; Michieli, Paolo

    2014-01-01

    Activation of MET by HGF plays a key role in tumor progression. Using a recently developed llama platform that generates human-like immunoglobulins, we selected 68 different antibodies that compete with HGF for binding to MET. HGF-competing antibodies recognized 4 distinct hotspots localized in different MET domains. We identified 1 hotspot that coincides with the known HGF β chain binding site on blades 2–3 of the SEMA domain β-propeller. We determined that a second and a third hotspot lie within blade 5 of the SEMA domain and IPT domains 2–3, both of which are thought to bind to HGF α chain. Characterization of the fourth hotspot revealed a region across the PSI-IPT 1 domains not previously associated with HGF binding. Individual or combined targeting of these hotspots effectively interrupted HGF/MET signaling in multiple cell-based biochemical and biological assays. Selected antibodies directed against SEMA blades 2–3 and the PSI-IPT 1 region inhibited brain invasion and prolonged survival in a glioblastoma multiforme model, prevented metastatic disease following neoadjuvant therapy in a triple-negative mammary carcinoma model, and suppressed cancer cell dissemination to the liver in a KRAS-mutant metastatic colorectal cancer model. These results identify multiple regions of MET responsible for HGF-mediated tumor progression, unraveling the complexity of HGF-MET interaction, and provide selective molecular tools for targeting MET activity in cancer. PMID:24865428

  1. Brucella melitensis Methionyl-tRNA-Synthetase (MetRS), a Potential Drug Target for Brucellosis

    PubMed Central

    Ranade, Ranae M.; Zhang, Zhongsheng; Dranow, David M.; Myers, Janette B.; Choi, Ryan; Nakazawa Hewitt, Steve; Edwards, Thomas E.; Davies, Douglas R.; Lorimer, Donald; Boyle, Stephen M.; Barrett, Lynn K.; Buckner, Frederick S.; Fan, Erkang; Van Voorhis, Wesley C.

    2016-01-01

    We investigated Brucella melitensis methionyl-tRNA-synthetase (BmMetRS) with molecular, structural and phenotypic methods to learn if BmMetRS is a promising target for brucellosis drug development. Recombinant BmMetRS was expressed, purified from wild type Brucella melitensis biovar Abortus 2308 strain ATCC/CRP #DD-156 and screened by a thermal melt assay against a focused library of one hundred previously classified methionyl-tRNA-synthetase inhibitors of the blood stage form of Trypanosoma brucei. Three compounds showed appreciable shift of denaturation temperature and were selected for further studies on inhibition of the recombinant enzyme activity and cell viability against wild type B. melitensis strain 16M. BmMetRS protein complexed with these three inhibitors resolved into three-dimensional crystal structures and was analyzed. All three selected methionyl-tRNA-synthetase compounds inhibit recombinant BmMetRS enzymatic functions in an aminoacylation assay at varying concentrations. Furthermore, growth inhibition of B. melitensis strain 16M by the compounds was shown. Inhibitor-BmMetRS crystal structure models were used to illustrate the molecular basis of the enzyme inhibition. Our current data suggests that BmMetRS is a promising target for brucellosis drug development. However, further studies are needed to optimize lead compound potency, efficacy and safety as well as determine the pharmacokinetics, optimal dosage, and duration for effective treatment. PMID:27500735

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

    PubMed Central

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

    2014-01-01

    Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide and most patients with HCC have limited treatment options. Focal Adhesion Kinase (FAK) is overexpressed in many HCC specimens, offering a potential target for HCC treatment. However, the role of FAK in hepatocarcinogenesis remains elusive. Establishing whether FAK expression plays a role in HCC development is necessary to determine whether it is a viable therapeutic target. In this study, we generated mice with hepatocyte-specific deletion of Fak and investigated the role of Fak in an oncogenic (c-MET/β-catenin, MET/CAT)-driven HCC model. We found that deletion of Fak in hepatocytes did not affect morphology, proliferation or apoptosis. However, Fak deficiency significantly repressed MET/CAT-induced tumor development and prolonged survival of animals with MET/CAT-induced HCC. In mouse livers and HCC cell lines, Fak was activated by MET, which induced the activation of Akt/Erk and up-regulated Cyclin D1 and tumor cell proliferation. CAT enhanced MET-stimulated FAK activation and synergistically induced the activation of the AKT/ERK-Cyclin D1 signaling pathway in a FAK kinase-dependent manner. In addition, FAK was required for CAT-induced Cyclin D1 expression in a kinase-independent fashion. Conclusion Fak is required for c-Met/β-catenin-driven hepatocarcinogenesis. Inhibition of FAK provides a potential strategy to treat HCC. PMID:25163657

  3. Perinatal ethanol exposure alters met-enkephalin levels of male and female rats.

    PubMed

    Lugo, Joaquin N; Wilson, Marlene A; Kelly, Sandra J

    2006-01-01

    This study used a rat model of Fetal Alcohol Syndrome to investigate whether combined prenatal and postnatal ethanol exposure affects met-enkephalin levels in the brains of male and female Long-Evans adult rats. Intragastric ethanol was administered to a group of rats (ET) from gestational day (GD) 1 through 22 and from postnatal day (PD) 2 through 10. The control groups consisted of a nontreated control group (NTC) and an intubated control group (IC) that received the intragastric intubation procedure but no exposure to ethanol. We measured met-enkephalin levels in the prefrontal cortex, nucleus accumbens, hypothalamus, central and basolateral nucleus of amygdala and ventral tegmental area. Met-enkephalin levels in the hypothalamus of male and female ET animals were significantly higher than those in either the NTC or IC animals. Met-enkephalin levels in the central nucleus of the amygdala of male and female ET animals were significantly lower than the levels in the NTC animals. Met-enkephalin levels in the nucleus accumbens of ET females were significantly greater than those in the IC females. These results demonstrate that the combination of prenatal and postnatal ethanol exposure affects basal met-enkephalin levels in specific regions in a sex-specific manner. These changes in met-enkephalin levels may explain how early ethanol exposure affects opioid-regulated behaviors such as social play, sexual behavior, and other social behaviors. PMID:16457985

  4. Mechanisms regulating c-met overexpression in liver-metastatic B16-LS9 melanoma cells.

    PubMed

    Elia, G; Ren, Y; Lorenzoni, P; Zarnegar, R; Burger, M M; Rusciano, D

    2001-01-01

    Liver selected B16-LS9 melanoma cells show a dramatic overexpression of the proto-oncogene c-met, the cellular receptor for hepatocyte growth factor/scatter factor. As a consequence, c-met becomes constitutively active, and the cells become more responsive to hepatocyte growth factor stimulation. We have investigated the molecular mechanisms regulating c-met expression in both the parental line B16-F1, which has low expression levels, and the liver-specific B16-LS9, overexpressing c-met. Overexpression is observed at the protein and mRNA levels, however without further evidence of gene amplification or rearrangement. c-met promoter activity was higher in B16-LS9 than B16-F1 cells, and also a nuclear run-off showed higher transcription levels in B16-LS9 cells. Moreover, we found that c-met mRNA had a longer half-life in B16-LS9 cells, thus indicating also the involvement of post-transcriptional regulation mechanisms. Finally, we found evidence that autonomous activation of the melanocortin receptor-1 (MCR-1) is at least partially responsible for c-met upregulation in B16-LS9 cells, since treatment of the cells with a potent MSH antagonist (the agouti peptide) has strong down-regulatory effects. PMID:11255230

  5. A novel multipurpose monoclonal antibody for evaluating human c-MET expression in preclinical and clinical settings

    PubMed Central

    Knudsen, Beatrice S.; Zhao, Ping; Resau, James; Cottingham, Sandra; Gherardi, Ermanno; Xu, Eric; Berghuis, Bree; Daugherty, Jennifer; Grabinski, Tessa; Toro, Jose; Giambernardi, Troy; Skinner, R. Scot; Gross, Milton; Hudson, Eric; Kort, Eric; Lengyel, Ernst; Ventura, Aviva; Xie, Qian; Hay, Rick; Woude, George Vande; Cao, Brian

    2010-01-01

    The inappropriate expression of the c-MET cell surface receptor in many human solid tumors necessitates the development of companion diagnostics to identify those patients who could benefit from c-MET targeted therapies. Tumor tissues are formalin-fixed and paraffin embedded (FFPE) for histopathological evaluation, making the development of an antibody against c-MET that accurately and reproducibly detects the protein in FFPE samples an urgent need. We have developed a monoclonal antibody, designated MET4, from a panel of MET-avid monoclonal antibodies, based on its specific staining pattern in FFPE preparations of normal human prostate tissues. The accuracy of MET4 immunohistochemistry (MET4-IHC) was assessed by comparing MET4-IHC in FFPE cell pellets with immunoblotting analysis. The technical reproducibility of MET4-IHC possessed a percentage coefficient of variability (%CV) of 6.25% in intra-assay and inter-assay testing. Comparison with other commercial c-MET antibody detection reagents demonstrated equal specificity and increased sensitivity for c-MET detection in prostate tissues. In two cohorts of ovarian cancers and gliomas, MET4 reacted with ovarian cancers of all histological subtypes (strong staining in 25%) and with 63% of gliomas. In addition, MET4 bound c-Met on the surfaces of cultured human cancer cells and tumor xenografts. In summary, the MET4 monoclonal antibody accurately and reproducibly measures c-MET expression by IHC in FFPE tissues and can be used for molecular imaging in-vivo. These properties encourage further development of MET4 as a multipurpose molecular diagnostics reagent to help to guide appropriate selection of patients being considered for treatment with c-MET-antagonistic drugs. PMID:18815565

  6. Characterization of an Oncolytic Adenovirus Vector Constructed to Target the cMet Receptor

    PubMed Central

    Sakr, Hany I; Coleman, David T; Cardelli, James A; Mathis, J Michael

    2015-01-01

    The cMet receptor is a homodimer with tyrosine kinase activity. Upon stimulation with its ligand, hepatocyte growth factor (HGF), the receptor mediates wide physiologic actions. The HGF-cMet signaling pathway is dysregulated in many cancers, which makes cMet an important target for novel therapeutic interventions. Oncolytic adenoviruses (Ads) have been used for the past three decades as a promising therapeutic approach for a wide array of neoplastic diseases. To date, achieving cancer-specific replication of oncolytic Ads has been accomplished by either viral genome deletions or by incorporating tumor selective promoters. To achieve novel specificity of oncolytic Ad infection of cancer cells that overexpress cMet, we inserted the HGF NK2 sequence, corresponding to a competitive antagonist of HGF binding to the cMet receptor, into the Ad serotype 5 (Ad5) fiber gene. The resulting vector, Ad5-pIX-RFP-FF/NK2, was rescued, amplified in HEK293 cells, and characterized. Binding specificity and viral infectivity were tested in various cancer cell lines that express varying levels of cMet and hCAR (the Ad5 receptor). We found that Ad5-pIX-RFP-FF/NK2 demonstrated binding specificity to the cMet receptor. In addition, there was enhanced viral infectivity and virus replication compared with a non-targeted Ad vector. Although NK2 weakly induces cMet receptor activation, our results showed no receptor phosphorylation in the context of an oncolytic Ad virus. In summary, these results suggest that an oncolytic Ad retargeted to the cMet receptor is a promising vector for developing a novel cancer therapeutic agent. PMID:26866014

  7. c-MET expression in colorectal adenomas and primary carcinomas with its corresponding metastases

    PubMed Central

    Abd El-Maqsoud, Nehad M. R.; El-Hameed El-Heeny, Amr Abd; Mohammed, Mostafa Fuad

    2015-01-01

    Background c-MET plays an important role in tumor proliferation, invasion and metastasis. In this study we examined the expression of c-MET in colorectal adenomas, primary adenocarcinomas and their corresponding lymph node, peritoneal and liver metastases. We correlated our findings with clinicopathological features. Methods Twenty three cases of colorectal adenoma and 102 cases of primary colorectal carcinoma and their corresponding metastases (44 lymph nodes, 21 peritoneal deposits and 16 liver metastases) were studied to evaluate c-MET expression by immunohistochemistry. For comparison, 12 sections of adjacent healthy colorectal mucosa were examined. Results Statistically significant differences were present among normal tissues, colorectal adenomas and primary colorectal carcinomas (P=0.011). Normal tissues showed a negative or weak reaction in 66.67% and 33.33% of cases respectively. Expression of c-MET was positive in 47.8% of adenomas. A significant positive association was identified between c-MET high expression and degree of dysplasia (P=0.024). c-MET was highly expressed in 66.7% of primary colorectal carcinoma. Significant positive correlations were detected between c-MET expression and TNM stage (P=0.036), lymph node metastasis (LNM), peritoneal deposits and liver metastasis (P=0.038, P=0.094 and P=0.045, respectively). c-MET expression in metastatic tissues was significantly higher than that of the primary tumor. Conclusions c-MET expression is gradually up-regulated in the development and progression of colorectal cancer (CRC) from normal epithelium to adenoma to colorectal carcinoma to metastases. PMID:26697193

  8. Cysteine Methylation Controls Radical Generation in the Cfr Radical AdoMet rRNA Methyltransferase

    PubMed Central

    Challand, Martin R.; Salvadori, Enrico; Driesener, Rebecca C.; Kay, Christopher W. M.; Roach, Peter L.; Spencer, James

    2013-01-01

    The ‘radical S-adenosyl-L-methionine (AdoMet)’ enzyme Cfr methylates adenosine 2503 of the 23S rRNA in the peptidyltransferase centre (P-site) of the bacterial ribosome. This modification protects host bacteria, notably methicillin-resistant Staphylococcus aureus (MRSA), from numerous antibiotics, including agents (e.g. linezolid, retapamulin) that were developed to treat such organisms. Cfr contains a single [4Fe-4S] cluster that binds two separate molecules of AdoMet during the reaction cycle. These are used sequentially to first methylate a cysteine residue, Cys338; and subsequently generate an oxidative radical intermediate that facilitates methyl transfer to the unreactive C8 (and/or C2) carbon centres of adenosine 2503. How the Cfr active site, with its single [4Fe-4S] cluster, catalyses these two distinct activities that each utilise AdoMet as a substrate remains to be established. Here, we use absorbance and electron paramagnetic resonance (EPR) spectroscopy to investigate the interactions of AdoMet with the [4Fe-4S] clusters of wild-type Cfr and a Cys338 Ala mutant, which is unable to accept a methyl group. Cfr binds AdoMet with high (∼ 10 µM) affinity notwithstanding the absence of the RNA cosubstrate. In wild-type Cfr, where Cys338 is methylated, AdoMet binding leads to rapid oxidation of the [4Fe-4S] cluster and production of 5'-deoxyadenosine (DOA). In contrast, while Cys338 Ala Cfr binds AdoMet with equivalent affinity, oxidation of the [4Fe-4S] cluster is not observed. Our results indicate that the presence of a methyl group on Cfr Cys338 is a key determinant of the activity of the enzyme towards AdoMet, thus enabling a single active site to support two distinct modes of AdoMet cleavage. PMID:23861844

  9. The c-Met Inhibitor MSC2156119J Effectively Inhibits Tumor Growth in Liver Cancer Models.

    PubMed

    Bladt, Friedhelm; Friese-Hamim, Manja; Ihling, Christian; Wilm, Claudia; Blaukat, Andree

    2014-01-01

    The mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase with hepatocyte growth factor (HGF) as its only high-affinity ligand. Aberrant activation of c-Met is associated with many human malignancies, including hepatocellular carcinoma (HCC). We investigated the in vivo antitumor and antimetastatic efficacy of the c-Met inhibitor MSC2156119J (EMD 1214063) in patient-derived tumor explants. BALB/c nude mice were inoculated with MHCC97H cells or with tumor fragments of 10 patient-derived primary liver cancer explants selected according to c-Met/HGF expression levels. MSC2156119J (10, 30, and 100 mg/kg) and sorafenib (50 mg/kg) were administered orally as single-agent treatment or in combination, with vehicle as control. Tumor response, metastases formation, and alpha fetoprotein (AFP) levels were measured. MSC2156119J inhibited tumor growth and induced complete regression in mice bearing subcutaneous and orthotopic MHCC97H tumors. AFP levels were undetectable after 5 weeks of MSC2156119J treatment, and the number of metastatic lung foci was reduced. Primary liver explant models with strong c-Met/HGF activation showed increased responsiveness to MSC2156119J, with MSC2156119J showing similar or superior activity to sorafenib. Tumors characterized by low c-Met expression were less sensitive to MSC2156119J. MSC2156119J was better tolerated than sorafenib, and combination therapy did not improve efficacy. These findings indicate that selective c-Met/HGF inhibition with MSC2156119J is associated with marked regression of c-Met high-expressing tumors, supporting its clinical development as an antitumor treatment for HCC patients with active c-Met signaling. PMID:25256830

  10. Biochemical and pharmacological characterization of human c-Met neutralizing monoclonal antibody CE-355621

    PubMed Central

    Michaud, Neil R.; Jani, Jitesh P.; Hillerman, Stephen; Tsaparikos, Konstantinos E.; Barbacci-Tobin, Elsa G.; Knauth, Elisabeth; Putz Jr., Henry; Campbell, Mary; Karam, George A.; Chrunyk, Boris; Gebhard, David F.; Green, Larry L.; Xu, Jinghai J.; Dunn, Margaret C.; Coskran, Tim M.; Lapointe, Jean-Martin; Cohen, Bruce D.; Coleman, Kevin G.; Bedian, Vahe; Vincent, Patrick; Kajiji, Shama; Steyn, Stefan J.; Borzillo, Gary V.; Los, Gerrit

    2012-01-01

    The c-Met proto-oncogene is a multifunctional receptor tyrosine kinase that is stimulated by its ligand, hepatocyte growth factor (HGF), to induce cell growth, motility and morphogenesis. Dysregulation of c-Met function, through mutational activation or overexpression, has been observed in many types of cancer and is thought to contribute to tumor growth and metastasis by affecting mitogenesis, invasion, and angiogenesis. We identified human monoclonal antibodies that bind to the extracellular domain of c-Met and inhibit tumor growth by interfering with ligand-dependent c-Met activation. We identified antibodies representing four independent epitope classes that inhibited both ligand binding and ligand-dependent activation of c-Met in A549 cells. In cells, the antibodies antagonized c-Met function by blocking receptor activation and by subsequently inducing downregulation of the receptor, translating to phenotypic effects in soft agar growth and tubular morphogenesis assays. Further characterization of the antibodies in vivo revealed significant inhibition of c-Met activity (≥ 80% lasting for 72–96 h) in excised tumors corresponded to tumor growth inhibition in multiple xenograft tumor models. Several of the antibodies identified inhibited the growth of tumors engineered to overexpress human HGF and human c-Met (S114 NIH 3T3) when grown subcutaneously in athymic mice. Furthermore, lead candidate antibody CE-355621 inhibited the growth of U87MG human glioblastoma and GTL-16 gastric xenografts by up to 98%. The findings support published pre-clinical and clinical data indicating that targeting c-Met with human monoclonal antibodies is a promising therapeutic approach for the treatment of cancer. PMID:23007574

  11. [Spectral Study on Coordination Reaction Between metMyoglobin and Nitric Oxide].

    PubMed

    Tang, Qian; Zhang, Yue; Cao, Hong-yu; Shi, Shan-shan; Zheng, Xue-fang

    2015-07-01

    As we all known, the instantaneous reaction between protein and ligands are very important to adjust the normal playing of biological function. And nitric oxide interactions with iron are the most important biological reactions in which NO participates. Unlike carbon monoxide or oxygen, NO can also bind reversibly to ferric iron. In this paper, UV-Vis absorption and CD spectra were used to study coordination reaction process between horse heart metMb and NO, to demonstrate the coordination reaction mechanism and to explore the influencing factors of metMb with NO. The experimental results showed that metMb could react with NO, and obtained three new peaks at 420 nm, 534 and 568 nm, respectively, which implied metMb and NO have reacted and generated a new complex-nitrosylmetmyoglobin (metMbNO). Then as time went on, NO concentration decreased in the solution, and the Fe-N bond fractured under the attack of H2O, then NO leaves slowly from metMbNO, and met-Mb was regenerated. In this experiment, we also found that external conditions such as buffer medium, ionic strength, pH, temperature, etc, had an important influence on the coordination reaction between metMb and NO. It was favorable for the coordination reaction, when the 0.01 mol x L(-1) phosphate buffer. solution is near neutral condition, the temperature is 280 K, the coordination reaction could reach equilibrium at a fastest speed. In addition, the CD date show that NO only reacts with Fe atom in the center of heme and has less effect on the secondary structuers of protein. The research of metMb and NO played an important role to further study the function of NO. Especially the establish of equilibrium reaction mechanism between NO and heme protein has an important research value on maintaining the balance of NO in vivo and keeping the normal function in the body's cells. PMID:26717761

  12. Met tyrosine kinase inhibitor, PF-2341066, suppresses growth and invasion of nasopharyngeal carcinoma

    PubMed Central

    Zhao, Yuanyuan; Zhang, Jing; Tian, Ying; Xue, Cong; Hu, Zhihuang; Zhang, Li

    2015-01-01

    Purpose We explored the effect of hepatocyte growth factor (HGF)/Met signaling pathway on nasopharyngeal carcinoma (NPC) cells in vitro and in vivo, and investigated the ability of Met tyrosine kinase inhibitor (TKI) to block HGF-induced biological signaling. Experimental design Met TKI inhibitor PF-2341066 alone, or in combination with cisplatin, was investigated for its ability to block HGF-induced signaling and biological effects in vitro and in vivo. HGF/Met expression and activation of signaling in NPC cells were detected by using Western blot and immunohistochemistry. Biological evaluation, including wound healing, cell proliferation, and invasion of NPC cells, was also examined, and the correlation between HGF/Met expression of primary and metastatic tumor in NPC patients and clinical prognosis were also analyzed. Results Met TKI inhibitor, PF-2341066, inhibited growth of NPC cells in vivo with half maximal inhibitory concentration of 0.79±0.21 μmol/L, and suppressed invasion and migration of NPC cells; also, the inhibition of PF-2341066 was synergized with cisplatin treatment. Compared with the control group, Met TKI inhibited metastasis of transplanted NPC in nude mice (the number of live metastases [mean ± SD]: 5.8±2.2 versus 11.8±2.2, P=0.03; the number of lung metastases: 2.3±1.5 versus 5.3±0.9, P=0.06). HGF was widely expressed in both primary and metastatic lesions while Met expression of metastatic lesions was higher than that of primary lesions (primary lesions: 24.7%; liver metastases: 40%; lung metastases: 29%; lymph node metastases: 29%, P<0.05), and overall survival of NPC patients with higher expression of Met was shorter (P=0.13). Conclusion Our results demonstrated that HGF/Met signaling promoted NPC growth, further resulting in metastasis and poor prognosis. Met TKI, PF-2341066, showed potent antitumor activity in vivo and in vitro which was enhanced by combination with cisplatin. Our study implied that HGF/Met signaling was the

  13. COMT Val158Met Polymorphism Is Associated with Verbal Working Memory in Neurofibromatosis Type 1

    PubMed Central

    Costa, Danielle de Souza; de Paula, Jonas J.; Alvim-Soares, Antonio M.; Pereira, Patrícia A.; Malloy-Diniz, Leandro F.; Rodrigues, Luiz O. C.; Romano-Silva, Marco A.; de Miranda, Débora M.

    2016-01-01

    Neurofibromatosis type I (NF1) is a neurogenetic disease marked by multiple cognitive and learning problems. Genetic variants may account for phenotypic variance in NF1. Here, we investigated the association between the catechol-O-methyltransferase (COMT) Val158Met polymorphism and working memory and arithmetic performance in 50 NF1 individuals. A significant association of the COMT polymorphism was observed only with verbal working memory, as measured by the backward digit-span task with an advantageous performance for Met/Met carriers. To study how genetic modifiers influence NF1 cognitive performance might be of importance to decrease the unpredictability of the cognitive profile among NF1 patients. PMID:27458360

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

    PubMed

    Landry, Mélissa; Pomerleau, Véronique; Saucier, Caroline

    2016-06-01

    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

  15. Overexpression of PI3K p110α contributes to acquired resistance to MET inhibitor, in MET-amplified SNU-5 gastric xenografts

    PubMed Central

    Ji, Fujian; Liu, Xuanwen; Wu, Yuanyu; Fang, Xuedong; Huang, Guomin

    2015-01-01

    Gastric cancer is one of the most virulent malignant diseases and is the second leading cause of cancer mortality in the world. The receptor tyrosine kinase MET is constitutively activated in many gastric cancers and its expression is strictly required for survival of some gastric cancer cells. Targeting gastric cancers with amplified or abnormally activated MET may have therapeutic benefit based on nonclinical and emerging clinical findings. However, one of the major problems of therapies targeting tyrosine kinases is that many tumors are not responsive to treatment or eventually develop resistance to the drugs. This study aims to understand the mechanisms of MET resistance in gastric SNU-5 xenografts which developed resistance to PHA665752, a MET inhibitor, through long-period tyrosine kinase inhibitor exposure. In the current study, we found that PI3K p110α is overexpressed in PHA665752-resistant SNU-5 xenografts. These findings showed that high PI3K p110α expression contributes to tyrosine kinase inhibitor resistance. In addition, we reported the development of a carcinogen-induced gastric cancer model that recapitulates PI3K p110α expression in human disease, which will serve as a useful model to study PI3K p110α’s biology and its effectiveness as a novel biomarker and a molecular target for gastric cancer. Ultimately, PI3K p110α represents a novel target for gastric cancer. PMID:26543351

  16. An engineered dimeric fragment of hepatocyte growth factor is a potent c-MET agonist

    PubMed Central

    Liu, Cassie J.; Jones, Douglas S.; Tsai, Ping-Chuan; Venkataramana, Abhishek; Cochran, Jennifer R.

    2015-01-01

    Hepatocyte growth factor (HGF), through activation of the c-MET receptor, mediates biological processes critical for tissue regeneration; however, its clinical application is limited by protein instability and poor recombinant expression. We previously engineered a HGF fragment (eNK1) that possesses increased stability and expression yield, and developed a c-MET agonist by coupling eNK1 through an introduced cysteine residue. Here, we further characterize this eNK1 dimer, and show it elicits significantly greater c-MET activation, cell migration, and proliferation than the eNK1 monomer. The efficacy of the eNK1 dimer was similar to HGF, suggesting its promise as a c-MET agonist. PMID:25451235

  17. Val66Met BDNF polymorphism is associated with Parkinson's disease cognitive impairment.

    PubMed

    Altmann, Vivian; Schumacher-Schuh, Artur F; Rieck, Mariana; Callegari-Jacques, Sidia M; Rieder, Carlos R M; Hutz, Mara H

    2016-02-26

    Parkinson's disease (PD) is one of the most common neurodegenerative diseases worldwide. Besides characteristic PD motor features, the disease has important non-motor characteristics such as cognitive impairment. The role of genetic factors in cognitive impairment associated with PD is still unclear. In this study, we examined whether BDNF Val66Met was associated with impaired cognition in Parkinson's disease. One hundred and seventy five patients with a clinical diagnosis of Parkinson's disease were included. Global cognitive abilities of the patients were measured by the Mini-Mental State Examination (MMSE). Poisson Regression models were used to test for association between 66Met carriers and cognitive impairment controlling for covariates. Carriers of at least one BDNF 66Met allele presented a higher prevalence of cognitive impairment (p=0.005 RR=1.45 IC=95% [1.1-1.8]). These results suggest a role for BDNF Val66Met polymorphism on cognitive impairment in PD. PMID:26806863

  18. Effects of Met-enkephalin on body temperature of normal and morphine-tolerant rats.

    PubMed

    Ferri, S; Arrigo Reina, R; Santagostino, A; Scoto, G M; Spadaro, C

    1978-07-19

    The endogenous opioid met-enkephalin intraventricularly adminstered to the rat at the dose of 100 microgram raised rectal temperature, whereas 400 microgram of the pentapeptide caused a diphasic effect, i.e., hypothermia followed by hyperthermia. Met-enkephalin was ineffective when administered i.p. The effects on temperature were substantially similar to those elicited, for both routes of administration, by morphine, which may either raise or lower rat temperature depending on the dose. More naloxone was required to antagonize thermic effects of met-enkephalin than morphine. Finally, there was a lack of effects on temperature for met-enkephalin centrally administered to morphine-tolerant animals, thus providing further evidence, in vivo, of cross tolerance between opiates and naturally occurring ligands of opiate receptors. PMID:98798

  19. Autism-Associated Promoter Variant in MET Impacts Functional and Structural Brain Networks

    PubMed Central

    Rudie, J. D.; Hernandez, L. M.; Brown, J. A.; Beck-Pancer, D.; Colich, N. L.; Gorrindo, P.; Thompson, P. M.; Geschwind, D. H.; Bookheimer, S. Y.; Levitt, P.; Dapretto, M.

    2012-01-01

    SUMMARY As genes that confer increased risk for autism spectrum disorder (ASD) are identified, a crucial next step is to determine how these risk factors impact brain structure and function and contribute to disorder heterogeneity. With three converging lines of evidence, we show that a common, functional ASD risk variant in the Met Receptor Tyrosine Kinase (MET) gene is a potent modulator of key social brain circuitry in children and adolescents with and without ASD. MET risk genotype predicted atypical fMRI activation and deactivation patterns to social stimuli (i.e., emotional faces), as well as reduced functional and structural connectivity in temporo-parietal regions known to have high MET expression, particularly within the default mode network. Notably, these effects were more pronounced in individuals with ASD. These findings highlight how genetic stratification may reduce heterogeneity and help elucidate the biological basis of complex neuropsychiatric disorders such as ASD. PMID:22958829

  20. Using Remote Sensing and Radar MET Data to Support Watershed Assessments Comprising IEM

    EPA Science Inventory

    Meteorological (MET) data required by watershed assessments that comprise Integrated Environmental Modeling (IEM) have traditionally been provided by land-based weather (gauge) stations; although these data may not be most appropriate for describing adequate spatial and temporal...

  1. Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma.

    PubMed Central

    Humphrey, P. A.; Zhu, X.; Zarnegar, R.; Swanson, P. E.; Ratliff, T. L.; Vollmer, R. T.; Day, M. L.

    1995-01-01

    Hepatocyte growth factor (scatter factor) and its receptor, the c-met proto-oncogene product (c-MET), have been implicated in embryogenesis, tissue reorganization, and tumor progression. Little is known, however, of the expression and functional significance of these molecules in prostatic cells and tissue. In this investigation, we assessed the expression of hepatocyte growth factor (HGF) and c-MET in prostatic tissues and cell lines and also determined the effect of purified recombinant HGF on cell proliferation and scattering of prostatic carcinoma cell lines. HGF was expressed by human prostatic stromal myofibroblasts in primary culture but not by three human prostatic carcinoma cell lines (LNCaP, DU 145, and PC-3) as assessed by Northern blot analysis. HGF was also detected by reverse transcriptase-polymerase chain reaction in both benign and malignant tissues from radical prostatectomy specimens. c-MET transcripts were identified by Northern blot in two androgen-insensitive human prostatic carcinoma cell lines (DU 145 and PC-3) but not the androgen-sensitive LNCaP cell line. Additional evidence of linkage of androgen responsiveness and c-MET was provided by experiments in which androgen deprivation of normal rat prostates via castration produced a marked up-regulation of c-MET expression as determined by Northern blot and immunohistochemistry. c-MET protein was detected by immunohistochemical analysis in a substantial percentage (58 of 128 or 45%) of prostatic carcinomas and was found more often in metastatic growths of human prostatic carcinoma (15 of 20 patients) compared with primary tumors (43 of 108 patients; P < 0.005). Moreover, in Dunning R-3327 rat prostatic carcinoma cell lines, c-MET expression was highest in the androgen-insensitive subline with the highest metastatic capacity. Purified recombinant human HGF induced dose-dependent cellular proliferation and scattering in the DU 145 carcinoma cell line. These data indicate that HGF may function in

  2. 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

  3. MET-XAlign: a metabolite cross-alignment tool for LC/MS-based comparative metabolomics.

    PubMed

    Zhang, Wenchao; Lei, Zhentian; Huhman, David; Sumner, Lloyd W; Zhao, Patrick X

    2015-09-15

    Liquid chromatography/mass spectrometry (LC/MS) metabolite profiling has been widely used in comparative metabolomics studies; however, LC/MS-based comparative metabolomics currently faces several critical challenges. One of the greatest challenges is how to effectively align metabolites across different LC/MS profiles; a single metabolite can give rise to multiple peak features, and the grouped peak features that can be used to construct a spectrum pattern of single metabolite can vary greatly between biochemical experiments and even between instrument runs. Another major challenge is that the observed retention time for a single metabolite can also be significantly affected by experimental conditions. To overcome these two key challenges, we present a novel metabolite-based alignment approach entitled MET-XAlign to align metabolites across LC/MS metabolomics profiles. MET-XAlign takes the deduced molecular mass and estimated compound retention time information that can be extracted by our previously published tool, MET-COFEA, and aligns metabolites based on this information. We demonstrate that MET-XAlign is able to cross-align metabolite compounds, either known or unknown, in LC/MS profiles not only across different samples but also across different biological experiments and different electrospray ionization modes. Therefore, our proposed metabolite-based cross-alignment approach is a great step forward and its implementation, MET-XAlign, is a very useful tool in LC/MS-based comparative metabolomics. MET-XAlign has been successfully implemented with core algorithm coding in C++, making it very efficient, and visualization interface coding in the Microsoft.NET Framework. The MET-XAlign software along with demonstrative data is freely available at http://bioinfo.noble.org/manuscript-support/met-xalign/ . PMID:26247233

  4. BI-14GENOMIC PROFILING OF A PREDICTIVE SIGNATURE FOR MET-TARGETED THERAPY IN GLIOBLASTOMA

    PubMed Central

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

    2014-01-01

    The success of molecular targeted therapy against cancer depends on discovering the tumor driver genes and the molecular determinants that control the pathway activity. Glioblastoma (GBM) is one of the most devastating cancers due to its highly infiltrating nature, and MET pathway activation is a major cause of invasion in both primary and recurrent tumors. Because MET inhibitors are in clinical trials against GBM, there may be clinical utility from developing more effective patient enrollment strategies tailored to targeted therapeutics. Previously, we reported (Xie et al., PNAS 2012) that GBM tumors with high levels of hepatocyte growth factor (HGF) often display HGF-autocrine activation through its receptor MET, which is a key molecular feature in sensitivity to MET inhibitors. In this study, we sought to develop a molecular signature that can be used as a biomarker to identify GBM patients whose tumor would be vulnerable to treatment with MET inhibitors. Because GBM is a heterogeneous disease in which drug response in the individual patient can be influenced by a variety of different mechanisms, the expression of a single gene was not anticipated to be sufficient to pinpoint sensitivity to the drug; rather, a hypothesis-driven, biomarker-based molecular signature would likely be of a higher value. We analyzed genomic data from GBM patients in The Cancer Genome Atlas (TCGA) Network as well as from preclinical tumor models. We found that GBM tumors sensitive to MET inhibitors share common genomic profiles. More importantly, using patient-derived xenograft models, a 25-gene molecular signature was identified that predicted sensitivity to MET inhibitors. Our findings are a proof-of-concept for the use of genomic signatures to identify GBM patients with greater vulnerability for MET-targeted therapy.

  5. Combined MET inhibition and topoisomerase I inhibition block cell growth of small cell lung cancer.

    PubMed

    Rolle, Cleo E; Kanteti, Rajani; Surati, Mosmi; Nandi, Suvobroto; Dhanasingh, Immanuel; Yala, Soheil; Tretiakova, Maria; Arif, Qudsia; Hembrough, Todd; Brand, Toni M; Wheeler, Deric L; Husain, Aliya N; Vokes, Everett E; Bharti, Ajit; Salgia, Ravi

    2014-03-01

    Small cell lung cancer (SCLC) is a devastating disease, and current therapies have not greatly improved the 5-year survival rates. Topoisomerase (Top) inhibition is a treatment modality for SCLC; however, the response is short lived. Consequently, our research has focused on improving SCLC therapeutics through the identification of novel targets. Previously, we identified MNNG HOS transforming gene (MET) to be overexpressed and functional in SCLC. Herein, we investigated the therapeutic potential of combinatorial targeting of MET using SU11274 and Top1 using 7-ethyl-10-hydroxycamptothecin (SN-38). MET and TOP1 gene copy numbers and protein expression were determined in 29 patients with limited (n = 11) and extensive (n = 18) disease. MET gene copy number was significantly increased (>6 copies) in extensive disease compared with limited disease (P = 0.015). Similar TOP1 gene copy numbers were detected in limited and extensive disease. Immunohistochemical staining revealed a significantly higher Top1 nuclear expression in extensive (0.93) versus limited (0.15) disease (P = 0.04). Interestingly, a significant positive correlation was detected between MET gene copy number and Top1 nuclear expression (r = 0.5). In vitro stimulation of H82 cells revealed hepatocyte growth factor (HGF)-induced nuclear colocalization of p-MET and Top1. Furthermore, activation of the HGF/MET axis enhanced Top1 activity, which was abrogated by SU11274. Combination of SN-38 with SU11274 dramatically decreased SCLC growth as compared with either drug alone. Collectively, these findings suggest that the combinatorial inhibition of MET and Top1 is a potentially efficacious treatment strategy for SCLC. PMID:24327519

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

    SciTech Connect

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

    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 MetView 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.

  7. 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

  8. Structural Basis for the Differential Regulation of DNA by the Methionine Repressor MetJ

    SciTech Connect

    Augustus, Anne; Reardon, Patrick; Heller, William T; Spicer, Leonard D.

    2006-01-01

    The Met regulon in Escherichia coli encodes several proteins responsible for the biosynthesis of methionine. Regulation of the expression of most of these proteins is governed by the methionine repressor protein MetJ and its co-repressor, the methionine derivative S-adenosylmethionine. Genes controlled by MetJ contain from two to five sequential copies of a homologous 8-bp sequence called the metbox. A crystal structure for one of the complexes, the repressor tetramer bound to two metboxes, has been reported (Somers, W. S., and S. E. Phillips (1992) Nature 359, 387-393), but little structural work on the larger assemblies has been done presumably because of the difficulties in crystallization and the variability in the number and sequences of metboxes for the various genes. Small angle neutron scattering was used to study complexes of MetJ and S-adenosylmethionine with double-stranded DNA containing two, three, and five metboxes. Our results demonstrate that the crystal structure of the two-metbox complex is not the native solution conformation of the complex. Instead, the system adopts a less compact conformation in which there is decreased interaction between the adjacent MetJ dimers. Models built of the higher order complexes from the scattering data show that the three-metbox complex is organized much like the two-metbox complex. However, the five-metbox complex differs significantly from the smaller complexes, providing much closer packing of the adjacent MetJ dimers and allowing additional contacts not available in the crystal structure. The results suggest that there is a structural basis for the differences observed in the regulatory effectiveness of MetJ for the various genes of the Met regulon.

  9. BDNF val66met affects hippocampal volume and emotion-related hippocampal memory activity.

    PubMed

    Molendijk, M L; van Tol, M-J; Penninx, B W J H; van der Wee, N J A; Aleman, A; Veltman, D J; Spinhoven, P; Elzinga, B M

    2012-01-01

    The val(66)met polymorphism on the BDNF gene has been reported to explain individual differences in hippocampal volume and memory-related activity. These findings, however, have not been replicated consistently and no studies to date controlled for the potentially confounding impact of early life stress, such as childhood abuse, and psychiatric status. Using structural and functional MRI, we therefore investigated in 126 depressed and/or anxious patients and 31 healthy control subjects the effects of val(66)met on hippocampal volume and encoding activity of neutral, positive and negative words, while taking into account childhood abuse and psychiatric status. Our results show slightly lower hippocampal volumes in carriers of a met allele (n=54) relative to val/val homozygotes (n=103) (P=0.02, effect size (Cohen's d)=0.37), which appeared to be independent of childhood abuse and psychiatric status. For hippocampal encoding activity, we found a val(66)met-word valence interaction (P=0.02) such that carriers of a met allele showed increased levels of activation in response to negative words relative to activation in the neutral word condition and relative to val/val homozygotes. This, however, was only evident in the absence of childhood abuse, as abused val/val homozygotes showed hippocampal encoding activity for negative words that was comparable to that of carriers of a met allele. Neither psychiatric status nor memory accuracy did account for these associations. In conclusion, BDNF val(66)met has a significant impact on hippocampal volume independently of childhood abuse and psychiatric status. Furthermore, early adverse experiences such as childhood abuse account for individual differences in hippocampal encoding activity of negative stimuli but this effect manifests differently as a function of val(66)met. PMID:22832736

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

    SciTech Connect

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

    2012-03-15

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

  11. HGF/Met Signaling in Head and Neck Cancer: Impact on the Tumor Microenvironment.

    PubMed

    Hartmann, Stefan; Bhola, Neil E; Grandis, Jennifer R

    2016-08-15

    Studies to date have revealed several major molecular alterations that contribute to head and neck squamous cell carcinoma (HNSCC) initiation, progression, metastatic spread, and therapeutic failure. The EGFR is the only FDA-approved therapeutic target, yet responses to cetuximab have been limited. Activation and cross-talk of cellular receptors and consequent activation of different signaling pathways contribute to limited activity of blockade of a single pathway. The hepatocyte growth factor (HGF) receptor, Met, has been implicated in HNSCC tumorigenesis and EGFR inhibitor resistance. HGF, the sole ligand of Met, is overexpressed in the tumor microenvironment. The role of HGF/Met signaling in proliferation, metastasis, and angiogenesis has been investigated in HNSCC, leading to clinical trials with various Met inhibitors and HGF antibodies. However, the role of the HGF/Met signaling axis in mediating the tumor microenvironment has been relatively understudied in HNSCC. In this review, we discuss the functional roles of Met and HGF in HNSCC with a focus on the tumor microenvironment and the immune system. Clin Cancer Res; 22(16); 4005-13. ©2016 AACR. PMID:27370607

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

    PubMed Central

    Golkar, Armita; Lindström, Kara M.; Haaker, Jan; Öhman, Arne; Schalling, Martin; Ingvar, Martin

    2015-01-01

    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. PMID:25103087

  13. DNA triplex-mediated inhibition of MET leads to cell death and tumor regression in hepatoma

    PubMed Central

    Singhal, G; Akhter, MZ; Stern, DF; Gupta, SD; Ahuja, A; Sharma, U; Jagannathan, NR; Rajeswari, MR

    2016-01-01

    Mesenchymal epithelial transition factor (MET) is one of the critical cell signaling molecules whose aberrant expression is reported in several human cancers. The aim of the study is to investigate the antigene and antiproliferative effect of short triplex forming oligonucleotides, TFO-1 (part of the positive regulatory element) and TFO-2 (away from the transcription start site) on MET expression. HepG2 cells transfected only with TFO-1 (but not with TFO-2 and non-specific TFO) significantly decreased MET levels, which is accompanied by decrease in antiapoptotic proteins and increase in pro-apoptotic proteins. Phosphoproteome-array analysis of 46 intracellular kinases revealed hypophosphorylation of about 15 kinases including ERK, AKT, Src and MEK, suggesting the growth inhibitory effect of TFO-1. Further, the efficacy of TFO-1 was tested on diethylnitrosamine-induced liver tumors in wistar rats. T2-weighted magnetic resonance imaging showed decrease in liver tumor volume up to 90% after treatment with TFO-1. Decreased MET expression and elevated apoptotic activity further indicate that TFO-1 targeted to c-met leads to cell death and tumor regression in hepatoma. Formation of stable DNA triplex between TFO-1 and targeted gene sequence was confirmed by circular dichroic spectroscopy and gel retardation assay. Therefore, it can be concluded that DNA triplex-based therapeutic approaches hold promise in the treatment of malignancies associated with MET overexpression. PMID:21660063

  14. In vivo positron emission tomography (PET) imaging of mesenchymal-epithelial transition (MET) receptor.

    PubMed

    Wu, Chunying; Tang, Zhe; Fan, Weiwen; Zhu, Wenxia; Wang, Changning; Somoza, Edurado; Owino, Norbert; Li, Ruoshi; Ma, Patrick C; Wang, Yanming

    2010-01-14

    We report the radiosynthesis and evaluation of 3-[3,5-dimethyl-4-(4-[11C]methylpiperazinecarbonyl)-1H-pyrrol-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chlorophenyl)methylamide, termed [11C]SU11274 ([11C]14) for in vivo imaging of mesenchymal-epithelial transition (MET) receptor by positron emission tomography (PET). Following the synthesis of the precursor (13) that was achieved in 10 steps with a total yield of 9.7%, [11C]14 was obtained through radiomethylation in a range of 5-10% radiochemical yield and over 95% radiochemical purity. For in vivo PET studies, two human lung cancer xenograft models were established using MET-positive NCI-H1975 and MET-negative NCI-H520 cell lines. Quantitative [11C]14-PET studies showed that the tumor uptake of [11C]14 in the NCI-H1975 xenografts was significantly higher than that in the NCI-H520 xenografts, which is consistent with their corresponding immunohistochemical tissue staining patterns of MET receptors from the same animals. These studies demonstrated that [11C]14-PET is an appropriate imaging marker for quantification of MET receptor in vivo, which can facilitate efficacy evaluation in the clinical development of MET-targeted cancer therapeutics. PMID:19968287

  15. Dosage effects of BDNF Val66Met polymorphism on cortical surface area and functional connectivity.

    PubMed

    Wang, Chao; Zhang, Yuanchao; Liu, Bing; Long, Haixia; Yu, Chunshui; Jiang, Tianzi

    2014-02-12

    The single nucleotide polymorphism (SNP) that leads to a valine-to-methionine substitution at codon 66 (Val66Met) in BDNF is correlated with differences in cognitive and memory functions, as well as with several neurological and psychiatric disorders. MRI studies have already shown that this genetic variant contributes to changes in cortical thickness and volume, but whether the Val66Met polymorphism affects the cortical surface area of healthy subjects remains unclear. Here, we used multimodal MRI to study whether this polymorphism would affect the cortical morphology and resting-state functional connectivity of a large sample of healthy Han Chinese human subjects. An SNP-wise general linear model analysis revealed a "dosage effect" of the Met allele, specifically a stepwise increase in cortical surface area of the right anterior insular cortex with increasing numbers of the Met allele. Moreover, we found enhanced functional connectivity between the anterior insular and the dorsolateral prefrontal cortices that was linked with the dosage of the Met allele. In conclusion, these data demonstrated a "dosage effect" of BDNF Val66Met on normal cortical structure and function, suggesting a new path for exploring the mechanisms underlying the effects of genotype on cognition. PMID:24523553

  16. 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

  17. HGF stimulates proliferation through the HGF/c-Met pathway in nasopharyngeal carcinoma cells

    PubMed Central

    SUN, RUI; ZHANG, QING; GUO, LING; CHEN, MING-YUAN; SUN, YING; CAO, BRIAN; SUN, JIAN

    2012-01-01

    Hepatocyte growth factor (HGF) and its receptor c-Met are important in the development and homeostasis of a variety of human malignancies. However, the role of the HGF/c-Met signaling pathway in nasopharyngeal carcinoma (NPC) has not been clearly elucidated. This study examined the effect of HGF/c-Met on proliferation and migration in several NPC cell lines. RT-PCR was used to detect the HGF gene in CNE-1, CNE-2, HK-1, HONE-1 and SUNE-1 NPC cells. However, HGF gene expression was not detected in any of these cells. Using immunoblotting analysis, the Met25 protein was identified in HONE-1, HK-1 and CNE-1 cells. Results from fluorescence-activated cell sorting (FACS) analysis revealed that anti-Met25 mAb specifically bound Met-expressing HONE-1, HK-1 and CNE-1 cells. It was further demonstrated that exogenous HGF was able to stimulate the proliferation of HONE-1 and HK-1 cells and the healing of scrape wounds in HONE-1 NPC cells. Our results reveal the potential therapeutic applications of combination therapy with antibodies targeting HGF in NPC patients. PMID:22783404

  18. Differential effects of BDNF val(66)met in repetitive associative learning paradigms.

    PubMed

    Freundlieb, Nils; Backhaus, Winifried; Brüggemann, Norbert; Gerloff, Christian; Klein, Christine; Pinnschmidt, Hans O; Hummel, Friedhelm C

    2015-09-01

    In healthy young subjects, the brain derived neurotropic factor (BDNF) val(66)met polymorphism negatively affects behavioural outcome in short-term motor cortex or hippocampus-based learning paradigms. In repetitive training paradigms over several days this effect can be overcome, in tests involving other brain areas even positive effects were found. To further specify the role of this polymorphism in cognitive processes, we used an associative vocabulary learning paradigm over four consecutive days and tested 38 young healthy subjects and 29 healthy elderly subjects. As a control paradigm, we designed a nonverbal haptic Braille letter-learning paradigm based on the same principles. Behavioural outcome was then associated with the BDNF-genotype. In the vocabulary learning task, met carrier (met/val and met/met) benefitted more from the repetitive training than val/val subjects. This was paralleled by a higher reduction of delayed answers during the course of the study, an effect that was also present in the haptic paradigm. However, in a group of healthy elderly subjects, no similar tendency was found. We conclude that the BDNF val(66)met polymorphism alters highly circumscribed answer behaviours in young healthy subjects. This might partly explain the high variability of previously published results. PMID:25933507

  19. HGF-MET signals via the MLL-ETS2 complex in hepatocellular carcinoma.

    PubMed

    Takeda, Shugaku; Liu, Han; Sasagawa, Satoru; Dong, Yiyu; Trainor, Paul A; Cheng, Emily H; Hsieh, James J

    2013-07-01

    HGF signals through its cognate receptor, MET, to orchestrate diverse biological processes, including cell proliferation, cell fate specification, organogenesis, and epithelial-mesenchymal transition. Mixed-lineage leukemia (MLL), an epigenetic regulator, plays critical roles in cell fate, stem cell, and cell cycle decisions. Here, we describe a role for MLL in the HGF-MET signaling pathway. We found a shared phenotype among Mll(-/-), Hgf(-/-), and Met(-/-) mice with common cranial nerve XII (CNXII) outgrowth and myoblast migration defects. Phenotypic analysis demonstrated that MLL was required for HGF-induced invasion and metastatic growth of hepatocellular carcinoma cell lines. HGF-MET signaling resulted in the accumulation of ETS2, which interacted with MLL to transactivate MMP1 and MMP3. ChIP assays demonstrated that activation of the HGF-MET pathway resulted in increased occupancy of the MLL-ETS2 complex on MMP1 and MMP3 promoters, where MLL trimethylated histone H3 lysine 4 (H3K4), activating transcription. Our results present an epigenetic link between MLL and the HGF-MET signaling pathway, which may suggest new strategies for therapeutic intervention. PMID:23934123

  20. MET1 Is a Thylakoid-Associated TPR Protein Involved in Photosystem II Supercomplex Formation and Repair in Arabidopsis

    PubMed Central

    Bhuiyan, Nazmul H.; Friso, Giulia; Poliakov, Anton; Ponnala, Lalit

    2015-01-01

    Photosystem II (PSII) requires constant disassembly and reassembly to accommodate replacement of the D1 protein. Here, we characterize Arabidopsis thaliana MET1, a PSII assembly factor with PDZ and TPR domains. The maize (Zea mays) MET1 homolog is enriched in mesophyll chloroplasts compared with bundle sheath chloroplasts, and MET1 mRNA and protein levels increase during leaf development concomitant with the thylakoid machinery. MET1 is conserved in C3 and C4 plants and green algae but is not found in prokaryotes. Arabidopsis MET1 is a peripheral thylakoid protein enriched in stroma lamellae and is also present in grana. Split-ubiquitin assays and coimmunoprecipitations showed interaction of MET1 with stromal loops of PSII core components CP43 and CP47. From native gels, we inferred that MET1 associates with PSII subcomplexes formed during the PSII repair cycle. When grown under fluctuating light intensities, the Arabidopsis MET1 null mutant (met1) showed conditional reduced growth, near complete blockage in PSII supercomplex formation, and concomitant increase of unassembled CP43. Growth of met1 in high light resulted in loss of PSII supercomplexes and accelerated D1 degradation. We propose that MET1 functions as a CP43/CP47 chaperone on the stromal side of the membrane during PSII assembly and repair. This function is consistent with the observed differential MET1 accumulation across dimorphic maize chloroplasts. PMID:25587003

  1. 43 CFR 404.19 - What requirements must be met before I can request assistance to conduct a feasibility study?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 43 Public Lands: Interior 1 2010-10-01 2010-10-01 false What requirements must be met before I can... SUPPLY PROGRAM Overview § 404.19 What requirements must be met before I can request assistance to conduct a feasibility study? All of the following requirements must be met before you can request...

  2. 20 CFR 404.1644 - How and when we determine whether the processing time standards are met.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 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... basis. The determination as to whether or not the processing time thresholds have been met is made...

  3. 20 CFR 416.1044 - How and when we determine whether the processing time standards are met.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 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... basis. The determination as to whether or not the processing time thresholds have been met is made...

  4. 36 CFR 51.36 - What conditions must be met before the Director determines that a concessioner is a preferred...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 36 Parks, Forests, and Public Property 1 2011-07-01 2011-07-01 false What conditions must be met... Determining a Preferred Offeror § 51.36 What conditions must be met before the Director determines that a... following conditions are met: (a) The concessioner was a satisfactory concessioner during the term of...

  5. 76 FR 11846 - 24th Meeting: RTCA Special Committee 206: EUROCAE WG 76 Plenary: AIS and MET Data Link Services

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-03

    ... MET Data Link Services AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Notice of RTCA Special Committee 206: EUROCAE WG 76 Plenary: AIS and MET Data Link Services meeting. SUMMARY: The FAA is...: AIS and MET Data Link Services. DATES: The meeting will be held March 21-25, 2011 from 9 a.m. to 5...

  6. 43 CFR 3137.131 - What happens if the unit terminated before the unit operator met the initial development...

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... the unit operator met the initial development obligations? 3137.131 Section 3137.131 Public Lands... before the unit operator met the initial development obligations? If the unit terminated before the unit operator met the initial development obligations, BLM's approval of the unit agreement is revoked. You,...

  7. 36 CFR 51.36 - What conditions must be met before the Director determines that a concessioner is a preferred...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 36 Parks, Forests, and Public Property 1 2013-07-01 2013-07-01 false What conditions must be met... Determining a Preferred Offeror § 51.36 What conditions must be met before the Director determines that a... following conditions are met: (a) The concessioner was a satisfactory concessioner during the term of...

  8. 20 CFR 404.1645 - How and when we determine whether the performance accuracy standard is met.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... performance accuracy standard is met. 404.1645 Section 404.1645 Employees' Benefits SOCIAL SECURITY... Performance Standards § 404.1645 How and when we determine whether the performance accuracy standard is met... quarterly basis. The determinations as to whether the performance accuracy threshold has been met is made...

  9. 43 CFR 404.19 - What requirements must be met before I can request assistance to conduct a feasibility study?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 43 Public Lands: Interior 1 2014-10-01 2014-10-01 false What requirements must be met before I can... SUPPLY PROGRAM Overview § 404.19 What requirements must be met before I can request assistance to conduct a feasibility study? All of the following requirements must be met before you can request...

  10. 20 CFR 416.1044 - How and when we determine whether the processing time standards are met.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 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... basis. The determination as to whether or not the processing time thresholds have been met is made...

  11. 36 CFR 51.36 - What conditions must be met before the Director determines that a concessioner is a preferred...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 36 Parks, Forests, and Public Property 1 2014-07-01 2014-07-01 false What conditions must be met... Determining a Preferred Offeror § 51.36 What conditions must be met before the Director determines that a... following conditions are met: (a) The concessioner was a satisfactory concessioner during the term of...

  12. 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... basis. The determination as to whether or not the processing time thresholds have been met is made...

  13. 20 CFR 404.1645 - How and when we determine whether the performance accuracy standard is met.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... performance accuracy standard is met. 404.1645 Section 404.1645 Employees' Benefits SOCIAL SECURITY... Performance Standards § 404.1645 How and when we determine whether the performance accuracy standard is met... quarterly basis. The determinations as to whether the performance accuracy threshold has been met is made...

  14. 20 CFR 404.1644 - How and when we determine whether the processing time standards are met.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 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... basis. The determination as to whether or not the processing time thresholds have been met is made...

  15. 20 CFR 404.1644 - How and when we determine whether the processing time standards are met.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 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... basis. The determination as to whether or not the processing time thresholds have been met is made...

  16. 75 FR 55847 - 22nd Meeting: RTCA Special Committee 206: EUROCAE WG 76 Plenary: AIS and MET Data Link Services

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-14

    ... MET Data Link Services AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Notice of RTCA Special Committee 206: EUROCAE WG 76 Plenary: AIS and MET Data Link Services meeting. SUMMARY: The FAA is...: AIS and MET Data Link Services. DATES: The meeting will be held October 5-7, 2010 from 9 a.m. to 5...

  17. 75 FR 29811 - 21st Meeting: RTCA Special Committee 206: EUROCAE WG 76 Plenary: AIS and MET Data Link Services

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-27

    ... MET Data Link Services AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Notice of RTCA Special Committee 206: EUROCAE WG 76 Plenary: AIS and MET Data Link Services meeting. SUMMARY: The FAA is...: AIS and MET Data Link Services. DATES: The meeting will be held June 14-18, 2010, from 9 a.m. to 5...

  18. 36 CFR 51.36 - What conditions must be met before the Director determines that a concessioner is a preferred...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 36 Parks, Forests, and Public Property 1 2012-07-01 2012-07-01 false What conditions must be met... Determining a Preferred Offeror § 51.36 What conditions must be met before the Director determines that a... following conditions are met: (a) The concessioner was a satisfactory concessioner during the term of...

  19. 20 CFR 416.1045 - How and when we determine whether the performance accuracy standard is met.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... performance accuracy standard is met. 416.1045 Section 416.1045 Employees' Benefits SOCIAL SECURITY... Performance Standards § 416.1045 How and when we determine whether the performance accuracy standard is met... quarterly basis. The determinations as to whether the performance accuracy threshold has been met is made...

  20. 43 CFR 404.19 - What requirements must be met before I can request assistance to conduct a feasibility study?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 43 Public Lands: Interior 1 2013-10-01 2013-10-01 false What requirements must be met before I can... SUPPLY PROGRAM Overview § 404.19 What requirements must be met before I can request assistance to conduct a feasibility study? All of the following requirements must be met before you can request...

  1. 20 CFR 416.1045 - How and when we determine whether the performance accuracy standard is met.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... performance accuracy standard is met. 416.1045 Section 416.1045 Employees' Benefits SOCIAL SECURITY... Performance Standards § 416.1045 How and when we determine whether the performance accuracy standard is met... quarterly basis. The determinations as to whether the performance accuracy threshold has been met is made...

  2. 75 FR 71183 - 23rd Meeting: RTCA Special Committee 206: EUROCAE WG 76 Plenary: AIS and MET Data Link Services

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-22

    ... MET Data Link Services AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Notice of RTCA Special Committee 206: EUROCAE WG 76 Plenary: AIS and MET Data Link Services meeting. SUMMARY: The FAA is...: AIS and MET Data Link Services. DATES: The meeting will be held December 14-16, 2010 from 9 a.m. to...

  3. 20 CFR 416.1045 - How and when we determine whether the performance accuracy standard is met.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... performance accuracy standard is met. 416.1045 Section 416.1045 Employees' Benefits SOCIAL SECURITY... Performance Standards § 416.1045 How and when we determine whether the performance accuracy standard is met... quarterly basis. The determinations as to whether the performance accuracy threshold has been met is made...

  4. 42 CFR 136.406 - Under what circumstances will the minimum standards of character be considered to be met?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... of character be considered to be met? 136.406 Section 136.406 Public Health PUBLIC HEALTH SERVICE... minimum standards of character be considered to be met? The minimum standards of character shall be considered met only after the individual has been the subject of a satisfactory background investigation....

  5. 20 CFR 416.1044 - How and when we determine whether the processing time standards are met.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 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... basis. The determination as to whether or not the processing time thresholds have been met is made...

  6. 43 CFR 404.19 - What requirements must be met before I can request assistance to conduct a feasibility study?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 43 Public Lands: Interior 1 2012-10-01 2011-10-01 true What requirements must be met before I can... SUPPLY PROGRAM Overview § 404.19 What requirements must be met before I can request assistance to conduct a feasibility study? All of the following requirements must be met before you can request...

  7. 43 CFR 3137.131 - What happens if the unit terminated before the unit operator met the initial development...

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... the unit operator met the initial development obligations? 3137.131 Section 3137.131 Public Lands... before the unit operator met the initial development obligations? If the unit terminated before the unit operator met the initial development obligations, BLM's approval of the unit agreement is revoked. You,...

  8. 20 CFR 416.1045 - How and when we determine whether the performance accuracy standard is met.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... performance accuracy standard is met. 416.1045 Section 416.1045 Employees' Benefits SOCIAL SECURITY... Performance Standards § 416.1045 How and when we determine whether the performance accuracy standard is met... quarterly basis. The determinations as to whether the performance accuracy threshold has been met is made...

  9. 20 CFR 404.1645 - How and when we determine whether the performance accuracy standard is met.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... performance accuracy standard is met. 404.1645 Section 404.1645 Employees' Benefits SOCIAL SECURITY... Performance Standards § 404.1645 How and when we determine whether the performance accuracy standard is met... quarterly basis. The determinations as to whether the performance accuracy threshold has been met is made...

  10. 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... basis. The determination as to whether or not the processing time thresholds have been met is made...

  11. 36 CFR 51.36 - What conditions must be met before the Director determines that a concessioner is a preferred...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 36 Parks, Forests, and Public Property 1 2010-07-01 2010-07-01 false What conditions must be met... Determining a Preferred Offeror § 51.36 What conditions must be met before the Director determines that a... following conditions are met: (a) The concessioner was a satisfactory concessioner during the term of...

  12. 20 CFR 416.1045 - How and when we determine whether the performance accuracy standard is met.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... performance accuracy standard is met. 416.1045 Section 416.1045 Employees' Benefits SOCIAL SECURITY... Performance Standards § 416.1045 How and when we determine whether the performance accuracy standard is met... quarterly basis. The determinations as to whether the performance accuracy threshold has been met is made...

  13. 42 CFR 136.406 - Under what circumstances will the minimum standards of character be considered to be met?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... of character be considered to be met? 136.406 Section 136.406 Public Health PUBLIC HEALTH SERVICE... minimum standards of character be considered to be met? The minimum standards of character shall be considered met only after the individual has been the subject of a satisfactory background investigation....

  14. 20 CFR 416.1044 - How and when we determine whether the processing time standards are met.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 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... basis. The determination as to whether or not the processing time thresholds have been met is made...

  15. 20 CFR 404.1644 - How and when we determine whether the processing time standards are met.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 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... basis. The determination as to whether or not the processing time thresholds have been met is made...

  16. 20 CFR 404.1645 - How and when we determine whether the performance accuracy standard is met.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... performance accuracy standard is met. 404.1645 Section 404.1645 Employees' Benefits SOCIAL SECURITY... Performance Standards § 404.1645 How and when we determine whether the performance accuracy standard is met... quarterly basis. The determinations as to whether the performance accuracy threshold has been met is made...

  17. 20 CFR 404.1645 - How and when we determine whether the performance accuracy standard is met.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... performance accuracy standard is met. 404.1645 Section 404.1645 Employees' Benefits SOCIAL SECURITY... Performance Standards § 404.1645 How and when we determine whether the performance accuracy standard is met... quarterly basis. The determinations as to whether the performance accuracy threshold has been met is made...

  18. 43 CFR 404.19 - What requirements must be met before I can request assistance to conduct a feasibility study?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 43 Public Lands: Interior 1 2011-10-01 2011-10-01 false What requirements must be met before I can... SUPPLY PROGRAM Overview § 404.19 What requirements must be met before I can request assistance to conduct a feasibility study? All of the following requirements must be met before you can request...

  19. 43 CFR 3137.131 - What happens if the unit terminated before the unit operator met the initial development...

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... the unit operator met the initial development obligations? 3137.131 Section 3137.131 Public Lands... before the unit operator met the initial development obligations? If the unit terminated before the unit operator met the initial development obligations, BLM's approval of the unit agreement is revoked. You,...

  20. 43 CFR 3137.131 - What happens if the unit terminated before the unit operator met the initial development...

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... the unit operator met the initial development obligations? 3137.131 Section 3137.131 Public Lands... before the unit operator met the initial development obligations? If the unit terminated before the unit operator met the initial development obligations, BLM's approval of the unit agreement is revoked. You,...

  1. The Prevalence of Metabolic Syndrome Using Three Different Diagnostic Criteria among Low Earning Nomadic Kazakhs in the Far Northwest of China: New Cut-Off Points of Waist Circumference to Diagnose MetS and Its Implications

    PubMed Central

    Guo, Heng; Liu, Jiaming; Zhang, Jingyu; Ma, Rulin; Ding, Yusong; Zhang, Mei; He, Jia; Xu, Shangzhi; Li, Shugang; Yan, Yizhong; Mu, Lati; Rui, Dongsheng; Niu, Qiang; Guo, Shuxia

    2016-01-01

    Background Although the epidemic of metabolic syndrome (MetS) has aroused wide public concern, most studies on MetS tend to examine urban and high income settings, and few studies cover nomadic areas and low earning populations. This research aims to investigate the prevalence of MetS and explore the cut-off point of waist circumference in a nomadic minority typical of low income populations in the remote northwest region of China. Methods A cross-sectional study was performed in a representative sample of 3900 Kazakh adults aged 18–84 years from 2009–2010. Three widely used criteria (ATP III\\IDF\\JIS) were employed to estimate the prevalence of MetS in Kazakhs to compare them with other populations. Receiver operator characteristic (ROC) curve analysis was used to explore the optimal cut-off values of waist circumference. Results The age-adjusted prevalence of MetS was 13.8%, 20.9%, and 24.8% based on the ATP III, IDF, and JIS criteria, respectively. The prevalence of MetS was higher in women and increased with age. Except for reduced HDL-cholesterol, the risk of other components of MetS increased with waist circumference enlargement. The cut-off point of waist circumference in screening at least two other components of MetS was 88 cm in men (Sensitivity = 61.1%, Specificity = 62.1%, ROC Curve Distance = 0.54) and 83 cm in women (Sensitivity = 60.0%, Specificity = 59.6%, ROC Curve Distance = 0.57). Conclusion The prevalence of MetS in Kazakhs is higher than the national level of China and falls in between the Euro-American and Asia levels, as their cut-off points of waist circumference differ from that recommended for Chinese. We suggest a cost-effective strategy to screen for MetS and prevent cardiovascular disease using new cut-off points of waist circumference in low earning nomadic Kazakhs. PMID:26901035

  2. c-Met inhibitors attenuate tumor growth of small cell hypercalcemic ovarian carcinoma (SCCOHT) populations.

    PubMed

    Otte, Anna; Rauprich, Finn; von der Ohe, Juliane; Yang, Yuanyuan; Kommoss, Friedrich; Feuerhake, Friedrich; Hillemanns, Peter; Hass, Ralf

    2015-10-13

    A cellular model (SCCOHT-1) of the aggressive small cell hypercalcemic ovarian carcinoma demonstrated constitutive chemokine and growth factor production including HGF. A simultaneous presence of c-Met in 41% SCCOHT-1 cells suggested an autocrine growth mechanism. Expression of c-Met was also observed at low levels in the corresponding BIN-67 cell line (6.5%) and at high levels in ovarian adenocarcinoma cells (NIH:OVCAR-3 (84.4%) and SK-OV-3 (99.3%)). Immunohistochemistry of c-Met expression in SCCOHT tumors revealed a heterogeneous distribution between undetectable levels and 80%. Further characterization of SCCOHT-1 and BIN-67 cells by cell surface markers including CD90 and EpCAM demonstrated similar patterns with differences to the ovarian adenocarcinoma cells. HGF stimulation of SCCOHT-1 cells was associated with c-Met phosphorylation at Tyr1349 and downstream Thr202/Tyr204 phosphorylation of p44/42 MAP kinase. This HGF-induced signaling cascade was abolished by the c-Met inhibitor foretinib. Cell cycle analysis after foretinib treatment demonstrated enhanced G2 accumulation and increasing apoptosis within 72 h. Moreover, the IC50 of foretinib revealed 12.4 nM in SCCOHT-1 cells compared to 411 nM and 481 nM in NIH:OVCAR-3 and SK-OV-3 cells, respectively, suggesting potential therapeutic effects. Indeed, SCCOHT-1 and BIN-67 tumor xenografts in NODscid mice exhibited an approximately 10-fold and 5-fold reduced tumor size following systemic application of foretinib, respectively. Furthermore, foretinib-treated tumors revealed a significantly reduced vascularization and little if any c-Met-mediated signal transduction. Similar findings of reduced proliferative capacity and declined tumor size were observed after siRNA-mediated c-Met knock-down in SCCOHT-1 cells demonstrating that in vivo inhibition of these pathways contributed to an attenuation of SCCOHT tumor growth. PMID:26436697

  3. 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. PMID:27551971

  4. c-Met inhibitors attenuate tumor growth of small cell hypercalcemic ovarian carcinoma (SCCOHT) populations

    PubMed Central

    Otte, Anna; Rauprich, Finn; von der Ohe, Juliane; Yang, Yuanyuan; Kommoss, Friedrich; Feuerhake, Friedrich; Hillemanns, Peter; Hass, Ralf

    2015-01-01

    A cellular model (SCCOHT-1) of the aggressive small cell hypercalcemic ovarian carcinoma demonstrated constitutive chemokine and growth factor production including HGF. A simultaneous presence of c-Met in 41% SCCOHT-1 cells suggested an autocrine growth mechanism. Expression of c-Met was also observed at low levels in the corresponding BIN-67 cell line (6.5%) and at high levels in ovarian adenocarcinoma cells (NIH:OVCAR-3 (84.4%) and SK-OV-3 (99.3%)). Immunohistochemistry of c-Met expression in SCCOHT tumors revealed a heterogeneous distribution between undetectable levels and 80%. Further characterization of SCCOHT-1 and BIN-67 cells by cell surface markers including CD90 and EpCAM demonstrated similar patterns with differences to the ovarian adenocarcinoma cells. HGF stimulation of SCCOHT-1 cells was associated with c-Met phosphorylation at Tyr1349 and downstream Thr202/Tyr204 phosphorylation of p44/42 MAP kinase. This HGF-induced signaling cascade was abolished by the c-Met inhibitor foretinib. Cell cycle analysis after foretinib treatment demonstrated enhanced G2 accumulation and increasing apoptosis within 72 h. Moreover, the IC50 of foretinib revealed 12.4 nM in SCCOHT-1 cells compared to 411 nM and 481 nM in NIH:OVCAR-3 and SK-OV-3 cells, respectively, suggesting potential therapeutic effects. Indeed, SCCOHT-1 and BIN-67 tumor xenografts in NODscid mice exhibited an approximately 10-fold and 5-fold reduced tumor size following systemic application of foretinib, respectively. Furthermore, foretinib-treated tumors revealed a significantly reduced vascularization and little if any c-Met-mediated signal transduction. Similar findings of reduced proliferative capacity and declined tumor size were observed after siRNA-mediated c-Met knock-down in SCCOHT-1 cells demonstrating that in vivo inhibition of these pathways contributed to an attenuation of SCCOHT tumor growth. PMID:26436697

  5. Predicting METs from the heart rate index in persons with Down syndrome.

    PubMed

    Agiovlasitis, Stamatis; Rossow, Lindy M; Yan, Huimin; Ranadive, Sushant M; Fahs, Christopher A; Motl, Robert W; Fernhall, Bo

    2014-10-01

    Persons with Down syndrome (DS) have altered heart rate modulation and very low aerobic fitness. These attributes may impact the relationship between metabolic equivalent units (METs) and the heart rate index (HRindex-the ratio between heart rate during activity and resting heart rate), thereby altering the HRindex thresholds for moderate- and vigorous-intensity physical activity. This study examined whether the relationship between METs and HRindex differs between persons with and without DS and attempted to develop thresholds for activity intensity based on the HRindex for persons with DS. METs were measured with portable spirometry and heart rate with a monitor in 18 persons with DS (25 ± 7 years; 10 women) and 18 persons without DS (26 ± 5 years; 10 women) during 6 over-ground walking trials, each lasting 6min, at the preferred walking speed and at 0.5, 0.75, 1.0, 1.25, and 1.5m/s. The relationship between METs and HRindex in the two groups was analyzed with multi-level modeling with random intercepts and slopes. Group, HRindex, and the square of HRindex were significant predictors of METs (p<0.001; R(2)=0.65). Absolute percent error did not differ significantly between groups across speeds (DS: 19.6 ± 14.4%; non-DS: 21.0 ± 14.5%). Bland-Altman plots demonstrated somewhat greater variability in the difference between actual and predicted METs in participants with than without DS. The HRindex threshold for moderate-intensity activity was 1.32 and 1.20 for persons with and without DS, respectively. The HRindex threshold for vigorous-intensity activity was 1.80 and 1.65 for persons with and without DS, respectively. Persons with DS have an altered relationship between METs and HRindex and higher HRindex thresholds for moderate- and vigorous-intensity physical activity. PMID:24981191

  6. C1GALT1 enhances proliferation of hepatocellular carcinoma cells via modulating MET glycosylation and dimerization.

    PubMed

    Wu, Yao-Ming; Liu, Chiung-Hui; Huang, Miao-Juei; Lai, Hong-Shiee; Lee, Po-Huang; Hu, Rey-Heng; Huang, Min-Chuan

    2013-09-01

    Altered glycosylation is a hallmark of cancer. The core 1 β1,3-galactosyltransferase (C1GALT1) controls the formation of mucin-type O-glycans, far overlooked and underestimated in cancer. Here, we report that C1GALT1 mRNA and protein are frequently overexpressed in hepatocellular carcinoma tumors compared with nontumor liver tissues, where it correlates with advanced tumor stage, metastasis, and poor survival. Enforced expression of C1GALT1 was sufficient to enhance cell proliferation, whereas RNA interference-mediated silencing of C1GALT1 was sufficient to suppress cell proliferation in vitro and in vivo. Notably, C1GALT1 attenuation also suppressed hepatocyte growth factor (HGF)-mediated phosphorylation of the MET kinase in hepatocellular carcinoma cells, whereas enforced expression of C1GALT1 enhanced MET phosphorylation. MET blockade with PHA665752 inhibited C1GALT1-enhanced cell viability. In support of these results, we found that the expression level of phospho-MET and C1GALT1 were associated in primary hepatocellular carcinoma tissues. Mechanistic investigations showed that MET was decorated with O-glycans, as revealed by binding to Vicia villosa agglutinin and peanut agglutinin. Moreover, C1GALT1 modified the O-glycosylation of MET, enhancing its HGF-induced dimerization and activation. Together, our results indicate that C1GALT1 overexpression in hepatocellular carcinoma activates HGF signaling via modulation of MET O-glycosylation and dimerization, providing new insights into how O-glycosylation drives hepatocellular carcinoma pathogenesis. PMID:23832667

  7. A Low-Noise DC seismic accelerometer based on a combination of MET/MEMS sensors.

    PubMed

    Neeshpapa, Alexander; Antonov, Alexander; Agafonov, Vadim

    2015-01-01

    Molecular-electronic transducers (MET) have a high conversion coefficient and low power consumption, and do not require precision mechanical components thus allowing the construction of cost- and power-efficient seismic accelerometers. Whereas the instrumental resolution of a MET accelerometer within the 0.1-100 Hz frequency range surpasses that of the best Micro-Electro Mechanical Systems (MEMS) and even some force-balanced accelerometers, the fundamental inability to register gravity or, in other words, zero frequency acceleration, significantly constrains the further spread of MET-based accelerometers. Ways of obviating this inherent zero frequency insensitivity within MET technology have so far, not been found. This article explores a possible approach to the construction of a hybrid seismic accelerometer combining the superb performance of a MET sensor in the middle and high frequency range with a conventional on chip MEMS accelerometer covering the lower frequencies and gravity. Though the frequency separation of a signal is widely used in various applications, the opposite task, i.e., the combining of two signals with different bandwidths is less common. Based on theoretical research and the analysis of actual sensors' performance, the authors determined optimal parameters for building a hybrid sensor. Description and results for implementation of the hybrid sensor are given in the Experimental section of the article. Completing a MET sensor with a cost-effective MEMS permitted the construction of a low noise DC accelerometer preserving the noise performance of a MET sensing element. The work presented herein may prove useful in designing other combined sensors based on different technologies. PMID:25549175

  8. 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

  9. Variant BDNF Val66Met polymorphism affects extinction of conditioned aversive memory.

    PubMed

    Yu, Hui; Wang, Yue; Pattwell, Siobhan; Jing, Deqiang; Liu, Ting; Zhang, Yun; Bath, Kevin G; Lee, Francis S; Chen, Zhe-Yu

    2009-04-01

    Brain-derived neurotrophic factor (BDNF) plays important roles in activity-dependent plasticity processes, such as long-term potentiation, learning, and memory. The recently reported human BDNF Val66Met (BDNF(Met)) polymorphism has been shown to lead to altered hippocampal volume and impaired hippocampal-dependent memory and is associated with a variety of neuropsychiatric disorders. There are few studies, however, that investigate the effect of the BDNF(Met) polymorphism on hippocampal-independent memory processes. A conditioned taste aversion (CTA) task was used for studying the mechanisms of long-term, hippocampal-independent, nondeclarative memory in the mammalian brain. Using the CTA paradigm, we found a novel impairment in extinction learning, but not acquisition or retention, of aversive memories resulting from the variant BDNF(Met). BDNF(Met) mice were slower to extinguish an aversive CTA memory compared with wild-type counterparts. Moreover, the BDNF(Met) was associated with smaller volume and decreased neuronal dendritic complexity in the ventromedial prefrontal cortex (vmPFC), which plays a significant role in extinction of CTA. Finally, this delay in extinction learning could be rescued pharmacologically with a cognitive enhancer, d-cycloserine (DCS). To our knowledge, this is the first evidence that the BDNF(Met) polymorphism contributes to abnormalities in memory extinction. This abnormality in extinction learning may be explained by alterations in neuronal morphology, as well as decreased neural activity in the vmPFC. Importantly, DCS was effective in rescuing this delay in extinction, suggesting that when coupled with behavior therapy, DCS may be an effective treatment option for anxiety disorders in humans with this genetic variant BDNF. PMID:19339601

  10. 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

  11. BDNF G196A (Val66Met) polymorphism associated with cognitive impairment in Parkinson's disease.

    PubMed

    Białecka, Monika; Kurzawski, Mateusz; Roszmann, Anna; Robowski, Piotr; Sitek, Emilia J; Honczarenko, Krystyna; Mak, Monika; Deptuła-Jarosz, Monika; Gołąb-Janowska, Monika; Droździk, Marek; Sławek, Jarosław

    2014-02-21

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin widely expressed in the mammalian brain, regulating neuronal survival and known to influence dopaminergic neurons and cognitive processes. The present study investigated the BDNF Val66Met polymorphism associations with PD risk, and cognitive impairment in PD. A total of 486 study subjects (244 PD and 242 age and sex matched controls) were included in the study. UPDRS score, Hoehn-Yahr staging and the Schwab-England scale were used to assess motor abilities and activity during daily life. The patients were classified into groups with dementia (PDD, n=69) and without it (nPDD, n=166) on the basis of neuropsychological assessment. The most common functional polymorphism in BDNF Val66Met (rs6265, G196A) gene was determined using TaqMan real-time PCR assay. Frequencies of evaluated BDNF alleles and genotypes were similar in PD and the controls. The mean age of disease onset among BDNF Met/Met carriers was later (65.00±6.13) in comparison to Val/Val (57.45±10.68) and Val/Met (56.33±10.91) subjects (p=0.077). The studied BDNF polymorphism was not associated with cognitive status in PD patients. However, patients with Met/Met alleles demonstrated better delayed recall of information than patients with Val/Val alleles. The results of multivariate logistic regression analysis revealed age (p=0.0003) and the disease stage (p=0.002) as independent risk factors predisposing to PD dementia. PMID:24394906

  12. No Association of the BDNF Val66met Polymorphism with Implicit Associative Vocabulary and Motor Learning

    PubMed Central

    Freundlieb, Nils; Philipp, Stephan; Schneider, Susanne A.; Brüggemann, Norbert; Klein, Christine; Gerloff, Christian; Hummel, Friedhelm C.

    2012-01-01

    Brain-derived neurotrophic factor (BDNF) has been suggested to play a major role in plasticity, neurogenesis and learning in the adult brain. The BDNF gene contains a common val66met polymorphism associated with decreased activity-dependent excretion of BDNF and a potential influence on behaviour, more specifically, on motor learning. The objective of this study was to determine the influence of the BDNF val66met polymorphism on short-term implicit associative learning and whether its influence is cognitive domain-specific (motor vs. language). A sample of 38 young healthy participants was genotyped, screened for background and neuropsychological differences, and tested with two associative implicit learning paradigms in two different cognitive domains, i.e., motor and vocabulary learning. Subjects performed the serial reaction time task (SRTT) to determine implicit motor learning and a recently established associative vocabulary learning task (AVL) for implicit learning of action and object words. To determine the influence of the BDNF polymorphism on domain-specific implicit learning, behavioural improvements in the two tasks were compared between val/val (n = 22) and met carriers (val/met: n = 15 and met/met: n = 1). There was no evidence for an impact of the BDNF val66met polymorphism on the behavioural outcome in implicit short-term learning paradigms in young healthy subjects. Whether this polymorphism plays a relevant role in long-term training paradigms or in subjects with impaired neuronal plasticity or reduced learning capacity, such as aged individuals, demented patients or patients with brain lesions, has to be determined in future studies. PMID:23152767

  13. A Low-Noise DC Seismic Accelerometer Based on a Combination of MET/MEMS Sensors

    PubMed Central

    Neeshpapa, Alexander; Antonov, Alexander; Agafonov, Vadim

    2015-01-01

    Molecular-electronic transducers (MET) have a high conversion coefficient and low power consumption, and do not require precision mechanical components thus allowing the construction of cost- and power-efficient seismic accelerometers. Whereas the instrumental resolution of a MET accelerometer within the 0.1–100 Hz frequency range surpasses that of the best Micro-Electro Mechanical Systems (MEMS) and even some force-balanced accelerometers, the fundamental inability to register gravity or, in other words, zero frequency acceleration, significantly constrains the further spread of MET-based accelerometers. Ways of obviating this inherent zero frequency insensitivity within MET technology have so far, not been found. This article explores a possible approach to the construction of a hybrid seismic accelerometer combining the superb performance of a MET sensor in the middle and high frequency range with a conventional on chip MEMS accelerometer covering the lower frequencies and gravity. Though the frequency separation of a signal is widely used in various applications, the opposite task, i.e., the combining of two signals with different bandwidths is less common. Based on theoretical research and the analysis of actual sensors' performance, the authors determined optimal parameters for building a hybrid sensor. Description and results for implementation of the hybrid sensor are given in the Experimental section of the article. Completing a MET sensor with a cost-effective MEMS permitted the construction of a low noise DC accelerometer preserving the noise performance of a MET sensing element. The work presented herein may prove useful in designing other combined sensors based on different technologies. PMID:25549175

  14. Meta-Analysis of the COMT Val158Met Polymorphism in Major Depressive Disorder: Effect of Ethnicity.

    PubMed

    Wang, Maiqiu; Ma, Yunlong; Yuan, Wenji; Su, Kunkai; Li, Ming D

    2016-09-01

    The COMT (catechol-O-methyltransferase) Val158Met polymorphism (rs4680) is a potential susceptibility variant for major depressive disorder (MDD). Although many genetic studies have examined the association between MDD and this polymorphism, the results were inconclusive. In the present study, we conducted a series of meta-analyses of samples consisting of 2905 MDD cases and 2403 controls with the goal of determining whether this variant indeed has any effect on MDD. We revealed a significant association in the comparison of Val/Val + Val/Met vs. Met/Met (OR =1.180; 95 % CI = 1.019, 1.367; P = 0.027), Val/Met vs. Val/Val (OR =1.18; 95 % CI = 1.038, 1.361; P = 0.013), and Val/Met vs. Met/Met (OR =1.229; 95 % CI = 1.053, 1.435; P = 0.009). Further meta-analyses of samples with European ancestry demonstrated a significant association of this SNP with MDD susceptibility in Val/Val + Val/Met vs. Met/Met (OR =1.231, 95 % CI = 1.046, 1.449; P = 0.013) and Val/Met vs. Met/Met (OR =1.284, 95 % CI = 1.050, 1.484; P = 0.012). For the samples with East Asian ancestry, we found a significant association in both allelic (Val vs. Met: OR =0.835; 95 % CI = 0.714, 0.975; P = 0.023) and genotypic (Met/Met + Val/Met vs. Val/Val: OR =1.431, 95 % CI = 1.143, 1.791; P = 0.002; Val/Met vs. Val/Val: OR =1.482, 95 % CI = 1.171, 1.871; P = 0.001) analyses. No evidence of heterogeneity among studies or publication bias was observed. Together, our results indicate that the COMT Val158Met polymorphism is a vulnerability factor for MDD with distinct effects in different ethnic populations. PMID:26803486

  15. Partners met via sex parties present significantly greater odds for condomless anal sex among MSM: An event-level analysis of venues where male partners are met

    PubMed Central

    Grov, Christian; Rendina, H. Jonathon; Ventuneac, Ana; Parsons, Jeffrey T.

    2014-01-01

    N=147 MSM completed time-line follow-back interviews about the venues where they met their male partners (n=1,180 sexual events with first-time partners, < 30 days). We ran multivariate models to determine the association between venues and condomless anal sex (CAS). After adjusting for known correlates of CAS, partners met at sex parties presented significantly greater odds for CAS, compared to meeting a partner at a gay bar/club (AOR=.44), online (AOR=.42), bathhouse (AOR=.35), or via “other” venues (AOR=.35), all p < .01. These findings highlight the need to develop innovative HIV/STI prevention initiatives for men who attend sex parties. PMID:25226209

  16. Activation of the Met kinase confers acquired drug resistance in FGFR-targeted lung cancer therapy.

    PubMed

    Kim, S-M; Kim, H; Yun, M R; Kang, H N; Pyo, K-H; Park, H J; Lee, J M; Choi, H M; Ellinghaus, P; Ocker, M; Paik, S; Kim, H R; Cho, B C

    2016-01-01

    Aberrant fibroblast growth factor receptor (FGFR) activation/expression is a common feature in lung cancer (LC). In this study, we evaluated the antitumor activity of and the mechanisms underlying acquired resistance to two potent selective FGFR inhibitors, AZD4547 and BAY116387, in LC cell lines. The antitumor activity of AZD4547 and BAY1163877 was screened in 24 LC cell lines, including 5 with FGFR1 amplification. Two cell lines containing FGFR1 amplifications, H1581 and DMS114, were sensitive to FGFR inhibitors (IC50<250 nm). Clones of FGFR1-amplified H1581 cells resistant to AZD4547 or BAY116387 (H1581AR and H1581BR cells, respectively) were established. Receptor tyrosine kinase (RTK) array and immunoblotting analyses showed strong overexpression and activation of Met in H1581AR/BR cells, compared with that in the parental cells. Gene set enrichment analysis against the Kyoto Encyclopedia of Genes and Genomes (KEGG) database showed that cytokine-cytokine receptor interaction pathways were significantly enriched in H1581AR/BR cells, with Met contributing significantly to the core enrichment. Genomic DNA quantitative PCR and fluorescent in situ hybridization analyses showed MET amplification in H1581AR, but not in H1581BR, cells. Met amplification drives acquired resistance to AZD4547 in H1581AR cells by activating ErbB3. Combination treatment with FGFR inhibitors and an anaplastic lymphoma kinase (ALK)/Met inhibitor, crizotinib, or Met-specific short interfering RNA (siRNA) synergistically inhibited cell proliferation in both H1581AR and H1581BR cells. Conversely, ectopic expression of Met in H1581 cells conferred resistance to AZD4547 and BAY1163877. Acquired resistance to FGFR inhibitors not only altered cellular morphology, but also promoted migration and invasion of resistant clones, in part by inducing epithelial-to-mesenchymal transition. Taken together, our data suggest that Met activation is sufficient to bypass dependency on FGFR signaling. Concurrent

  17. Durable complete response of metastatic gastric cancer with anti-Met therapy followed by resistance at recurrence

    PubMed Central

    Catenacci, Daniel V.T.; Henderson, Les; Xiao, Shu-Yuan; Penuel, Elicia; Patel, Premal; Yauch, Robert L.; Peterson, Amy; Salgia, Ravi

    2011-01-01

    A 48 year-old female with chemo-refractory metastatic gastric cancer to the liver was treated on a Phase I clinical trial with MetMAb, a monoclonal antibody targeting the Met tyrosine kinase receptor. The primary tumor had high MET gene polysomy and evidence for an autocrine production of HGF, the growth factor ligand of Met. A complete response was obtained lasting two years; the cancer recurred as a peritoneal deposit invading into the transverse colon and a gastrohepatic ligament node. Compassionate use of MetMAb therapy at recurrence achieved a mixed response - a partial response of the two initial lesions, but with development of multiple new foci of carcinomatosis. Tissue and serum studies evaluating the Met signaling pathway did correlate with MetMAb treatment response initially and at the time of recurrence. PMID:22389872

  18. Understanding and Targeting MET Signaling in Solid Tumors - Are We There Yet?

    PubMed Central

    Ariyawutyakorn, Witthawat; Saichaemchan, Siriwimon; Varella-Garcia, Marileila

    2016-01-01

    The MET signaling pathway plays an important role in normal physiology and its deregulation has proved critical for development of numerous solid tumors. Different technologies have been used to investigate the genomic and proteomic status of MET in cancer patients and its association with disease prognosis. Moreover, with the development of targeted therapeutic drugs, there is an urgent need to identify potential biomarkers for selection of patients who are more likely to derive benefit from these agents. Unfortunately, the variety of technical platforms and analysis criteria for diagnosis has brought confusion to the field and a lack of agreement in the evaluation of MET status as a prognostic or predictive marker for targeted therapy agents. We review the molecular mechanisms involved in the deregulation of the MET signaling pathway in solid tumors, the different technologies used for diagnosis, and the main factors that affect the outcome, emphasizing the urge for completing analytical and clinical validation of these tests. We also review the current clinical studies with MET targeted agents, which mostly focus on lung cancer. PMID:27076844

  19. 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

  20. A Meta-Analysis of the Val158Met COMT Polymorphism and Violent Behavior in Schizophrenia

    PubMed Central

    Singh, Jay P.; Volavka, Jan; Czobor, Pál; Van Dorn, Richard A.

    2012-01-01

    We conducted a meta-analysis of studies examining the association between the Val158Met COMT polymorphism and violence against others in schizophrenia. A systematic search current to November 1, 2011 was conducted using MEDLINE, EMBASE, CINAHL, PsycINFO, ProQuest, and the National Criminal Justice Reference Service and identified 15 studies comprising 2,370 individuals with schizophrenia for inclusion. Bivariate analyses of study sensitivities and specificities were conducted. This methodology allowed for the calculation of pooled diagnostic odds ratios (DOR). Evidence of a significant association between the presence of a Met allele and violence was found such that men's violence risk increased by approximately 50% for those with at least one Met allele compared with homozygous Val individuals (DOR = 1.45; 95% CI = 1.05–2.00; z = 2.37, p = 0.02). No significant association between the presence of a Met allele and violence was found for women or when outcome was restricted to homicide. We conclude that male schizophrenia patients who carry the low activity Met allele in the COMT gene are at a modestly elevated risk of violence. This finding has potential implications for the pharmacogenetics of violent behavior in schizophrenia. PMID:22905266

  1. The microwave electro-thermal (MET) thruster: A new technology for satellite propulsion and attitude control

    SciTech Connect

    Brandenburg, J.E.; Micci, M.M.

    1996-03-01

    This paper discusses the current research status of the MET (Microwave Electro-Thermal) thruster. In the MET thruster, an electrodeless, vortex stabilized, plasma is produced in a microwave resonator cavity for the purpose of heating gaseous fuel to produce a high temperature rocket exhaust for space propulsion. The higher specific impulse (momentum transfer per unit weight) of these heated gases offers advantages over traditional chemical rockets in terms of reduced fuel mass. In MET devices, dense plasmas have been produced in various possible fuel gases, nitrogen, hydrogen, and ammonia, using 600 to 2200 Watts of microwave power at a frequency of 2.45 GHz. Ammonia has been found to give a specific impulse of 550 sec. It has been found that the plasma is a 98{percent} absorber of microwave power leading to negligible reflection of power back to the microwave source and making the cavity operate at low {ital Q}. Taking advantage of this effect, it has been found that a very compact MET thruster design could be operated, with the magnetron microwave source and resonator cavity joined in one unit. The MET can run at a variety of power levels and use many fuels, including H{sub 2}O. {copyright} {ital 1996 American Institute of Physics.}

  2. Gender effect of catechol-O-methyltransferase Val158Met polymorphism on suicidal behavior.

    PubMed

    Lee, Hwa-Young; Kim, Yong-Ku

    2011-01-01

    Genetic factors and catecholaminergic dysfunction have been suggested as the etiology of suicide. The catechol-O-methyltransferase (COMT) 158Val/Met polymorphism affects COMT activity; that is, the alleles encoding Val and Met are associated with relatively high and relatively low COMT activity, respectively. We aimed to identify the role of the COMT Val158Met polymorphism in suicidal attempt behavior. The COMT 158Val/Met polymorphisms were analyzed in 197 suicide attempters (male/female: 70/127), 170 control subjects (male/female: 85/85). All subjects were ethnic Korean. The Lethality Suicide Attempt Rating Scale (LSARS) and risk-rescue rating (RRR) system were explored. For the male subjects, there was a significant difference in genotype distributions and allele frequencies between control subjects and suicide attempters. That is, Val/Val genotype and Val carriers were more frequent in suicide attempters than in control subjects. For the female subjects, however, no significant difference was shown in genotype distributions and allele frequencies between control subjects and suicide attempters. There were no significant differences in LSARS and RRR according to the genotypes. The distribution of the COMT 158Val/Met polymorphism showed a biologically meaningful difference between control subjects and suicide attempters among the male subjects although selection bias should be considered. PMID:21304229

  3. c-Met Modulates RPE Migratory Response to Laser-Induced Retinal Injury

    PubMed Central

    Lashkari, Kameran

    2012-01-01

    Retinal laser injuries are often associated with aberrant migration of the retinal pigment epithelium (RPE), which can cause expansion of the scar beyond the confines of the original laser burn. In this study, we devised a novel method of laser-induced injury to the RPE layer in mouse models and began to dissect the mechanisms associated with pathogenesis and progression of laser-induced RPE injury. We have hypothesized that the proto-oncogene receptor, c-Met, is intimately involved with migration of RPE cells, and may be an early responder to injury. Using transgenic mouse models, we show that constitutive activation of c-Met induces more robust RPE migration into the outer retina of laser-injured eyes, while abrogation of the receptor using a cre-lox method reduces these responses. We also demonstrate that retinal laser injury increases expression of both HGF and c-Met, and activation of c-Met after injury is correlated with RPE cell migration. RPE migration may be responsible for clinically significant anatomic changes observed after laser injury. Abrogation of c-Met activity may be a therapeutic target to minimize retinal damage from aberrant RPE cell migration. PMID:22808260

  4. Genetic disruption of Met signaling impairs GABAergic striatal development and cognition.

    PubMed

    Martins, G J; Shahrokh, M; Powell, E M

    2011-03-10

    The largest structure of the basal ganglia, the striatum, modulates motor activity and cognitive function and is composed of GABAergic projection neurons and interneurons. To better understand the mechanisms underlying the development of the striatal neurons and their assembly into functional circuits, we used a mouse with a targeted conditional Met mutation in post-mitotic cells of the ventral telencephalon. Characterization of the ontogeny of the striatal neuronal populations demonstrated that disruption of Met signaling specifically altered the GABAergic interneurons. Medium spiny neurons (MSNs) and cholinergic interneurons were largely unaffected. Mice lacking Met signaling have increased numbers of striatal GABAergic interneurons in the lateral sensorimotor areas with distinct behavioral deficits. Motor function and memory formation and consolidation appeared intact, but procedural learning on the cued task of the Morris water maze was delayed. MET is a susceptibility gene in Tourette syndrome and autism, which are human disorders with impaired procedural learning. This study reveals how a striatal targeted disruption in Met signaling after generation of striatal neurons produces behavioral phenotypes shared by Tourette syndrome and autism, linking the human genetics with the mechanism underlying the disorders. PMID:21195751

  5. MetSign: a computational platform for high-resolution mass spectrometry-based metabolomics.

    PubMed

    Wei, Xiaoli; Sun, Wenlong; Shi, Xue; Koo, Imhoi; Wang, Bing; Zhang, Jun; Yin, Xinmin; Tang, Yunan; Bogdanov, Bogdan; Kim, Seongho; Zhou, Zhanxiang; McClain, Craig; Zhang, Xiang

    2011-10-15

    Data analysis in metabolomics is currently a major challenge, particularly when large sample sets are analyzed. Herein, we present a novel computational platform entitled MetSign for high-resolution mass spectrometry-based metabolomics. By converting the instrument raw data into mzXML format as its input data, MetSign provides a suite of bioinformatics tools to perform raw data deconvolution, metabolite putative assignment, peak list alignment, normalization, statistical significance tests, unsupervised pattern recognition, and time course analysis. MetSign uses a modular design and an interactive visual data mining approach to enable efficient extraction of useful patterns from data sets. Analysis steps, designed as containers, are presented with a wizard for the user to follow analyses. Each analysis step might contain multiple analysis procedures and/or methods and serves as a pausing point where users can interact with the system to review the results, to shape the next steps, and to return to previous steps to repeat them with different methods or parameter settings. Analysis of metabolite extract of mouse liver with spiked-in acid standards shows that MetSign outperforms the existing publically available software packages. MetSign has also been successfully applied to investigate the regulation and time course trajectory of metabolites in hepatic liver. PMID:21932828

  6. The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer.

    PubMed

    Moran-Jones, Kim

    2016-06-01

    Survival rates for ovarian cancer have remained relatively stable for the past 2 decades despite advances in surgical techniques and cytotoxic chemotherapeutics, indicating a requirement for better therapies. One pathway currently proposed for targeting is the HGF/cMET pathway. Upregulated in a number of tumour types, cMET is a tyrosine kinase receptor expressed on epithelial cells. In ovarian cancer, it has been identified as highly expressed in the four major subtypes, with expression estimates ranging from 11 to 68 % of cases. HGF, the only known ligand for cMET, is found at high levels in both serum and ascites in women with ovarian cancer, and is proposed to induce both migration and metastasis. However, clinically validated biomarkers are not yet available for either HGF or cMET, preventing a clear understanding of the true rate of overexpression, or its correlation with prognosis. Despite this, a number of agents against HGF and cMET are currently being investigated in clinical trials for multiple tumour types, including ovarian. However, a lack of patient selection, biomarker usage, and post hoc analysis correlating response with expression has resulted in the majority of these trials showing little beneficial effect from these agents, indicating that additional research is required to determine their usefulness in patients with ovarian cancer. PMID:27139908

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

    PubMed Central

    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 PMID:27242035

  8. PI3 Kinase Pathway and MET Inhibition is Efficacious in Malignant Pleural Mesothelioma.

    PubMed

    Kanteti, Rajani; Riehm, Jacob J; Dhanasingh, Immanuel; Lennon, Frances E; Mirzapoiazova, Tamara; Mambetsariev, Bolot; Kindler, Hedy L; Salgia, Ravi

    2016-01-01

    Malignant pleural mesothelioma (MPM) is an aggressive cancer that is commonly associated with prior asbestos exposure. Receptor tyrosine kinases (RTKs) such as MET and its downstream target PI3K are overexpressed and activated in a majority of MPMs. Here, we studied the combinatorial therapeutic efficacy of the MET/ALK inhibitor crizotinib, with either a pan-class I PI3K inhibitor, BKM120, or with a PI3K/mTOR dual inhibitor, GDC-0980, in mesothelioma. Cell viability results showed that MPM cells were highly sensitive to crizotinib, BKM120 and GDC-0980 when used individually and their combination was more effective in suppressing growth. Treatment of MPM cells with these inhibitors also significantly decreased cell migration, and the combination of them was synergistic. Treatment with BKM120 alone or in combination with crizotinib induced G2-M arrest and apoptosis. Both crizotinib and BKM120 strongly inhibited the activity of MET and PI3K as evidenced by the decreased phosphorylation of MET, AKT and ribosomal S6 kinase. Using a PDX mouse model, we showed that a combination of crizotinib with BKM120 was highly synergetic in inhibiting MPM tumor growth. In conclusion our findings suggest that dual inhibition of PI3K and MET pathway is an effective strategy in treating MPM as compared to a single agent. PMID:27623107

  9. 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. PMID:26520222

  10. DynaMet: a fully automated pipeline for dynamic LC-MS data.

    PubMed

    Kiefer, Patrick; Schmitt, Uwe; Müller, Jonas E N; Hartl, Johannes; Meyer, Fabian; Ryffel, Florian; Vorholt, Julia A

    2015-10-01

    Dynamic isotope labeling data provides crucial information about the operation of metabolic pathways and are commonly generated via liquid chromatography-mass spectrometry (LC-MS). Metabolome-wide analysis is challenging as it requires grouping of metabolite features over different samples. We developed DynaMet for fully automated investigations of isotope labeling experiments from LC-high-resolution MS raw data. DynaMet enables untargeted extraction of metabolite labeling profiles and provides integrated tools for expressive data visualization. To validate DynaMet we first used time course labeling data of the model strain Bacillus methanolicus from (13)C methanol resulting in complex spectra in multicarbon compounds. Analysis of two biological replicates revealed high robustness and reproducibility of the pipeline. In total, DynaMet extracted 386 features showing dynamic labeling within 10 min. Of these features, 357 could be fitted by implemented kinetic models. Feature identification against KEGG database resulted in 215 matches covering multiple pathways of core metabolism and major biosynthetic routes. Moreover, we performed time course labeling experiment with Escherichia coli on uniformly labeled (13)C glucose resulting in a comparable number of detected features with labeling profiles of high quality. The distinct labeling patterns of common central metabolites generated from both model bacteria can readily be explained by one versus multicarbon compound metabolism. DynaMet is freely available as an extension package for Python based eMZed2, an open source framework built for rapid development of LC-MS data analysis workflows. PMID:26366644

  11. Science Signaling Podcast for 21 June 2016: MET and skin cancer.

    PubMed

    Yuspa, Stuart H; VanHook, Annalisa M

    2016-01-01

    This Podcast features an interview with Stuart Yuspa, senior author of a Research Article that appears in the 21 June 2016 issue of Science Signaling, about how activation of the receptor tyrosine kinase MET stimulates the formation of squamous cell carcinoma in the skin. Hepatocyte growth factor (HGF) is produced by mesenchymal cells and stimulates MET, which is present on the surface of epithelial cells. HGF-MET signaling directs the proliferation and migration of epithelial cells during the development of various organs and is important during wound healing. Aberrant MET activation has been implicated in several types of cancer, including squamous cell carcinoma. Using a model in which mice overexpressing HGF develop spontaneous squamous cell carcinomas in the skin, Cataisson et al found that MET promoted the development of squamous tumors by stimulating the synthesis and release of ligands that activate the epidermal growth factor receptor (EGFR). This mechanism was similar to that through which oncogenic RAS promotes skin tumors. Blocking EGFR signaling caused HGF-induced squamous tumors to regress, suggesting that EGFR inhibitors might be useful for treating squamous cell carcinomas.Listen to Podcast. PMID:27330186

  12. 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. PMID:27242035

  13. Evolved cobalamin-independent methionine synthase (MetE) improves the acetate and thermal tolerance of Escherichia coli.

    PubMed

    Mordukhova, Elena A; Pan, Jae-Gu

    2013-12-01

    Acetate-mediated growth inhibition of Escherichia coli has been found to be a consequence of the accumulation of homocysteine, the substrate of the cobalamin-independent methionine synthase (MetE) that catalyzes the final step of methionine biosynthesis. To improve the acetate resistance of E. coli, we randomly mutated the MetE enzyme and isolated a mutant enzyme, designated MetE-214 (V39A, R46C, T106I, and K713E), that conferred accelerated growth in the E. coli K-12 WE strain in the presence of acetate. Additionally, replacement of cysteine 645, which is a unique site of oxidation in the MetE protein, with alanine improved acetate tolerance, and introduction of the C645A mutation into the MetE-214 mutant enzyme resulted in the highest growth rate in acetate-treated E. coli cells among three mutant MetE proteins. E. coli WE strains harboring acetate-tolerant MetE mutants were less inhibited by homocysteine in l-isoleucine-enriched medium. Furthermore, the acetate-tolerant MetE mutants stimulated the growth of the host strain at elevated temperatures (44 and 45°C). Unexpectedly, the mutant MetE enzymes displayed a reduced melting temperature (Tm) but an enhanced in vivo stability. Thus, we demonstrate improved E. coli growth in the presence of acetate or at elevated temperatures solely due to mutations in the MetE enzyme. Furthermore, when an E. coli WE strain carrying the MetE mutant was combined with a previously found MetA (homoserine o-succinyltransferase) mutant enzyme, the MetA/MetE strain was found to grow at 45°C, a nonpermissive growth temperature for E. coli in defined medium, with a similar growth rate as if it were supplemented by l-methionine. PMID:24123739

  14. Evolved Cobalamin-Independent Methionine Synthase (MetE) Improves the Acetate and Thermal Tolerance of Escherichia coli

    PubMed Central

    Mordukhova, Elena A.

    2013-01-01

    Acetate-mediated growth inhibition of Escherichia coli has been found to be a consequence of the accumulation of homocysteine, the substrate of the cobalamin-independent methionine synthase (MetE) that catalyzes the final step of methionine biosynthesis. To improve the acetate resistance of E. coli, we randomly mutated the MetE enzyme and isolated a mutant enzyme, designated MetE-214 (V39A, R46C, T106I, and K713E), that conferred accelerated growth in the E. coli K-12 WE strain in the presence of acetate. Additionally, replacement of cysteine 645, which is a unique site of oxidation in the MetE protein, with alanine improved acetate tolerance, and introduction of the C645A mutation into the MetE-214 mutant enzyme resulted in the highest growth rate in acetate-treated E. coli cells among three mutant MetE proteins. E. coli WE strains harboring acetate-tolerant MetE mutants were less inhibited by homocysteine in l-isoleucine-enriched medium. Furthermore, the acetate-tolerant MetE mutants stimulated the growth of the host strain at elevated temperatures (44 and 45°C). Unexpectedly, the mutant MetE enzymes displayed a reduced melting temperature (Tm) but an enhanced in vivo stability. Thus, we demonstrate improved E. coli growth in the presence of acetate or at elevated temperatures solely due to mutations in the MetE enzyme. Furthermore, when an E. coli WE strain carrying the MetE mutant was combined with a previously found MetA (homoserine o-succinyltransferase) mutant enzyme, the MetA/MetE strain was found to grow at 45°C, a nonpermissive growth temperature for E. coli in defined medium, with a similar growth rate as if it were supplemented by l-methionine. PMID:24123739

  15. Plasma native and peptidase-derivable Met-enkephalin responses to restraint stress in rats. Adaptation to repeated restraint.

    PubMed Central

    Pierzchala, K; Van Loon, G R

    1990-01-01

    Met-enkephalin and related proenkephalin A-derived peptides circulate in plasma at picomolar concentration as free, native pentapeptide and at nanomolar concentration in cryptic forms. We have optimized conditions for measurement of immunoreactive Met-enkephalin in plasma and for generation by trypsin and carboxypeptidase B of much greater amounts of total peptidase-derivable Met-enkephalin in plasma of rats, dogs, and humans. Free Met-enkephalin (11 pM) is constituted by native pentapeptide and its sulfoxide. Characterization of plasma total Met-enkephalin derived by peptidic hydrolysis revealed a small amount (38 pM) of Met-enkephalin associated with peptides of molecular mass less than 30,000 D, and probably derived from proenkephalin A, but much larger amounts of Met-enkephalin associated with albumin (1.2 nM) and with a globulin-sized protein (2.8 nM). Thus, plasma protein precursors for peptidase-derivable Met-enkephalin differ structurally and chemically from proenkephalin A. Met-enkephalin generated from plasma by peptidic hydrolysis showed naloxone-reversible bioactivity comparable to synthetic Met-enkephalin. Prolonged exposure of adult, male rats to restraint stress produced biphasic plasma responses, with peaks occurring at 30 s and 30 min in both free native and total peptidase-derivable Met-enkephalin. Repeated daily exposure to this 30-min stress resulted in adaptive loss of responses of both forms to acute restraint. Initial plasma responses of Met-enkephalin paralleled those of epinephrine and norepinephrine, but subsequently showed divergence of response. In conclusion, Met-enkephalin circulates in several forms, some of which may be derived from proteins other than proenkephalin A, and plasma levels of both free native, and peptidase-derivable Met-enkephalin are modulated physiologically. PMID:2312729

  16. The Association between EGFR and cMET Expression and Phosphorylation and Its Prognostic Implication in Patients with Breast Cancer

    PubMed Central

    Chae, Young Kwang; Gagliato, Debora de Melo; Pai, Sachin Gopalkrishna; Carneiro, Benedito; Mohindra, Nisha; Giles, Francis Joseph; Ramakrishnan-Geethakumari, Praveen; Sohn, Joohyuk; Liu, Shuying; Chen, Huiqin; Ueno, Naoto; Hortobagyi, Gabriel; Gonzalez-Angulo, Ana Maria

    2016-01-01

    EGFR and cMET cross-talk is involved in breast cancer (BC) progression and resistance to different targeted therapies, however little is known about the co-expression patterns of EGFR and cMET or its prognostic significance in BC. Protein levels of EGFR, cMET and their phosphorylated proteins were measured in 825 BC samples using reverse phase protein array (RPPA). Given unimodal distribution of proteins, the median was selected as a cut-off after sensitivity analyses. Kaplan-Meier survival curves were used to estimate relapse-free (RFS) and overall survival (OS). Cox-proportional hazards models were utilized to determine associations between EGFR and cMET with outcomes. Mean age was 58 years with 457 (55%) hormone receptor (HR) positive, 211 (26%) triple-negative (TN) and 148 (18%) HER2 positive tumors (HER2+). HER2+ was associated with higher EGFR expression and phosphorylation, compared to HR and TN (p<0.05). High EGFR expression was associated with higher phosphorylated-cMET (p-cMET) but not cMET (ANOVA p-cMET p < 0.001; cMET p = 0.34). The same association was found with high phosphorylated-EGFR (p-EGFR) group at Tyr992 and Tyr1068 (both p < 0.001). High expressions in either of two p-EGFRs were linked with higher cMET as well (all p<0.001). For the TN subtype, high expression in EGFR and p-EGFR at Tyr992 but not at Tyr1068 was associated with higher p-cMET (p<0.00, p = 0.012, p = 0.4 respectively). Only high expression in p-EGFR at Tyr992 was linked with higher expression of cMET (p = 0.02). In contrast, among HER2 subtype, high expression in p-EGFR at Tyr1068 but not at Tyr992 was associated with higher cMET and p-cMET (cMET p = 0.023;p-cMET p<0.001). Four subgroups of patients defined by dichotomized EGFR/p-EGFR and cMET/p-cMET level demonstrated no significant differences in survival. In multivariate analyses, neither cMET nor EGFR expression/activation was found to be an independent prognostic factor in survival outcome. PMID:27055285

  17. A comprehensive analysis of adiponectin QTLs using SNP association, SNP cis-effects on peripheral blood gene expression and gene expression correlation identified novel metabolic syndrome (MetS) genes with potential role in carcinogenesis and systemic inflammation

    PubMed Central

    2013-01-01

    Background Metabolic syndrome (MetS) is an aberration associated with increased risk for cancer and inflammation. Adiponectin, an adipocyte-produced abundant protein hormone, has countering effect on the diabetogenic and atherogenic components of MetS. Plasma levels of adiponectin are negatively correlated with onset of cancer and cancer patient mortality. We previously performed microsatellite linkage analyses using adiponectin as a surrogate marker and revealed two QTLs on chr5 (5p14) and chr14 (14q13). Methods Using individuals from 85 extended families that contributed to the linkage and who were measured for 42 clinical and biologic MetS phenotypes, we tested QTL-based SNP associations, peripheral white blood cell (PWBC) gene expression, and the effects of cis-acting SNPs on gene expression to discover genomic elements that could affect the pathophysiology and complications of MetS. Results Adiponectin levels were found to be highly intercorrelated phenotypically with the majority of MetS traits. QTL-specific haplotype-tagging SNPs associated with MetS phenotypes were annotated to 14 genes whose function could influence MetS biology as well as oncogenesis or inflammation. These were mechanistically categorized into four groups: cell-cell adhesion and mobility, signal transduction, transcription and protein sorting. Four genes were highly prioritized: cadherin 18 (CDH18), myosin X (MYO10), anchor protein 6 of AMPK (AKAP6), and neuronal PAS domain protein 3 (NPAS3). PWBC expression was detectable only for the following genes with multi-organ or with multi-function properties: NPAS3, MARCH6, MYO10 and FBXL7. Strong evidence of cis-effects on the expression of MYO10 in PWBC was found with SNPs clustered near the gene’s transcription start site. MYO10 expression in PWBC was marginally correlated with body composition (p= 0.065) and adipokine levels in the periphery (p = 0.064). Variants of genes AKAP6, NPAS3, MARCH6 and FBXL7 have been previously reported to be

  18. IGF1R and c-met as therapeutic targets for colorectal cancer.

    PubMed

    Shali, Hajar; Ahmadi, Majid; Kafil, Hossein Samadi; Dorosti, Abbasali; Yousefi, Mehdi

    2016-08-01

    The type 1 IGF receptor (IGF1R) and mesenchymal-epithelial transition (MET) are hetrodimeric and transmembrane receptor tyrosine kinases, which are frequently overexpressed by several tumor types, including colorectal cancer (CRC). These receptors bind to their specific ligands, insulin growth factors (IGFs) and hepatocyte growth factor (HGF), respectively, and promote signaling cascades which mediates many functions such as proliferation and protection against apoptosis, cell scattering, tumor cell motility, invasion and metastasis. In patients with metastatic colorectal cancer (mCRC), IGF1R and c-met expression confer resistance to cetuximab (monoclonal antibodies against EGFR). Therefore, the c-met and IGF1R are now an attractive novel target for anticancer therapy. In this review, we will describe correlation between two receptors and their activation effects in tumor cells, and finally introduce useful and available strategies for their targeting. PMID:27470393

  19. Role of HGF/MET axis in resistance of lung cancer to contemporary management.

    PubMed

    Raghav, Kanwal Pratap Singh; Gonzalez-Angulo, Ana Maria; Blumenschein, George R

    2012-09-01

    Lung cancer is the number one cause of cancer related mortality with over 1 million cancer deaths worldwide. Numerous therapies have been developed for the treatment of lung cancer including radiation, cytotoxic chemotherapy and targeted therapies. Histology, stage of presentation and molecular aberrations are main determinants of prognosis and treatment strategy. Despite the advances that have been made, overall prognosis for lung cancer patients remains dismal. Chemotherapy and/or targeted therapy yield objective response rates of about 35% to 60% in advanced stage non-small cell lung cancer (NSCLC). Even with good initial responses, median overall survival of is limited to about 12 months. This reflects that current therapies are not universally effective and resistance develops quickly. Multiple mechanisms of resistance have been proposed and the MET/HGF axis is a potential key contributor. The proto-oncogene MET (mesenchymal-epithelial transition factor gene) and its ligand hepatocyte growth factor (HGF) interact and activate downstream signaling via the mitogen-activated protein kinase (ERK/MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K/AKT) pathways that regulate gene expression that promotes carcinogenesis. Aberrant MET/HGF signaling promotes emergence of an oncogenic phenotype by promoting cellular proliferation, survival, migration, invasion and angiogenesis. The MET/HGF axis has been implicated in various tumor types including lung cancers and is associated with adverse clinicopathological profile and poor outcomes. The MET/HGF axis plays a major role in development of radioresistance and chemoresistance to platinums, taxanes, camtothecins and anthracyclines by inhibiting apoptosis via activation of PI3K-AKT pathway. DNA damage from these agents induces MET and/or HGF expression. Another resistance mechanism is inhibition of chemoradiation induced translocation of apoptosis-inducing factor (AIF) thereby preventing apoptosis. Furthermore, this

  20. 1 Protein Methyltransferases: Their Distribution Among the Five Structural Classes of AdoMet-Dependent Methyltransferases.

    PubMed

    Schubert, Heidi L; Blumenthal, Robert M; Cheng, Xiaodong

    2006-01-01

    S-adenosyl-l-methionine (AdoMet) dependent methyltransferases (MTases) are involved in biosynthesis, signal transduction, protein repair, chromatin regulation, and gene silencing. Five different structural folds (designated I through V) have been described that bind AdoMet and catalyze methyltransfer to diverse substrates, although the great majority of known MTases have the Class I fold. Even within a particular MTase class the amino-acid sequence similarity can be as low as 10%. Thus, the structural and catalytic requirements for methyltransfer from AdoMet appear to be remarkably flexible. MTases that act on protein substrates have been found to date among three of the five structural classes (I, the classical fold; III, the corrin MTase fold; and V, the SET fold). "There are many paths to the top of the mountain, but the view is always the same."-Chinese proverb The Columbia World of Quotations, New York, Columbia University Press, 1996. PMID:26718035

  1. Role of HGF/MET axis in resistance of lung cancer to contemporary management

    PubMed Central

    Raghav, Kanwal Pratap Singh; Gonzalez-Angulo, Ana Maria

    2012-01-01

    Lung cancer is the number one cause of cancer related mortality with over 1 million cancer deaths worldwide. Numerous therapies have been developed for the treatment of lung cancer including radiation, cytotoxic chemotherapy and targeted therapies. Histology, stage of presentation and molecular aberrations are main determinants of prognosis and treatment strategy. Despite the advances that have been made, overall prognosis for lung cancer patients remains dismal. Chemotherapy and/or targeted therapy yield objective response rates of about 35% to 60% in advanced stage non-small cell lung cancer (NSCLC). Even with good initial responses, median overall survival of is limited to about 12 months. This reflects that current therapies are not universally effective and resistance develops quickly. Multiple mechanisms of resistance have been proposed and the MET/HGF axis is a potential key contributor. The proto-oncogene MET (mesenchymal-epithelial transition factor gene) and its ligand hepatocyte growth factor (HGF) interact and activate downstream signaling via the mitogen-activated protein kinase (ERK/MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K/AKT) pathways that regulate gene expression that promotes carcinogenesis. Aberrant MET/HGF signaling promotes emergence of an oncogenic phenotype by promoting cellular proliferation, survival, migration, invasion and angiogenesis. The MET/HGF axis has been implicated in various tumor types including lung cancers and is associated with adverse clinicopathological profile and poor outcomes. The MET/HGF axis plays a major role in development of radioresistance and chemoresistance to platinums, taxanes, camtothecins and anthracyclines by inhibiting apoptosis via activation of PI3K-AKT pathway. DNA damage from these agents induces MET and/or HGF expression. Another resistance mechanism is inhibition of chemoradiation induced translocation of apoptosis-inducing factor (AIF) thereby preventing apoptosis. Furthermore, this

  2. Derivation of clones close to met by preparative field inversion gel electrophoresis

    SciTech Connect

    Michiels, F.; Burmeister, M.; Lehrach, H.

    1987-06-05

    The molecular analysis of genes identified by mutations is a major problems in mammalian genetics. As a step toward this goal, preparative field inversion gel electrophoresis (FIGE) was used to selectively isolate clones from the environment of genetically linked markers, and to select a subset of these clones containing sequences next to specific restriction sites rare in mammalian DNA. This approach has been used to generate a library highly enriched in sequences closely linked to the cystic fibrosis marker met. One clone derived from the end of a Not I restriction fragment containing the met sequence was analyzed in detail and localized within a long range map to a position of 300 kilobase pairs 5' of the metD sequence.

  3. Genetic Role of BDNF Val66Met and 5-HTTLPR Polymorphisms on Depressive Disorder

    PubMed Central

    Lee, Kyu Young; Jeong, Seong Hoon; Kim, Se Hyun; Ahn, Yong Min; Kim, Yong Sik; Jung, Hee Yeon; Bang, Yang Weon

    2014-01-01

    Objective We investigated possible association between depressive disorders and BDNF Val66Met and 5-HTTLPR. Brain derived neurotrophic factor (BDNF) gene and serotonin transporter (SLC6A4) gene are promising candidate genes for depressive disorders. It has been suggested that BDNF promotes the survival and differentiation of serotonergic neurons and that serotonergic transmission exerts powerful control over BDNF gene expression. Methods Final analyses were performed on 186 patients with depressive disorders and 1032 controls. Val66Met polymorphism of BDNF gene and 5-HTTLPR polymorphism of serotonin transporter gene were genotyped and allele and genotypic associations on the diagnosis of depression and age at onset of depression were analyzed. Results The 5-HTTLPR was positively associated with depressive affected status in the total sample and in females (p=0.038 for allelewise, p=0.015 for genotype-wise associations), but, not in males. The BDNF Val66Met showed no association with depression. BDNF Val66Met and 5-HTTLPR alone were not associated with age at onset of depression. Additional analysis on the interaction between BDNF Val66Met and 5-HTTLPR found a significant association with age at onset of depression in the entire patient group. This association was also found in the female but not in the male patient group. None of the positive results survived Bonferroni correction for multiple testing. Conclusion This result suggested that BDNF Val66Met and 5-HTTLPR may contribute to depressive disorders in a complex way and that the genetic effect could differ by gender. Further studies with large number of patients will be necessary. PMID:24843376

  4. Met signaling in cardiomyocytes is required for normal cardiac function in adult mice.

    PubMed

    Arechederra, María; Carmona, Rita; González-Nuñez, María; Gutiérrez-Uzquiza, Alvaro; Bragado, Paloma; Cruz-González, Ignacio; Cano, Elena; Guerrero, Carmen; Sánchez, Aránzazu; López-Novoa, José Miguel; Schneider, Michael D; Maina, Flavio; Muñoz-Chápuli, Ramón; Porras, Almudena

    2013-12-01

    Hepatocyte growth factor (HGF) and its receptor, Met, are key determinants of distinct developmental processes. Although HGF exerts cardio-protective effects in a number of cardiac pathologies, it remains unknown whether HGF/Met signaling is essential for myocardial development and/or physiological function in adulthood. We therefore investigated the requirement of HGF/Met signaling in cardiomyocyte for embryonic and postnatal heart development and function by conditional inactivation of the Met receptor in cardiomyocytes using the Cre-α-MHC mouse line (referred to as α-MHCMet-KO). Although α-MHCMet-KO mice showed normal heart development and were viable and fertile, by 6 months of age, males developed cardiomyocyte hypertrophy, associated with interstitial fibrosis. A significant upregulation in markers of myocardial damage, such as β-MHC and ANF, was also observed. By the age of 9 months, α-MHCMet-KO males displayed systolic cardiac dysfunction. Mechanistically, we provide evidence of a severe imbalance in the antioxidant defenses in α-MHCMet-KO hearts involving a reduced expression and activity of catalase and superoxide dismutase, with consequent reactive oxygen species accumulation. Similar anomalies were observed in females, although with a slower kinetics. We also found that Met signaling down-regulation leads to an increase in TGF-β production and a decrease in p38MAPK activation, which may contribute to phenotypic alterations displayed in α-MHCMet-KO mice. Consistently, we show that HGF acts through p38α to upregulate antioxidant enzymes in cardiomyocytes. Our results highlight that HGF/Met signaling in cardiomyocytes plays a physiological cardio-protective role in adult mice by acting as an endogenous regulator of heart function through oxidative stress control. PMID:23994610

  5. Methoprene-tolerant (Met) knockdown in the adult female cockroach, Diploptera punctata completely inhibits ovarian development.

    PubMed

    Marchal, Elisabeth; Hult, Ekaterina F; Huang, Juan; Pang, Zhenguo; Stay, Barbara; Tobe, Stephen S

    2014-01-01

    Independent of the design of the life cycle of any insect, their growth and reproduction are highly choreographed through the action of two versatile hormones: ecdysteroids and juvenile hormones (JH). However, the means by which JH can target tissues and exert its pleiotropic physiological effects is currently still not completely elucidated. Although the identity of the one JH receptor is currently still elusive, recent evidence seems to point to the product of the Methoprene-tolerant gene (Met) as the most likely contender in transducing the action of JH. Studies on the role of this transcription factor have mostly been focused on immature insect stages. In this study we used the viviparous cockroach Diploptera punctata, a favorite model in studying JH endocrinology, to examine the role of Met during reproduction. A tissue distribution and developmental profile of transcript levels was determined for Met and its downstream partners during the first gonadotropic cycle of this cockroach. Using RNA interference, our study shows that silencing Met results in an arrest of basal oocyte development; vitellogenin is no longer transcribed in the fat body and no longer taken up by the ovary. Patency is not induced in these animals which fail to produce the characteristic profile of JH biosynthesis typical of the first gonadotropic cycle. Moreover, the ultrastructure of the follicle cells showed conspicuous whorls of rough endoplasmic reticulum and a failure to form chorion. Our study describes the role of Met on a cellular and physiological level during insect reproduction, and confirms the role of Met as a key factor in the JH signaling pathway. PMID:25197795

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

    DOE PAGESBeta

    Wurtele, Eve Syrkin; Li, Jie; Diao, Lixia; Zhang, Hailong; Foster, Carol M.; Fatland, Beth; Dickerson, Julie; Brown, Andrew; Cox, Zach; Cook, Dianne; et al

    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 usingmore » simple fuzzy cognitive maps. FCModeler is intended to develop and evaluate hypotheses, and provide a modelling framework for assessing the large amounts of data captured by high-throughput gene expression experiments. FCModeler and MetNetDB are currently being extended to three-dimensional virtual reality display. The MetNet map, together with gene expression data, can be viewed using multivariate graphics tools in GGobi linked with the data analytic tools in R. Users can highlight different parts of the metabolic network and see the relevant expression data highlighted in other data plots. Multi-dimensional expression data can be rotated through different dimensions. Statistical analysis can be computed alongside the visual. MetNet is designed to provide a framework for the formulation of testable hypotheses regarding the function of specific genes, and in the long term provide the basis for identification of metabolic and regulatory networks that control plant composition and development.« less

  7. Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults.

    PubMed

    Meyer, Bernhard M; Huemer, Julia; Rabl, Ulrich; Boubela, Roland N; Kalcher, Klaudius; Berger, Andreas; Banaschewski, Tobias; Barker, Gareth; Bokde, Arun; Büchel, Christian; Conrod, Patricia; Desrivières, Sylvane; Flor, Herta; Frouin, Vincent; Gallinat, Jurgen; Garavan, Hugh; Heinz, Andreas; Ittermann, Bernd; Jia, Tianye; Lathrop, Mark; Martinot, Jean-Luc; Nees, Frauke; Rietschel, Marcella; Smolka, Michael N; Bartova, Lucie; Popovic, Ana; Scharinger, Christian; Sitte, Harald H; Steiner, Hans; Friedrich, Max H; Kasper, Siegfried; Perkmann, Thomas; Praschak-Rieder, Nicole; Haslacher, Helmuth; Esterbauer, Harald; Moser, Ewald; Schumann, Gunter; Pezawas, Lukas

    2016-01-01

    Prefrontal dopamine levels are relatively increased in adolescence compared to adulthood. Genetic variation of COMT (COMT Val158Met) results in lower enzymatic activity and higher dopamine availability in Met carriers. Given the dramatic changes of synaptic dopamine during adolescence, it has been suggested that effects of COMT Val158Met genotypes might have oppositional effects in adolescents and adults. The present study aims to identify such oppositional COMT Val158Met effects in adolescents and adults in prefrontal brain networks at rest. Resting state functional connectivity data were collected from cross-sectional and multicenter study sites involving 106 healthy young adults (mean age 24 ± 2.6 years), gender matched to 106 randomly chosen 14-year-olds. We selected the anterior medial prefrontal cortex (amPFC) as seed due to its important role as nexus of the executive control and default mode network. We observed a significant age-dependent reversal of COMT Val158Met effects on resting state functional connectivity between amPFC and ventrolateral as well as dorsolateral prefrontal cortex, and parahippocampal gyrus. Val homozygous adults exhibited increased and adolescents decreased connectivity compared to Met homozygotes for all reported regions. Network analyses underscored the importance of the parahippocampal gyrus as mediator of observed effects. Results of this study demonstrate that adolescent and adult resting state networks are dose-dependently and diametrically affected by COMT genotypes following a hypothetical model of dopamine function that follows an inverted U-shaped curve. This study might provide cues for the understanding of disease onset or dopaminergic treatment mechanisms in major neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder. PMID:25319752

  8. 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.

  9. Changes in Met- and Leu-enkephalin concentrations in brain structures of rats with burn shock

    SciTech Connect

    Zaets, T.L.; Borodulin, A.G.; Maizelis, M.Ya.; Shikhov, S.N.; Sologub, V.K.; Zabludovskii, A.L.

    1986-06-01

    This paper studies concentrations of Met- and Leu-enkephalins in brain structurers of rats with severe thermal burns in order to elucidate the role of the endogeneous antinociceptive system in the pathogenesis of burn shock. Concentrations of Met- and Leu-enkephalins in the cerebral cortex and hypothalamus were investigated by radioimmunoasay immediattely after burning and 30 min and 2 h later. The hypothalamus of intact rats contained significantly more Metand Leu-enkephalins than the cerebral cortex, but immediately before burning there was a tendency for the Leu-enkephalin concentration in the hypothalamus to rise.

  10. Blocking c-Met signaling enhances bone morphogenetic protein-2-induced osteoblast differentiation

    PubMed Central

    Shibasaki, Seiji; Kitano, Sachie; Karasaki, Miki; Tsunemi, Sachi; Sano, Hajime; Iwasaki, Tsuyoshi

    2015-01-01

    We previously demonstrated that blocking hepatocyte growth factor (HGF) receptor/c-Met signaling inhibited arthritis and articular bone destruction in mouse models of rheumatoid arthritis (RA). In the present study, we investigated the role of c-Met signaling in osteoblast differentiation using the C2C12 myoblast cell line derived from murine satellite cells and the MC3T3-E1 murine pre-osteoblast cell line. Osteoblast differentiation was induced by treatment with bone morphogenetic protein (BMP)-2 or osteoblast-inducer reagent in the presence or absence of either HGF antagonist (NK4) or c-Met inhibitor (SU11274). Osteoblast differentiation was confirmed by Runx2 expression, and alkaline phosphatase (ALP) and osteocalcin production by the cells. Production of ALP, osteocalcin and HGF was verified by enzyme-linked immunosorbent assay. Runx2 expression was confirmed by reverse transcription-PCR analysis. The phosphorylation status of ERK1/2, AKT, and Smads was determined by Western blot analysis. Both NK4 and SU11274 enhanced Runx2 expression, and ALP and osteocalcin production but suppressed HGF production in BMP-2-stimulated C2C12 cells. SU11274 also enhanced ALP and osteocalcin production in osteoblast-inducer reagent-stimulated MC3T3-E1 cells. SU11274 inhibited ERK1/2 and AKT phosphorylation in HGF-stimulated C2C12 cells. This result suggested that ERK and AKT were functional downstream of the c-Met signaling pathway. However, both mitogen-activated protein kinase/ERK kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) inhibitor suppressed osteocalcin and HGF production in BMP-2-stimulated C2C12 cells. Furthermore, SU11274, MEK, and PI3K inhibitor suppressed Smad phosphorylation in BMP-2-stimulated C2C12 cells. These results indicate that although the c-Met-MEK-ERK-Smad and c-Met-PI3K-AKT-Smad signaling pathways positively regulate osteoblast differentiation, c-Met signaling negatively regulates osteoblast differentiation, independent of the MEK-ERK-Smad and PI3

  11. Blocking c-Met signaling enhances bone morphogenetic protein-2-induced osteoblast differentiation.

    PubMed

    Shibasaki, Seiji; Kitano, Sachie; Karasaki, Miki; Tsunemi, Sachi; Sano, Hajime; Iwasaki, Tsuyoshi

    2015-01-01

    We previously demonstrated that blocking hepatocyte growth factor (HGF) receptor/c-Met signaling inhibited arthritis and articular bone destruction in mouse models of rheumatoid arthritis (RA). In the present study, we investigated the role of c-Met signaling in osteoblast differentiation using the C2C12 myoblast cell line derived from murine satellite cells and the MC3T3-E1 murine pre-osteoblast cell line. Osteoblast differentiation was induced by treatment with bone morphogenetic protein (BMP)-2 or osteoblast-inducer reagent in the presence or absence of either HGF antagonist (NK4) or c-Met inhibitor (SU11274). Osteoblast differentiation was confirmed by Runx2 expression, and alkaline phosphatase (ALP) and osteocalcin production by the cells. Production of ALP, osteocalcin and HGF was verified by enzyme-linked immunosorbent assay. Runx2 expression was confirmed by reverse transcription-PCR analysis. The phosphorylation status of ERK1/2, AKT, and Smads was determined by Western blot analysis. Both NK4 and SU11274 enhanced Runx2 expression, and ALP and osteocalcin production but suppressed HGF production in BMP-2-stimulated C2C12 cells. SU11274 also enhanced ALP and osteocalcin production in osteoblast-inducer reagent-stimulated MC3T3-E1 cells. SU11274 inhibited ERK1/2 and AKT phosphorylation in HGF-stimulated C2C12 cells. This result suggested that ERK and AKT were functional downstream of the c-Met signaling pathway. However, both mitogen-activated protein kinase/ERK kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) inhibitor suppressed osteocalcin and HGF production in BMP-2-stimulated C2C12 cells. Furthermore, SU11274, MEK, and PI3K inhibitor suppressed Smad phosphorylation in BMP-2-stimulated C2C12 cells. These results indicate that although the c-Met-MEK-ERK-Smad and c-Met-PI3K-AKT-Smad signaling pathways positively regulate osteoblast differentiation, c-Met signaling negatively regulates osteoblast differentiation, independent of the MEK-ERK-Smad and PI3

  12. International Space Station (ISS) Metal Oxide (MetOx) Odor Anomaly

    NASA Technical Reports Server (NTRS)

    Prokhorov, Kimberlee; Lewis, John; Graf, John; Perry, Jay

    2004-01-01

    On occasion, seemingly normal operations can have significant effects upon the closed environment of the International Space Station (ISS). An example of such a case occurred on February 20, 2002 when a nominal Metal Oxide (MetOx) canister regeneration operation onboard the ISS resulted in an unexpected, foul odor that affected the crew and station operations. A case study summarizing the root cause for the event and steps taken to ensure that future MetOx regeneration operations proceed safely is presented. Included in the summary are engineering analyses and environmental monitoring results supporting the root cause assessment as well as testing conducted and flight operations changes implemented to ensure safe operations.

  13. The hepatocyte growth factor (HGF)-MET receptor tyrosine kinase signaling pathway: Diverse roles in modulating immune cell functions.

    PubMed

    Ilangumaran, Subburaj; Villalobos-Hernandez, Alberto; Bobbala, Diwakar; Ramanathan, Sheela

    2016-06-01

    Hepatocyte growth factor (HGF) signaling via the MET receptor is essential for embryonic development and tissue repair. On the other hand, deregulated MET signaling promotes tumor progression in diverse types of cancers. Even though oncogenic MET signaling remains the major research focus, the HGF-MET axis has also been implicated in diverse aspects of immune cell development and functions. In the presence of other hematopoietic growth factors, HGF promotes the development of erythroid, myeloid and lymphoid lineage cells and thrombocytes. In monocytes and macrophages responding to inflammatory stimuli, induction of autocrine HGF-MET signaling can contribute to tissue repair via stimulating anti-inflammatory cytokine production. HGF-MET signaling can also modulate adaptive immune response by facilitating the migration of Langerhans cells and dendritic cells to draining lymph nodes. However, MET signaling has also been shown to induce tolerogenic dendritic cells in mouse models of graft-versus-host disease and experimental autoimmune encephalomyelitis. HGF-MET axis is also implicated in promoting thymopoiesis and the survival and migration of B lymphocytes. Recent studies have shown that MET signaling induces cardiotropism in activated T lymphocytes. Further understanding of the HGF-MET axis in the immune system would allow its therapeutic manipulation to improve immune cell reconstitution, restore immune homeostasis and to treat immuno-inflammatory diseases. PMID:26822708

  14. Effects of the BDNF Val66Met Polymorphism on Gray Matter Volume in Typically Developing Children and Adolescents

    PubMed Central

    Hashimoto, Teruo; Fukui, Kento; Takeuchi, Hikaru; Yokota, Susumu; Kikuchi, Yoshie; Tomita, Hiroaki; Taki, Yasuyuki; Kawashima, Ryuta

    2016-01-01

    The Val66Met polymorphism of brain-derived neurotrophic factor (BDNF) is associated with psychiatric disorders and regional gray matter volume (rGMV) in adults. However, the relationship between BDNF and rGMV in children has not been clarified. In this 3-year cross-sectional/longitudinal (2 time points) study, we investigated the effects of BDNF genotypes on rGMV in 185 healthy Japanese children aged 5.7–18.4 using magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) analyses. We found that the volume of the right cuneus in Met homozygotes (Met/Met) was greater than in Val homozygotes (Val/Val) in both exams, and the left insula and left ventromedial prefrontal cortex volumes were greater in Val homozygotes versus Met homozygotes in Exam l. In addition, Met homozygous subjects exhibited higher processing speed in intelligence indices than Val homozygotes and Val/Met heterozygotes at both time points. Longitudinal analysis showed that the left temporoparietal junction volume of Val/Met heterozygotes increased more substantially over the 3-year study period than in Val homozygotes, and age-related changes were observed for the Val/Met genotype. Our findings suggest that the presence of 2 Met alleles may have a positive effect on rGMV at the developmental stages analyzed in this study. PMID:26830347

  15. Effects of the BDNF Val66Met Polymorphism on Gray Matter Volume in Typically Developing Children and Adolescents.

    PubMed

    Hashimoto, Teruo; Fukui, Kento; Takeuchi, Hikaru; Yokota, Susumu; Kikuchi, Yoshie; Tomita, Hiroaki; Taki, Yasuyuki; Kawashima, Ryuta

    2016-04-01

    The Val66Met polymorphism of brain-derived neurotrophic factor (BDNF) is associated with psychiatric disorders and regional gray matter volume (rGMV) in adults. However, the relationship between BDNF and rGMV in children has not been clarified. In this 3-year cross-sectional/longitudinal (2 time points) study, we investigated the effects of BDNF genotypes on rGMV in 185 healthy Japanese children aged 5.7-18.4 using magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) analyses. We found that the volume of the right cuneus in Met homozygotes (Met/Met) was greater than in Val homozygotes (Val/Val) in both exams, and the left insula and left ventromedial prefrontal cortex volumes were greater in Val homozygotes versus Met homozygotes in Exam l. In addition, Met homozygous subjects exhibited higher processing speed in intelligence indices than Val homozygotes and Val/Met heterozygotes at both time points. Longitudinal analysis showed that the left temporoparietal junction volume of Val/Met heterozygotes increased more substantially over the 3-year study period than in Val homozygotes, and age-related changes were observed for the Val/Met genotype. Our findings suggest that the presence of 2 Met alleles may have a positive effect on rGMV at the developmental stages analyzed in this study. PMID:26830347

  16. Small molecule inhibitor of c-Met (PHA665752) suppresses the growth of ovarian cancer cells and reverses cisplatin resistance.

    PubMed

    Li, Enze; Hu, Zheng; Sun, Yi; Zhou, Qi; Yang, Bin; Zhang, Zhiguo; Cao, Wenwu

    2016-06-01

    c-Met as a tyrosine-kinase receptor plays a major role in tumorigenesis, invasion, and metastatic spread of human tumors, including ovarian cancer. Expressing high levels of c-Met proteins is often associated with resistance to chemotherapy and an adverse prognosis. In this study, we have determined the effect of PHA665752, a small molecule inhibitor of c-Met proteins, with and without cisplatin and the role of c-Met in several ovarian cancer cell lines having high c-Met expression. The methyl thiazolyl tetrazolium (MTT) assay was used to detect cell proliferation, and apoptosis was evaluated by flow cytometry. Western blotting was carried out to determine protein expression levels. Gene silencing was used to detect the influence of c-Met gene silence on the resistance to cisplatin. Compared to more sensitive ovarian cancer cell lines SKOV3 and 3AO, we found that the expression of c-Met was significantly increased in SKOV3(DDP), OVCAR3, and OV-90 ovarian cancer cell lines, which were resistant to cisplatin. Our data indicated that cisplatin sustained activated phosphor-Met in SKOV3(DDP), OVCAR3, and OV-90 cell lines. We also observed a significant transient activation of c-Met phosphorylation in SKOV3 and 3AO cells. Treatment with PHA665752 inhibited c-Met expression inhibited cell growth, induced apoptosis, and enhanced cisplatin-induced proliferation inhibition and apoptosis in c-Met over-expressed cell lines. In addition, blocking c-Met expression with small interfering RNA (siRNA) overcame the resistance of cancer cells to cisplatin. Thus, blocking c-Met expression presents a promising therapeutic approach for ovarian cancer. PMID:26695152

  17. Both Met(109) and Met(112) are Utilized for Cu(II) Coordination to the Amyloidogenic Fragment of the Human Prion Protein

    SciTech Connect

    Shearer, J.; Soh, P; Lentz, S

    2008-01-01

    The prion protein is a ubiquitous neuronal membrane protein. Misfolding of the prion protein has been implicated in transmissible spongiform encephalopathies (prion diseases). It has been demonstrated that the human prion protein (PrP) is capable of coordinating at least five Cu{sup II} ions under physiological conditions; four copper binding sites can be found in the octarepeat domain between residues 61 and 91, while another copper binding site can be found in the unstructured 'amyloidogenic' domain between residues 91 and 126 PrP(91-126). Herein we expand upon a previous study (J. Shearer, P. Soh, Inorg. Chem. 46 (2007) 710-719) where we demonstrated that the physiologically relevant high affinity Cu{sup II} coordination site within PrP(91-126) is found between residues 106 and 114. It was shown that Cu{sup II} is contained within a square planar (N/O){sub 3}S coordination environment with one His imidazole ligand (H(111)) and one Met thioether ligand (either M(109) or M(112)). The identity of the Met thioether ligand was not identified in that study. In this study we perform a detailed investigation of the Cu{sup II} coordination environment within the PrP fragment containing residues 106-114 (PrP(106-114)) involving optical, X-ray absorption, EPR, and fluorescence spectroscopies in conjunction with electronic structure calculations. By using derivatives of PrP(106-114) with systematic Met {yields} Ile 'mutations' we show that the Cu{sup II} coordination environment within PrP(106-114) is actually comprised of a mixture of two major species; one CuII(N/O){sub 3}S center with the M(109) thioether coordinated to Cu{sup II} and another Cu{sup II}(N/O){sub 3}S center with the M(112) thioether coordinated to Cu{sup II}. Furthermore, deletion of one or more Met residues from the primary sequence of PrP(106-114) both reduces the Cu{sup II} affinity of the peptide by two to seven fold, and renders the resulting Cu{sup II} metallopeptides redox inactive. The biological

  18. c-Met targeting in advanced gastric cancer: An open challenge.

    PubMed

    Marano, Luigi; Chiari, Rita; Fabozzi, Alessio; De Vita, Ferdinando; Boccardi, Virginia; Roviello, Giandomenico; Petrioli, Roberto; Marrelli, Daniele; Roviello, Franco; Patriti, Alberto

    2015-08-28

    Despite significant improvements in systemic chemotherapy over the last two decades, the prognosis of patients with advanced gastric and gastroesophageal junction adenocarcinoma (GC) remains poor. Because of molecular heterogeneity, it is essential to classify tumors based on the underlying oncogenic pathways and to develop targeted therapies acting on individual tumors. High-quality research and advances in technology have contributed to the elucidation of molecular pathways underlying disease progression and have stimulated many clinical studies testing target therapies in an advanced disease setting. In particular, strong preclinical evidence for the aberrant activation of the HGF/c-Met signaling pathways in GC cancers exists. This review will cover the c-Met pathway, the mechanisms of c-Met activation and the different strategies of its inhibition. Next, we will focus on the current state of the art in the clinical evaluation of c-Met-targeted therapies and the description of ongoing randomized trials with the idea that in this disease, high quality translational research to identify and validate biomarkers is a priority task. PMID:26049023

  19. Discovery of orally active pyrrolopyridine- and aminopyridine-based Met kinase inhibitors

    SciTech Connect

    Cai, Zhen-Wei; Wei, Donna; Schroeder, Gretchen M.; Cornelius, Lyndon A.M.; Kim, Kyoung; Chen, Xiao-Tao; Schmidt, Robert J.; Williams, David K.; Tokarski, John S.; An, Yongmi; Sack, John S.; Manne, Veeraswamy; Kamath, Amrita; Zhang, Yueping; Marathe, Punit; Hunt, John T.; Lombardo, Louis J.; Fargnoli, Joseph; Borzilleri, Robert M.

    2008-09-10

    A series of acylurea analogs derived from pyrrolopyridine and aminopyridine scaffolds were identified as potent inhibitors of Met kinase activity. The SAR at various positions of the two kinase scaffolds was investigated. These studies led to the discovery of compounds 3b and 20b, which demonstrated favorable pharmacokinetic properties in mice and significant antitumor activity in a human gastric carcinoma xenograft model.

  20. Arts Enrichment in Afterschool. MetLife Foundation Afterschool Alert. Issue Brief No. 56

    ERIC Educational Resources Information Center

    Afterschool Alliance, 2012

    2012-01-01

    The Afterschool Alliance, in partnership with MetLife Foundation, is proud to present the second in its latest series of four issue briefs examining critical issues facing middle school youth and the vital role afterschool programs play in addressing these issues. This brief explores afterschool and arts enrichment. The arts have the remarkable…

  1. Profiling the Dynamics of a Human Phosphorylome Reveals New Components in HGF/c-Met Signaling

    PubMed Central

    Wan, Jun; Xia, Shuli; Newman, Robert; Hu, Jianfei; Zhang, Jin; Hayward, S. Diane; Qian, Jiang; Laterra, John; Zhu, Heng

    2013-01-01

    Protein phosphorylation is a dynamic and reversible event that greatly influences cellular function. Identifying the key regulatory elements that determine cellular phenotypes during development and oncogenesis requires the ability to dynamically monitor proteome-wide events. Here, we report the development of a new strategy to monitor dynamic changes of protein phosphorylation in cells and tissues using functional protein microarrays as the readout. To demonstrate this technology's ability to identify condition-dependent phosphorylation events, human protein microarrays were incubated with lysates from cells or tissues under activation or inhibition of c-Met, a receptor tyrosine kinase involved in tissue morphogenesis and malignancy. By comparing the differences between the protein phosphorylation profiles obtained using the protein microarrays, we were able to recover many of the proteins that are known to be specifically activated (i.e., phosphorylated) upon c-Met activation by the hepatocyte growth factor (HGF). Most importantly, we discovered many proteins that were differentially phosphorylated by lysates from cells or tissues when the c-Met pathway was active. Using phosphorylation-specific antibodies, we were able to validate several candidate proteins as new downstream components of the c-Met signaling pathway in cells. We envision that this new approach, like its DNA microarray counterpart, can be further extended toward profiling dynamics of global protein phosphorylation under many different physiological conditions both in cellulo and in vivo in a high-throughput and cost-effective fashion. PMID:24023761

  2. 8 CFR 273.4 - Demonstration by carrier that screening requirements were met.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 8 Aliens and Nationality 1 2010-01-01 2010-01-01 false Demonstration by carrier that screening... UNDER SECTION 273 OF THE ACT § 273.4 Demonstration by carrier that screening requirements were met. (a... carrier's document screening procedures at ports of embarkation to determine compliance with...

  3. Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors

    PubMed Central

    Du, Yi; Yamaguchi, Hirohito; Wei, Yongkun; Hsu, Jennifer L.; Wang, Hung-Ling; Hsu, Yi-Hsin; Lin, Wan-Chi; Yu, Wen-Hsuan; Leonard, Paul G.; Lee, Gilbert R.; Chen, Mei-Kuang; Nakai, Katsuya; Hsu, Ming-Chuan; Chen, Chun-Te; Sun, Ye; Wu, Yun; Chang, Wei-Chao; Huang, Wen-Chien; Liu, Chien-Liang; Chang, Yuan-Ching; Chen, Chung-Hsuan; Park, Morag; Jones, Philip; Hortobagyi, Gabriel N.; Hung, Mien-Chie

    2016-01-01

    Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials1. One PARP inhibitor, olaparib (Lynparza™, AstraZeneca), was recently approved by the FDA to treat ovarian cancer with BRCA mutations. BRCA1 and BRCA2 play essential roles in repairing DNA double strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition2,3. Here we show that receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907. Phosphorylation of PARP1 Tyr907 increases PARP1 enzymatic activity and reduces binding to a PARP inhibitor, thereby rendering cancer cells resistant to PARP inhibition. Combining c-Met and PARP1 inhibitors synergized to suppress growth of breast cancer cells in vitro and xenograft tumor models. Similar synergistic effects were observed in a lung cancer xenograft tumor model. These results suggest that PARP1 pTyr907 abundance may predict tumor resistance to PARP inhibitors, and that treatment with a combination of c-Met and PARP inhibitors may benefit patients bearing tumors with high c-Met expression who do not respond to PARP inhibition alone. PMID:26779812

  4. Collegiate Schemas: The Influence of Institutional Met Expectations on Tenure-Track Faculty Job Satisfaction

    ERIC Educational Resources Information Center

    Pontius, Jason Lewis

    2012-01-01

    "Met expectations" research into job satisfaction (Locke, 1976; Porter & Steers, 1973) has shown that the expectations employees bring to their jobs influence their overall job satisfaction. At colleges and universities, faculty job satisfaction is important because it can provide a measure of overall institutional effectiveness…

  5. Long-time dynamics of Met-enkephalin: comparison of theory with Brownian dynamics simulations.

    PubMed Central

    Kostov, K S; Freed, K F

    1999-01-01

    A recent theory for the long time dynamics of flexible chain molecules is applied for the first time to a peptide of biological importance, the neurotransmitter met-enkephalin. The dynamics of met-enkephalin is considerably more complicated than that of the previously studied glycine oligomers; met-enkephalin contains the interesting motions of phenyl groups and of side chains relative to the backbone, motions that are present in general flexible peptides. The theory extends the generalized Rouse (GR) model used to study the dynamics of polymers by providing a systematic procedure for including the contributions from the memory function matrices neglected in the GR theory. The new method describes the dynamics by time correlation functions instead of individual trajectories. These correlation functions are analytically expressed in terms of a set of equilibrium averages and the eigenvalues and eigenfunctions of the diffusion operator. The predictions of the theory are compared with Brownian dynamics (BD) simulations, so that both theory and simulation use identical potential functions and solvent models. The theory thus contains no adjustable parameters. Inclusion of the memory function contributions profoundly affects the dynamics. The theory produces very good agreement with the BD simulations for the global motions of met-enkephalin. It also correctly predicts the long-time relaxation rate for local motions. PMID:9876130

  6. 42 CFR 55a.104 - What confidentiality requirements must be met?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false What confidentiality requirements must be met? 55a.104 Section 55a.104 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS PROGRAM GRANTS FOR BLACK LUNG CLINICS General Provisions § 55a.104 What...

  7. 42 CFR 55a.104 - What confidentiality requirements must be met?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false What confidentiality requirements must be met? 55a.104 Section 55a.104 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS PROGRAM GRANTS FOR BLACK LUNG CLINICS General Provisions § 55a.104 What...

  8. 42 CFR 55a.104 - What confidentiality requirements must be met?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false What confidentiality requirements must be met? 55a.104 Section 55a.104 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS PROGRAM GRANTS FOR BLACK LUNG CLINICS General Provisions § 55a.104 What...

  9. 42 CFR 55a.104 - What confidentiality requirements must be met?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false What confidentiality requirements must be met? 55a.104 Section 55a.104 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS PROGRAM GRANTS FOR BLACK LUNG CLINICS General Provisions § 55a.104 What...

  10. 42 CFR 55a.104 - What confidentiality requirements must be met?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false What confidentiality requirements must be met? 55a.104 Section 55a.104 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS PROGRAM GRANTS FOR BLACK LUNG CLINICS General Provisions § 55a.104 What...

  11. 77 FR 25080 - Safety Zones; TriMet Bridge Project, Willamette River, Portland, OR

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-27

    ...The Coast Guard is establishing safety zones encompassing the work trestles and construction cranes involved in the construction of the TriMet Bridge on the Willamette River, in Portland, OR. This action is necessary to ensure the safety of recreational vessels and commercial vessels transiting in close proximity to cranes and overhead work associated with this construction project. These......

  12. Met Expectations Hypothesis: The Use of Direct Measures to Develop Participant Surveys

    ERIC Educational Resources Information Center

    Banks, Claretha H.

    2005-01-01

    This study uses met expectations hypothesis, a form of expectancy theory, to develop survey instruments to identify and compare the goals, expectations, and perceived outcomes stakeholders held for the Faculty Development Institute (FDI). The stakeholders had similar expectations for the outcomes during and/or immediately following the initial FDI…

  13. Children in the Criminal Justice and Secure Care Systems: How Their Mental Health Needs Are Met.

    ERIC Educational Resources Information Center

    Kurtz, Zarrina; Thornes, Rosemary; Bailey, Susan

    1998-01-01

    Describes survey of mental-health needs of young people in England and Wales considered for secure placement. Findings confirm that highly disturbed young people may present to a wide range of services, and that their mental-health needs are neither well recognized, widely understood, nor adequately met. (Author/JDM)

  14. COMT Val108/158 Met Genotype Affects Neural but not Cognitive Processing in Healthy Individuals

    PubMed Central

    Need, Anna C.; LaBar, Kevin S.; Waters-Metenier, Sheena; Cirulli, Elizabeth T.; Kragel, James; Goldstein, David B.; Cabeza, Roberto

    2010-01-01

    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. PMID:19641018

  15. When Allport Met Freud: Using Anecdotes in the Teaching of Psychology.

    ERIC Educational Resources Information Center

    Kaufman, James C.; Bristol, Adam S.

    2001-01-01

    Proposes using anecdotes in introductory psychology courses to teach key points, principles, and people. Offers theoretical and empirical support for anecdotes as teaching tools. Believes that anecdotes, such as when Gordon Allport met Sigmund Freud, provide an enjoyable experience and enable students to better remember information. (CMK)

  16. Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors.

    PubMed

    Du, Yi; Yamaguchi, Hirohito; Wei, Yongkun; Hsu, Jennifer L; Wang, Hung-Ling; Hsu, Yi-Hsin; Lin, Wan-Chi; Yu, Wen-Hsuan; Leonard, Paul G; Lee, Gilbert R; Chen, Mei-Kuang; Nakai, Katsuya; Hsu, Ming-Chuan; Chen, Chun-Te; Sun, Ye; Wu, Yun; Chang, Wei-Chao; Huang, Wen-Chien; Liu, Chien-Liang; Chang, Yuan-Ching; Chen, Chung-Hsuan; Park, Morag; Jones, Philip; Hortobagyi, Gabriel N; Hung, Mien-Chie

    2016-02-01

    Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials. One PARP inhibitor, olaparib (Lynparza, AstraZeneca), was recently approved by the FDA to treat ovarian cancer with mutations in BRCA genes. BRCA1 and BRCA2 have essential roles in repairing DNA double-strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition. Here we show that the receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907 (PARP1 pTyr907 or pY907). PARP1 pY907 increases PARP1 enzymatic activity and reduces binding to a PARP inhibitor, thereby rendering cancer cells resistant to PARP inhibition. The combination of c-Met and PARP1 inhibitors synergized to suppress the growth of breast cancer cells in vitro and xenograft tumor models, and we observed similar synergistic effects in a lung cancer xenograft tumor model. These results suggest that the abundance of PARP1 pY907 may predict tumor resistance to PARP inhibitors, and that treatment with a combination of c-Met and PARP inhibitors may benefit patients whose tumors show high c-Met expression and who do not respond to PARP inhibition alone. PMID:26779812

  17. 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

  18. Circles within circles: crosstalk between protein Ser/Thr/Tyr-phosphorylation and Met oxidation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Reversible posttranslational protein modifications such as phosphorylation of Ser/Thr/Tyr and Met oxidation are critical for both metabolic regulation and cellular signalling. Although these modifications are typically studied individually, herein we describe the potential for cross-talk...

  19. 34 CFR 472.32 - What other requirements must be met under this program?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 34 Education 3 2014-07-01 2014-07-01 false What other requirements must be met under this program? 472.32 Section 472.32 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION NATIONAL WORKPLACE LITERACY...

  20. 34 CFR 472.32 - What other requirements must be met under this program?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 34 Education 3 2013-07-01 2013-07-01 false What other requirements must be met under this program? 472.32 Section 472.32 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION NATIONAL WORKPLACE LITERACY...

  1. 34 CFR 472.32 - What other requirements must be met under this program?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 34 Education 3 2012-07-01 2012-07-01 false What other requirements must be met under this program? 472.32 Section 472.32 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION NATIONAL WORKPLACE LITERACY...

  2. 34 CFR 472.32 - What other requirements must be met under this program?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 34 Education 3 2011-07-01 2011-07-01 false What other requirements must be met under this program? 472.32 Section 472.32 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION NATIONAL WORKPLACE LITERACY...

  3. 34 CFR 472.32 - What other requirements must be met under this program?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 3 2010-07-01 2010-07-01 false What other requirements must be met under this program? 472.32 Section 472.32 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION NATIONAL WORKPLACE LITERACY...

  4. 21 CFR 111.75 - What must you do to determine whether specifications are met?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... submit a petition, under 21 CFR 10.30, to request an exemption from the testing requirements in paragraph... specifications are met? 111.75 Section 111.75 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH... Production and Process Control System § 111.75 What must you do to determine whether specifications are...

  5. 21 CFR 111.75 - What must you do to determine whether specifications are met?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... submit a petition, under 21 CFR 10.30, to request an exemption from the testing requirements in paragraph... specifications are met? 111.75 Section 111.75 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH... Production and Process Control System § 111.75 What must you do to determine whether specifications are...

  6. 21 CFR 111.75 - What must you do to determine whether specifications are met?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... submit a petition, under 21 CFR 10.30, to request an exemption from the testing requirements in paragraph... specifications are met? 111.75 Section 111.75 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH... Production and Process Control System § 111.75 What must you do to determine whether specifications are...

  7. 21 CFR 111.75 - What must you do to determine whether specifications are met?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... submit a petition, under 21 CFR 10.30, to request an exemption from the testing requirements in paragraph... specifications are met? 111.75 Section 111.75 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH... Production and Process Control System § 111.75 What must you do to determine whether specifications are...

  8. Evaluation of the EuroMET Web-Based Course in Meteorology.

    ERIC Educational Resources Information Center

    Phelps, Julia; Reynolds, Ross

    The EuroMET (European Meteorological Education and Training) project was created to address the education and training needs of professional meteorologists and students in tertiary education throughout Europe and more widely. Two courses, each modular in format, have been developed for the World Wide Web. The courses have been evaluated at three…

  9. Learning about Teaching: Initial Findings from the Measures of Effective Teaching Project. Policy Brief. 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 recognizing effective teaching. The project's goal is to help build fair and reliable systems for teacher observation and feedback to help teachers improve and administrators make better personnel decisions.…

  10. Validation Engine for Observational Protocols. Measures of Effective Teaching (MET) Project

    ERIC Educational Resources Information Center

    Bill & Melinda Gates Foundation, 2010

    2010-01-01

    In the fall of 2009, the Bill and Melinda Gates Foundation launched the two-year Measures of Effective Teaching (MET) project to rigorously develop and test multiple measures of teacher effectiveness. As part of the project, partners from more than a dozen reputable academic, non-profit and for-profit organizations collected and analyzed data from…

  11. Plant MetGenMAP: an integrative analysis system for plant systems biology

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We have developed a web-based system, Plant MetGenMAP, which can identify significantly altered biochemical pathways and highly affected biological processes, predict functional roles of pathway genes, and potential pathway-related regulatory motifs from transcript and metabolite profile datasets. P...

  12. 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

    2016-01-01

    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. PMID:27138567

  13. Digital Media & Learning in Afterschool. MetLife Foundation Afterschool Alert. Issue Brief No. 58

    ERIC Educational Resources Information Center

    Afterschool Alliance, 2013

    2013-01-01

    The Afterschool Alliance, in partnership with MetLife Foundation, is proud to present the final issue brief in its latest series of four issue briefs examining critical issues facing middle school youth and the vital role afterschool programs play in addressing these issues. This brief explores afterschool and digital learning. At the core of…

  14. Association between the COMTVal158Met Genotype and Alzheimer's Disease in the Han Chinese Population

    PubMed Central

    Ji, Yong; Shi, Zhihong; Liu, Mengyuan; Liu, Shuai; Liu, Shuling; Wang, Jinhuan

    2014-01-01

    Background Alzheimer's disease (AD) is the leading cause of dementia worldwide and is associated with individual, familial and social burdens. Catechol-O-methyltransferase (COMT) may have a prominent role in AD pathophysiology by affecting the metabolism of catecholamine neurotransmitters and estrogen. Although the COMT rs4680 gene polymorphism has been investigated as a susceptibility factor for AD, the results are inconsistent. The aim of this study was to examine the influence of the COMT rs4680 gene polymorphism as a risk factor for AD in the Han Chinese population and its synergistic effect with the apolipoprotein E (APOE)gene. Methods A total of 137 AD patients and 194 healthy controls were analyzed. Clinical criteria and neuropsychological tests were used to establish diagnostic groups. All subjects were analyzed for the COMTrs4680 polymorphism and APOEgenotype. Results No significant differences were observed between AD and control subjects regarding the COMT genotype frequencies of Val/Val, Val/Met and Met/Met, but Met alleles were higher in AD than in control subjects (35.4 and 28.1%, p = 0.045). A minor synergistic effect between the genotypes GG and APOEε4 was observed in AD patients (OR: 5.707, 95% CI: 2.505-13.002, p < 0.001). This synergistic effect was greater in women, who showed higher OR of AD (16.007, 95% CI: 4.606-56.118, p < 0.001) versus the AD group with APOE ε4 (11.972, 95% CI: 5.534-25.902, p < 0.001). Furthermore, the COMT Met allele was an independent risk factor for AD without APOE ε4 allele carriers (OR: 1.806, 95% CI: 1.160-2.810, p = 0.009), especially in men (OR: 4.904, 95% CI: 2.381-10.099, p < 0.001). Conclusion The COMT(Val158Met) polymorphism is not an independent risk factor for AD but shows a synergistic effect between the genotypes GG and APOEε4 that proves greater in women with AD. The COMT Met allele represents a risk factor in AD without APOE ε4 allele carriers, which is notable in men with AD. PMID:24575113

  15. Oxidative Stress Inactivates Cobalamin-Independent Methionine Synthase (MetE) in Escherichia coli

    PubMed Central

    2004-01-01

    In nature, Escherichia coli are exposed to harsh and non-ideal growth environments—nutrients may be limiting, and cells are often challenged by oxidative stress. For E. coli cells confronting these realities, there appears to be a link between oxidative stress, methionine availability, and the enzyme that catalyzes the final step of methionine biosynthesis, cobalamin-independent methionine synthase (MetE). We found that E. coli cells subjected to transient oxidative stress during growth in minimal medium develop a methionine auxotrophy, which can be traced to an effect on MetE. Further experiments demonstrated that the purified enzyme is inactivated by oxidized glutathione (GSSG) at a rate that correlates with protein oxidation. The unique site of oxidation was identified by selectively cleaving N-terminally to each reduced cysteine and analyzing the results by liquid chromatography mass spectrometry. Stoichiometric glutathionylation of MetE by GSSG occurs at cysteine 645, which is strategically located at the entrance to the active site. Direct evidence of MetE oxidation in vivo was obtained from thiol-trapping experiments in two different E. coli strains that contain highly oxidizing cytoplasmic environments. Moreover, MetE is completely oxidized in wild-type E. coli treated with the thiol-oxidizing agent diamide; reduced enzyme reappears just prior to the cells resuming normal growth. We argue that for E. coli experiencing oxidizing conditions in minimal medium, MetE is readily inactivated, resulting in cellular methionine limitation. Glutathionylation of the protein provides a strategy to modulate in vivo activity of the enzyme while protecting the active site from further damage, in an easily reversible manner. While glutathionylation of proteins is a fairly common mode of redox regulation in eukaryotes, very few proteins in E. coli are known to be modified in this manner. Our results are complementary to the independent findings of Leichert and Jakob

  16. COMT Val 158 Met polymorphism is associated with nonverbal cognition following mild traumatic brain injury.

    PubMed

    Winkler, Ethan A; Yue, John K; McAllister, Thomas W; Temkin, Nancy R; Oh, Sam S; Burchard, Esteban G; Hu, Donglei; Ferguson, Adam R; Lingsma, Hester F; Burke, John F; Sorani, Marco D; Rosand, Jonathan; Yuh, Esther L; Barber, Jason; Tarapore, Phiroz E; Gardner, Raquel C; Sharma, Sourabh; Satris, Gabriela G; Eng, Celeste; Puccio, Ava M; Wang, Kevin K W; Mukherjee, Pratik; Valadka, Alex B; Okonkwo, David O; Diaz-Arrastia, Ramon; Manley, Geoffrey T

    2016-01-01

    Mild traumatic brain injury (mTBI) results in variable clinical outcomes, which may be influenced by genetic variation. A single-nucleotide polymorphism in catechol-o-methyltransferase (COMT), an enzyme which degrades catecholamine neurotransmitters, may influence cognitive deficits following moderate and/or severe head trauma. However, this has been disputed, and its role in mTBI has not been studied. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val (158) Met polymorphism influences outcome on a cognitive battery 6 months following mTBI--Wechsler Adult Intelligence Test Processing Speed Index Composite Score (WAIS-PSI), Trail Making Test (TMT) Trail B minus Trail A time, and California Verbal Learning Test, Second Edition Trial 1-5 Standard Score (CVLT-II). All patients had an emergency department Glasgow Coma Scale (GCS) of 13-15, no acute intracranial pathology on head CT, and no polytrauma as defined by an Abbreviated Injury Scale (AIS) score of ≥3 in any extracranial region. Results in 100 subjects aged 40.9 (SD 15.2) years (COMT Met (158) /Met (158) 29 %, Met (158) /Val (158) 47 %, Val (158) /Val (158) 24 %) show that the COMT Met (158) allele (mean 101.6 ± SE 2.1) associates with higher nonverbal processing speed on the WAIS-PSI when compared to Val (158) /Val (158) homozygotes (93.8 ± SE 3.0) after controlling for demographics and injury severity (mean increase 7.9 points, 95 % CI [1.4 to 14.3], p = 0.017). The COMT Val (158) Met polymorphism did not associate with mental flexibility on the TMT or with verbal learning on the CVLT-II. Hence, COMT Val (158) Met may preferentially modulate nonverbal cognition following uncomplicated mTBI.Registry: ClinicalTrials.gov Identifier NCT01565551. PMID:26576546

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

    PubMed Central

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

    2013-01-01

    Background 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. Methods 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. Results 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. Conclusion 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. PMID:24092988

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

    PubMed

    Xie, Zhihui; Eagleson, Kathie L; Wu, Hsiao-Huei; Levitt, Pat

    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 tyrosine(142) (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

  19. 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

  20. 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

  1. Association of MET with social and communication phenotypes in individuals with autism spectrum disorder.

    PubMed

    Campbell, Daniel B; Warren, Dana; Sutcliffe, James S; Lee, Evon Batey; Levitt, Pat

    2010-03-01

    Autism is a complex neurodevelopmental disorder diagnosed by impairments in social interaction, communication, and behavioral flexibility. Autism is highly heritable, but it is not known whether a genetic risk factor contributes to all three core domains of the disorder or autism results from the confluence of multiple genetic risk factors for each domain. We and others reported previously association of variants in the gene encoding the MET receptor tyrosine kinase in five independent samples. We further described enriched association of the MET promoter variant rs1858830 C allele in families with co-occurring autism and gastrointestinal conditions. To test the contribution of this functional MET promoter variant to the domains of autism, we analyzed its association with quantitative scores derived from three instruments used to diagnose and describe autism phenotypes: the Autism Diagnostic Interview-Revised (ADI-R), the Autism Diagnostic Observation Schedule (ADOS), and both the parent and the teacher report forms of the Social Responsiveness Scale (SRS). In 748 individuals from 367 families, the transmission of the MET C allele from parent to child was consistently associated with both social and communication phenotypes of autism. Stratification by gastrointestinal conditions revealed a similar pattern of association with both social and communication phenotypes in 242 individuals with autism from 118 families with co-occurring gastrointestinal conditions, but a lack of association with any domain in 181 individuals from 96 families with ASD and no co-occurring gastrointestinal condition. These data indicate that the MET C allele influences at least two of the three domains of the autism triad. PMID:19548256

  2. A Meteorological Distribution System for High Resolution Terrestrial Modeling (MicroMet)

    NASA Astrophysics Data System (ADS)

    Liston, G. E.; Elder, K.

    2004-12-01

    Spatially distributed terrestrial models generally require atmospheric forcing data on horizontal grids that are of higher resolution than available meteorological data. Furthermore, the meteorological data collected may not necessarily represent the area of interest's meteorological variability. To address these deficiencies, computationally efficient and physically realistic methods must be developed to take available meteorological data sets (e.g., meteorological tower observations) and generate high-resolution atmospheric-forcing distributions. This poster describes MicroMet, a quasi-physically-based, but simple meteorological distribution model designed to produce high-resolution (e.g., 5-m to 1-km horizontal grid increments) meteorological data distributions required to run spatially distributed terrestrial models over a wide variety of landscapes. The model produces distributions of the seven fundamental atmospheric forcing variables required to run most terrestrial models: air temperature, relative humidity, wind speed, wind direction, incoming solar radiation, incoming longwave radiation, and precipitation. MicroMet includes a preprocessor that analyzes meteorological station data and identifies and repairs potential data deficiencies. The model uses known relationships between meteorological variables and the surrounding area (primarily topography) to distribute those variables over any given landscape. MicroMet performs two kinds of adjustments to available meteorological data: 1) when there are data at more than one location, at a given time, the data are spatially interpolated over the domain using a Barnes objective analysis scheme, and 2) physical sub-models are applied to each MicroMet variable to improve its realism at a given point in space and time with respect to the terrain. The three, 25-km by 25-km, Cold Land Processes Experiment (CLPX) mesoscale study areas (MSAs: Fraser, North Park, and Rabbit Ears) will be used as example MicroMet

  3. 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

  4. Pre-Osteoblasts Stimulate Migration of Breast Cancer Cells via the HGF/MET Pathway

    PubMed Central

    Vallet, Sonia; Malvestiti, Stefano; Schneeweiss, Andreas; Wuchter, Patrick; Jäger, Dirk; Podar, Klaus

    2016-01-01

    Introduction The occurrence of skeletal metastases in cancer, e.g. breast cancer (BC), deteriorates patient life expectancy and quality-of-life. Current treatment options against tumor-associated bone disease are limited to anti-resorptive therapies and aimed towards palliation. There remains a lack of therapeutic approaches, which reverse or even prevent the development of bone metastases. Recent studies demonstrate that not only osteoclasts (OCs), but also osteoblasts (OBs) play a central role in the pathogenesis of skeletal metastases, partly by producing hepatocyte growth factor (HGF), which promotes tumor cell migration and seeding into the bone. OBs consist of a heterogeneous cell pool with respect to their maturation stage and function. Recent studies highlight the critical role of pre-OBs in hematopoiesis. Whether the development of bone metastases can be attributed to a particular OB maturation stage is currently unknown. Methods and Results Pre-OBs were generated from healthy donor (HD)-derived bone marrow stromal cells (BMSC) as well as the BMSC line KM105 and defined as ALPlow OPNlow RUNX2high OSX high CD166high. Conditioned media (CM) of pre-OBs, but not of undifferentiated cells or mature OBs, enhanced migration of metastatic BC cells. Importantly, HGF mRNA was significantly up-regulated in pre-OBs versus mature OBs, and CM of pre-OBs activated the MET signaling pathway. Highlighting a key role for HGF, CM from HGF-negative pre-OBs derived from the BMSC line HS27A did not support migration of BC cells. Genetically (siMET) or pharmacologically (INCB28060) targeting MET inhibited both HGF- and pre-OB CM- mediated BC cell migration. Conclusions Our data demonstrate for the first time a role for pre-OBs in mediating HGF/MET- dependent migration of BC cells and strongly support the clinical evaluation of INCB28060 and other MET inhibitors to limit and/or prevent BC-associated bone metastases. PMID:26934743

  5. 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. PMID:23023098

  6. Effects of brain derived neurotrophic factor Val66Met polymorphism in patients with cervical spondylotic myelopathy.

    PubMed

    Abode-Iyamah, Kingsley O; Stoner, Kirsten E; Grossbach, Andrew J; Viljoen, Stephanus V; McHenry, Colleen L; Petrie, Michael A; Dahdaleh, Nader S; Grosland, Nicole M; Shields, Richard K; Howard, Matthew A

    2016-02-01

    Cervical spondylotic myelopathy (CSM) is the leading cause of spinal cord related disability in the elderly. It results from degenerative narrowing of the spinal canal, which causes spinal cord compression. This leads to gait instability, loss of dexterity, weakness, numbness and urinary dysfunction. There has been indirect data that implicates a genetic component to CSM. Such a finding may contribute to the variety in presentation and outcome in this patient population. The Val66Met polymorphism, a mutation in the brain derived neurotrophic factor (BDNF) gene, has been implicated in a number of brain and psychological conditions, and here we investigate its role in CSM. Ten subjects diagnosed with CSM were enrolled in this prospective study. Baseline clinical evaluation using the modified Japanese Orthopaedic Association (mJOA) scale, Nurick and 36-Item Short Form Health Survey (SF-36) were collected. Each subject underwent objective testing with gait kinematics, as well as hand functioning using the Purdue Peg Board. Blood samples were analyzed for the BDNF Val66Met mutation. The prevalence of the Val66Met mutation in this study was 60% amongst CSM patients compared to 32% in the general population. Individuals with abnormal Met allele had worse baseline mJOA and Nurick scores. Moreover, baseline gait kinematics and hand functioning testing were worse compared to their wild type counterpart. BDNF Val66Met mutation has a higher prevalence in CSM compared to the general population. Those with BDNF mutation have a worse clinical presentation compared to the wild type counterpart. These findings suggest implication of the BDNF mutation in the development and severity of CSM. PMID:26461908

  7. COMT Val158Met and cognitive and functional outcomes after traumatic brain injury.

    PubMed

    Willmott, Catherine; Withiel, Toni; Ponsford, Jennie; Burke, Richard

    2014-09-01

    There is significant variability in long-term outcomes after traumatic brain injury (TBI), making accurate prognosis difficult. In seeking to enhance understanding of outcomes, this study aimed to investigate whether COMT Val(158)Met allele status was associated with performance on neuropsychological measures of attention and working memory, executive functioning, learning and memory, and speed of information processing in the early rehabilitation phase. The study also aimed to examine whether the COMT polymorphism was associated with longer-term functional outcomes. A total of 223 participants (71.3% male) with moderate-to-severe TBI were recruited as rehabilitation inpatients to participate in a prospective, longitudinal head injury outcome study. The three COMT genotype groups (Val/Val, Val/Met, and Met/Met) were well matched for estimated full-scale IQ, years of education, age at injury, and injury severity. Results showed no significant difference between genotypes on neuropsychological measures (all p>0.05) or functional outcome, as measured by the Glasgow Outcome Scale-Extended (GOS-E), after controlling for age, education, and severity of injury. The presence of frontal lobe pathology was also not associated with cognitive performance. Those with greater injury severity (i.e., longer duration of post-traumatic amnesia) performed more poorly on measures of processing speed and verbal new learning and recall. It was concluded that there was little support for the influence of COMT Val(158)Met on cognitive function, or functional outcome measures, in the acute rehabilitation phase after TBI. PMID:24786534

  8. Met-ase: Cloning and distinct chromosomal location of a serine protease preferentially expressed in human natural killer cells

    SciTech Connect

    Smyth, M.J.; Trapani, J.A. ); Sayers, T.J.; Wiltrout, T. ); Powers, J.C. )

    1993-12-01

    A cDNA clone encoding a human NK serine protease was obtained by screening a [lambda]-gt10 library from the Lopez NK leukemia with the rat natural killer Met-ase (RNK-Met-1) cDNA clone. In Northern blot analysis human Met-ase (Hu-Met-1) cDNA hybridized with a 0.9-kb mRNA in two human NK leukemia cell lines, unstimulated human PBMC, and untreated purified CD3[sup [minus

  9. The brain-derived neurotrophic factor Val66Met polymorphism moderates early deprivation effects on attention problems.

    PubMed

    Gunnar, Megan R; Wenner, Jennifer A; Thomas, Kathleen M; Glatt, Charles E; McKenna, Morgan C; Clark, Andrew G

    2012-11-01

    Adverse early care is associated with attention regulatory problems, but not all so exposed develop attention problems. In a sample of 612 youth (girls = 432, M = 11.82 years, SD = 1.5) adopted from institutions (e.g., orphanages) in 25 countries, we examined whether the Val66Met polymorphism of the brain-derived neurotrophic factor gene moderates attention problems associated with the duration of institutional care. Parent-reported attention problem symptoms were collected using the MacArthur Health and Behavior Questionnaire. DNA was genotyped for the brain-derived neurotrophic factor Val66Met (rs6265) single nucleotide polymorphism. Among youth from Southeast (SE) Asia, the predominant genotype was valine/methionine (Val/Met), whereas among youth from Russia/Europe and Caribbean/South America, the predominant genotype was Val/Val. For analysis, youth were grouped as carrying Val/Val or Met/Met alleles. Being female, being from SE Asia, and being younger when adopted were associated with fewer attention regulatory problem symptoms. Youth carrying at least one copy of the Met allele were more sensitive to the duration of deprivation, yielding an interaction that followed a differential susceptibility pattern. Thus, youth with Val/Met or Met/Met genotypes exhibited fewer symptoms than Val/Val genotypes when adoption was very early and more symptoms when adoption occurred later in development. Similar patterns were observed when SE Asian youth and youth from other parts of the world were analyzed separately. PMID:23062292

  10. Preventing the Return of Fear Using Reconsolidation Update Mechanisms Depends on the Met-Allele of the Brain Derived Neurotrophic Factor Val66Met Polymorphism

    PubMed Central

    Asthana, Manish Kumar; Brunhuber, Bettina; Mühlberger, Andreas; Reif, Andreas; Schneider, Simone

    2016-01-01

    Background: Memory reconsolidation is the direct effect of memory reactivation followed by stabilization of newly synthesized proteins. It has been well proven that neural encoding of both newly and reactivated memories requires synaptic plasticity. Brain derived neurotrophic factor (BDNF) has been extensively investigated regarding its role in the formation of synaptic plasticity and in the alteration of fear memories. However, its role in fear reconsolidation is still unclear; hence, the current study has been designed to investigate the role of the BDNF val66met polymorphism (rs6265) in fear memory reconsolidation in humans. Methods: An auditory fear-conditioning paradigm was conducted, which comprised of three stages (acquisition, reactivation, and spontaneous recovery). One day after fear acquisition, the experimental group underwent reactivation of fear memory followed by the extinction training (reminder group), whereas the control group (non-reminder group) underwent only extinction training. On day 3, both groups were subjected to spontaneous recovery of earlier learned fearful memories. The treat-elicited defensive response due to conditioned threat was measured by assessing the skin conductance response to the conditioned stimulus. All participants were genotyped for rs6265. Results: The results indicate a diminishing effect of reminder on the persistence of fear memory only in the Met-allele carriers, suggesting a moderating effect of the BDNF polymorphism in fear memory reconsolidation. Conclusions: Our findings suggest a new role for BDNF gene variation in fear memory reconsolidation in humans. PMID:26721948

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

    PubMed

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

    2013-10-01

    In terms of infection incidence, the yeast Candida parapsilosis is the second after Candida albicans as causative agent of candidiases in humans. The major virulence factors of C. parapsilosis are secreted aspartic proteases (SAPPs) which help the pathogen to disseminate, acquire nutrients and dysregulate the mechanisms of innate immunity of the host. In the current work we characterized the action of two major extracellular proteases of C. parapsilosis, SAPP1 and SAPP2, on human kininogens, proteinaceous precursors of vasoactive and proinflammatory bradykinin-related peptides, collectively called the kinins. The kininogens, preferably the form with lower molecular mass, were effectively cleaved by SAPPs, with the release of two uncommon kinins, Met-Lys-bradykinin and Leu-Met-Lys-bradykinin. While optimal at acidic pH (4-5), the kinin release yield was only 2-3-fold lower at neutral pH. These peptides were able to interact with cellular kinin receptors of B2 subtype and to stimulate the human endothelial cells HMEC-1 to increased secretion of proinflammatory interleukins (ILs), IL-1β and IL-6. The analysis of the stability of SAPP-generated kinins in plasma suggested that they are biologically equivalent to bradykinin, the best agonist of B2 receptor subtype and can be quickly converted to des-Arg(9)-bradykinin, the agonist of inflammation-inducible B1 receptors. PMID:23954712

  12. Making MetPetDB a tool for reconnaissance studies of metamorphism and metamorphic rocks

    NASA Astrophysics Data System (ADS)

    Hallett, B. W.; Spear, F. S.; Horkley, L. K.; Adali, S.; Fox, P. A.

    2012-12-01

    Recent data mining efforts have significantly increased the coverage and quantity of published data that form the foundation of MetPetDB: the Database for Metamorphic Petrology. Mineral assemblage, metamorphic grade, geochemical mineral and whole rock analyses, and image data from over 600 published papers have been compiled and uploaded, with focus on a number of particularly well-studied metamorphic belts of regional extent. As a result of data mining efforts in the past several years, MetPetDB now contains data for over 9,000 samples, over 10,000 mineral and whole rock (major or trace element) analyses, and over 20,000 images including maps, thin section scans, photomicrographs, SE and BSE images, and X-ray maps. These data are available for searching and download, exportable in spreadsheets and/or as placemark layers in a Google Earth .kml file. Each Google Earth placemark contains a link to the full data available through MetPetDB's web interface. The improved spatial coverage provides a starting point for a geoscientist to rapidly gather sample and geochemical data for a growing inventory of distinct metamorphic belts. Regional searches can be performed by choosing a user-defined bounding box, or any of a number of bounding polygons that delineate distinct metamorphic belts, such as the Greenland Caledonides, or the Bohemian Massif. MetPetDB is a tool for researchers to share, compile, and organize sample information, both published and unpublished, enabling production of a dynamic GIS to aid in planning field work, producing geologic maps, or making inventory of geochemical data for metamorphic rocks. In addition to regional queries, published metamorphic rock samples with non-spatial commonalities may be queried and compiled using MetPetDB. For example, a petrologist with an interest in the equilibrium exchange of yttrium between garnet and monazite at mid-crustal conditions could easily find garnet with a certain range of yttrium content in amphibolite

  13. 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

  14. Quantitative Phosphokinome Analysis of the Met Pathway Activated by the Invasin Internalin B from Listeria monocytogenes*

    PubMed Central

    Reinl, Tobias; Nimtz, Manfred; Hundertmark, Claudia; Johl, Thorsten; Kéri, György; Wehland, Jürgen; Daub, Henrik; Jänsch, Lothar

    2009-01-01

    Stimulated by its physiological ligand, hepatocyte growth factor, the transmembrane receptor tyrosine kinase Met activates a signaling machinery that leads to mitogenic, motogenic, and morphogenic responses. Remarkably, the food-borne human pathogen Listeria monocytogenes also promotes autophosphorylation of Met through its virulence factor internalin B (InlB) and subsequently exploits Met signaling to induce phagocytosis into a broad range of host cells. Although the interaction between InlB and Met has been studied in detail, the signaling specificity of components involved in InlB-triggered cellular responses remains poorly characterized. The analysis of regulated phosphorylation events on protein kinases is therefore of particular relevance, although this could not as yet be characterized systematically by proteomics. Here, we implemented a new pyridopyrimidine-based strategy that enabled the efficient capture of a considerable subset of the human kinome in a robust one-step affinity chromatographic procedure. Additionally, and to gain functional insights into the InlB/Met-induced bacterial invasion process, a quantitative survey of the phosphorylation pattern of these protein kinases was accomplished. In total, the experimental design of this study comprises affinity chromatographic procedures for the systematic enrichment of kinases, as well as phosphopeptides; the quantification of all peptides based on the iTRAQTM reporter system; and a rational statistical strategy to evaluate the quality of phosphosite regulations. With this improved chemical proteomics strategy, we determined and relatively quantified 143 phosphorylation sites detected on 94 human protein kinases. Interestingly, InlB-mediated signaling shows striking similarities compared with the natural ligand hepatocyte growth factor that was intensively studied in the past. In addition, this systematic approach suggests a new subset of protein kinases including Nek9, which are differentially

  15. 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

  16. HGF and c-Met Participate in Paracrine Tumorigenic Pathways in Head and Neck Squamous Cell Cancer

    PubMed Central

    Knowles, Lynn M.; Stabile, Laura P.; Egloff, Ann Marie; Rothstein, Mary E.; Thomas, Sufi M.; Gubish, Christopher T.; Lerner, Edwina C.; Seethala, Raja R.; Suzuki, Shinsuke; Quesnelle, Kelly M.; Morgan, Sarah; Ferris, Robert L.; Grandis, Jennifer R.; Siegfried, Jill M.

    2011-01-01

    Purpose We determined hepatocyte growth factor (HGF) and c-Met expression and signaling in human head and neck squamous cell carcinoma (HNSCC) cells and primary tissues and tested the ability of c-Met tyrosine kinase inhibitors (TKI) to block HGF-induced biological signaling. Experimental Design Expression and signaling were determined using immunoblotting, ELISA, and immunohistochemistry. Biological end points included wound healing, cell proliferation, and invasion. c-Met TKIs were tested for their ability to block HGF-induced signaling and biological effects in vitro and in xenografts established in nude mice. Results c-Met was expressed and functional in HNSCC cells. HGF was secreted by HNSCC tumor-derived fibroblasts, but not by HNSCC cells. Activation of c-Met promoted phosphorylation of AKT and mitogen-activated protein kinase as well as release of the inflammatory cytokine interleukin-8. Cell growth and wound healing were also stimulated by HGF. c-Met TKIs blocked HGF-induced signaling, interleukin-8 release, and wound healing. Enhanced invasion of HNSCC cells induced by the presence of tumor-derived fibroblasts was completely blocked with a HGF-neutralizing antibody. PF-2341066, a c-Met TKI, caused a 50% inhibition of HNSCC tumor growth in vivo with decreased proliferation and increased apoptosis within the tumors. In HNSCC tumor tissues, both HGF and c-Met protein were increased compared with expression in normal mucosa. Conclusions These results show that HGF acts mainly as a paracrine factor in HNSCC cells, the HGF/c-Met pathway is frequently up-regulated and functional in HNSCC, and a clinically relevant c-Met TKI shows antitumor activity in vivo. Blocking the HGF/c-Met pathway may be clinically useful for the treatment of HNSCC. PMID:19470725

  17. A seamless approach to understanding and predicting Arctic sea ice in Met Office modelling systems.

    PubMed

    Hewitt, Helene T; Ridley, Jeff K; Keen, Ann B; West, Alex E; Peterson, K Andrew; Rae, Jamie G L; Milton, Sean F; Bacon, Sheldon

    2015-07-13

    Recent CMIP5 models predict large losses of summer Arctic sea ice, with only mitigation scenarios showing sustainable summer ice. Sea ice is inherently part of the climate system, and heat fluxes affecting sea ice can be small residuals of much larger air-sea fluxes. We discuss analysis of energy budgets in the Met Office climate models which point to the importance of early summer processes (such as clouds and meltponds) in determining both the seasonal cycle and the trend in ice decline. We give examples from Met Office modelling systems to illustrate how the seamless use of models for forecasting on time scales from short range to decadal might help to unlock the drivers of high latitude biases in climate models. PMID:26032316

  18. PKCδ activated by c-MET enhances infiltration of human glioblastoma cells through NOTCH2 signaling

    PubMed Central

    Kang, Seok-Gu; Kim, Rae-Kwon; Cui, Yan-Hong; Lee, Hae-June; Kim, Min-Jung; Lee, Jae-Seong; Kim, In-Gyu; Suh, Yongjoon; Lee, Su-Jae

    2016-01-01

    Poor prognosis of glioblastoma (GBM) is attributable to the propensity of tumor cells to infiltrate into the brain parenchyma. Protein kinase C (PKC) isozymes are highly expressed or aberrantly activated in GBM. However, how this signaling node translates to GBM cell invasiveness remains unknown. Here, we report that among PKC isoforms, PKCδ is strongly associated with infiltration of GBM cells. Notably, PKCδ enhanced Tyr418 phosphorylation of the non-receptor tyrosine kinase SRC, which in turn activated STAT3 and subsequent NOTCH2 signaling, ultimately leading to GBM cell invasiveness. Furthermore, we showed that PKCδ was aberrantly activated in GBM cells by c-MET, a receptor tyrosine kinase hyperactivated in GBM. In agreement, inhibition either component in the c-MET/PKCδ/SRC/STAT3 signaling axis effectively blocked the NOTCH2 signaling and invasiveness of GBM cells. Taken together, our findings shed a light on the signaling mechanisms behind the constitutive activation of PKCδ signaling in GBM. PMID:26700818

  19. Superstatistics analysis of the ion current distribution function: Met3PbCl influence study.

    PubMed

    Miśkiewicz, Janusz; Trela, Zenon; Przestalski, Stanisław; Karcz, Waldemar

    2010-09-01

    A novel analysis of ion current time series is proposed. It is shown that higher (second, third and fourth) statistical moments of the ion current probability distribution function (PDF) can yield new information about ion channel properties. The method is illustrated on a two-state model where the PDF of the compound states are given by normal distributions. The proposed method was applied to the analysis of the SV cation channels of vacuolar membrane of Beta vulgaris and the influence of trimethyllead chloride (Met(3)PbCl) on the ion current probability distribution. Ion currents were measured by patch-clamp technique. It was shown that Met(3)PbCl influences the variance of the open-state ion current but does not alter the PDF of the closed-state ion current. Incorporation of higher statistical moments into the standard investigation of ion channel properties is proposed. PMID:20354691

  20. In Brief: U.K. Met Office forecast for Atlantic hurricane season

    NASA Astrophysics Data System (ADS)

    2007-07-01

    GloSea, the U.K. Meteorological Office's computer model of the global atmosphere-ocean system, has predicted a cooling trend in sea surface temperatures in the tropical North Atlantic that will result in a less active hurricane season. The Met Office has predicted that there is a 70% chance of a less active hurricane season in the North Atlantic this year, with only 7-13 named storms occurring within the remaining five months of the season (July through November). There have already been two named storms this year-Andrea and Barry. From 1990-2005, there were an average of 12.4 storms during July-November. The U.K. Met Office forecast contrasts with NOAA's, which was released in May and predicted a busier season than average, with 13-17 named storms.

  1. In Vivo Impact of Met221 Substitution in GOB Metallo-β-Lactamase

    PubMed Central

    Morán-Barrio, Jorgelina; Lisa, María-Natalia

    2012-01-01

    Metallo-β-lactamases (MβLs) represent one of the main mechanisms of bacterial resistance against β-lactam antibiotics. The elucidation of their mechanism has been limited mostly by the structural diversity among their active sites. All MβLs structurally characterized so far present a Cys or a Ser residue at position 221, which is critical for catalysis. GOB lactamases stand as an exception within this picture, possessing a Met residue in this location. We studied different mutants in this position, and we show that Met221 is essential for protein stability, most likely due to its involvement in a hydrophobic core. In contrast to other known MβLs, residue 221 is not involved in metal binding or in catalysis in GOB enzymes, further highlighting the structural diversity of MβLs. We also demonstrate the usefulness of protein periplasmic profiles to assess the contribution of protein stability to antibiotic resistance. PMID:22252824

  2. Molecular diagnosis of the transthyretin (TTR) Met111 mutation in familial amyloid cardiomyopathy of Danish origin.

    PubMed

    Nordvåg, B Y; Husby, G; Ranløv, I; el-Gewely, M R

    1992-06-01

    Familial amyloid cardiomyopathy in a Danish kindred is associated with a specific mutation (Met for Leu111) in the transthyretin (TTR) gene, causing the loss of a recognition site for the restriction enzyme DdeI in the gene. We describe a diagnostic test for the molecular detection of this mutation. A sequence of the TTR gene containing the mutation was amplified by the polymerase chain reaction from isolated genomic DNA of two affected patients and several controls. DdeI digestion of the amplified DNA from the patients revealed 3 bands by gel-electrophoresis, whereas amplified DNA of the controls showed only 2 bands, consistent with complete digestion. Thus, the assumed heterozygous TTR Met111 mutation was confirmed in the affected patients. PMID:1618497

  3. A new challenge for meteorological measurements: The "MeteoMet" project - Metrology for meteorology

    NASA Astrophysics Data System (ADS)

    Merlone, A.; Lopardo, G.; Antonsen, I.; Bell, S.; Benyon, R.; Boese, N.; del Campo, D.; Dobre, M.; Drnovšek, J.; Elkatmis, A.; Georgin, E.; Grudniewicz, E.; Heinonen, M.; Holstein-Rathlou, C.; Johansson, J.; Klason, P.; Knorova, R.; Melvad, C.; Merrison, J.; Migała, K.; de Podesta, M.; Saathoff, H.; Smorgon, D.; Sparasci, F.; Strnad, R.; Szmyrka-Grzebyk, A.; Vuillermoz, E.

    2013-09-01

    Climate change and its consequences require immediate actions in order to safeguard the environment and economy in Europe and in the rest of world. Aiming to enhance data reliability and reduce uncertainties in climate observations, a joint research project called "MeteoMet - Metrology for Meteorology" started in October 2011 coordinated by the Italian Istituto Nazionale di Ricerca Metrologica (INRiM). The project is focused on the traceability of measurements involved in climate change: surface and upper air measurements of temperature, pressure, humidity, wind speed and direction, solar irradiance and reciprocal influences between measurands. This project will provide the first definition at the European level of validated climate parameters with associated uncertainty budgets and novel criteria for interpretation of historical data series. The big challenge is the propagation of a metrological measurement perspective to meteorological observations. When such an approach will be adopted the requirement of reliable data and robust datasets over wide scales and long terms could be better met.

  4. No association of brain-derived neurotrophic factor Val66Met polymorphism with anorexia nervosa in Japanese.

    PubMed

    Ando, Tetsuya; Ishikawa, Toshio; Hotta, Mari; Naruo, Tetsuro; Okabe, Kenjiro; Nakahara, Toshihiro; Takii, Masato; Kawai, Keisuke; Mera, Takashi; Nakamoto, Chiemi; Takei, Michiko; Yamaguchi, Chikara; Nagata, Toshihiko; Okamoto, Yuri; Ookuma, Kazuyoshi; Koide, Masanori; Yamanaka, Takao; Murata, Shiho; Tamura, Naho; Kiriike, Nobuo; Ichimaru, Yuhei; Komaki, Gen

    2012-01-01

    The Met66 allele of the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene has been reported to be associated with anorexia nervosa (AN), and also lower minimum body mass index (BMI) and higher harm avoidance in AN. We genotyped the Val66Met polymorphism (rs6265) in 689 AN cases and 573 control subjects. There were no significant differences in the genotype or allele frequencies of the Val66Met between AN and control subjects (allele wise, odds ratio = 0.920, 95% CI 0.785-1.079, P = 0.305). No difference was found in minimum BMIs related to Val66Met in AN (one-way ANOVA, P > 0.05). Harm avoidance scores on the Temperament and Character Inventory were lower in the Met66 allele carriers (P = 0.0074) contrary to the previous report. Thus we were unable to replicate the previous findings that the Met66 allele of the BDNF is associated with AN and that the minimum BMI is lower or the harm avoidance score is higher in AN patients with the Met66 allele. PMID:22127997

  5. 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

  6. Metabolism of selenium (Se) in rats chronically poisoned with D- or L-selenomethionine (SeMet), selenite or selenate

    SciTech Connect

    McAdam, P.A.; Levander, O.A.

    1986-03-01

    L-SeMet is a potential cancer chemoprevention agent for humans. Little difference was seen in the acute toxicity of L vs. D-SeMet in rats. To study chronic toxicity, weanling male rats were fed purified diets containing 2.5, 5.0 or 10 ppm Se as L-SeMet, D-SeMet, Na/sub 2/SeO/sub 3/ or Na/sub 2/SeO/sub 4/ for 6 weeks. Controls received 0.1 ppm Se as selenite. All rats fed 10 ppm Se died within 29 days. Se fed as D-SeMet was retained in the tissues as strongly as L-SeMet. Rats fed D or L-SeMet deposited large amounts of Se in muscle not reflected by proportionate increases in either plasma or RBC Se. Therefore, attempts to follow increases in Se body burden in individuals supplemented with large doses of L-SeMet by monitoring plasma or whole blood Se levels should be interpreted with caution.

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

    SciTech Connect

    Liu, Tongxin; Li, Qi; Sun, Quanquan; Zhang, Yuqin; Yang, Hua; Wang, Rong; Chen, Longhua; Wang, Wei

    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 mediated 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.

  8. Variant brain-derived neurotrophic factor Val66Met polymorphism alters vulnerability to stress and response to antidepressants.

    PubMed

    Yu, Hui; Wang, Dong-Dong; Wang, Yue; Liu, Ting; Lee, Francis S; Chen, Zhe-Yu

    2012-03-21

    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 (BDNF(Met)) polymorphism could alter stress vulnerability remains controversial. More importantly, the molecular and structural mechanisms underlying the interaction between the BDNF(Met) 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) mice exhibited 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 BDNF(Met) 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

  9. Nuclear and cytoplasmic expression of Met in oral squamous cell carcinoma and in an organotypic oral cancer model.

    PubMed

    Brusevold, Ingvild J; Søland, Tine M; Khuu, Cuong; Christoffersen, Thoralf; Bryne, Magne

    2010-08-01

    Met, the hepatocyte growth factor receptor, is important in transducing signals for tumour growth and metastasis. The aim of this study was to examine the pattern of Met expression and its value as a prognostic factor in oral squamous cell carcinomas (OSCCs). The material consisted of 53 OSCCs and five healthy controls from normal oral mucosa supplied with cell lines, 10 organotypic models supplied with oral cancer cells, and three organotypic models supplied with normal keratinocytes. Met protein expression was assessed by immunohistochemistry and western blotting. Met expression was scarce and limited to the basal layer in normal oral mucosa, but was more extensive in the tumours. Cytoplasmic expression of Met was found in the majority of the tumours, and nuclear expression was found in 72%, including a high fraction of the cells located at the invasive front. Organotypic models with normal or malignant oral cells yielded principally similar results as in the mucosa and the cancers, respectively. A smaller amount of Met immunoreactivity was detected, by western blotting, in the nuclear fraction of cultured oral cancer cells. In conclusion, Met was upregulated in OSCCs and was also found in the nucleus. However, Met was not a marker for prognosis in this study. PMID:20662906

  10. Brain-derived neurotrophic factor val66met polymorphism and hippocampal activation during episodic encoding and retrieval tasks.

    PubMed

    Dennis, Nancy A; Cabeza, Roberto; Need, Anna C; Waters-Metenier, Sheena; Goldstein, David B; LaBar, Kevin S

    2011-09-01

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin which has been shown to regulate cell survival and proliferation, as well as synaptic growth and hippocampal long-term potentiation. A naturally occurring single nucleotide polymorphism in the human BDNF gene (val66met) has been associated with altered intercellular trafficking and regulated secretion of BDNF in met compared to val carriers. Additionally, previous studies have found a relationship between the BDNF val66met genotype and functional activity in the hippocampus during episodic and working memory tasks in healthy young adults. Specifically, studies have found that met carriers exhibit both poorer performance and reduced neural activity within the medial temporal lobe (MTL) when performing episodic memory tasks. However, these studies have not been well replicated and have not considered the role of behavioral differences in the interpretation of neural differences. The current study sought to control for cognitive performance in investigating the role of the BDNF val66met genotype on neural activity associated with episodic memory. Across item and relational memory tests, met carriers exhibited increased MTL activation during both encoding and retrieval stages, compared to noncarriers. The results suggest that met carriers are able to recruit MTL activity to support successful memory processes, and reductions in cognitive performance observed in prior studies are not a ubiquitous effect associated with variants of the BDNF val66met genotype. PMID:20865733

  11. 33 CFR 165.T13-209 - Safety Zones; TriMet Bridge Project, Willamette River; Portland, OR.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 33 Navigation and Navigable Waters 2 2014-07-01 2014-07-01 false Safety Zones; TriMet Bridge... Coast Guard District § 165.T13-209 Safety Zones; TriMet Bridge Project, Willamette River; Portland, OR.... In accordance with the general regulations in 33 CFR Part 165, Subpart C, no vessel operator...

  12. 33 CFR 165.T13-209 - Safety Zones; TriMet Bridge Project, Willamette River; Portland, OR.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 33 Navigation and Navigable Waters 2 2012-07-01 2012-07-01 false Safety Zones; TriMet Bridge... Coast Guard District § 165.T13-209 Safety Zones; TriMet Bridge Project, Willamette River; Portland, OR.... In accordance with the general regulations in 33 CFR Part 165, Subpart C, no vessel operator...

  13. Ubiquitin-conjugating enzyme Cdc34 mediates cadmium resistance in budding yeast through ubiquitination of the transcription factor Met4

    SciTech Connect

    Hwang, Gi-Wook; Furuchi, Takemitsu; Naganuma, Akira

    2007-11-23

    Overexpression of the ubiquitin-conjugating enzyme Cdc34 conferred strong cadmium resistance on budding yeast. Proteasome activity, which is involved in the degradation of ubiquitinated proteins, was not essential for the acquisition of resistance to cadmium. The overexpression of Cdc34 accelerated the ubiquitination of the transcription factor Met4 and reduced expression of MET25 gene, which is a target of Met4. A MET25-disrupted strain of yeast was more resistant to cadmium than was the wild-type strain, but overexpression of Cdc34 in the MET25-disrupted cells did not affect sensitivity to cadmium. Met25 is an enzyme that catalyzes the synthesis of homocysteine from sulfide (S{sup 2-}) and O-acetylhomocysteine and we detected the increased production of S{sup 2-} upon overexpression of Cdc34. Our results suggest that overexpression of Cdc34 inactivates Met4 and interferes with expression of the MET25, with subsequent production of CdS, which has low toxicity, and, thus, a decrease in the cadmium toxicity.

  14. The contribution of methionine to the stability of the Escherichia coli MetNIQ ABC transporter - substrate binding protein complex

    PubMed Central

    Nguyen, Phong T.; Li, Qi Wen; Kadaba, Neena S.; Lai, Jeffrey Y.; Yang, Janet G.; Rees, Douglas C.

    2015-01-01

    Despite the ubiquitous role of ATP Binding Cassette (ABC) importers in nutrient uptake, only the E. coli maltose and vitamin B12 ABC transporters have been structurally characterized in multiple conformations relevant to the alternating access transport mechanism. To complement our previous structure determination of the E. coli MetNI methionine importer in the inward facing conformation (Kadaba et al. (2008) Science 321, 250–253), we have explored conditions stabilizing the outward facing conformation. Using two variants, the Walker B E166Q mutation with ATP+EDTA to stabilize MetNI in the ATP-bound conformation and the N229A variant of the binding protein MetQ, shown in this work to disrupt methionine binding, a high affinity MetNIQ complex was formed with a dissociation constant measured to be 27 nM. Using wild type MetQ containing a co-purified methionine (for which the crystal structure is reported at 1.6 Å resolution), the dissociation constant for complex formation with MetNI is measured to be ~40-fold weaker, indicating that complex formation lowers the affinity of MetQ for methionine by this amount. Preparation of a stable MetNIQ complex is an essential step towards the crystallographic analysis of the outward facing conformation, a key intermediate in the uptake of methionine by this transport system. PMID:25803078

  15. 41 CFR 301-10.108 - What requirements must be met to use a non-contract fare?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 41 Public Contracts and Property Management 4 2010-07-01 2010-07-01 false What requirements must be met to use a non-contract fare? 301-10.108 Section 301-10.108 Public Contracts and Property... What requirements must be met to use a non-contract fare? (a) Before purchasing a non-contract fare...

  16. 29 CFR 780.158 - Examples of other practices within section 3(f) if requirements are met.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 3 2012-07-01 2012-07-01 false Examples of other practices within section 3(f) if requirements are met. 780.158 Section 780.158 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR... within Section 3(f) § 780.158 Examples of other practices within section 3(f) if requirements are met....

  17. 25 CFR 171.705 - What criteria must be met for my land to be granted an Annual Assessment Waiver?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 25 Indians 1 2013-04-01 2013-04-01 false What criteria must be met for my land to be granted an Annual Assessment Waiver? 171.705 Section 171.705 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE... must be met for my land to be granted an Annual Assessment Waiver? For your land to be granted...

  18. 45 CFR 158.240 - Rebating premium if the applicable medical loss ratio standard is not met.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 45 Public Welfare 1 2011-10-01 2011-10-01 false Rebating premium if the applicable medical loss ratio standard is not met. 158.240 Section 158.240 Public Welfare DEPARTMENT OF HEALTH AND HUMAN... ratio standard is not met. (a) General requirement. For each MLR reporting year, an issuer must...

  19. 41 CFR 301-10.108 - What requirements must be met to use a non-contract fare?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 41 Public Contracts and Property Management 4 2013-07-01 2012-07-01 true What requirements must be met to use a non-contract fare? 301-10.108 Section 301-10.108 Public Contracts and Property Management... requirements must be met to use a non-contract fare? (a) Before purchasing a non-contract fare you must...

  20. 45 CFR 264.77 - How will we determine if a State met its Contingency Fund expenditure requirements?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 45 Public Welfare 2 2011-10-01 2011-10-01 false How will we determine if a State met its Contingency Fund expenditure requirements? 264.77 Section 264.77 Public Welfare Regulations Relating to Public... Contingency Fund? § 264.77 How will we determine if a State met its Contingency Fund expenditure...

  1. 45 CFR 264.77 - How will we determine if a State met its Contingency Fund expenditure requirements?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 45 Public Welfare 2 2013-10-01 2012-10-01 true How will we determine if a State met its Contingency Fund expenditure requirements? 264.77 Section 264.77 Public Welfare Regulations Relating to Public... Contingency Fund? § 264.77 How will we determine if a State met its Contingency Fund expenditure...

  2. 45 CFR 158.240 - Rebating premium if the applicable medical loss ratio standard is not met.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 45 Public Welfare 1 2012-10-01 2012-10-01 false Rebating premium if the applicable medical loss ratio standard is not met. 158.240 Section 158.240 Public Welfare DEPARTMENT OF HEALTH AND HUMAN... ratio standard is not met. (a) General requirement. For each MLR reporting year, an issuer must...

  3. 45 CFR 264.77 - How will we determine if a State met its Contingency Fund expenditure requirements?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 2 2010-10-01 2010-10-01 false How will we determine if a State met its Contingency Fund expenditure requirements? 264.77 Section 264.77 Public Welfare Regulations Relating to Public... Contingency Fund? § 264.77 How will we determine if a State met its Contingency Fund expenditure...

  4. 41 CFR 301-10.108 - What requirements must be met to use a non-contract fare?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 41 Public Contracts and Property Management 4 2011-07-01 2011-07-01 false What requirements must be met to use a non-contract fare? 301-10.108 Section 301-10.108 Public Contracts and Property... What requirements must be met to use a non-contract fare? (a) Before purchasing a non-contract fare...

  5. 29 CFR 780.158 - Examples of other practices within section 3(f) if requirements are met.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 3 2010-07-01 2010-07-01 false Examples of other practices within section 3(f) if requirements are met. 780.158 Section 780.158 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR... within Section 3(f) § 780.158 Examples of other practices within section 3(f) if requirements are met....

  6. 41 CFR 301-10.108 - What requirements must be met to use a non-contract fare?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 41 Public Contracts and Property Management 4 2014-07-01 2014-07-01 false What requirements must be met to use a non-contract fare? 301-10.108 Section 301-10.108 Public Contracts and Property... What requirements must be met to use a non-contract fare? (a) Before purchasing a non-contract fare...

  7. 41 CFR 301-10.108 - What requirements must be met to use a non-contract fare?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 41 Public Contracts and Property Management 4 2012-07-01 2012-07-01 false What requirements must be met to use a non-contract fare? 301-10.108 Section 301-10.108 Public Contracts and Property... What requirements must be met to use a non-contract fare? (a) Before purchasing a non-contract fare...

  8. 45 CFR 158.240 - Rebating premium if the applicable medical loss ratio standard is not met.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 45 Public Welfare 1 2014-10-01 2014-10-01 false Rebating premium if the applicable medical loss ratio standard is not met. 158.240 Section 158.240 Public Welfare Department of Health and Human... ratio standard is not met. (a) General requirement. For each MLR reporting year, an issuer must...

  9. 25 CFR 171.705 - What criteria must be met for my land to be granted an Annual Assessment Waiver?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 25 Indians 1 2014-04-01 2014-04-01 false What criteria must be met for my land to be granted an Annual Assessment Waiver? 171.705 Section 171.705 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE... must be met for my land to be granted an Annual Assessment Waiver? For your land to be granted...

  10. 25 CFR 171.705 - What criteria must be met for my land to be granted an Annual Assessment Waiver?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 25 Indians 1 2011-04-01 2011-04-01 false What criteria must be met for my land to be granted an Annual Assessment Waiver? 171.705 Section 171.705 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE... must be met for my land to be granted an Annual Assessment Waiver? For your land to be granted...

  11. 25 CFR 171.705 - What criteria must be met for my land to be granted an Annual Assessment Waiver?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 25 Indians 1 2012-04-01 2011-04-01 true What criteria must be met for my land to be granted an Annual Assessment Waiver? 171.705 Section 171.705 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE... must be met for my land to be granted an Annual Assessment Waiver? For your land to be granted...

  12. 29 CFR 780.158 - Examples of other practices within section 3(f) if requirements are met.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 3 2011-07-01 2011-07-01 false Examples of other practices within section 3(f) if requirements are met. 780.158 Section 780.158 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR... within Section 3(f) § 780.158 Examples of other practices within section 3(f) if requirements are met....

  13. 78 FR 44108 - MET West Trading LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes Request...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-23

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission MET West Trading LLC; Supplemental Notice That Initial Market- Based Rate... notice in the above-referenced proceeding, of MET West Trading LLC's application for market-based...

  14. 29 CFR 780.158 - Examples of other practices within section 3(f) if requirements are met.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 3 2013-07-01 2013-07-01 false Examples of other practices within section 3(f) if requirements are met. 780.158 Section 780.158 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR... within Section 3(f) § 780.158 Examples of other practices within section 3(f) if requirements are met....

  15. 45 CFR 264.77 - How will we determine if a State met its Contingency Fund expenditure requirements?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 45 Public Welfare 2 2012-10-01 2012-10-01 false How will we determine if a State met its Contingency Fund expenditure requirements? 264.77 Section 264.77 Public Welfare Regulations Relating to Public... Contingency Fund? § 264.77 How will we determine if a State met its Contingency Fund expenditure...

  16. 78 FR 44108 - MET New York Trading LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-23

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission MET New York Trading LLC; Supplemental Notice That Initial Market-Based Rate... notice in the above-referenced proceeding, of MET New York Trading LLC's application for...

  17. 29 CFR 780.158 - Examples of other practices within section 3(f) if requirements are met.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 3 2014-07-01 2014-07-01 false Examples of other practices within section 3(f) if requirements are met. 780.158 Section 780.158 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR... within Section 3(f) § 780.158 Examples of other practices within section 3(f) if requirements are met....

  18. 77 FR 74658 - MET Southwest Trading LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-17

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission MET Southwest Trading LLC; Supplemental Notice That Initial Market-Based... above-referenced proceeding, of MET Southwest Trading LLC's application for market-based rate...

  19. 45 CFR 158.240 - Rebating premium if the applicable medical loss ratio standard is not met.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 45 Public Welfare 1 2013-10-01 2013-10-01 false Rebating premium if the applicable medical loss ratio standard is not met. 158.240 Section 158.240 Public Welfare DEPARTMENT OF HEALTH AND HUMAN... ratio standard is not met. (a) General requirement. For each MLR reporting year, an issuer must...

  20. 45 CFR 264.77 - How will we determine if a State met its Contingency Fund expenditure requirements?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 45 Public Welfare 2 2014-10-01 2012-10-01 true How will we determine if a State met its Contingency Fund expenditure requirements? 264.77 Section 264.77 Public Welfare Regulations Relating to Public... Contingency Fund? § 264.77 How will we determine if a State met its Contingency Fund expenditure...