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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. [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

  3. 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

  4. 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

  5. Fragmentation Chemistry of [Met-Gly]•+, [Gly-Met]•+, and [Met-Met]•+ Radical Cations

    NASA Astrophysics Data System (ADS)

    Lau, Justin Kai-Chi; Lo, Seydina; Zhao, Junfang; Siu, K. W. Michael; Hopkinson, Alan C.

    2013-04-01

    Radical cations [Met-Gly]•+, [Gly-Met]•+, and [Met-Met]•+ have been generated through collision-induced dissociation (CID) of [CuII(CH3CN)2(peptide)]•2+ complexes. Their fragmentation patterns and dissociation mechanisms have been studied both experimentally and theoretically using density functional theory at the UB3LYP/6-311++G(d,p) level. The captodative structure, in which the radical is located at the α-carbon of the N-terminal residue and the proton is on the amide oxygen, is the lowest energy structure on each potential energy surface. The canonical structure, with the charge and spin both located on the sulfur, and the distonic ion with the proton on the terminal amino group, and the radical on the α-carbon of the C-terminal residue have similar energies. Interconversion between the canonical structures and the captodative isomers is facile and occurs prior to fragmentation. However, isomerization to produce the distonic structure is energetically less favorable and cannot compete with dissociation except in the case of [Gly-Met]•+. Charge-driven dissociations result in formation of [ b n - H]•+ and a 1 ions. Radical-driven dissociation leads to the loss of the side chain of methionine as CH3-S-CH = CH2 producing α-glycyl radicals from both [Gly-Met]•+ and [Met-Met]•+. For [Met-Met]•+, loss of the side chain occurs at the C-terminal as shown by both labeling experiments and computations. The product, the distonic ion of [Met-Gly]•+, NH3 +CH(CH2CH2SCH3)CONHCH•COOH dissociates by loss of CH3S•. The isomeric distonic ion NH3 +CH2CONHC•(CH2CH2SCH3)COOH is accessible directly from the canonical [Gly-Met]•+ ion. A fragmentation pathway that characterizes this ion (and the distonic ion of [Met-Met]•+) is homolytic fission of the Cβ-Cγ bond to lose CH3SCH2 •.

  6. 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.

  7. MET expression during prostate cancer progression

    PubMed Central

    Verhoef, Esther I.; van der Steen, Berdine; Hoogland, A. Marije; Sleddens, Hein F.B.M.; Looijenga, Leendert H.J.; van Leenders, Geert J.L.H.

    2016-01-01

    Tyrosine-kinase inhibitors of the hepatocyte growth factor receptor MET are under investigation for the treatment of hormone-refractory prostate cancer (HRPC) metastasis. Analysis of MET protein expression and genetic alterations might contribute to therapeutic stratification of prostate cancer patients. Our objective was to investigate MET on protein, DNA and RNA level in clinical prostate cancer at various stages of progression. Expression of MET was analyzed in hormone-naive primary prostate cancers (N=481), lymph node (N=40) and bone (N=8) metastases, as well as HRPC (N=54) and bone metastases (N=15). MET protein expression was analyzed by immunohistochemistry (D1C2 C-terminal antibody). MET mRNA levels and MET DNA copy numbers were determined by in situ hybridization. None of the hormone-naive primary prostate cancer or lymph node metastases demonstrated MET protein or mRNA expression. In contrast, MET protein was expressed in 12/52 (23%) evaluable HRPC resections. RNA in situ demonstrated cytoplasmic signals in 14/54 (26%) of the HRPC patients, and was associated with MET protein expression (p=0.025, χ2), in absence of MET amplification or polysomy. MET protein expression was present in 7/8 (88%) hormone-naive and 10/15 (67%) HRPC bone metastases, without association of HRPC (p=0.37; χ2), with MET polysomy in 8/13 (61%) evaluable cases. In conclusion, MET was almost exclusively expressed in HRPC and prostate cancer bone metastasis, but was not related to MET amplification or polysomy. Evaluation of MET status could be relevant for therapeutic stratification of late stage prostate cancer. PMID:27105539

  8. 75 FR 1007 - MetLife, Inc. and MetLife Capital Trust V; Notice of Application

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-07

    ... COMMISSION MetLife, Inc. and MetLife Capital Trust V; Notice of Application December 30, 2009. AGENCY.... Summary of Application: MetLife Capital Trust V (the ``Trust'') and MetLife, Inc. (``MetLife'') request an... and pursuant to a Declaration of Trust that MetLife signed as sponsor. As sponsor, MetLife...

  9. 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

  10. Met1-linked ubiquitination in immune signalling

    PubMed Central

    Fiil, Berthe K; Gyrd-Hansen, Mads

    2014-01-01

    N-terminal methionine-linked ubiquitin (Met1-Ub), or linear ubiquitin, has emerged as a central post-translational modification in innate immune signalling. The molecular machinery that assembles, senses and, more recently, disassembles Met1-Ub has been identified, and technical advances have enabled the identification of physiological substrates for Met1-Ub in response to activation of innate immune receptors. These discoveries have significantly advanced our understanding of how nondegradative ubiquitin modifications control proinflammatory responses mediated by nuclear factor-κB and mitogen-activated protein kinases. In this review, we discuss the current data on Met1-Ub function and regulation, and point to some of the questions that still remain unanswered. PMID:25060092

  11. 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.

  12. 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

  13. 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

  14. MetBaro - Pressure Instrument for Mars MetNet Lander

    NASA Astrophysics Data System (ADS)

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

    2009-04-01

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

  15. MetHumi - Humidity Instrument for Mars MetNet Lander

    NASA Astrophysics Data System (ADS)

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

    2009-04-01

    THE METNET MISSION FOCUSED ON THE Martian atmospheric science is based on a new semihard landing vehicle called the MetNet Lander (MNL). The MNL will have a versatile science payload focused on the atmospheric science of Mars. The scientific payload of the MetNet Mission encompasses separate instrument packages for the atmospheric entry and descent phase and for the surface operation phase. MetHumi is the humidity instrument of MetNet Lander designed to work on Martian surface. It is based on Humicap® technology developed by Vaisala, Inc. MetHumi is a capacitic type of sensing device where an active polymer film changes capacitance as function of relative humidity. One MetHumi device package consists of one humidity transducer including three Humicap® sensor heads, an accurate temperature sensor head (Thermocap® by Vaisala, Inc.) and constant reference channels. MetHumi is very small, lightweighed and has low power consumption. It weighs only about 15 g without wires, and consumes 15 mW of power. MetHumi can make meaningful relative humidity measurements in range of 0 - 100%RH down to -70°C ambient temperature, but it survives even -135°C ambient temperature. Similar device is part of the Mars Science Laboratory REMS -instrument (to be launched 2011).

  16. Weldability of AerMet 100

    SciTech Connect

    Kautz, D.D.; Hoffman, D.E.; Westrich, C.N.

    1991-01-01

    Several test welds were made on AerMet 100 alloy. Both electron beam and pulsed Nd:YAG laser beam welding processes were used to make the welds. All welds were satisfactory, with no cracking or porosity noted in weld cross-sections. 2 refs., 6 figs.

  17. 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

  18. 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

  19. 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

  20. 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

  1. Phoenix `07 MET Pressure sensor: Instrument

    NASA Astrophysics Data System (ADS)

    Polkko, J.; Kahanpää, H.; Harri, A.-M.; Schmidt, W.; Genzer, M.; Mäkelä, M.; Savijarvi, H.; Kauhanen, J.

    2008-09-01

    Abstract The Phoenix '07 Lander landed successfully on the Martian northern polar region 25.5.2008. The mission is part of the National Aeronautics and Space Administration's (NASA's) Scout program. The seminal questions for the Phoenix mission are: (1) can the Martian arctic support life, (2) what is the history of water at the landing site, and (3) how is the Martian climate affected by polar dynamics. These translate into practical science goals and tasks of characterizing the surface, analyzing samples of the soil and ice, and to observing and monitoring the atmospheric conditions and phenomena. Meteorology experiment (MET) onboard the Phoenix '07 lander will provide the first surface based observations of atmospheric pressure, temperature and wind in the Martian polar region above the polar circle. The MET instrument also includes a lidar for detecting dust and ice particles in the air column above the lander. Pressure observations are crucial for the success of the MET experiment. The Martian atmosphere goes through a large scale atmospheric pressure cycle due to the annual condensation and sublimation of the atmospheric carbon dioxide. Pressure also exhibits short period variations associated with dust storms, tides and other atmospheric events. A series of pressure measurements can hence tell us about the large scale state and dynamics of the atmosphere. The shorter time scale phenomena are also important in contributing to our understanding of mixing and transport of heat, dust and water vapour. The pressure observations are performed by a FMI (Finnish Meteorological Institute) instrument, based on micro machined Barocap capacitic pressure sensor heads manufactured by Vaisala Inc. Similar instruments have been used in several earlier missions (Mars-96, Mars Polar Lander, Beagle-2 and Huygens), Phoenix being the first successful landing on Mars. A similar instrument is included also in the Mars Science Laboratory '09 rover. Pressure sensor technology

  2. Met-enkephalin levels during PTCA-induced myocardial ischemia.

    PubMed

    Parlapiano, C; Borgia, M C; Tonnarini, G; Giancaspro, G; Pizzuto, F; Campana, E; Giovanniello, T; Pantone, P; Vincentelli, G M; Alegiani, F; Negri, M

    2001-07-01

    Met-enkephalin (Met-enk) has been demonstrated to modulate myocardial-ischemia mechanisms via the opioid receptors, but no studies are now available on Met-enk levels in the coronary circulation. In this experience Met-enk levels were evaluated in aortic root and in coronary sinus at baseline (T0), during PTCA induced transient ischemia (T1) and during reperfusion (T2). No significant differences were found at any time. Thus, it appears that there is no Met-enk extraction from the coronary circulation during provoked myocardial ischemia and no Met-enk release from the ischemic heart. PMID:11445249

  3. 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.

  4. The Met-allele of the BDNF Val66Met polymorphism enhances task switching in elderly.

    PubMed

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

    2011-12-01

    In this study we examined the relevance of the functional brain-derived neurotrophic factor (BDNF) Val66Met polymorphism as a modulator of task-switching performance in healthy elderly by using behavioral and event-related potential (ERP) measures. Task switching was examined in a cue-based and a memory-based paradigm. Val/Val carriers were generally slower, showed enhanced reaction time variability and higher error rates, particularly during memory-based task switching than the Met-allele individuals. On a neurophysiological level these dissociative effects were reflected by variations in the N2 and P3 ERP components. The task switch-related N2 was increased while the P3 was decreased in Met-allele carriers, while the Val/Val genotype group revealed the opposite pattern of results. In cue-based task-switching no behavioral and ERP differences were seen between the genotypes. These data suggest that superior memory-based task-switching performance in elderly Met-allele carriers may emerge due to more efficient response selection processes. The results implicate that under special circumstances the Met-allele renders cognitive processes more efficient than the Val/Val genotype in healthy elderly, corroborating recent findings in young subjects.

  5. 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.

  6. NARSTO EPA SS ATLANTA 1999 CHEM PM MET DATA

    Atmospheric Science Data Center

    2014-04-25

    NARSTO EPA SS ATLANTA 1999 CHEM PM MET DATA Note: The negative sign is ... the longitude in the following data files: NARSTO_EPA_SS_ATLANTA_GAS_GAS_DATA_1_KB_V1.csv and NARSTO_EPA_SS_ATLANTA_MET_MET_DATA_1_KB_V1.csv Project Title:  NARSTO ...

  7. 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.

  8. Protein synthesis in rabbit reticulocytes. A study of Met-tRNA f Met binding factor(s) and Met-tRNA f Met binding to ribosomes and AUG codon.

    PubMed

    Gupta, N K; Chatterjee, B; Chen, Y C; Majumdar, A

    1975-02-10

    The effects of additions of Mg-2+, ribosomes, and AUG codon on the Met-tRNAf Met-initiation factor-GTP complex were studied using a Millipore filtration method (J. Biol. Chem. 248, 4500 (1973)). Upon addition of increasing concentration of Mg-2+, the Met-tRNAf Met-initiation factor-GTP complex dissociates into free Met-tRNAf Met and initiation factor (GTP), with an infection around 1.5 to 2 mM Mg-2+. The Mg-2+-induced dissociation of Met-tRNAf Met-initiation factor-GTP complex was enhanced at ice bath temperature. At 37 degrees and in the presence of 1.5 to 2mM Mg-2+, the Met-tRNAf Met-initiation factor-GTP complex catalyzes the transfer of Met-tRNAf Met to ribosomes and AUG codon. Ribosome bound Met-tRNAf Met is stable to Mg-2+ and low temperature. A Millipore filtration assay for studies of (35S)Met-tRNAf Met binding to ribosomes and Aug codon has been developed. The assay procedure is carried out in three stages. In Stage I, the Met-tRNAf Met is bound to initiation factor in the presence of GTP, AUG codon (required for Stage II reaction), and 3.7 times 10-5 M aurintricarboxylic acid. The incubation is carried out at 37 degrees for 5 min. In Stage II, ribosomes and Mg-2+ (1.5 to 2mM final concentration) are added and the incubation is continued at 37 degrees for 10 min. In Stage III, more Mg-2+ is added to make the final Mg-2+ concentration of the incubation mixture 5 mM, and the reactions are further incubated at ice bath temperature for 10 min. The reactions are then terminated by addition of excess cold wash buffer and filtered through Millipore filters. Under the standard assay conditions, the radioactivity bound to Millipore filters in the absence of ribosomes and AUG codon is markedly reduced. Addition of ribosomes alone gave a significant increase in the radioactivity bound to Millipore filters. A further 2- to 3-fold stimulation of binding of (35S)Met-tRNAf Met to Millipore filters was observed when both ribosomes and AUG codon were added. The Met

  9. The modified obstetric metabolic equivalent (MET): finding a MET that fits in pregnancy.

    PubMed

    Campbell, C G; Foster, R C; Lanningham-Foster, L M; Smith, K M

    2012-06-01

    The Compendium of Physical Activities (CPA) provides the energy expenditure (EE) for hundreds of daily activities reported in metabolic equivalents (MET). It remains to be determined if the metabolic changes of pregnancy alter the use of the CPA MET (METCPA) in this population. The energy cost of rest, activities of daily living (ADL; typing, folding laundry and sweeping) and treadmill walking [2.0, 2.5, 3.0 mph (0% incline), 3.0 mph (3% incline)] were compared with the METCPA from the 2000 and 2011 CPA in 30 pregnant women (10-14 weeks gestation) using indirect calorimetry (IC). The METCPA for each activity was compared against two measured IC values: METabsolute (3.5 ml O2/kg/min) and METratio (EEactivity/EErest). Means for both comparisons were tested by one-sample t-test. Measured MET correlated with the 2011 METCPA: METabsolute v. METCPA R 2 = 0.906, P < 0.0001; METratio v. METCPA R 2 = 0.861, P < 0.0001. Differences between measured MET values and the 2011 METCPA ranged from 16% underestimation to 48% overestimation. Using the absolute definition, the METCPA significantly overestimated the ADL (P < 0.0005); yet, no significant differences were found between walking at 0% grade and METCPA. Conversely, only folding laundry was significantly different with the ratio definition, whereas walking at a level grade was significantly underestimated (P < 0.0001). Similar observations were found using the 2000 CPA. The use of the METCPA to estimate EE in pregnant women can result in significant over- or underestimation, depending on the activity and the definition of the MET that is used.

  10. Absence of tpr-met and expression of c-met in human gastric mucosa and carcinoma.

    PubMed

    Heideman, D A; Snijders, P J; Bloemena, E; Meijer, C J; Offerhaus, G J; Meuwissen, S G; Gerritsen, W R; Craanen, M E

    2001-08-01

    The c-met proto-oncogene, encoding the hepatocyte growth factor receptor, can be activated by various mechanisms. These include, among others, gene amplification with concomitant overexpression and the tpr-met oncogenic rearrangement. In the case of gastric cancer, contradictory results on the presence of the tpr-met oncogenic rearrangement have been published. The current study aimed therefore to assess the prevalence of tpr-met expression in Caucasian gastric adenocarcinomas, to evaluate the importance of this oncogene in their carcinogenesis. In addition, the level of c-met expression was determined, to evaluate the role of this alternative mode of activation of the proto-oncogene. A series of Caucasian gastric adenocarcinomas (n=43) and normal gastric mucosal samples (n=14) was analysed for tpr-met and c-met expression. Expression of tpr-met mRNA in the samples was performed by two reverse transcriptase polymerase chain reaction (RT-PCR) assays, with excellent correlation. The specificity of both methods was confirmed by direct sequencing of the PCR products of the MNNG-HOS cell line, which is known to contain the rearrangement. The level of c-met expression was assessed using semi-quantitative RT-PCR assays and immunohistochemistry (IHC). None of the normal gastric mucosal or gastric adenocarcinoma samples expressed tpr-met mRNA, as determined by both RT-PCR assays. Seventy per cent of the adenocarcinomas showed overexpression of c-met, according to elevated c-met mRNA levels, compared with the expression level of normal gastric mucosa. A significant correlation was found between the level of c-met mRNA and protein expression. In conclusion, these results strongly suggest that tpr-met activation does not play a role in Caucasian gastric carcinogenesis, while overexpression of the c-met gene occurs in the majority of Caucasian gastric adenocarcinomas.

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

    PubMed

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

    2008-03-01

    The authors developed a model of how raise expectations influence the relationship between merit pay raises and employee reactions and tested it using a sample of hospital employees. Pay-for-performance (PFP) perceptions were consistently related to personal reactions (e.g., pay raise happiness, pay-level satisfaction, and turnover intentions). Merit pay raises were strongly related to reactions only among employees with high raise expectations and high PFP perceptions. The interactive effects of under-met/over-met expectations and PFP perceptions were mediated by the extent to which participants saw the raise as generous and they were happy with the raises they received. The authors discuss the implications of these findings for expectation-fulfillment theories, merit pay research, and the administration of incentives. PMID:18361641

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

    PubMed

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

    2008-03-01

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

  13. 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.

  14. 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

  15. Salmonella typhimurium metC operator-constitutive mutations.

    PubMed

    Park, Y M; Stauffer, G V

    1989-07-15

    We used an Escherichia coli lac deletion strain lysogenized with a metC-lacZ fusion phage (lambda Clac) to select operator-constitutive mutations in the Salmonella typhimurium metC gene control region. The mutations were located in a region containing 2 tandemly repeated 8 bp palindromes previously proposed to be the MetJ repressor binding site. Lysogens carrying lambda Clac mutant phage exhibit high beta-galactosidase levels that are only partially repressible by methionine. The results suggest that the mutations disrupt the methionine control system mediated by the metJ gene product. PMID:2506106

  16. Oncogenic activation of the Met receptor tyrosine kinase fusion protein, Tpr-Met, involves exclusion from the endocytic degradative pathway.

    PubMed

    Mak, H H L; Peschard, P; Lin, T; Naujokas, M A; Zuo, D; Park, M

    2007-11-01

    Multiple mechanisms of dysregulation of receptor tyrosine kinases (RTKs) are observed in human cancers. In addition to gain-of-function, loss of negative regulation also contributes to oncogenic activation of RTKs. Negative regulation of many RTKs involves their internalization and degradation in the lysosome, a process regulated through ubiquitination. RTK oncoproteins activated following chromosomal translocation, are no longer transmembrane proteins, and are predicted to escape lysosomal degradation. To test this, we used the Tpr-Met oncogene, generated following chromosomal translocation of the hepatocyte growth factor receptor (Met). Unlike Met, Tpr-Met is localized in the cytoplasm and also lacks the binding site for Cbl ubiquitin ligases. We determined whether subcellular localization of Tpr-Met, and/or loss of its Cbl-binding site, is important for oncogenic activity. Presence of a Cbl-binding site and ubiquitination of cytosolic Tpr-Met oncoproteins does not alter their transforming activity. In contrast, plasma membrane targeting allows Tpr-Met to enter the endocytic pathway, and Tpr-Met transforming activity as well as protein stability are decreased in a Cbl-dependent manner. We show that transformation by Tpr-Met is in part dependent on its ability to escape normal downregulatory mechanisms. This provides a paradigm for many RTK oncoproteins activated following chromosomal translocation.

  17. 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

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

    PubMed

    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.

  19. 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…

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

    PubMed

    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

  1. Imaging the Met Receptor Tyrosine Kinase (Met) and Assessing Tumor Responses to a Met Tyrosine Kinase Inhibitor in Human Xenograft Mouse Models with a [99mTc] (AH-113018) or Cy 5** (AH-112543) Labeled Peptide.

    PubMed

    Jagoda, Elaine M; Bhattacharyya, Sibaprasad; Kalen, Joseph; Riffle, Lisa; Leeder, Avrum; Histed, Stephanie; Williams, Mark; Wong, Karen J; Xu, Biying; Szajek, Lawrence P; Elbuluk, Osama; Cecchi, Fabiola; Raffensperger, Kristen; Golla, Meghana; Bottaro, Donald P; Choyke, Peter

    2015-01-01

    Developing an imaging agent targeting the hepatocyte growth factor receptor protein (Met) status of cancerous lesions would aid in the diagnosis and monitoring of Met-targeted tyrosine kinase inhibitors (TKIs). A peptide targeting Met labeled with [(99m)Tc] had high affinity in vitro (Kd = 3.3 nM) and detected relative changes in Met in human cancer cell lines. In vivo [(99m)Tc]-Met peptide (AH-113018) was retained in Met-expressing tumors, and high-expressing Met tumors (MKN-45) were easily visualized and quantitated using single-photon emission computed tomography or optical imaging. In further studies, MKN-45 mouse xenografts treated with PHA 665752 (Met TKI) or vehicle were monitored weekly for tumor responses by [(99m)Tc]-Met peptide imaging and measurement of tumor volumes. Tumor uptake of [(99m)Tc]-Met peptide was significantly decreased as early as 1 week after PHA 665752 treatment, corresponding to decreases in tumor volumes. These results were comparable to Cy5**-Met peptide (AH-112543) fluorescence imaging using the same treatment model. [(99m)Tc] or Cy5**-Met peptide tumor uptake was further validated by histologic (necrosis, apoptosis) and immunoassay (total Met, p Met, and plasma shed Met) assessments in imaged and nonimaged cohorts. These data suggest that [(99m)Tc] or Cy5**-Met peptide imaging may have clinical diagnostic, prognostic, and therapeutic monitoring applications. PMID:26461980

  2. 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

  3. 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.

  4. 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

  5. MET Receptor Tyrosine Kinase as an Autism Genetic Risk Factor

    PubMed Central

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

    2014-01-01

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

  6. 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 ... Nitrogen Oxides Ozone Surface Winds Air Temperature Humidity Solar Irradiance Particulate Matter Ultraviolet Radiation Surface Pressure Nitric Acid Aerosol Extinction Aerosol Backscatter ...

  7. NARSTO PAC2001 LANGLEY GAS PM MET DATA

    Atmospheric Science Data Center

    2014-04-25

    NARSTO PAC2001 LANGLEY GAS PM MET DATA Project Title:  NARSTO Discipline:  ... Chemiliminescence GC-MS Ion Chromatograph Pressure Sensor Temperature Probe Humidity Sensor Wind Sensor UV Ozone Detector ...

  8. COMT val158met predicts reward responsiveness in humans.

    PubMed

    Lancaster, T M; Linden, D E; Heerey, E A

    2012-11-01

    A functional variant of the catechol-O-methyltransferase (COMT) gene [val158met (rs4680)] is frequently implicated in decision-making and higher cognitive functions. It may achieve its effects by modulating dopamine-related decision-making and reward-guided behaviour. Here we demonstrate that individuals with the met/met polymorphism have greater responsiveness to reward than carriers of the val allele and that this correlates with risk-seeking behaviour. We assessed performance on a reward responsiveness task and the Balloon analogue risk task, which measure how participants (N = 70, western European, university and postgraduate students) respond to reward and take risks in the presence of available reward. Individuals with the met/met genotype (n = 19) showed significantly higher reward responsiveness, F2,64 = 4.02, P = 0.02, and reward-seeking behaviour, F(2,68) = 4.52, P = 0.01, than did either val/met (n = 25) or val/val (n = 26) carriers. These results highlight a scenario in which genotype-dependent reward responsiveness shapes reward-seeking, therefore suggesting a novel framework by which COMT may modulate behaviour. PMID:22900954

  9. 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

  10. Mars MetNet Mission - Martian Atmospheric Observational Post Network

    NASA Astrophysics Data System (ADS)

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

    2016-10-01

    A new kind of planetary exploration mission for Mars is under development in collaboration between the Finnish Meteorological Institute (FMI), Lavochkin Association (LA), Space Research Institute (IKI) and Institutio Nacional de Tecnica Aerospacial (INTA). The Mars MetNet mission is based on a new semi-hard landing vehicle called MetNet Lander (MNL).The scientific payload of the Mars MetNet Precursor mission is divided into three categories: Atmospheric instruments, Optical devices and Composition and structure devices. Each of the payload instruments will provide significant insights in to the Martian atmospheric behavior.The key technologies of the MetNet Lander have been qualified and the electrical qualification model (EQM) of the payload bay has been built and successfully tested.Full Qualification Model (QM) of the MetNet landing unit with the Precursor Mission payload is currently under functional tests. In the near future the QM unit will be exposed to environmental tests with qualification levels including vibrations, thermal balance, thermal cycling and mechanical impact shock. One complete flight unit of the entry, descent and landing systems (EDLS) has been manufactured and tested with acceptance levels. Another flight-like EDLS has been exposed to most of the qualification tests, and hence it may be used for flight after refurbishments. Accordingly two flight-capable EDLS systems exist. The eventual goal is to create a network of atmospheric observational posts around the Martian surface. The next step in the MetNet Precursor Mission is the demonstration of the technical robustness and scientific capabilities of the MetNet type of landing vehicle. Definition of the Precursor Mission and discussions on launch opportunities are currently under way. The baseline program development funding exists for the next five years. Flight unit manufacture of the payload bay takes about 18 months, and it will be commenced after the Precursor Mission has been defined.

  11. 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

  12. 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

  13. 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

  14. Met interacts with EGFR and Ron in canine osteosarcoma.

    PubMed

    McCleese, J K; Bear, M D; Kulp, S K; Mazcko, C; Khanna, C; London, C A

    2013-06-01

    The receptor tyrosine kinase (RTK) Met is known to be over-expressed in canine osteosarcoma (OSA). In human cancers, the RTKs Met, epidermal growth factor receptor (EGFR) and Ron are frequently co-expressed and engage in heterodimerization, altering signal transduction and promoting resistance to targeted therapeutics. We found that EGFR and Ron are expressed in canine OSA cell lines and primary tissues, EGFR and Ron are frequently phosphorylated in OSA tumour samples, and Met is co-associated with EGFR and Ron in canine OSA cell lines. Transforming growth factor alpha (TGFα) and hepatocyte growth factor (HGF) stimulation induced amplification of ERK1/2 and STAT3 phosphorylation in OSA cells and Met was phosphorylated following TGFα stimulation providing evidence for receptor cross-talk. Lastly, treatment of OSA cells with combined gefitinib and crizotinib inhibited cell proliferation in an additive manner. Together, these data support the notion that Met, EGFR and Ron interact in OSA cells and as such, may represent viable targets for therapeutic intervention.

  15. Met interacts with EGFR and Ron in canine osteosarcoma

    PubMed Central

    McCleese, J. K.; Bear, M. D.; Kulp, S. K.; Mazcko, C.; Khanna, C.; London, C. A.

    2014-01-01

    The receptor tyrosine kinase (RTK) Met is known to be over-expressed in canine osteosarcoma (OSA). In human cancers, the RTKs Met, epidermal growth factor receptor (EGFR) and Ron are frequently co-expressed and engage in heterodimerization, altering signal transduction and promoting resistance to targeted therapeutics. We found that EGFR and Ron are expressed in canine OSA cell lines and primary tissues, EGFR and Ron are frequently phosphorylated in OSA tumour samples, and Met is co-associated with EGFR and Ron in canine OSA cell lines. Transforming growth factor alpha (TGFα) and hepatocyte growth factor (HGF) stimulation induced amplification of ERK1/2 and STAT3 phosphorylation in OSA cells and Met was phosphorylated following TGFα stimulation providing evidence for receptor cross-talk. Lastly, treatment of OSA cells with combined gefitinib and crizotinib inhibited cell proliferation in an additive manner. Together, these data support the notion that Met, EGFR and Ron interact in OSA cells and as such, may represent viable targets for therapeutic intervention. PMID:22235915

  16. MetAmyl: A METa-Predictor for AMYLoid Proteins

    PubMed Central

    Emily, Mathieu; Talvas, Anthony; Delamarche, Christian

    2013-01-01

    The aggregation of proteins or peptides in amyloid fibrils is associated with a number of clinical disorders, including Alzheimer's, Huntington's and prion diseases, medullary thyroid cancer, renal and cardiac amyloidosis. Despite extensive studies, the molecular mechanisms underlying the initiation of fibril formation remain largely unknown. Several lines of evidence revealed that short amino-acid segments (hot spots), located in amyloid precursor proteins act as seeds for fibril elongation. Therefore, hot spots are potential targets for diagnostic/therapeutic applications, and a current challenge in bioinformatics is the development of methods to accurately predict hot spots from protein sequences. In this paper, we combined existing methods into a meta-predictor for hot spots prediction, called MetAmyl for METapredictor for AMYLoid proteins. MetAmyl is based on a logistic regression model that aims at weighting predictions from a set of popular algorithms, statistically selected as being the most informative and complementary predictors. We evaluated the performances of MetAmyl through a large scale comparative study based on three independent datasets and thus demonstrated its ability to differentiate between amyloidogenic and non-amyloidogenic polypeptides. Compared to 9 other methods, MetAmyl provides significant improvement in prediction on studied datasets. We further show that MetAmyl is efficient to highlight the effect of point mutations involved in human amyloidosis, so we suggest this program should be a useful complementary tool for the diagnosis of these diseases. PMID:24260292

  17. 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

  18. Novel interaction partners of the TPR/MET tyrosine kinase.

    PubMed

    Schaaf, Christian P; Benzing, Jörg; Schmitt, Thomas; Erz, Dorothee H R; Tewes, Magdalena; Bartram, Claus R; Janssen, Johannes W G

    2005-02-01

    A large variety of biological processes is mediated by stimulation of the receptor tyrosine kinase MET. Screening a mouse embryo cDNA library, we were able to identify several novel, putative intracellular TPR/MET-substrates: SNAPIN, DCOHM, VAV-1, Sorting nexin 2, Death associated protein kinase 3, SMC-1, Centromeric protein C, and hTID-1. Interactions as identified by yeast two-hybrid analysis were validated in vitro and in vivo by mammalian two-hybrid studies, a far-western assay and coimmunoprecipitation. Participation in apoptosis-regulating mechanisms through interaction with DAPK-3 and cell cycle control via binding to nuclear proteins such as CENPC and SMC-1 are possible new aspects of intracellular MET signaling.

  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. 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…

  1. 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 ...

  2. 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 ...

  3. 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 10.133 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF... order to qualify for free entry or a lower rate of duty unless the language of the particular...

  4. 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,…

  5. NARSTO SOS99NASH SURFACE MET CHEM DATA

    Atmospheric Science Data Center

    2014-04-25

    NARSTO SOS99NASH SURFACE MET CHEM DATA Project Title:  NARSTO Discipline:  Tropospheric Chemistry Field Campaigns Aerosols Level:  L2 ... Sulfur Dioxide Ozone Solar Radiation Humidity Surface Winds Air Temperature Order Data:  ASDC Order Tool: ...

  6. 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…

  7. 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 ... Aethaelometer Anemometer Rain Gauge Pressure Sensor Radiometers Temperature Sensor Weighing Balance AA ... Amount Surface Pressure Solar Radiation Surface Air Temperature Particulates Trace Metals Order Data:  ...

  8. 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…

  9. NARSTO PAC2001 SLOCAN PARK GAS PM MET DATA

    Atmospheric Science Data Center

    2014-04-25

    NARSTO PAC2001 SLOCAN PARK GAS PM MET DATA Project Title:  NARSTO Discipline:  ... Ground Station, Tethered Balloon Instrument:  Temperature Probe Humidity Sensor Wind Sensor UV Ozone Detector Chemiliminescence TEOM GC-MS Ion Chromatograph Pressure Sensor Aethaelometer Fluorescence Spectroscopy IR CO2 ...

  10. 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.

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

    PubMed

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

    2012-12-01

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

  12. The EGFR/ErbB3 Pathway Acts as a Compensatory Survival Mechanism upon c-Met Inhibition in Human c-Met+ Hepatocellular Carcinoma

    PubMed Central

    Steinway, Steven N.; Dang, Hien; You, Hanning; Rountree, C. Bart; Ding, Wei

    2015-01-01

    Background c-Met, a high-affinity receptor for Hepatocyte Growth Factor (HGF), plays a critical role in tumor growth, invasion, and metastasis. Hepatocellular carcinoma (HCC) patients with activated HGF/c-Met signaling have a significantly worse prognosis. Targeted therapies using c-Met tyrosine kinase inhibitors are currently in clinical trials for HCC, although receptor tyrosine kinase inhibition in other cancers has demonstrated early success. Unfortunately, therapeutic effect is frequently not durable due to acquired resistance. Methods We utilized the human MHCC97-H c-Met positive (c-Met+) HCC cell line to explore the compensatory survival mechanisms that are acquired after c-Met inhibition. MHCC97-H cells with stable c-Met knockdown (MHCC97-H c-Met KD cells) were generated using a c-Met shRNA vector with puromycin selection and stably transfected scrambled shRNA as a control. Gene expression profiling was conducted, and protein expression was analyzed to characterize MHCC97-H cells after blockade of the c-Met oncogene. A high-throughput siRNA screen was performed to find putative compensatory survival proteins, which could drive HCC growth in the absence of c-Met. Findings from this screen were validated through subsequent analyses. Results We have previously demonstrated that treatment of MHCC97-H cells with a c-Met inhibitor, PHA665752, results in stasis of tumor growth in vivo. MHCC97-H c-Met KD cells demonstrate slower growth kinetics, similar to c-Met inhibitor treated tumors. Using gene expression profiling and siRNA screening against 873 kinases and phosphatases, we identified ErbB3 and TGF-α as compensatory survival factors that are upregulated after c-Met inhibition. Suppressing these factors in c-Met KD MHCC97-H cells suppresses tumor growth in vitro. In addition, we found that the PI3K/Akt signaling pathway serves as a negative feedback signal responsible for the ErbB3 upregulation after c-Met inhibition. Furthermore, in vitro studies demonstrate

  13. Estimation of METs by Accelerometers while Walking and Running

    NASA Astrophysics Data System (ADS)

    Kurihara, Yosuke; Watanabe, Kajiro; Yoneyama, Mitsuru

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

  14. 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.

  15. 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

  16. 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.

  17. COMT Val158Met Polymorphism Modulates Huntington's Disease Progression

    PubMed Central

    Rebeix, Isabelle; Dupoux, Emmanuel; Durr, Alexandra; Brice, Alexis; Charles, Perrine; Cleret de Langavant, Laurent; Youssov, Katia; Verny, Christophe; Damotte, Vincent; Azulay, Jean-Philippe; Goizet, Cyril; Simonin, Clémence; Tranchant, Christine; Maison, Patrick; Rialland, Amandine; Schmitz, David; Jacquemot, Charlotte; Fontaine, Bertrand; Bachoud-Lévi, Anne-Catherine

    2016-01-01

    Little is known about the genetic factors modulating the progression of Huntington’s disease (HD). Dopamine levels are affected in HD and modulate executive functions, the main cognitive disorder of HD. We investigated whether the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, which influences dopamine (DA) degradation, affects clinical progression in HD. We carried out a prospective longitudinal multicenter study from 1994 to 2011, on 438 HD gene carriers at different stages of the disease (34 pre-manifest; 172 stage 1; 130 stage 2; 80 stage 3; 17 stage 4; and 5 stage 5), according to Total Functional Capacity (TFC) score. We used the Unified Huntington’s Disease Rating Scale to evaluate motor, cognitive, behavioral and functional decline. We genotyped participants for COMT polymorphism (107 Met-homozygous, 114 Val-homozygous and 217 heterozygous). 367 controls of similar ancestry were also genotyped. We compared clinical progression, on each domain, between groups of COMT polymorphisms, using latent-class mixed models accounting for disease duration and number of CAG (cytosine adenine guanine) repeats. We show that HD gene carriers with fewer CAG repeats and with the Val allele in COMT polymorphism displayed slower cognitive decline. The rate of cognitive decline was greater for Met/Met homozygotes, which displayed a better maintenance of cognitive capacity in earlier stages of the disease, but had a worse performance than Val allele carriers later on. COMT polymorphism did not significantly impact functional and behavioral performance. Since COMT polymorphism influences progression in HD, it could be used for stratification in future clinical trials. Moreover, DA treatments based on the specific COMT polymorphism and adapted according to disease duration could potentially slow HD progression. PMID:27657697

  18. Worldwide distribution of PSEN1 Met146Leu mutation

    PubMed Central

    Bernardi, L.; Colao, R.; Rubino, E.; Smirne, N.; Frangipane, F.; Terni, B.; Curcio, S.A.M.; Mirabelli, M.; Clodomiro, A.; Di Lorenzo, R.; Maletta, R.; Anfossi, M.; Gallo, M.; Geracitano, S.; Tomaino, C.; Muraca, M. G.; Leotta, A.; Lio, S. G.; Pinessi, L.; Rainero, I.; Sorbi, S.; Nee, L.; Milan, G.; Pappatá, S.; Postiglione, A.; Abbamondi, N.; Forloni, G.; St. George Hyslop, P.; Rogaeva, E.; Bugiani, O.; Giaccone, G.; Foncin, J. F.; Spillantini, M. G.; Puccio, G.

    2010-01-01

    Objective: Large kindreds segregating familial Alzheimer disease (FAD) offer the opportunity of studying clinical variability as observed for presenilin 1 (PSEN1) mutations. Two early-onset FAD (EOFAD) Calabrian families with PSEN1 Met146Leu (ATG/CTG) mutation constitute a unique population descending from a remote common ancestor. Recently, several other EOFAD families with the same mutation have been described worldwide. Methods: We searched for a common founder of the PSEN1 Met146Leu mutation in families with different geographic origins by genealogic and molecular analyses. We also investigated the phenotypic variability at onset in a group of 50 patients (mean age at onset 40.0 ± 4.8 years) by clinical, neuropsychological, and molecular methodologies. Results: EOFAD Met146Leu families from around the world resulted to be related and constitute a single kindred originating from Southern Italy before the 17th century. Phenotypic variability at onset is broad: 4 different clinical presentations may be recognized, 2 classic for AD (memory deficits and spatial and temporal disorientation), whereas the others are expressions of frontal impairment. The apathetic and dysexecutive subgroups could be related to orbital-medial prefrontal cortex and dorsolateral prefrontal cortex dysfunction. Conclusions: Genealogic and molecular findings provided evidence that the PSEN1 Met146Leu families from around the world analyzed in this study are related and represent a single kindred originating from Southern Italy. The marked phenotypic variability might reflect early involvement by the pathologic process of different cortical areas. Although the clinical phenotype is quite variable, the neuropathologic and biochemical characteristics of the lesions account for neurodegenerative processes unmistakably of Alzheimer nature. PMID:20164095

  19. 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

  20. LoVo colon cancer cells resistant to oxaliplatin overexpress c-MET and VEGFR-1 and respond to VEGF with dephosphorylation of c-MET.

    PubMed

    Mezquita, Belén; Pineda, Estela; Mezquita, Jovita; Mezquita, Pau; Pau, Montserrat; Codony-Servat, Jordi; Martínez-Balibrea, Eva; Mora, Conchi; Maurel, Joan; Mezquita, Cristóbal

    2016-05-01

    Oxaliplatin-resistant LoVo colon cancer cells overexpressing c-MET and VEGFR-1 were selected to study several signaling pathways involved in chemoresistance, as well as the effect of increasing amounts of VEGF in the regulation of c-MET. In comparison with chemosensitive LoVo colon cancer cells, oxaliplatin-resistant cells (LoVoR) overexpress and phosphorylate c-MET, upregulate the expression of transmembrane and soluble VEGFR-1 and, unexpectedly, downregulate VEGF. In addition, LoVoR cells activate other transduction pathways involved in chemoresistance such as Akt, β-catenin-TCF4 and E-cadherin. While c-MET is phosphorylated in LoVoR cells expressing low levels of VEGF, c-MET phosphorylation decreases when recombinant VEGF is added into the culture medium. Inhibition of c-MET by VEGF is mediated by VEGFR-1, since phosphorylation of c-MET in the presence of VEGF is restored after silencing VEGFR-1. Dephosphorylation of c-MET by VEGF suggests that tumors coexpressing VEGFR-1 and c-MET may activate c-MET as a result of anti-VEGF therapy.

  1. 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.

  2. Promise and challenges on the horizon of MET-targeted cancer therapeutics

    PubMed Central

    Zhang, Yu-Wen

    2015-01-01

    MET (MNNG HOS transforming gene) is one of the receptor tyrosine kinases whose activities are frequently altered in human cancers, and it is a promising therapeutic target. MET is normally activated by its lone ligand, hepatocyte growth factor (HGF), eliciting its diverse biological activities that are crucial for development and physiology. Alteration of the HGF-MET axis results in inappropriate activation of a cascade of intracellular signaling pathways that contributes to hallmark cancer events including deregulated cell proliferation and survival, angiogenesis, invasion, and metastasis. Aberrant MET activation results from autocrine or paracrine mechanisms due to overexpression of HGF and/or MET or from a ligand-independent mechanism caused by activating mutations or amplification of MET. The literature provides compelling evidence for the role of MET signaling in cancer development and progression. The finding that cancer cells often use MET activation to escape therapies targeting other pathways strengthens the argument for MET-targeted therapeutics. Diverse strategies have been explored to deactivate MET signaling, and compounds and biologics targeting the MET pathway are in clinical development. Despite promising results from various clinical trials, we are still waiting for true MET-targeted therapeutics in the clinic. This review will explore recent progress and hurdles in the pursuit of MET-targeted cancer drugs and discuss the challenges in such development. PMID:26009700

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

    PubMed

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

    2011-08-10

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

  4. 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

  5. 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.

  6. 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.

  7. 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

  8. Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer

    PubMed Central

    Bardelli, Alberto; Corso, Simona; Bertotti, Andrea; Hobor, Sebastijan; Valtorta, Emanuele; Siravegna, Giulia; Sartore-Bianchi, Andrea; Scala, Elisa; Cassingena, Andrea; Zecchin, Davide; Apicella, Maria; Migliardi, Giorgia; Galimi, Francesco; Lauricella, Calogero; Zanon, Carlo; Perera, Timothy; Veronese, Silvio; Corti, Giorgio; Amatu, Alessio; Gambacorta, Marcello; Diaz, Luis A.; Sausen, Mark; Velculescu, Victor E.; Comoglio, Paolo; Trusolino, Livio; Di Nicolantonio, Federica; Giordano, Silvia; Siena, Salvatore

    2014-01-01

    EGFR targeted monoclonal antibodies are effective in a subset of metastatic colorectal tumors (mCRC). Inevitably, all patients develop resistance, which occurs through emergence of KRAS mutations in approximately 50% of the cases. We show that amplification of the MET proto-oncogene is associated with acquired resistance in patients who do not develop KRAS mutations during anti-EGFR therapy. Amplification of the MET locus was present in circulating tumor DNA before relapse was clinically evident. Functional studies demonstrate that MET activation confers resistance to anti-EGFR therapy both in vitro and in vivo. Notably, in patient-derived CRC xenografts, MET amplification correlated with resistance to EGFR blockade which could be overcome by MET kinase inhibitors. These results highlight the role of MET in mediating primary and secondary resistance to anti-EGFR therapies in CRC and encourage the use of MET inhibitors in patients displaying resistance as a result of MET amplification. PMID:23729478

  9. 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

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

    ERIC Educational Resources Information Center

    MetLife, Inc., 2011

    2011-01-01

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

  11. 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…

  12. 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.

  13. Relationship between the COMT-Val158Met and BDNF-Val66Met Polymorphisms, Childhood Trauma and Psychotic Experiences in an Adolescent General Population Sample

    PubMed Central

    Ramsay, Hugh; Kelleher, Ian; Flannery, Padraig; Clarke, Mary C.; Lynch, Fionnuala; Harley, Michelle; Connor, Dearbhla; Fitzpatrick, Carol; Morris, Derek W.; Cannon, Mary

    2013-01-01

    Objective Psychotic experiences occur at a much greater prevalence in the population than psychotic disorders. There has been little research to date, however, on genetic risk for this extended psychosis phenotype. We examined whether COMT or BDNF genotypes were associated with psychotic experiences or interacted with childhood trauma in predicting psychotic experiences. Method Psychiatric interviews and genotyping for COMT-Val158Met and BDNF-Val66Met were carried out on two population-based samples of 237 individuals aged 11-15 years. Logistic regression was used to examine for main effects by genotype and childhood trauma, controlling for important covariates. This was then compared to a model with a term for interaction between genotype and childhood trauma. Where a possible interaction was detected, this was further explored in stratified analyses. Results While childhood trauma showed a borderline association with psychotic experiences, COMT-Val158Met and BDNF-Val66Met genotypes were not directly associated with psychotic experiences in the population. Testing for gene x environment interaction was borderline significant in the case of COMT-Val158Met with individuals with the COMT-Val158Met Val-Val genotype, who had been exposed to childhood trauma borderline significantly more likely to report psychotic experiences than those with Val-Met or Met-Met genotypes. There was no similar interaction by BDNF-Val66Met genotype. Conclusion The COMT-Val158Met Val-Val genotype may be a genetic moderator of risk for psychotic experiences in individuals exposed to childhood traumatic experiences. PMID:24224001

  14. 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.

  15. 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.

  16. 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.

  17. Coordination of platinum therapeutic agents to met-rich motifs of human copper transport protein1.

    PubMed

    Crider, Sarah E; Holbrook, Robert J; Franz, Katherine J

    2010-01-01

    Platinum therapeutic agents are widely used in the treatment of several forms of cancer. Various mechanisms for the transport of the drugs have been proposed including passive diffusion across the cellular membrane and active transport via proteins. The copper transport protein Ctr1 is responsible for high affinity copper uptake but has also been implicated in the transport of cisplatin into cells. Human hCtr1 contains two methionine-rich Mets motifs on its extracellular N-terminus that are potential platinum-binding sites: the first one encompasses residues 7-14 with amino acid sequence Met-Gly-Met-Ser-Tyr-Met-Asp-Ser and the second one spans residues 39-46 with sequence Met-Met-Met-Met-Pro-Met-Thr-Phe. In these studies, we use liquid chromatography and mass spectrometry to compare the binding interactions between cisplatin, carboplatin and oxaliplatin with synthetic peptides corresponding to hCtr1 Mets motifs. The interactions of cisplatin and carboplatin with Met-rich motifs that contain three or more methionines result in removal of the carrier ligands of both platinum complexes. In contrast, oxaliplatin retains its cyclohexyldiamine ligand upon platinum coordination to the peptide.

  18. 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

  19. Quantitative imaging for development of companion diagnostics to drugs targeting HGF/MET

    PubMed Central

    Huang, Fangjin; Ma, Zhaoxuan; Pollan, Sara; Yuan, Xiaopu; Swartwood, Steven; Gertych, Arkadiusz; Rodriguez, Maria; Mallick, Jayati; Bhele, Sanica; Guindi, Maha; Dhall, Deepti; Walts, Ann E; Bose, Shikha; de Peralta Venturina, Mariza; Marchevsky, Alberto M; Luthringer, Daniel J; Feller, Stephan M; Berman, Benjamin; Freeman, Michael R; Alvord, W Gregory; Vande Woude, George; Amin, Mahul B

    2016-01-01

    Abstract The limited clinical success of anti‐HGF/MET drugs can be attributed to the lack of predictive biomarkers that adequately select patients for treatment. We demonstrate here that quantitative digital imaging of formalin fixed paraffin embedded tissues stained by immunohistochemistry can be used to measure signals from weakly staining antibodies and provides new opportunities to develop assays for detection of MET receptor activity. To establish a biomarker panel of MET activation, we employed seven antibodies measuring protein expression in the HGF/MET pathway in 20 cases and up to 80 cores from 18 human cancer types. The antibodies bind to epitopes in the extra (EC)‐ and intracellular (IC) domains of MET (MET4EC, SP44_METIC, D1C2_METIC), to MET‐pY1234/pY1235, a marker of MET kinase activation, as well as to HGF, pSFK or pMAPK. Expression of HGF was determined in tumour cells (T_HGF) as well as in stroma surrounding cancer (St_HGF). Remarkably, MET4EC correlated more strongly with pMET (r = 0.47) than SP44_METIC (r = 0.21) or D1C2_METIC (r = 0.08) across 18 cancer types. In addition, correlation coefficients of pMET and T_HGF (r = 0.38) and pMET and pSFK (r = 0.56) were high. Prediction models of MET activation reveal cancer‐type specific differences in performance of MET4EC, SP44_METIC and anti‐HGF antibodies. Thus, we conclude that assays to predict the response to HGF/MET inhibitors require a cancer‐type specific antibody selection and should be developed in those cancer types in which they are employed clinically. PMID:27785366

  20. MET expression and copy number heterogeneity in nonsquamous non-small cell lung cancer (nsNSCLC)

    PubMed Central

    Taus, Álvaro; Pijuan, Lara; Arumí, Miriam; Lorenzo, Marta; Menéndez, Silvia; Cañadas, Israel; Albanell, Joan; Serrano, Sergio; Espinet, Blanca; Salido, Marta; Arriola, Edurne

    2015-01-01

    Objective We aimed to assess MET intratumoral heterogeneity and its potential impact on biomarker-based patient selection as well as potential surrogate biomarkers of MET activation. Methods Our study included 120 patients with non-squamous Non-small-cell Lung Cancer (nsNSCLC), of which 47 were incorporated in tissue microarrays (TMA). Four morphologically distinct tumor areas were selected to assess MET heterogeneity. MET positivity by immunohistochemistry (IHC) was defined as an above-median H-score and by +2/+3 staining intensity in >50% of tumor cells (Metmab criteria). MET FISH positivity was defined by MET/CEP7 ratio ≥ 2.0 and/or MET ≥ 5.0. MET staining pattern (cytoplasmic vs. membranous) and mesenchymal markers were investigated as surrogates of MET activation. Results Median MET H-score was 140 (range 0–400) and 47.8% of patients were MET positive by Metmab criteria. Eight cases (6.8%) were MET FISH positive and showed higher H-scores (p = 0.021). MET positivity by IHC changed in up to 40% of cases among different tumor areas, and MET amplification in 25–50%. Cytoplasmic MET staining and positivity for vimentin predicted poor survival (p = 0.042 and 0.047, respectively). Conclusions MET status is highly heterogeneous among different nsNSCLC tumor areas, hindering adequate patient selection for MET-targeted therapies. MET cytoplasmic staining and vimentin might represent surrogate markers for MET activation. PMID:26041880

  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. Wild-type p53 controls cell motility and invasion by dual regulation of MET expression

    PubMed Central

    Hwang, Chang-Il; Matoso, Andres; Corney, David C.; Flesken-Nikitin, Andrea; Körner, Stefanie; Wang, Wei; Boccaccio, Carla; Thorgeirsson, Snorri S.; Comoglio, Paolo M.; Hermeking, Heiko; Nikitin, Alexander Yu.

    2011-01-01

    Recent observations suggest that p53 mutations are responsible not only for growth of primary tumors but also for their dissemination. However, mechanisms involved in p53-mediated control of cell motility and invasion remain poorly understood. By using the primary ovarian surface epithelium cell culture, we show that conditional inactivation of p53 or expression of its mutant forms results in overexpression of MET receptor tyrosine kinase, a crucial regulator of invasive growth. At the same time, cells acquire increased MET-dependent motility and invasion. Wild-type p53 negatively regulates MET expression by two mechanisms: (i) transactivation of MET-targeting miR-34, and (ii) inhibition of SP1 binding to MET promoter. Both mechanisms are not functional in p53 absence, but mutant p53 proteins retain partial MET promoter suppression. Accordingly, MET overexpression, cell motility, and invasion are particularly high in p53-null cells. These results identify MET as a critical effector of p53 and suggest that inhibition of MET may be an effective antimetastatic approach to treat cancers with p53 mutations. These results also show that the extent of advanced cancer traits, such as invasion, may be determined by alterations in individual components of p53/MET regulatory network. PMID:21831840

  3. Mutant p53 enhances MET trafficking and signalling to drive cell scattering and invasion.

    PubMed

    Muller, P A J; Trinidad, A G; Timpson, P; Morton, J P; Zanivan, S; van den Berghe, P V E; Nixon, C; Karim, S A; Caswell, P T; Noll, J E; Coffill, C R; Lane, D P; Sansom, O J; Neilsen, P M; Norman, J C; Vousden, K H

    2013-03-01

    Tumour-derived mutant p53 proteins promote invasion, in part, by enhancing Rab coupling protein (RCP)-dependent receptor recycling. Here we identified MET as an RCP-binding protein and showed that mutant p53 promoted MET recycling. Mutant p53-expressing cells were more sensitive to hepatocyte growth factor, the ligand for MET, leading to enhanced MET signalling, invasion and cell scattering that was dependent on both MET and RCP. In cells expressing the p53 family member TAp63, inhibition of TAp63 also lead to cell scattering and MET-dependent invasion. However, in cells that express very low levels of TAp63, the ability of mutant p53 to promote MET-dependent cell scattering was independent of TAp63. Taken together, our data show that mutant p53 can enhance MET signalling to promote cell scattering and invasion through both TAp63-dependent and -independent mechanisms. MET has a predominant role in metastatic progression and the identification of mechanisms through which mutations in p53 can drive MET signalling may help to identify and direct therapy.

  4. Dynamic expression and localization of c-MET isoforms in the developing rat pancreas.

    PubMed

    Wu, Yulong; Cheng, Mei; Shi, Zhen; Feng, Zhenqing; Guan, Xiaohong

    2014-01-01

    Pancreata from Sprague Dawley rats of different developmental stages were studied to determine the expression and cellular localization of different c-MET isoforms in the developing rat pancreas. Pancreatic mRNA and protein expression levels of c-MET at different developmental stages from embryo to adult were detected by reverse transcription-polymerase chain reaction and by western blotting. To identify the cellular localization of c-MET protein in the developing rat pancreas, double immunofluorescent staining was performed using antibodies for cell type-specific markers and for c-MET. The expression of two isoforms of c-MET (190 kDa and 170 kDa) coincided with the development of the pancreas. The 190 kDa isoform of c-MET is expressed during embryonic stages, and its expression is replaced by the expression of the 170 kDa isoform as the pancreas develops. Only the 170 kDa isoform is expressed in the adult rat pancreas. Throughout all stages of pancreatic development, c-MET is expressed by vimentin-positive cells. In contrast, c-MET staining was stronger in rat pancreata from newborn to adult stages and overlapped with insulin-positive beta-cells. The dynamic expression and localization of different c-MET isoforms in the rat pancreas during different developmental stages indicates that distinct c-MET isoform might be involved in different aspects of pancreatic development.

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

    PubMed

    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.

  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. 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

  9. 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)

  10. 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

  11. 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.

  12. The role of met-enkephalin in silent myocardial ischemia in diabetic patients.

    PubMed

    Parlapiano, C; Borgia, M C; Tonnarini, G; Campana, E; Giancaspro, G; Pantone, P; Giovanniello, T; Cardarelli, G; Vincentelli, G M; Alegiani, F; Negri, M

    2001-01-01

    Met-enkephalin plasma levels were evaluated in 20 cardioischemic diabetic patients. All the patients had ECG ischemic signs. Ten patients with diabetic autonomic neuropathy, experienced no pain during myocarial ischemia. Met-enkephalin levels in the diabetic patients with silent myiocardial ischemia were significantly lower compared to those in the symptomatic patients. This demonstrates that the absence of myocardial ischemic pain in neuropathic diabetic patients is not accounted for by met-enkephalin action. PMID:11958273

  13. 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

  14. Activation of HER family members in gastric carcinoma cells mediates resistance to MET inhibition

    PubMed Central

    2010-01-01

    Background Gastric cancer 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. Thus, MET is considered a good candidate for targeted therapeutic intervention in this type of tumor, and MET inhibitors recently entered clinical trials. 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. Perspective studies are thus mandatory to identify the molecular mechanisms that could cause resistance to these therapies. Results Our in vitro and in vivo results demonstrate that, in MET-addicted gastric cancer cells, the activation of HER (Human Epidermal Receptor) family members induces resistance to MET silencing or inhibition by PHA-665752 (a selective kinase inhibitor). We provide molecular evidences highlighting the role of EGFR, HER3, and downstream signaling pathways common to MET and HER family in resistance to MET inhibitors. Moreover, we show that an in vitro generated gastric cancer cell line resistant to MET-inhibition displays overexpression of HER family members, whose activation contributes to maintenance of resistance. Conclusions Our findings predict that gastric cancer tumors bearing constitutive activation of HER family members are poorly responsive to MET inhibition, even if this receptor is constitutively active. Moreover, the appearance of these alterations might also be responsible for the onset of resistance in initially responsive tumors. PMID:20500904

  15. 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.

  16. 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.

  17. Methionine uptake in Corynebacterium glutamicum by MetQNI and by MetPS, a novel methionine and alanine importer of the NSS neurotransmitter transporter family.

    PubMed

    Trötschel, Christian; Follmann, Martin; Nettekoven, Jeannine A; Mohrbach, Tobias; Forrest, Lucy R; Burkovski, Andreas; Marin, Kay; Krämer, Reinhard

    2008-12-01

    The soil bacterium Corynebacterium glutamicum is a model organism in amino acid biotechnology. Here we present the identification of two different L-methionine uptake systems including the first characterization of a bacterial secondary methionine carrier. The primary carrier MetQNI is a high affinity ABC-type transporter specific for l-methionine. Its expression is under the control of the transcription factor McbR, the global regulator of sulfur metabolism in C. glutamicum. Besides MetQNI, a novel secondary methionine uptake system of the NSS (neurotransmitter:sodium symporter) family was identified and named MetP. The MetP system is characterized by a lower affinity for methionine and uses Na(+) ions for energetic coupling. It is also the main alanine transporter in C. glutamicum and is expressed constitutively. These observations are consistent with models of methionine, alanine, and leucine bound to MetP, derived from the X-ray crystal structure of the LeuT transporter from Aquifex aeolicus. Complementation studies show that MetP consists of two components, a large subunit with 12 predicted transmembrane segments and, surprisingly, an additional subunit with one predicted transmembrane segment only. Thus, this new member of the NSS transporter family adds a novel feature to this class of carriers, namely, the functional dependence on an additional small subunit.

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  4. Hepatocyte growth factor/cMET pathway activation enhances cancer hallmarks in adrenocortical carcinoma

    PubMed Central

    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

    2015-01-01

    Adrenocortical carcinoma (ACC) 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 ACC has not been examined. In this study, we investigated the association between HGF/cMET expression and cancer hallmarks of ACC. Transcriptomic and immunohistochemical analyses indicated that increased HGF/cMET expression in human ACC samples was positively associated with cancer-related biological processes including proliferation and angiogenesis, and negatively correlated with apoptosis. Accordingly, treatment of ACC cells with exogenous HCG resulted in increased cell proliferation in vitro and in vivo while short hairpin RNA-mediated knockdown or pharmacological 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 ACC 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

  5. 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..., AS AMENDED Continuation of Pay Eligibility for Cop § 10.205 What conditions must be met to receive COP? (a) To be eligible for COP, a person must: (1) Have a “traumatic injury” as defined at §...

  6. 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...' COMPENSATION ACT, AS AMENDED Continuation of Pay Eligibility for Cop § 10.205 What conditions must be met to receive COP? (a) To be eligible for COP, a person must: (1) Have a “traumatic injury” as defined at §...

  7. 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..., AS AMENDED Continuation of Pay Eligibility for Cop § 10.205 What conditions must be met to receive COP? (a) To be eligible for COP, a person must: (1) Have a “traumatic injury” as defined at §...

  8. 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...' COMPENSATION ACT, AS AMENDED Continuation of Pay Eligibility for Cop § 10.205 What conditions must be met to receive COP? (a) To be eligible for COP, a person must: (1) Have a “traumatic injury” as defined at §...

  9. 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...' COMPENSATION ACT, AS AMENDED Continuation of Pay Eligibility for Cop § 10.205 What conditions must be met to receive COP? (a) To be eligible for COP, a person must: (1) Have a “traumatic injury” as defined at §...

  10. 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…

  11. RNAi technology and lentiviral delivery as a powerful tool to suppress Tpr-Met-mediated tumorigenesis.

    PubMed

    Taulli, Riccardo; Accornero, Paolo; Follenzi, Antonia; Mangano, Tony; Morotti, Alessandro; Scuoppo, Claudio; Forni, Paolo E; Bersani, Francesca; Crepaldi, Tiziana; Chiarle, Roberto; Naldini, Luigi; Ponzetto, Carola

    2005-05-01

    Tpr-Met, the oncogenic counterpart of the Met receptor, has been detected in gastric cancers, as well as in precursor lesions and in the adjacent normal gastric mucosa. This has prompted the suggestion that Tpr-Met may predispose to the development of gastric tumors. Given the sequence specificity of RNA interference, oncogenes activated by point mutation or rearrangements can be targeted while spearing the product of the wild-type allele. In this work, we report specific suppression of Tpr-Met expression and inhibition of Tpr-Met-mediated transformation and tumorigenesis by means of a short interfering RNA (siRNA) directed toward the Tpr-Met junction (anti-TM2). When delivered by a lentiviral vector, anti-TM2 siRNA was effective also in mouse embryonal fibroblasts or epithelial cells expressing high levels of Tpr-Met. Our results suggest that lentiviral-mediated delivery of anti-TM2 siRNA may be developed into a powerful tool to treat Tpr-Met-positive cancers.

  12. 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.

  13. "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…

  14. 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…

  15. Rewarding Results: The MetLife Foundation Community College Excellence Award

    ERIC Educational Resources Information Center

    Kazis, Richard; Newton, Anne

    2004-01-01

    At the 2004 AACC Annual Convention, Sybil Jacobson, president and CEO of MetLife Foundation, announced the two recipients of the 2004 MetLife Foundation Community College Excellence Award. The award, won by City College of San Francisco (CCSF) and Community College of Denver (CCD), honors two colleges that have made great strides in helping…

  16. Silencing Met receptor tyrosine kinase signaling decreased oral tumor growth and increased survival of nude mice

    PubMed Central

    Tao, X.; Hill, K.S.; Gaziova, I.; Sastry, S.K.; Qui, S.; Szaniszlo, P.; Fennewald, S.; Resto, V.A.; Elferink, L.A.

    2013-01-01

    SUMMARY Objectives The hepatocyte growth factor receptor (Met) is frequently overexpressed in Head and Neck Squamous Cell Carcinoma (HNSCC), correlating positively with high-grade tumors and shortened patient survival. As such, Met may represent an important therapeutic target. The purpose of this study was to explore the role of Met signaling for HNSCC growth and locoregional dissemination. Materials and methods Using a lentiviral system for RNA interference, we knocked down Met in established HNSCC cell lines that express high levels of the endogenous receptor. The effect of Met silencing on in vitro proliferation, cell survival and migration was examined using western analysis, immunohisto-chemistry and live cell imaging. In vivo tumor growth, dissemination and mouse survival was assessed using an orthotopic tongue mouse model for HNSCC. Results We show that Met knockdown (1) impaired activation of downstream MAPK signaling; (2) reduced cell viability and anchorage independent growth; (3) abrogated HGF-induced cell motility on laminin; (4) reduced In vivo tumor growth by increased cell apoptosis; (5) caused reduced incidence of tumor dissemination to regional lymph nodes and (6) increased the survival of nude mice with orthotopic xenografts. Conclusion Met signaling is important for HNSCC growth and locoregional dissemination In vivo and that targeting Met may be an important strategy for therapy. PMID:24268630

  17. 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…

  18. 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…

  19. Non-autocrine, constitutive activation of Met in human anaplastic thyroid carcinoma cells in culture

    PubMed Central

    Bergström, J D; Hermansson, A; Ståhl, T Diaz de; Heldin, N-E

    1999-01-01

    Activation of Met by its ligand HGF has been shown to elicit both mitogenic and motogenic responses in thyrocytes in vitro. In the present study we have investigated the expression of Met in human anaplastic thyroid carcinoma cells in culture. There was a variation in expression level and size of Met in the different cell lines; high Met expression was found in four cell lines, compared to non-neoplastic human thyrocytes. Treatment with glucoproteinase F showed that the size differences observed were due to variances in the degree of glycosylation. Interestingly, in cell lines with high expression of Met, the receptor proteins were found to be constitutively tyrosine phosphorylated. None of these cell lines expressed HGF mRNA, and addition of suramin did not affect the level of tyrosine phosphorylation of Met in unstimulated cells, suggesting the absence of autocrine stimulatory pathways. Furthermore, we did not observe MET gene amplification, activating mutations or phosphatase defects. The tyrosine phosphorylated receptors appeared functionally active since the receptors associated with the adaptor molecule Shc. In summary, we have found ligand-independent constitutively activated Met in four out of six anaplastic thyroid carcinoma cell lines. © 1999 Cancer Research Campaign PMID:10360640

  20. 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?...

  1. 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?...

  2. 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?...

  3. 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?...

  4. 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?...

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

    PubMed

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

    2013-10-16

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

  6. Association between the BDNF Val66Met Polymorphism and Chronicity of Depression

    PubMed Central

    Lee, Yujin; Lim, Shinn Won; Kim, Soo Yeon; Chung, Jae Won; Kim, Jinwoo; Myung, Woojae; Song, Jihae; Kim, Seonwoo; Carroll, Bernard J

    2013-01-01

    Objective Both clinical and biological factors influence the course of depressive disorders. This study tested for associations between the brain-derived neurotrophic factor (BDNF) gene at the Val66Met locus and the course of major depressive disorder (MDD). Methods Three hundred ten Korean subjects (209 patients, 101 controls) were genotyped for rs6265 at nucleotide 196 (G/A), which produces an amino acid substitution at codon 66 (Val66Met) of the gene for BDNF. Course of illness was evaluated both by chronicity of current episode (episode duration >24 months) and by the lifetime history of recurrences. Results Patients with the Met/Met BDNF genotype had a significantly higher rate of chronic depression than all others. There was a significant dose effect of the Met allele on chronicity. Compared with the Val/Val genotype, the relative risk of chronicity was 1.67 for the Val/Met genotype, and 2.58 for the Met/Met genotype. Lifetime history of recurrent episodes was not related to BDNF genotypes but was significantly associated with younger age of onset and with a history of depression in first degree relatives. Conclusion BDNF genotyping may be informative for anticipating chronicity in major depression. PMID:23482723

  7. 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

  8. 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.

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

    PubMed

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

    2016-05-31

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

  10. The clinical and functional significance of c-Met in breast cancer: a review.

    PubMed

    Ho-Yen, Colan M; Jones, J Louise; Kermorgant, Stephanie

    2015-04-08

    c-Met is a receptor tyrosine kinase that upon binding of its ligand, hepatocyte growth factor (HGF), activates downstream pathways with diverse cellular functions that are important in organ development and cancer progression. Anomalous c-Met signalling has been described in a variety of cancer types, and the receptor is regarded as a novel therapeutic target. In breast cancer there is a need to develop new treatments, particularly for the aggressive subtypes such as triple-negative and basal-like cancer, which currently lack targeted therapy. Over the last two decades, much has been learnt about the functional role of c-Met signalling in different models of breast development and cancer. This work has been complemented by clinical studies, establishing the prognostic significance of c-Met in tissue samples of breast cancer. While the clinical trials of anti-c-Met therapy in advanced breast cancer progress, there is a need to review the existing evidence so that the potential of these treatments can be better appreciated. The aim of this article is to examine the role of HGF/c-Met signalling in in vitro and in vivo models of breast cancer, to describe the mechanisms of aberrant c-Met signalling in human tissues, and to give a brief overview of the anti-c-Met therapies currently being evaluated in breast cancer patients. We will show that the HGF/c-Met pathway is associated with breast cancer progression and suggest that there is a firm basis for continued development of anti-c-Met treatment, particularly for patients with basal-like and triple-negative breast cancer.

  11. Demethylation of a LINE-1 antisense promoter in the cMet locus impairs Met signalling through induction of illegitimate transcription.

    PubMed

    Weber, B; Kimhi, S; Howard, G; Eden, A; Lyko, F

    2010-10-28

    The cytosine analogues 5-azacytidine and 5-aza-2'-deoxycytidine are currently the most advanced drugs for epigenetic cancer therapy. Both drugs function as DNA methyltransferase (DNMT) inhibitors and lead to the reactivation of epigenetically silenced tumour suppressor genes. However, not much is known about their target sequence specificity and their possible side effects on normally methylated sequences such as long interspersed nuclear element (LINE)-1 retroelements. It has been shown that demethylation and activation of the LINE-1 antisense promoter can drive the transcription of neighbouring sequences. In this study, we show that demethylation of the colon carcinoma cell line HCT116, either by treatment with DNMT inhibitors or by genetic disruption of the major DNMTs, induces the expression of an illegitimate fusion transcript between an intronic LINE-1 element and the proto-oncogene cMet (L1-cMet). Similar findings were also obtained with myeloid leukaemia cells, an established cellular model for the approved indication of azacytidine and decitabine. Interestingly, upregulation of L1-cMet transcription resulted in reduced cMet expression, which in turn led to decreased cMet receptor signalling. Our results thus provide an important paradigm for demethylation-dependent modulation of gene expression, even if the promoter of the corresponding gene is unmethylated.

  12. 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

  13. 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

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

    PubMed

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

    2014-11-01

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

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

    PubMed

    Ojo, Kayode K; 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

  16. Biological significance and targeting of c-Met tyrosine kinase receptor in cancer.

    PubMed

    Goetsch, Liliane; Caussanel, Veronique; Corvaia, Nathalie

    2013-01-01

    c-Met is a tyrosine kinase receptor largely described to be involved in cancer progression and metastasis. In such pathologic situation, many alterations of this receptor were noticed that include transcriptional overexpression, gene amplification, somatic or germline mutations and/or ligand dependent autocrine/paracrine loops. More recently it has also been suggested that c-Met would be involved in resistance to targeted therapies directed towards EGFR or angiogenesis. Major efforts from a large number of pharmaceutical companies are invested dedicated to evaluate the efficacy of either small molecule inhibitors or monoclonal antibodies directed against c-Met or its unique ligand HGF. A series of promising results from the first completed clinical trials indicated that compounds targeting c-Met have an acceptable toxicity profile and that efficacy was noticed in some treated patients. Non squamous NSCLC patients that express more often high levels of c-Met seemed to represent a most sensitive subset for and anti-c-Met/erlotinib therapy. Many Phase III trials are currently recruiting and a particular effort was performed in order to discover biomarkers associated with efficacy and patient selection. This review will provide an overview of the current knowledge on the c-Met axis for development of novel therapeutics in Oncology.

  17. 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

  18. 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

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

    PubMed

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

    2015-01-01

    The catechol-O-methyltransferase (COMT) Val(158)Met polymorphism impacts cortical dopamine (DA) levels and may influence cortical electrical activity in the human brain. This study investigated whether COMT genotype influences resting-state electroencephalogram (EEG) power in the frontal, parietal and midline regions in healthy volunteers. EEG recordings were conducted in the resting-state in 13 postmenopausal healthy woman carriers of the Val/Val genotype and 11 with the Met/Met genotype. The resting EEG spectral absolute power in the frontal (F3, F4, F7, F8, FC3 and FC4), parietal (CP3, CP4, P3 and P4) and midline (Fz, FCz, Cz, CPz, Pz and Oz) was analyzed during the eyes-open and eyes-closed conditions. The frequency bands considered were the delta, theta, alpha1, alpha2, beta1 and beta2. EEG data of the Val/Val and Met/Met genotypes, brain regions and conditions were analyzed using a general linear model analysis. In the individuals with the Met/Met genotype, delta activity was increased in the eyes-closed condition, theta activity was increased in the eyes-closed and in the eyes-open conditions, and alpha1 band, alpha2 band and beta1band activity was increased in the eyes-closed condition. A significant interaction between COMT genotypes and spectral bands was observed. Met homozygote individuals exhibited more delta, theta and beta1 activity than individuals with the Val/Val genotype. No significant interaction between COMT genotypes and the resting-state EEG regional power and conditions were observed for the three brain regions studied. Our findings indicate that the COMT Val(158)Met polymorphism does not directly impact resting-state EEG regional power, but instead suggest that COMT genotype can modulate resting-state EEG spectral power in postmenopausal healthy women. PMID:25883560

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

  2. 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

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

    PubMed Central

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

    2014-01-01

    Background Decreased expression of brain-derived neurotrophic factor (BDNF) is implicated in enhanced stress responses. The BDNF Val66Met polymorphism is associated with psychological changes; for example, carriers of the Met allele exhibit increased harm avoidance as well as a higher prevalence of depression and anxiety disorder. Methods To analyze the effects of BDNF Val66Met on stress responses, we tested 226 university students (88 women and 138 men) using a social stress procedure (Trier Social Stress Test [TSST]) and an electrical stimulation stress test. Stress indices were derived from repeated measurements of salivary α-amylase, salivary cortisol, heart rate, and psychological testing during the stress tests. All subjects were genotyped for the Val66Met polymorphism (G196A). Results A significant three-way interaction (time [3 levels] × BDNF [Val/Val, Val/Met, Met/Met]; P<0.05) was demonstrated that revealed different salivary cortisol responses in the TSST but not in electrical stimulation. Met/Met women had stronger cortisol responses than Val/Met and Val/Val individuals in the TSST. Met/Met men exhibited stronger salivary cortisol responses than Val/Met and Val/Val individuals in the TSST. Conclusion These results indicate that a common, functionally significant polymorphism in BDNF had different effects on hypothalamic–pituitary–adrenocortical axis reactivity but not on sympathetic adrenomedullary reactivity in TSST and electrical stimulation tests. PMID:25419135

  4. Effects of the BDNF Val66Met polymorphism on white matter microstructure in healthy adults.

    PubMed

    Tost, Heike; Alam, Tajvar; Geramita, Matthew; Rebsch, Christine; Kolachana, Bhaskar; Dickinson, Dwight; Verchinski, Beth A; Lemaitre, Herve; Barnett, Alan S; Trampush, Joey W; Weinberger, Daniel R; Marenco, Stefano

    2013-02-01

    The BDNF Val(66)Met polymorphism, a possible risk variant for mental disorders, is a potent modulator of neural plasticity in humans and has been linked to deficits in gray matter structure, function, and cognition. The impact of the variant on brain white matter structure, however, is controversial and remains poorly understood. Here, we used diffusion tensor imaging to examine the effects of BDNF Val(66)Met genotype on white matter microstructure in a sample of 85 healthy Caucasian adults. We demonstrate decreases of fractional anisotropy and widespread increases in radial diffusivity in Val/Val homozygotes compared with Met-allele carriers, particularly in prefrontal and occipital pathways. These data provide an independent confirmation of prior imaging genetics work, are consistent with complex effects of the BDNF Val(66)Met polymorphism on human brain structure, and may serve to generate hypotheses about variation in white matter microstructure in mental disorders associated with this variant. PMID:23132269

  5. Effects of the BDNF Val66Met Polymorphism on White Matter Microstructure in Healthy Adults

    PubMed Central

    Tost, Heike; Alam, Tajvar; Geramita, Matthew; Rebsch, Christine; Kolachana, Bhaskar; Dickinson, Dwight; Verchinski, Beth A; Lemaitre, Herve; Barnett, Alan S; Trampush, Joey W; Weinberger, Daniel R; Marenco, Stefano

    2013-01-01

    The BDNF Val66Met polymorphism, a possible risk variant for mental disorders, is a potent modulator of neural plasticity in humans and has been linked to deficits in gray matter structure, function, and cognition. The impact of the variant on brain white matter structure, however, is controversial and remains poorly understood. Here, we used diffusion tensor imaging to examine the effects of BDNF Val66Met genotype on white matter microstructure in a sample of 85 healthy Caucasian adults. We demonstrate decreases of fractional anisotropy and widespread increases in radial diffusivity in Val/Val homozygotes compared with Met-allele carriers, particularly in prefrontal and occipital pathways. These data provide an independent confirmation of prior imaging genetics work, are consistent with complex effects of the BDNF Val66Met polymorphism on human brain structure, and may serve to generate hypotheses about variation in white matter microstructure in mental disorders associated with this variant. PMID:23132269

  6. 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...

  7. 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

  8. 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

  9. The MET Oncogene as a Therapeutical Target in Cancer Invasive Growth

    PubMed Central

    Luraghi, Paolo; Schelter, Florian; Krüger, Achim; Boccaccio, Carla

    2012-01-01

    The MET proto-oncogene, encoding the tyrosine kinase receptor for Hepatocyte Growth Factor (HGF) regulates invasive growth, a genetic program that associates control of cell proliferation with invasion of the extracellular matrix and protection from apoptosis. Physiologically, invasive growth takes place during embryonic development, and, in post-natal life, in wound healing and regeneration of several tissues. The MET oncogene is overexpressed and/or genetically mutated in many tumors, thereby sustaining pathological invasive growth, a prerequisite for metastasis. MET is the subject of intense research as a target for small molecule kinase inhibitors and, together with its ligand HGF, for inhibitory antibodies. The tight interplay of MET with the protease network has unveiled mechanisms to be exploited to achieve effective inhibition of invasive growth. PMID:22973229

  10. The Mars Phoenix MET Pressure Sensor - Technical Implementation, Quality of Data and Data Processing

    NASA Astrophysics Data System (ADS)

    Kahanpää, H.; Polkko, J.; Harri, A.; Genzer, M.; Schmidt, W.

    2009-05-01

    Meteorological conditions on the landing site of the Mars Phoenix lander were monitored with the MET experiment, provided by Canadian Space Agency (CSA). The MET experiment includes a LIDAR, three temperature sensors and a pressure sensor. The Phoenix MET pressure sensor is provided by Finnish Meteorological Institute (FMI) and is based on technology developed by Vaisala corporate. Three Barocap sensor heads are used to measure pressure and two Thermocap sensor heads to measure housekeeping temperature. The engineering data measured by the Phoenix MET pressure sensor is introduced. This data includes sensor level tests, spacecraft level tests, measurements during the interplanetary cruise and health check measurements during the mission on Mars. The following characteristics of the sensor are determined using this data: resolution, repeatability, temperature dependence, stability, total accuracy and time constant. Data processing methods used to calculate corrected pressure readings from the raw data are introduced.

  11. 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

  12. 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

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

    PubMed

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

    2013-08-01

    A statewide needs assessment of persons living with HIV/AIDS (PLWHA) was conducted to determine what is known about access to care, utilization of services, and perceived barriers to receiving care and services. Our objective was to determine which needs were being met or unmet among PLWHA in Mississippi to provide a better understanding of how effectively to allocate funding to provide for the needs of that group. In this cross-sectional study, a true random sample of PLWHA in Mississippi was interviewed in 2005-2006. Questions were asked to identify opinions about respondents' experiences with 23 health care services and 30 public or private assistance services. The kappa statistic was used to measure agreement between level of services needed and level of services provided. Services with the lowest kappa scores revealed which services were being either mostly unmet, or even overly met. Greatest service needs were HIV viral load test, Pap smear, CD4/T-cell count test, and medication for HIV/AIDS, which were reasonably well met. The most significantly unmet needs were dental care and dental exams, eye care and eye exams, help paying for housing, subsidized housing assistance, mental health therapy or counseling, access to emotional support groups, and job placement or employment. Overly met services included medical care at a physician's office or clinic and free condoms. This study identified needs perceived to be significantly unmet by PLWHA, as well as areas that were perceived to be adequately or overly met. This information may be used to target areas with the greatest impact for improvement and provide insight into how to effectively allocate health care resources and public/private assistance. PMID:23252519

  14. 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/ .

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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

    2012-01-31

    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.

  20. 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

  1. Fumarase tumor suppressor gene and MET oncogene cooperate in upholding transformation and tumorigenesis.

    PubMed

    Costa, Barbara; Dettori, Daniela; Lorenzato, Annalisa; Bardella, Chiara; Coltella, Nadia; Martino, Cosimo; Cammarata, Cristina; Carmeliet, Peter; Olivero, Martina; Di Renzo, Maria Flavia

    2010-08-01

    Loss of the fumarate hydratase (FH) tumor suppressor gene results in the development of benign tumors that rarely, but regrettably, progress to very aggressive cancers. Using mouse embryo fibroblasts (MEFs) to model transformation, we found that fh knockdown results in increased expression of the met oncogene-encoded tyrosine kinase receptor through hypoxia-inducible factor (hif) stabilization. MET-increased expression was alone able to stabilize hif, thus establishing a feed forward loop that might enforce tumor progression. The fh-defective MEFs showed increased motility and protection from apoptosis. Motility, but not survival, relied on hif-1alpha and was greatly enhanced by MET ligand hepatocyte growth factor. Met cooperated with a weakly oncogenic ras in making MEFs transformed and tumorigenic, as shown by in vitro and in vivo assays. Loss of fh was not equally effective by itself but enhanced the transformed and tumorigenic phenotype induced by ras and MET. Consistently, the rescue of fumarase expression abrogated the motogenic and transformed phenotype of fh-defective MEFs. In conclusion, the data suggest that the progression of tumors where FH is lost might be boosted by activation of the MET oncogene, which is able to drive cell-autonomous tumor progression and is a strong candidate for targeted therapy. PMID:20354140

  2. 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.

  3. (-)-Oleocanthal as a c-Met inhibitor for the control of metastatic breast and prostate cancers.

    PubMed

    Elnagar, Ahmed Y; Sylvester, Paul W; El Sayed, Khalid A

    2011-07-01

    The proto-oncogene receptor tyrosine kinase c-Met encodes the high-affinity receptor for hepatocyte growth factor (HGF). Dysregulation of the HGF-c-Met pathway plays a significant oncogenic role in many tumors. Overexpression of c-Met is a prognostic indicator for some transitional cell carcinomas. Extra-virgin olive oil (EVOO) provides a variety of minor phenolic compounds with beneficial properties. (-)-Oleocanthal (1) is a naturally occurring minor secoiridoid isolated from EVOO, which showed potent anti-inflammatory activity via its ability to inhibit COX-1 and COX-2. It altered the structure of neurotoxic proteins believed to contribute to the debilitating effects of Alzheimer's disease. Computer-Assisted Molecular Design (CAMD) identified 1 as a potential virtual c-Met inhibitor hit. Oleocanthal inhibited the proliferation, migration, and invasion of the epithelial human breast and prostate cancer cell lines MCF7, MDA-MB-231, and PC-3, respectively, with an IC (50) range of 10-20 µM, and demonstrated anti-angiogenic activity via downregulating the expression of the microvessel density marker CD31 in endothelial colony forming cells with an IC (50) of 4.4 µM. It inhibited the phosphorylation of c-Met kinase IN VITRO in the Z'-LYTE™ assay, with an IC (50) value of 4.8 µM. (-)-Oleocanthal and EVOO can have potential therapeutic use for the control of c-Met-dependent malignancies. PMID:21328179

  4. The development of MetAP-2 inhibitors in cancer treatment.

    PubMed

    Yin, S-Q; Wang, J-J; Zhang, C-M; Liu, Z-P

    2012-01-01

    Methionine aminopeptidases (MetAPs), which remove methionine residue from newly synthesized polypeptide chains, are a class of metalloproteases ubiquitously distributed in both eukaryotes and prokaryotes. MetAP-2 inhibition can induce G1 cell cycle arrest, cytostasis in tumor cells in vitro and inhibition of tumor growth in vivo. The discovery of fumagillin with potent antiangiogenic and antiproliferative activities promoted the development of fumagillin analogues as a novel class of anticancer agents. Early drug discovery efforts have focused on analogs of fumagillin, which irreversibly inhibit MetAP-2 through covalent modification of an epoxide. Several fumagillin analogs, like CKD-732, TNP-470 and PPI-2458, were found to be potent selective inhibitors of MetAP-2 (proteolytic activity) and endothelial cell proliferation. Further, they have entered in clinical trials for the treatment of different types of tumors. Recently, attention has been paid to reversible human MetAP-2 inhibitors, such as bengamides, 2-hydroxy-3-aminoamides, anthranilic acid sulfonamides and triazole analogs, which have demonstrated their potential to inhibit angiogenesis and tumor growth in vivo as well. This review article mainly discussed the development of MetAP-2 inhibitors in cancer therapy and also summarized their structure-activity relationships. PMID:22229417

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

    PubMed Central

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

    2016-01-01

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

  6. 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

  7. FAK kinase activity is required for the progression of c-Met/β-catenin-driven HCC

    PubMed Central

    Shang, Na; Arteaga, Maribel; Zaidi, Ali; Cotler, Scott J.; Breslin, Peter; Ding, Xianzhong; Kuo, Paul; Nishimura, Michael; Zhang, Jiwang; Qiu, Wei

    2016-01-01

    Background & Aims There is an urgent need to develop new and more effective therapeutic strategies and agents to treat hepatocellular carcinoma (HCC). We have recently found that deletion of Fak in hepatocytes before tumors form inhibits tumor development and prolongs survival of animals in a c-Met (MET)/β-catenin (CAT)-driven HCC mouse model. However, it has yet to be determined whether FAK expression in hepatocytes promotes MET/CAT-induced HCC progression after tumor initiation. In addition, it remains unclear whether FAK promotes HCC development through its kinase activity. Methods We generated hepatocyte-specific inducible Fak-deficient mice (Alb-creERT2; Fakflox/flox) to examine the role of FAK in HCC progression. We re-expressed wild-type and mutant FAK in Fak-deficient mice to determine FAK’s kinase activity in HCC development. We also examined the efficacy of a FAK kinase inhibitor PF-562271 on HCC inhibition. Results We found that deletion of Fak after tumors form significantly repressed MET/CAT-induced tumor progression. Ectopic FAK expression restored HCC formation in hepatocyte-specific Fak-deficient mice. However, overexpression of a FAK kinase-dead mutant led to reduced tumor load compared to mice which express wild-type FAK. Furthermore, PF-562271 significantly suppressed progression of MET/CAT-induced HCC. Conclusion Fak kinase activity is important for MET/CAT-induced HCC progression. Inhibiting FAK kinase activity provides a potential therapeutic strategy to treat HCC. PMID:27142958

  8. Hepatocyte Growth Factor/Scatter Factor and MET Are Involved in Arterial Repair and Atherogenesis

    PubMed Central

    McKinnon, Heather; Gherardi, Ermanno; Reidy, Michael; Bowyer, David

    2006-01-01

    Several studies have shown that in the arterial wall hepatocyte growth factor/scatter factor (HGF/SF) is expressed by smooth muscle cells (SMCs) but acts on endothelial cells, not SMCs. Other studies, however, have indicated that SMCs can respond to HGF/SF. We have reinvestigated expression and activity of HGF/SF and its receptor MET in arterial SMC and endothelial cell cultures and in whole arteries after superficial or deep injury or atherogenesis. High-density cultures of SMCs produced HGF/SF but did not express MET, whereas SMCs, at the leading edge of injured cultures, expressed both ligand and receptor and showed a dramatic motility and growth response to HGF/SF. In line with these results, HGF/SF and MET expression was undetectable in the media of uninjured carotid arteries but was induced after deep arterial injury in areas of SMC migration in the neointima. Strong MET expression was also observed in the SMCs of the atherosclerotic lesions of homozygous apoE−/− mice, whereas HGF/SF was expressed by macrophage-derived foam cells. These results demonstrate that MET is induced in migrating and proliferating SMCs and that HGF/SF and MET are key mediators of the SMC response in atherogenesis. PMID:16400035

  9. 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

  10. An association between BDNF Val66Met polymorphism and impulsivity in methamphetamine abusers.

    PubMed

    Su, Hang; Tao, Jingyan; Zhang, Jie; Xie, Ying; Sun, Yeming; Li, Liren; Xu, Ke; Han, Bin; Lu, Yuling; Sun, Haiwei; Wei, Youdan; Wang, Yue; Zhang, Yu; Zou, Shengzhen; Wu, Wenxiu; Zhang, Jiajia; Zhang, Xiangyang; He, Jincai

    2014-10-17

    Recent studies showed an association between a functional polymorphism of BDNF gene (Val66Met) and the susceptibility to methamphetamine addiction. We hypothesized that this polymorphism was associated with methamphetamine abuse and impulsivity in methamphetamine-abuse patients. The polymorphism was genotyped in 200 methamphetamine-abuse patients and 219 healthy controls. The association of the Val66Met polymorphism of the BDNF gene and impulsivity in 138 methamphetamine abusers were assessed using Barratt Impulsivity Scale-11(BIS-11) Chinese version. The relationship between the polymorphism and age of onset of methamphetamine abuse was also examined. Our results showed no significant differences in genotype and allele distributions between the methamphetamine abusers and controls. Within the methamphetamine-abuse group, subjects carried the Met allele had significantly higher attentional impulsivity scores of BIS compared to those with the Val/Val genotype. The Met allele was also associated with earlier age onset of methamphetamine use. Our findings suggest that the BDNF Val66Met gene polymorphism may influence attentional impulsivity in methamphetamine abusers. Moreover, the BDNF Val66Met gene polymorphism may contribute to onset age of methamphetamine use.

  11. 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

  12. BDNF Val66Met Polymorphism Influences Visuomotor Associative Learning and the Sensitivity to Action Observation

    PubMed Central

    Taschereau-Dumouchel, Vincent; Hétu, Sébastien; Michon, Pierre-Emmanuel; Vachon-Presseau, Etienne; Massicotte, Elsa; De Beaumont, Louis; Fecteau, Shirley; Poirier, Judes; Mercier, Catherine; Chagnon, Yvon C.; Jackson, Philip L.

    2016-01-01

    Motor representations in the human mirror neuron system are tuned to respond to specific observed actions. This ability is widely believed to be influenced by genetic factors, but no study has reported a genetic variant affecting this system so far. One possibility is that genetic variants might interact with visuomotor associative learning to configure the system to respond to novel observed actions. In this perspective, we conducted a candidate gene study on the Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism, a genetic variant linked to motor learning in regions of the mirror neuron system, and tested the effect of this polymorphism on motor facilitation and visuomotor associative learning. In a single-pulse TMS study carried on 16 Met (Val/Met and Met/Met) and 16 Val/Val participants selected from a large pool of healthy volunteers, Met participants showed significantly less muscle-specific corticospinal sensitivity during action observation, as well as reduced visuomotor associative learning, compared to Val homozygotes. These results are the first evidence of a genetic variant tuning sensitivity to action observation and bring to light the importance of considering the intricate relation between genetics and associative learning in order to further understand the origin and function of the human mirror neuron system. PMID:27703276

  13. MET1 is a thylakoid-associated TPR protein involved in photosystem II supercomplex formation and repair in Arabidopsis.

    PubMed

    Bhuiyan, Nazmul H; Friso, Giulia; Poliakov, Anton; Ponnala, Lalit; van Wijk, Klaas J

    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.

  14. 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

  15. Exposure-response analysis of rilotumumab in gastric cancer: the role of tumour MET expression

    PubMed Central

    Zhu, M; Tang, R; Doshi, S; Oliner, K S; Dubey, S; Jiang, Y; Donehower, R C; Iveson, T; Loh, E Y; Zhang, Y

    2015-01-01

    Background: Rilotumumab, an investigational, monoclonal antibody, inhibits MET-mediated signalling. In a randomized phase 2 trial of rilotumumab±epirubicin/cisplatin/capecitabine in gastric or oesophagogastric junction cancer, patients receiving rilotumumab showed a trend towards improved survival, especially in MET-positive patients, but no clear dose–response relationship was observed. Exposure-response and biomarker analyses were used for dose selection and to differentiate patient subpopulations that may benefit most from treatment. Here, we analyse rilotumumab exposure–survival and exposure–safety and the impact of MET expression on these relationships. Methods: Individual rilotumumab exposure parameters were generated using population pharmacokinetic modelling. Relationships among rilotumumab dose (7.5 and 15 mg kg−1), exposure, and clinical outcomes (progression-free survival (PFS) and overall survival (OS)) were evaluated with Cox regression models and Kaplan–Meier plots. MET status and other baseline covariates were evaluated in subgroup and multivariate analyses. Treatment-emergent adverse events were summarised by exposure. Results: Among MET-positive patients, higher rilotumumab exposure, vs placebo and low exposure, was associated with improved median PFS (80% CI: 7.0 (5.7–9.7) vs 4.4 (2.9–4.9) and 5.5 (4.2–6.8) months) and OS (13.4 (10.6–18.6) vs 5.7 (4.7–10.2) and 8.1 (6.9–11.1) months) without increased toxicity. No rilotumumab benefit was seen among MET-negative patients. Conclusions: Rilotumumab had an exposure-dependent treatment effect in patients with MET-positive gastric or oesophagogastric junction cancer. PMID:25584489

  16. 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

  17. 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

  18. 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.

  19. 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

  20. 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

  1. Replication study implicates COMT val158met polymorphism as a modulator of probabilistic reward learning.

    PubMed

    Lancaster, T M; Heerey, E A; Mantripragada, K; Linden, D E J

    2015-07-01

    Previous studies suggest that a single nucleotide polymorphism in the catechol-O-methyltransferase (COMT) gene (val158met) may modulate reward-guided decision making in healthy individuals. The polymorphism affects dopamine catabolism and thus modulates prefrontal dopamine levels, which may lead to variation in individual responses to risk and reward. We previously showed, using tasks that index reward responsiveness (measured by responses bias towards reinforced stimuli) and risk taking (measured by the Balloon Analogue Risk Task), that COMT met homozygotes had increased reward responsiveness and, thus, an increased propensity to seek reward. In this study, we sought to replicate these effects in a larger, independent cohort of Caucasian UK university students and staff with similar demographic characteristics (n = 101; 54 females, mean age: 22.2 years). Similarly to our previous study, we observed a significant trial × COMT genotype interaction (P = 0.047; η(2) = 0.052), which was driven by a significant effect of COMT on the incremental acquisition of response bias [response bias at block 3 - block 1 (met/met > val/val: P = 0.028) and block 3 - block 2 (met/met > val/val: P = 0.007)], suggesting that COMT met homozygotes demonstrated higher levels of reward responsiveness by the end of the task. However, we failed to see main effects of COMT genotype on overall response bias or risk-seeking behaviour. These results provide additional evidence that prefrontal dopaminergic variation may have a role in reward responsiveness, but not risk-seeking behaviour. Our findings may have implications for neuropsychiatric disorders characterized by clinical deficits in reward processing such as anhedonia. PMID:26096878

  2. 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

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

    PubMed

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

    2015-01-01

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

  4. 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

  5. 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

  6. 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

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

    PubMed Central

    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

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

    PubMed Central

    Martins, Gabriela J.; Shahrokh, Mondona; Powell, Elizabeth M.

    2011-01-01

    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 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

  9. 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.

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

    PubMed Central

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

    2015-01-01

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

  11. OTULIN Antagonizes LUBAC Signaling by Specifically Hydrolyzing Met1-Linked Polyubiquitin

    PubMed Central

    Keusekotten, Kirstin; Elliott, Paul Ronald; Glockner, Laura; Fiil, Berthe Katrine; Damgaard, Rune Busk; Kulathu, Yogesh; Wauer, Tobias; Hospenthal, Manuela Kathrin; Gyrd-Hansen, Mads; Krappmann, Daniel; Hofmann, Kay; Komander, David

    2013-01-01

    Summary The linear ubiquitin (Ub) chain assembly complex (LUBAC) is an E3 ligase that specifically assembles Met1-linked (also known as linear) Ub chains that regulate nuclear factor κB (NF-κB) signaling. Deubiquitinases (DUBs) are key regulators of Ub signaling, but a dedicated DUB for Met1 linkages has not been identified. Here, we reveal a previously unannotated human DUB, OTULIN (also known as FAM105B), which is exquisitely specific for Met1 linkages. Crystal structures of the OTULIN catalytic domain in complex with diubiquitin reveal Met1-specific Ub-binding sites and a mechanism of substrate-assisted catalysis in which the proximal Ub activates the catalytic triad of the protease. Mutation of Ub Glu16 inhibits OTULIN activity by reducing kcat 240-fold. OTULIN overexpression or knockdown affects NF-κB responses to LUBAC, TNFα, and poly(I:C) and sensitizes cells to TNFα-induced cell death. We show that OTULIN binds LUBAC and that overexpression of OTULIN prevents TNFα-induced NEMO association with ubiquitinated RIPK1. Our data suggest that OTULIN regulates Met1-polyUb signaling. PMID:23746843

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

    PubMed Central

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

    2015-01-01

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

  13. 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

  14. PAK1 mediates pancreatic cancer cell migration and resistance to MET inhibition

    PubMed Central

    Zhou, Wei; Jubb, Adrian M; Lyle, Karen; Xiao, Qian; Ong, Christy C; Desai, Rupal; Fu, Ling; Gnad, Florian; Song, Qinghua; Haverty, Peter M; Aust, Daniela; Grützmann, Robert; Romero, Mally; Totpal, Klara; Neve, Richard M; Yan, Yibing; Forrest, William F; Wang, Yulei; Raja, Rajiv; Pilarsky, Christian; de Jesus-Acosta, Ana; Belvin, Marcia; Friedman, Lori S; Merchant, Mark; Jaffee, Elizabeth M; Zheng, Lei; Koeppen, Hartmut; Hoeflich, Klaus P

    2015-01-01

    Pancreatic adenocarcinoma (PDAC) is a major unmet medical need and a deeper understanding of molecular drivers is needed to advance therapeutic options for patients. We report here that p21-activated kinase 1 (PAK1) is a central node in PDAC cells downstream of multiple growth factor signalling pathways, including hepatocyte growth factor (HGF) and MET receptor tyrosine kinase. PAK1 inhibition blocks signalling to cytoskeletal effectors and tumour cell motility driven by HGF/MET. MET antagonists, such as onartuzumab and crizotinib, are currently in clinical development. Given that even highly effective therapies have resistance mechanisms, we show that combination with PAK1 inhibition overcomes potential resistance mechanisms mediated either by activation of parallel growth factor pathways or by direct amplification of PAK1. Inhibition of PAK1 attenuated in vivo tumour growth and metastasis in a model of pancreatic adenocarcinoma. In human tissues, PAK1 is highly expressed in a proportion of PDACs (33% IHC score 2 or 3; n = 304) and its expression is significantly associated with MET positivity (p < 0.0001) and linked to a widespread metastatic pattern in patients (p = 0.067). Taken together, our results provide evidence for a functional role of MET/PAK1 signalling in pancreatic adenocarcinoma and support further characterization of therapeutic inhibitors in this indication. PMID:25074413

  15. 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

  16. 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

  17. HGF/MET signaling promotes glioma growth via up-regulation of Cox-2 expression and PGE2 production

    PubMed Central

    Zhao, Yan; Sun, Ying; Zhang, Haiyan; Liu, Xing; Du, Wenzong; Li, Yongli; Zhang, Junhe; Chen, Lingchao; Jiang, Chuanlu

    2015-01-01

    Cyclooxygenase2 (Cox-2) is well known for glioma growth through up-regulation of prostaglandin E2 (PGE2) levels. MET, a hepatocyte growth factor (HGF) receptor, is also frequently high expressed in glioma, which promotes glioma growth and invasion. Here, we demonstrate that HGF/MET signaling can promote PGE2 production in glioma cells via Cox-2 up-regulation. RNA inhibition of MET suggested that MET signaling is essential for Cox-2 up-regulation. Moreover, HGF could enhance Cox-2 expression and PGE2 release. Knockdown of Cox-2 inhibited growth-promoting effects of HGF, suggesting that HGF/MET functioned via Cox-2/PGE2 pathway. Therefore, our work reveals a critical relationship of Cox-2/PGE2 and HGF/MET signaling in promoting glioma cells proliferation. Further, targeting MET and Cox-2 may represent an attractive target therapy for glioma. PMID:26097553

  18. 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

  19. 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

  20. 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.

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

    PubMed

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

    2010-08-23

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

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

    PubMed

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

    2016-08-01

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

  3. The effects of met expectations on newcomer attitudes and behaviors: a review and meta-analysis.

    PubMed

    Wanous, J P; Poland, T D; Premack, S L; Davis, K S

    1992-06-01

    A review of research on the effects of met expectations for newcomers to organizations located 31 studies of 17,241 people. A meta-analysis found mean (corrected) correlations of .39 for job satisfaction and organizational commitment, .29 for intent to leave, .19 for job survival, and .11 for job performance. However, all of these mean correlations had significant between-studies variance. By using strict conformity with Porter and Steer's (1973) definition of met expectations, we identified a subset of studies that had nonsignificant between-studies variance for all correlations except job satisfaction. Furthermore, the mean correlations in these subgroups were very similar to those for the entire group. Future research should consider both the direction of the met expectations discrepancy (i.e., over- vs. underfulfillment) and alternative ways to measure organizational reality.

  4. 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

  5. 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.

  6. BDNF val66met Polymorphism Affects Aging of Multiple Types of Memory

    PubMed Central

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

    2014-01-01

    The BDNF val66met polymorphism (rs6265) influences activity-dependent secretion of brain-derived neurotrophic factor in the synapse, which is crucial for learning and memory. Individuals homozygous or heterozygous for the met allele have lower BDNF secretion than val homozygotes and may be at risk for reduced declarative memory performance, but it remains unclear which types of declarative memory may be affected and how aging of memory across the lifespan is impacted by the BDNF val66met polymorphism. This cross-sectional study investigated the effects of BDNF polymorphism on multiple indices of memory (item, associative, prospective, subjective complaints) in a lifespan sample of 116 healthy adults aged 20-93 years. Advancing age showed a negative effect on item, associative and prospective memory, but not on subjective memory complaints. For item and prospective memory, there were significant age x BDNF group interactions, indicating the adverse effect of age on memory performance across the lifespan was much stronger in the BDNF met carriers than for the val homozygotes. BDNF met carriers also endorsed significantly greater subjective memory complaints, regardless of age, and showed a trend (p < .07) toward poorer associative memory performance compared to val homozygotes. These results suggest that genetic predisposition to the availability of brain-derived neurotrophic factor, by way of the BDNF val66met polymorphism, exerts an influence on multiple indices of episodic memory – in some cases in all individuals regardless of age (subjective memory and perhaps associative memory), in others as an exacerbation of age-related differences in memory across the lifespan (item and prospective memory). PMID:25264352

  7. 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.

  8. Inactivation of MET10 in brewer's yeast specifically increases SO2 formation during beer production.

    PubMed

    Hansen, J; Kielland-Brandt, M C

    1996-11-01

    Sulfite is widely used as an antioxidant in food production. In beer brewing, sulfite has the additional role of stabilizing the flavor by forming adducts with aldehydes. Inadequate amounts of sulfite are sometimes produced by brewer's yeasts, so means of controlling the sulfite production are desired. In Saccharomyces yeasts, MET10 encodes a subunit of sulfite reductase. Partial or full elimination of MET10 gene activity in a brewer's yeast resulted in increased sulfite accumulation. Beer produced with such yeasts was quite satisfactory and showed increased flavor stability.

  9. 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.

  10. 'MetLife V. Glenn': the Court addresses a conflict over conflicts in ERISA benefit administration.

    PubMed

    Jost, Timothy Stoltzfus

    2008-01-01

    In its June 2008 decision in MetLife v. Glenn, the Supreme Court held that federal courts reviewing claim denials by Employee Retirement Income Security Act (ERISA) employee benefit plan administrators should take into account the fact that plan administrators (insurers or self-insured plans) face a conflict of interest because they pay claims out of their own pockets and arguably stand to profit by denying claims. This paper analyzes the history of the conflict in the courts over this issue; the Supreme Court's resolution of it in MetLife; and the implications of this decision for plans, beneficiaries, and health policy.

  11. PKG II reverses HGF-triggered cellular activities by phosphorylating serine 985 of c-Met in gastric cancer cells

    PubMed Central

    Zhu, Miaolin; Qian, Hai; Jiang, Lu; Lan, Ting; Wu, Min; Pang, Ji; Chen, Yongchang

    2016-01-01

    Previous studies showed that type II cGMP-dependent protein kinase G (PKG II) could inhibit the activation of epidermal growth factor receptor (EGFR). Both c-Met and EGFR belong to family of receptor tyrosine kinases (RTKs) and have high molecular analogy. However, the effect of PKG II on c-Met activation is unclear. This study was designed to investigate the inhibitory effect of PKG II on the activation of c-Met and consequent biological activities. The results from CCK8 assay, Transwell assay and TUNEL assay showed that HGF enhanced cell proliferation and migration, and decreased cell apoptosis. Activated PKG II reversed the above changes caused by HGF. Immunoprecipitation and Western blotting results showed that PKG II could bind with c-Met and phosphorylate its Ser985, and thereby inhibited HGF-induced activation of c-Met and MAPK/ERK and PI3K/Akt/mTOR mediated signal transduction. When Ser985 of c-Met was mutated to Alanine for preventing phosphorylation of this site, the blocking effect of PKG II on c-Met activation was annulled. When Ser985 of c-Met was mutated to Aspartic acid for mimicking phosphorylation of this site, HGF-induced activation of c-Met was prevented. In conclusion, the results indicated that PKG II could block c-Met activation via phosphorylating Ser985 of this RTK. PMID:27147579

  12. 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

  13. Both Met(109) and Met(112) Are Utilized For Cu(II) Coordination By The Amyloidogenic Fragment of The Human Prion Protein at Physiological pH

    PubMed Central

    Shearer, Jason; Soh, Pamela; Lentz, Stefanie

    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 CuII ions under physiological conditions; four copper binding sites can be found in the octarepeat domain between residues 61 – 91, while another copper binding site can be found in the unstructured “amyloidogenic” domain between residues 91 – 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 CuII coordination site within PrP(91–126) is found between residues 106–114. It was shown that CuII is contained within a square planar (N/O)3S 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 CuII 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 → Ile “mutations” we show that the CuII coordination environment within PrP(106–114) is actually comprised of a mixture of two major species; one CuII(N/O)3S center with the M(109) thioether coordinated to CuII and another CuII(N/O)3S center with the M(112) thioether coordinated to CuII. Furthermore, deletion of one or more Met residues from the primary sequence of PrP(106–114) both reduces the CuII affinity of the peptide by two to seven fold, and renders the resulting CuII metallopeptides redox inactive. The biological implications of these findings are discussed. PMID:18778855

  14. 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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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 resolution if the ME...

  16. 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

  17. 21 CFR 111.75 - What must you do to determine whether specifications are met?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... Production and Process Control System § 111.75 What must you do to determine whether specifications are met... submit a petition, under 21 CFR 10.30, to request an exemption from the testing requirements in paragraph...) Rely on a certificate of analysis from the supplier of the component that you receive, provided...

  18. Molecular determinants of azo reduction activity in the strain Pseudomonas putida MET94.

    PubMed

    Mendes, Sónia; Pereira, Luciana; Batista, Carlos; Martins, Lígia O

    2011-10-01

    Azo dyes are the major group of synthetic colourants used in industry and are serious environmental pollutants. In this study, Pseudomonas putida MET94 was selected from 48 bacterial strains on the basis of its superior ability to degrade a wide range of structurally diverse azo dyes. P. putida is a versatile microorganism with a well-recognised potential for biodegradation or bioremediation applications. P. putida MET94 removes, in 24 h and under anaerobic growing conditions, more than 80% of the majority of the structurally diverse azo dyes tested. Whole cell assays performed under anaerobic conditions revealed up to 90% decolourisation in dye wastewater bath models. The involvement of a FMN dependent NADPH: dye oxidoreductase in the decolourisation process was suggested by enzymatic measurements in cell crude extracts. The gene encoding a putative azoreductase was cloned from P. putida MET94 and expressed in Escherichia coli. The purified P. putida azoreductase is a 40 kDa homodimer with broad substrate specificity for azo dye reduction. The presence of dioxygen leads to the inhibition of the decolourisation activity in agreement with the results of cell cultures. The kinetic mechanism follows a ping-pong bi-bi reaction scheme and aromatic amine products were detected in stoichiometric amounts by high-performance liquid chromatography. Overall, the results indicate that P. putida MET94 is a promising candidate for bioengineering studies aimed at generating more effective dye-reducing strains.

  19. 42 CFR 59.5 - What requirements must be met by a family planning project?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... requirements must be met by a family planning project? (a) Each project supported under this part must: (1..., race, color, national origin, handicapping condition, age, sex, number of pregnancies, or marital...) Prenatal care and delivery; (B) Infant care, foster care, or adoption; and (C) Pregnancy termination....

  20. 42 CFR 59.5 - What requirements must be met by a family planning project?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... requirements must be met by a family planning project? (a) Each project supported under this part must: (1..., race, color, national origin, handicapping condition, age, sex, number of pregnancies, or marital...) Prenatal care and delivery; (B) Infant care, foster care, or adoption; and (C) Pregnancy termination....

  1. MetaCoMET: a web platform for discovery and visualization of the core microbiome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A key component of the analysis of microbiome datasets is the identification of OTUs shared between multiple experimental conditions, commonly referred to as the core microbiome. Results: We present a web platform named MetaCoMET that enables the discovery and visualization of the core microbiome an...

  2. 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)

  3. 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…

  4. Simple and effective procedure for conformational search of macromolecules. Application to Met- and Leu-Enkephalin

    SciTech Connect

    Meirovitch, H.; Meirovitch, E. ); Michel, A.G. ); Vasquez, M. )

    1994-06-23

    A simple and efficient method for searching the conformational space of macromolecules is presented. With this method an initial set of relatively low-energy structures is generated, and their energies are further minimized with a procedure that enables escaping from local energy minima. Illustrative calculations are described for Met- and Leu-enkephalin. 37 refs., 1 tab.

  5. Association of functional COMT Val108/Met polymorphism with smoking cessation in a nicotine replacement therapy.

    PubMed

    Sun, Hongqiang; Guo, Song; Chen, Dafang; Yang, Fude; Zou, Yizhuang; Di, Xiaolan; Cao, Yanjun; Kosten, Thomas; Lu, Lin; Zhang, Xiang Yang

    2012-12-01

    Nicotine replacement treatment (NRT) can be efficacious for smoking cessation, but used by only a minority of smokers in China. Pharmacogenetic matching may improve treatment outcomes for NRT in subgroups of smokers. We evaluated the efficacy and safety of sublingual nicotine tablets (SNT) for smoking cessation and the association of catechol-O-methyltransferase (COMT) genotype with efficacy in this smoking cessation trial among Chinese smokers. We conducted a double-blind, placebo-controlled, 8-week trial of SNT with a follow-up at week 12 among 250 Chinese smokers. Efficacy and safety were evaluated at day 4 and weeks 2, 4, 6, 8, and 12. Abstinence was biochemically verified by exhaled carbon monoxide (CO) and urine cotinine. The COMT Val108Met genotype was determined as a restriction fragment length polymorphism. Our results showed that the success rates for complete abstinence were greater for active versus placebo treatments at 8 weeks (48 vs. 17 %) and 12 weeks (52 vs. 19 %) (both p < 0.0001). Craving was significantly reduced from week 2 on active treatment compared to placebo. Adverse events were mild and tolerable. We found a genotype by treatment interaction at 12 weeks with greater abstinence rates in the COMT Val/Val (50 vs. 15 %) than the Met/Val + Met/Met genotypes (46 vs. 25 %). We found that SNT significantly increased smoking abstinence, reduced craving and was well tolerated, and the COMT Val/Val genotype was associated with a greater improvement in smoking cessation.

  6. 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…

  7. 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

  8. 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…

  9. Radioimmunoassay of met-enkephalin in microdissected areas of paraformaldehyde-fixed rat brain

    SciTech Connect

    Correa, F.M.A.; Saavedra, J.M.

    1984-02-27

    The effects were studied of various sample preparation procedures on rat brain met-enkephalin content, measured by radioimmunoassay. Whole brain met-enkephalin content of rats killed by decapitation followed by immediate tissue freezing was similar to that of rats killed by microwave irradiation and to those of rats anesthetized with pentobarbital or halothane before killing, whether previously perfused with paraformaldehyde or not. In contrast, a decrease (up to 80%) in met-enkephalin concentrations was observed when brain samples were frozen and thawed to mimic the procedure utilized in the ''punch'' technique for analysis of discrete brain nuclei. This decrease was totally prevented by paraformaldehyde perfusion of the brain prior to sacrifice. Brain perfusion did not alter the amount of immunoassayable met-enkephalin extracted from tissue or its profile after Sephadex chromatography. Paraformaldehyde perfusion results in better morphological tissue preservation and facilitates the ''punch'' dissecting technique. Paraformaldehyde perfusion may be the procedure of choice for the measurement of neuropeptides in specific brain nuclei dissected by the ''punch'' technique.

  10. 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.…

  11. 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…

  12. 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...

  13. 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...

  14. 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...

  15. 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...

  16. 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…

  17. 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...

  18. The MetLife Survey of the American Teacher: Teachers, Parents and the Economy

    ERIC Educational Resources Information Center

    MetLife, Inc., 2012

    2012-01-01

    "The MetLife Survey of the American Teacher: Teachers, Parents and the Economy" (2011) examines the teaching profession and parent-school engagement at a time when there has been a prolonged economic downturn. The survey explores how teachers, parents and schools are working together to promote student learning and healthy development in the…

  19. 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...

  20. 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.

  1. Catechol O-methyltransferase Val158Met polymorphism is associated with cognitive performance in nondemented adults.

    PubMed

    de Frias, Cindy M; Annerbrink, Kristina; Westberg, Lars; Eriksson, Elias; Adolfsson, Rolf; Nilsson, Lars-Göran

    2005-07-01

    The catechol O-methyltransferase (COMT) gene is essential in the metabolic degradation of dopamine in the prefrontal cortex. In the present study, we examined the effect of a Val158Met polymorphism in the COMT gene on individual differences and changes in cognition (executive functions and visuospatial ability) in adulthood and old age. The participants were 292 nondemented men (initially aged 35-85 years) from a random sample of the population (i.e., the Betula study) tested at two occasions with a 5-year interval. Confirmatory factor analyses were used to test the underlying structure of three indicators of executive functions (verbal fluency, working memory, and Tower of Hanoi). Associations between COMT, age, executive functioning, and visuospatial (block design) tasks were examined using repeated-measures analyses of variance. Carriers of the Val allele (with higher enzyme activity) compared with carriers of the Met/Met genotype (with low enzyme activity) performed worse on executive functioning and visuospatial tasks. Individuals with the Val/Val genotype declined in executive functioning over the 5-year period, whereas carriers of the Met allele remained stable in performance. An Age x COMT interaction for visuospatial ability located the effect for middle-aged men only. This COMT polymorphism is a plausible candidate gene for executive functioning and fluid intelligence in nondemented middle-aged and older adults. PMID:16102234

  2. 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

  3. Genetic susceptibility to family environment: BDNF Val66met and 5-HTTLPR influence depressive symptoms.

    PubMed

    Dalton, Elizabeth D; Hammen, Constance L; Najman, Jake M; Brennan, Patricia A

    2014-12-01

    Functional genetic polymorphisms associated with Brain-Derived Neurotrophic Factor (BDNF) and serotonin (5-HTTLPR) have demonstrated associations with depression in interaction with environmental stressors. In light of evidence for biological connections between BDNF and serotonin, it is prudent to consider genetic epistasis between variants in these genes in the development of depressive symptoms. The current study examined the effects of val66met, 5-HTTLPR, and family environment quality on youth depressive symptoms in adolescence and young adulthood in a longitudinal sample oversampled for maternal depression history. A differential susceptibility model was tested, comparing the effects of family environment on depression scores across different levels of a cumulative plasticity genotype, defined as presence of both, either, or neither plasticity alleles (defined here as val66met Met and 5-HTTLPR 'S'). Cumulative plasticity genotype interacted with family environment quality to predict depression among males and females at age 15. After age 15, however, the interaction of cumulative plasticity genotype and early family environment quality was only predictive of depression among females. Results supported a differential susceptibility model at age 15, such that plasticity allele presence was associated with more or less depressive symptoms depending on valence of the family environment, and a diathesis-stress model of gene-environment interaction after age 15. These findings, although preliminary because of the small sample size, support prior results indicating interactive effects of 5-HTTLPR, val66met, and environmental stress, and suggest that family environment may have a stronger influence on genetically susceptible women than men.

  4. 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...

  5. Contributions of COMT Val158Met to cognitive stability and flexibility in infancy

    PubMed Central

    Markant, Julie; Cicchetti, Dante; Hetzel, Susan; Thomas, Kathleen M.

    2014-01-01

    Adaptive behavior requires focusing on relevant tasks while remaining sensitive to novel information. In adult studies of cognitive control, cognitive stability involves maintaining robust cognitive representations while cognitive flexibility involves updating of representations in response to novel information. Previous adult research has shown that the Met allele of the COMT Val158Met gene is associated with enhanced cognitive stability whereas the Val allele is associated with enhanced cognitive flexibility. Here we propose that the stability/flexibility framework can also be applied to infant research, with stability mapping onto early indices of behavioral regulation and flexibility mapping onto indices of behavioral reactivity. From this perspective, the present study examined whether COMT genotype was related to 7-month-old infants’ reactivity to novel stimuli and behavioral regulation. Cognitive stability and flexibility were assessed using (1) a motor approach task, (2) a habituation task, and (3) a parental-report measure of temperament. Val carriers were faster to reach for novel toys during the motor approach task and received higher scores on the temperament measure of approach to novelty. Met carriers showed enhanced dishabituation to the novel stimulus during the habituation task and received higher scores on the temperament measures of sustained attention and behavioral regulation. Overall, these results are consistent with adult research suggesting that the Met and Val alleles are associated with increased cognitive stability and flexibility, respectively, and thus suggest that COMT genotype may similarly affect cognitive function in infancy. PMID:24410746

  6. 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...

  7. 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...

  8. 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...

  9. 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...

  10. 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...

  11. 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

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

    PubMed

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

    2013-03-19

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

  13. The BDNF Val66Met Polymorphism Modulates Sleep Intensity: EEG Frequency- and State-Specificity

    PubMed Central

    Bachmann, Valérie; Klein, Carina; Bodenmann, Sereina; Schäfer, Nikolaus; Berger, Wolfgang; Brugger, Peter; Landolt, Hans-Peter

    2012-01-01

    Study Objectives: EEG slow waves are the hallmark of deep NREM sleep and may reflect the restorative functions of sleep. Evidence suggests that increased sleep slow waves after sleep deprivation reflect plastic synaptic processes, and that brain-derived neurotrophic factor (BDNF) is causally involved in their homeostatic regulation. The functional Val66Met polymorphism of the gene encoding pro-BDNF causes impaired activity-dependent secretion of mature BDNF protein. We investigated whether this polymorphism contributes to the pronounced inter-individual variation in sleep slow wave activity (SWA) in humans. Setting: Sleep laboratory in temporal isolation unit. Participants: Eleven heterozygous Met allele carriers and 11 individually sex- and age-matched Val/Val homozygotes. Interventions: Forty hours prolonged wakefulness. Measurements and Results: Cognitive performance, subjective state, and waking and sleep EEG in baseline and after sleep deprivation were studied. Val/Val homozygotes showed better response accuracy than Met allele carriers on a verbal 2-back working memory task. This difference did not reflect genotype-dependent differences in sleepiness, well-being, or sustained attention. In baseline and recovery nights, deep stage 4 sleep and NREM sleep intensity as quantified by EEG SWA (0.75-4.5 Hz) were higher in Val/Val compared to Val/Met genotype. Similar to sleep deprivation, the difference was most pronounced in the first NREM sleep episode. By contrast, increased activity in higher EEG frequencies (> 6 Hz) in wakefulness and REM sleep was distinct from the effects of prolonged wakefulness. Conclusion: BDNF contributes to the regulation of sleep slow wave oscillations, suggesting that genetically determined variation in neuronal plasticity modulates NREM sleep intensity in humans. Citation: Bachmann V; Klein C; Bodenmann S; Schäfer N; Berger W; Brugger P; Landolt HP. The BDNF Val66Met polymorphism modulates sleep intensity: EEG frequency- and state

  14. 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

  15. 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

  16. 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.

  17. Clinicopathological Significance and Diagnostic Accuracy of c-MET Expression by Immunohistochemistry in Gastric Cancer: A Meta-Analysis

    PubMed Central

    Pyo, Jung-Soo; Kang, Guhyun

    2016-01-01

    Purpose The aim of the present study was to elucidate the clinicopathological significance and diagnostic accuracy of immunohistochemistry (IHC) for determining the mesenchymal epidermal transition (c-MET) expression in patients with gastric cancer (GC). Materials and Methods The present meta-analysis investigated the correlation between c-MET expression as determined by IHC and the clinicopathological parameters in 8,395 GC patients from 37 studies that satisfied the eligibility criteria. In addition, a concordance analysis was performed between c-MET expression as determined by IHC and c-MET amplification, and the diagnostic test accuracy was reviewed. Results The estimated rate of c-MET overexpression was 0.403 (95% confidence interval [CI], 0.327~0.484) and it was significantly correlated with male patients, poor differentiation, lymph node metastasis, higher TNM stage, and human epidermal growth factor receptor 2 (HER2) positivity in IHC analysis. There was a significant correlation between c-MET expression and worse overall survival rate (hazard ratio, 1.588; 95% CI, 1.266~1.992). The concordance rates between c-MET expression and c-MET amplification were 0.967 (95% CI, 0.916~0.987) and 0.270 (95% CI, 0.173~0.395) for cases with non-overexpressed and overexpressed c-MET, respectively. In the diagnostic test accuracy review, the pooled sensitivity and specificity were 0.56 (95% CI, 0.50~0.63) and 0.79 (95% CI, 0.77~0.81), respectively. Conclusions The c-MET overexpression as determined by IHC was significantly correlated with aggressive tumor behavior and positive IHC status for HER2 in patients with GC. In addition, the c-MET expression status could be useful in the screening of c-MET amplification in patients with GC. PMID:27752391

  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. 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.

  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. 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

  2. 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

  3. Association between the catechol-o-methyltransferase val158met polymorphism with susceptibility and severity of carpal tunnel syndrome

    PubMed Central

    Eroğlu, P; Görükmez, O; Özemri Sağ, Ş; Yakut, T

    2015-01-01

    Abstract Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy of the upper extremity. In this study, we aimed to clarify the relationships between the catechol-O-methyltransferase (COMT) gene Val158Met (rs4680) polymorphism and development, functional and clinical status of CTS. Ninety-five women with electro diagnostically confirmed CTS and 95 healthy controls were enrolled in the study. The functional and clinical status of the patients was measured by the Turkish version of the Boston Questionnaire and intensity of pain related to the past 2 weeks was evaluated on a visual analog scale (VAS). The Val158Met polymorphism was determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), method. We divided patients according to the genotypes of the Val158Met polymorphism as Val/Val, Val/Met and Met/Met. There were not any significant differences in terms of Val158Met polymorphisms between patients and healthy controls (p >0.05). We also did not find any relationships between the Val158Met polymorphism and CTS (p >0.05). In conclusion, although we did not find any relationships between CTS and the Val158Met polymorphism, we could not generalize this result to the general population. Future studies are warranted to conclude precise associations.

  4. 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

  5. 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

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

    PubMed Central

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

    2009-01-01

    The establishment of appropriate neural circuitry depends upon the coordination of multiple developmental events across space and time. These events include proliferation, migration, differentiation, and survival - all of which can be mediated by hepatocyte growth factor (HGF) signaling through the Met receptor tyrosine kinase. We previously found a functional promoter variant of the MET gene to be associated with autism spectrum disorder, suggesting that forebrain circuits governing social and emotional function may be especially vulnerable to developmental disruptions in HGF/Met signaling. However, little is known about the spatiotemporal distribution of Met expression in the forebrain during the development of such circuits. To advance our understanding of the neurodevelopmental influences of Met activation, we employed complementary Western blotting, in situ hybridization and immunohistochemistry to comprehensively map Met transcript and protein expression throughout perinatal and postnatal development of the mouse forebrain. Our studies reveal complex and dynamic spatiotemporal patterns of expression during this period. Spatially, Met transcript is localized primarily to specific populations of projection neurons within the neocortex and in structures of the limbic system, including the amygdala, hippocampus and septum. Met protein appears to be principally located in axon tracts. Temporally, peak expression of transcript and protein occurs during the second postnatal week. This period is characterized by extensive neurite outgrowth and synaptogenesis, supporting a role for the receptor in these processes. Collectively, these data suggest that Met signaling may be necessary for the appropriate wiring of forebrain circuits with particular relevance to social and emotional dimensions of behavior. PMID:19226509

  7. Quantitative phosphokinome analysis of the Met pathway activated by the invasin internalin B from Listeria monocytogenes.

    PubMed

    Reinl, Tobias; Nimtz, Manfred; Hundertmark, Claudia; Johl, Thorsten; Kéri, György; Wehland, Jürgen; Daub, Henrik; Jänsch, Lothar

    2009-12-01

    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 iTRAQ 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

  8. Roles of hepatocyte growth factor/scatter factor and the met receptor in the early development of the metanephros.

    PubMed

    Woolf, A S; Kolatsi-Joannou, M; Hardman, P; Andermarcher, E; Moorby, C; Fine, L G; Jat, P S; Noble, M D; Gherardi, E

    1995-01-01

    Several lines of evidence suggest that hepatocyte growth factor/scatter factor (HGF/SF), a soluble protein secreted by embryo fibroblasts and several fibroblast lines, may elicit morphogenesis in adjacent epithelial cells. We investigated the role of HGF/SF and its membrane receptor, the product of the c-met protooncogene, in the early development of the metanephric kidney. At the inception of the mouse metanephros at embryonic day 11, HGF/SF was expressed in the mesenchyme, while met was expressed in both the ureteric bud and the mesenchyme, as assessed by reverse transcription PCR, in situ hybridization, and immunohistochemistry. To further investigate the expression of met in renal mesenchyme, we isolated 13 conditionally immortal clonal cell lines from transgenic mice expressing a temperature-sensitive mutant of the SV-40 large T antigen. Five had the HGF/SF+/met+ phenotype and eight had the HGF/SF-/met+ phenotype. None had the HGF/SF+/met- nor the HGF/SF-/met- phenotypes. Thus the renal mesenchyme contains cells that express HGF/SF and met or met alone. When metanephric rudiments were grown in serum-free organ culture, anti-HGF/SF antibodies (a) inhibited the differentiation of metanephric mesenchymal cells into the epithelial precursors of the nephron; (b) increased cell death within the renal mesenchyme; and (c) perturbed branching morphogenesis of the ureteric bud. These data provide the first demonstration for coexpression of the HGF/SF and met genes in mesenchymal cells during embryonic development and also imply an autocrine and/or paracrine role for HGF/SF and met in the survival of the renal mesenchyme and in the mesenchymal-epithelial transition that occurs during nephrogenesis. They also confirm the postulated paracrine role of HGF/SF in the branching of the ureteric bud.

  9. 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

  10. System for expression of microsporidian methionine amino peptidase type 2 (MetAP2) in the yeast Saccharomyces cerevisiae.

    PubMed

    Upadhya, Rajendra; Zhang, Hong Shan; Weiss, Louis M

    2006-10-01

    Microsporidia are parasitic protists of all classes of vertebrates and most invertebrates. They recently emerged as important infections in various immunosuppressed and immunocompetent patient populations. They are also important veterinary and agricultural pathogens. Current therapies for microsporidiosis include benzimidazoles, which bind tubulin-inhibiting microtubule assembly, and fumagillin and its derivatives, which bind and inhibit methionine amino peptidase type 2 (MetAP2). Benzimidazoles are not active against Enterocytozoon bieneusi, the most common cause of human microsporidiosis. Fumagillin is active against most microsporidia, including E. bieneusi, but thrombocytopenia has been a problem in clinical trials. There is a pressing need for more-specific microsporidian MetAP2 inhibitors. To expedite and facilitate the discovery of safe and effective MetAP2 inhibitors, we have engineered Saccharomyces cerevisiae to be dependent on Encephalitozoon cuniculi MetAP2 (EcMetAP2) for its growth, where EcMetAP2 is harbored on an episomal uracil-selectable tetracycline-regulated plasmid. We have also constructed a leucine-selectable tetracycline-regulated expression plasmid into which any MetAP2 gene can be cloned. By utilizing a 5-fluoroorotic acid-mediated plasmid shuffle in the EcMetAP2 yeast strain, a yeast strain can be generated whose growth is dependent on MetAP2 from any organism. The level of heterologous MetAP2 gene expression can be controlled by the addition of tetracycline to the growth medium. These yeast strains should permit high-throughput screening for the identification of new inhibitors with high specificity and activity toward microsporidian MetAP2.

  11. 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.

  12. 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.

  13. Incorporation of UK Met Office's radiation scheme into CPTEC's global model

    NASA Astrophysics Data System (ADS)

    Chagas, Júlio C. S.; Barbosa, Henrique M. J.

    2009-03-01

    Current parameterization of radiation in the CPTEC's (Center for Weather Forecast and Climate Studies, Cachoeira Paulista, SP, Brazil) operational AGCM has its origins in the work of Harshvardhan et al. (1987) and uses the formulation of Ramaswamy and Freidenreich (1992) for the short-wave absorption by water vapor. The UK Met Office's radiation code (Edwards and Slingo, 1996) was incorporated into CPTEC's global model, initially for short-wave only, and some impacts of that were shown by Chagas and Barbosa (2006). Current paper presents some impacts of the complete incorporation (both short-wave and long-wave) of UK Met Office's scheme. Selected results from off-line comparisons with line-by-line benchmark calculations are shown. Impacts on the AGCM's climate are assessed by comparing output of climate runs of current and modified AGCM with products from GEWEX/SRB (Surface Radiation Budget) project.

  14. 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.

  15. 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.

  16. ICMJE authorship criteria are not met in a substantial proportion of manuscripts submitted to Biochemia Medica

    PubMed Central

    Šupak-Smolčić, Vesna; Mlinarić, Ana; Antončić, Dragana; Horvat, Martina; Omazić, Jelena; Šimundić, Ana-Maria

    2015-01-01

    Introduction Our aim was to investigate if: (a) authors of Biochemia Medica meet authorship criteria given by International Committee of Medical Journal Editors (ICMJE), (b) authorship violations are more frequent in submissions containing some type of scientific misconduct. Materials and methods Self-reported authorship contributions regarding the three ICMJE criteria were analysed for all submissions to Biochemia Medica (February 2013-April 2015) which were forwarded to peer-review. To test the differences in frequencies we used Chi-squared test. P < 0.05 was considered statistically significant. Results 186 manuscripts were authored by 804 authors. All ICMJE criteria were met by 487/804 (61%) authors. The first and the last author met all the criteria more frequently than those authors in between (P < 0.001). The degree to which ICMJE criteria was met for the first author did not differ between manuscripts authored by only one author and those authored by >1 author (P = 0.859). In 9% of the manuscripts ICMJE criteria were not met by a single author. Authors of the 171/186 manuscripts declared that all persons qualify for authorship but only 49% of them satisfied all ICMJE criteria. Authors have failed to acknowledge contributors in 88/186 (47%) manuscripts; instead these contributors have been listed as authors without fulfilling ICMJE criteria. Authorship violation was not more common in 42 manuscripts with some type of scientific misconduct (P = 0.135). Conclusion Large proportion of authors of the manuscripts submitted to Biochemia Medica do not fulfil ICMJE criteria. Violation of authorship criteria is not more common for manuscripts with some type of scientific misconduct. PMID:26526700

  17. COMT val158met and 5-HTTLPR genetic polymorphisms moderate executive control in cannabis users.

    PubMed

    Verdejo-García, Antonio; Fagundo, Ana Beatriz; Cuenca, Aida; Rodriguez, Joan; Cuyás, Elisabet; Langohr, Klaus; de Sola Llopis, Susana; Civit, Ester; Farré, Magí; Peña-Casanova, Jordi; de la Torre, Rafael

    2013-07-01

    The adverse effects of cannabis use on executive functions are still controversial, fostering the need for novel biomarkers able to unveil individual differences in the cognitive impact of cannabis consumption. Two common genetic polymorphisms have been linked to the neuroadaptive impact of Δ9-tetrahydrocannabinol (THC) exposure and to executive functions in animals: the catechol-O-methyltransferase (COMT) gene val158met polymorphism and the SLC6A4 gene 5-HTTLPR polymorphism. We aimed to test if these polymorphisms moderate the harmful effects of cannabis use on executive function in young cannabis users. We recruited 144 participants: 86 cannabis users and 58 non-drug user controls. Both groups were genotyped and matched for genetic makeup, sex, age, education, and IQ. We used a computerized neuropsychological battery to assess different aspects of executive functions: sustained attention (CANTAB Rapid Visual Information Processing Test, RVIP), working memory (N-back), monitoring/shifting (CANTAB ID/ED set shifting), planning (CANTAB Stockings of Cambridge, SOC), and decision-making (Iowa Gambling Task, IGT). We used general linear model-based analyses to test performance differences between cannabis users and controls as a function of genotypes. We found that: (i) daily cannabis use is not associated with executive function deficits; and (ii) COMT val158met and 5-HTTLPR polymorphisms moderate the link between cannabis use and executive performance. Cannabis users carrying the COMT val/val genotype exhibited lower accuracy of sustained attention, associated with a more strict response bias, than val/val non-users. Cannabis users carrying the COMT val allele also committed more monitoring/shifting errors than cannabis users carrying the met/met genotype. Finally, cannabis users carrying the 5-HTTLPR s/s genotype had worse IGT performance than s/s non-users. COMT and SLC6A4 genes moderate the impact of cannabis use on executive functions.

  18. Simultaneous extraction of. beta. -endorphin and leu- and met-enkephalins from human and rat plasma

    SciTech Connect

    Bhathena, S.J.; Smith, P.M.; Kennedy, B.W. ); Voyles, N.R.; Recant, L. )

    1989-01-01

    A simple, rapid and reliable procedure is described to simultaneously concentrated and purify {beta}-endorphin, leu-and met-enkephalins from small volumes of human and rat plasma before radioimmunoassay is performed. It uses C{sub 18} Sep-Pak reverse phase cartridges. The effectiveness of different protease inhibitors in preventing degradation of opiates by plasma and different solvent systems for eluting opiates is also evaluated.

  19. Atomic models of de novo designed cc beta-Met amyloid-like fibrils.

    PubMed

    Steinmetz, Michel O; Gattin, Zrinka; Verel, Rene; Ciani, Barbara; Stromer, Thusnelda; Green, Janelle M; Tittmann, Peter; Schulze-Briese, Clemens; Gross, Heinz; van Gunsteren, Wilfred F; Meier, Beat H; Serpell, Louise C; Müller, Shirley A; Kammerer, Richard A

    2008-02-22

    The common characteristics of amyloid and amyloid-like fibrils from disease- and non-disease-associated proteins offer the prospect that well-defined model systems can be used to systematically dissect the driving forces of amyloid formation. We recently reported the de novo designed cc beta peptide model system that forms a native-like coiled-coil structure at low temperatures and which can be switched to amyloid-like fibrils by increasing the temperature. Here, we report a detailed molecular description of the system in its fibrillar state by characterizing the cc beta-Met variant using several microscopic techniques, circular dichroism spectroscopy, X-ray fiber diffraction, solid-state nuclear magnetic resonance, and molecular dynamics calculations. We show that cc beta-Met forms amyloid-like fibrils of different morphologies on both the macroscopic and atomic levels, which can be controlled by variations of assembly conditions. Interestingly, heterogeneity is also observed along single fibrils. We propose atomic models of the cc beta-Met amyloid-like fibril, which are in good agreement with all experimental data. The models provide a rational explanation why oxidation of methionine residues completely abolishes cc beta-Met amyloid fibril formation, indicating that a small number of site-specific hydrophobic interactions can play a major role in the packing of polypeptide-chain segments within amyloid fibrils. The detailed structural information available for the cc beta model system provides a strong molecular basis for understanding the influence and relative contribution of hydrophobic interactions on native-state stability, kinetics of fibril formation, fibril packing, and polymorphism.

  20. Three-dimensional structure of Escherichia coli initiator tRNA/f//Met/

    NASA Technical Reports Server (NTRS)

    Woo, N. H.; Rich, A.; Roe, B. A.

    1980-01-01

    The crystal structure of Escherichia coli tRNA(f)(Met), an initiator transfer RNA, has been determined. While grossly similar to that of the chain-elongating yeast tRNA(Phe), there are three major differences. One involves the folding of the anticodon loop; in particular, the position of the constant uridine, U33. This difference was unexpected and may be of functional significance.

  1. Meteor detections at the Metsähovi Fundamental Geodetic Research Station (Finland)

    NASA Astrophysics Data System (ADS)

    Raja-Halli, A.; Gritsevich, M.; Näränen, J.; Moreno-Ibáñez, M.; Lyytinen, E.; Virtanen, J.; Zubko, N.; Peltoniemi, J.; Poutanen, M.

    2016-01-01

    We provide an overview and present some spectacular examples of the recent meteor observations at the Metsähovi Geodetic Research Station. In conjunction with the Finnish Fireball Network the all-sky images are used to reconstruct atmospheric trajectories and to calculate the pre-impact meteor orbits in the Solar System. In addition, intensive collaborative work is pursued with the meteor research groups worldwide. We foresee great potential of this activity also for educational and outreach purposes.

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

    PubMed

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

    2009-08-01

    The purpose of this study was to establish ecological validity and initial construct validity of a Virtual Multiple Errands Test (VMET) as an assessment tool for executive functions. It was implemented within the Virtual Mall (VMall), a novel functional video-capture virtual shopping environment. The main objectives were (1) to examine the relationships between the performance of three groups of participants in the Multiple Errands Test (MET) carried out in a real shopping mall and their performance in the VMET, (2) to assess the relationships between the MET and VMET of the post-stroke participant's level of executive functioning and independence in instrumental activities of daily living, and (3) to compare the performance of post-stroke participants to those of healthy young and older controls in both the MET and VMET. The study population included three groups; post-stroke participants (n = 9), healthy young participants (n = 20), and healthy older participants (n = 20). The VMET was able to differentiate between two age groups of healthy participants and between healthy and post-stroke participants thus demonstrating that it is sensitive to brain injury and ageing and supports construct validity between known groups. In addition, significant correlations were found between the MET and the VMET for both the post-stroke participants and older healthy participants. This provides initial support for the ecological validity of the VMET as an assessment tool of executive functions. However, further psychometric data on temporal stability are needed, namely test-retest reliability and responsiveness, before it is ready for clinical application. Further research using the VMET as an assessment tool within the VMall with larger groups and in additional populations is also recommended. PMID:19058093

  3. MetLife Survey of the American Teacher: The Homework Experience. A Survey of Students, Teachers and Parents

    ERIC Educational Resources Information Center

    MetLife, Inc., 2007

    2007-01-01

    This report is the twenty-fourth in a series of surveys sponsored annually by MetLife since 1984 as a public service. This "MetLife Survey" examines the perspectives and experiences of teachers, students and parents regarding the purposes, quantity, quality, and value of homework. The Survey also includes an online strategy session with public…

  4. 33 CFR 165.T13-209 - Safety Zones; TriMet Bridge Project, Willamette River; Portland, OR.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    .... In accordance with the general regulations in 33 CFR Part 165, Subpart C, no vessel operator may... 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,...

  5. 33 CFR 165.T13-209 - Safety Zones; TriMet Bridge Project, Willamette River; Portland, OR.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    .... In accordance with the general regulations in 33 CFR Part 165, Subpart C, no vessel operator may... 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,...

  6. 33 CFR 165.T13-209 - Safety Zones; TriMet Bridge Project, Willamette River; Portland, OR.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    .... In accordance with the general regulations in 33 CFR Part 165, Subpart C, no vessel operator may... 33 Navigation and Navigable Waters 2 2013-07-01 2013-07-01 false Safety Zones; TriMet Bridge... Coast Guard District § 165.T13-209 Safety Zones; TriMet Bridge Project, Willamette River; Portland,...

  7. 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

  8. 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

  9. 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

  10. 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.

  11. Met Receptor Tyrosine Kinase Signaling Induces Secretion of the Angiogenic Chemokine Interleukin-8/CXCL8 in Pancreatic Cancer

    PubMed Central

    Hill, Kristen S.; Gaziova, Ivana; Harrigal, Lindsay; Guerra, Yvette A.; Qiu, Suimin; Sastry, Sarita K.; Arumugam, Thiruvengadam; Logsdon, Craig D.; Elferink, Lisa A.

    2012-01-01

    At diagnosis, the majority of pancreatic cancer patients present with advanced disease when curative resection is no longer feasible and current therapeutic treatments are largely ineffective. An improved understanding of molecular targets for effective intervention of pancreatic cancer is thus urgent. The Met receptor tyrosine kinase is one candidate implicated in pancreatic cancer. Notably, Met is over expressed in up to 80% of invasive pancreatic cancers but not in normal ductal cells correlating with poor overall patient survival and increased recurrence rates following surgical resection. However the functional role of Met signaling in pancreatic cancer remains poorly understood. Here we used RNA interference to directly examine the pathobiological importance of increased Met signaling for pancreatic cancer. We show that Met knockdown in pancreatic tumor cells results in decreased cell survival, cell invasion, and migration on collagen I in vitro. Using an orthotopic model for pancreatic cancer, we provide in vivo evidence that Met knockdown reduced tumor burden correlating with decreased cell survival and tumor angiogenesis, with minimal effect on cell growth. Notably, we report that Met signaling regulates the secretion of the pro-angiogenic chemokine interleukin-8/CXCL8. Our data showing that the interleukin-8 receptors CXCR1 and CXCR2 are not expressed on pancreatic tumor cells, suggests a paracrine mechanism by which Met signaling regulates interleukin-8 secretion to remodel the tumor microenvironment, a novel finding that could have important clinical implications for improving the effectiveness of treatments for pancreatic cancer. PMID:22815748

  12. Metaphor or Met-Before? The Effects of Previous Experience on Practice and Theory of Learning Mathematics

    ERIC Educational Resources Information Center

    McGowen, Mercedes A.; Tall, David O.

    2010-01-01

    While the general notion of "metaphor" may offer a thoughtful analysis of the nature of mathematical thinking, this paper suggests that it is even more important to take into account the particular mental structures available to the individual that have been built from experience that the individual has "met-before." The notion of "met-before"…

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

    PubMed

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

    2011-09-01

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

  14. BDNF Val66Met modifies the risk of childhood trauma on obsessive-compulsive disorder.

    PubMed

    Hemmings, Sian Megan Joanna; Lochner, Christine; van der Merwe, Lize; Cath, Danielle C; Seedat, Soraya; Stein, Dan J

    2013-12-01

    Childhood trauma has been linked to the development of later psychopathology, including obsessive-compulsive disorder (OCD). Although evidence exists to suggest that genetic and environmental factors are involved in the aetiology of OCD, little attention has been paid to the interactions that exist between genes and environment. The aim of this study was to investigate gene-by-environment interactions between childhood trauma and the BDNF Val66Met variant in patients with OCD. Childhood trauma was assessed in 134 OCD patients and 188 controls using the Childhood Trauma Questionnaire (CTQ). Linear regression models were used for statistical analyses. Gene-environment interactions were estimated by including a combined genotype and CTQ score in the models as interaction terms. All analyses were adjusted for age, gender, CTQ minimisation-denial score and home language by including them in the logistic regression models as covariates. Childhood trauma, specifically emotional abuse and neglect, increased the odds of having OCD significantly (p < 0.001). Although no significant association was observed between BDNF Val66Met and the development of OCD, interaction analysis indicated that the BDNF Met-allele interacted with childhood emotional abuse to increase the risk of OCD significantly in a dose-dependent manner (p = 0.024). To our knowledge, this is one of the first studies to investigate gene-environment interactions in OCD, and the findings indicate the importance of collating genetic and environmental variables in future studies.

  15. The SEMATECH Berkeley MET pushing EUV development beyond 22-nm half pitch

    SciTech Connect

    Naulleau, P.; Anderson, C. N.; Backlea-an, L.-M.; Chan, D.; Denham, P.; George, S.; Goldberg, K. A.; Hoef, B.; Jones, G.; Koh, C.; La Fontaine, B.; McClinton, B.; Miyakawa, R.; Montgomery, W.; Rekawa, S.; Wallow, T.

    2010-03-18

    Microfield exposure tools (METs) play a crucial role in the development of extreme ultraviolet (EUV) resists and masks, One of these tools is the SEMATECH Berkeley 0.3 numerical aperture (NA) MET, Using conventional illumination this tool is limited to approximately 22-nm half pitch resolution. However, resolution enhancement techniques have been used to push the patterning capabilities of this tool to half pitches of 18 nm and below, This resolution was achieved in a new imageable hard mask which also supports contact printing down to 22 nm with conventional illumination. Along with resolution, line-edge roughness is another crucial hurdle facing EUV resists, Much of the resist LER, however, can be attributed to the mask. We have shown that intenssionally aggressive mask cleaning on an older generation mask causes correlated LER in photoresist to increase from 3.4 nm to 4,0 nm, We have also shown that new generation EUV masks (100 pm of substrate roughness) can achieve correlated LER values of 1.1 nm, a 3x improvement over the correlated LER of older generation EUV masks (230 pm of substrate roughness), Finally, a 0.5-NA MET has been proposed that will address the needs of EUV development at the 16-nm node and beyond, The tool will support an ultimate resolution of 8 nm half-pitch and generalized printing using conventional illumination down to 12 nm half pitch.

  16. Endosomal Na+/H+ exchanger NHE5 influences MET recycling and cell migration.

    PubMed

    Fan, Steven Hung-Yi; Numata, Yuka; Numata, Masayuki

    2016-02-15

    Increased recycling and elevated cell surface expression of receptors serve as a mechanism for persistent receptor-mediated signaling. We show that the neuron-enriched Na(+)/H(+) exchanger NHE5 is abundantly expressed in C6 glioma cells and plays an important part in regulating cell surface expression of the receptor tyrosine kinases MET and EGF receptor. NHE5 is associated with transferrin receptor (TfR)- and Rab11-positive recycling endosomal membranes, and NHE5 knockdown by short hairpin RNA significantly elevates pH of TfR-positive recycling endosomes. We present evidence that NHE5 facilitates MET recycling to the plasma membrane, protects MET from degradation, and modulates HGF-induced phosphatidylinositol-3-kinase and mitogen-activated protein kinase signaling. Moreover, NHE5 depletion abrogates Rac1 and Cdc42 signaling and actin cytoskeletal remodeling. We further show that NHE5 knockdown impairs directed cell migration and causes loss of cell polarity. Our study highlights a possible role of recycling endosomal pH in regulating receptor-mediated signaling through vesicular trafficking.

  17. COMT Val158Met genotype influences neurodegeneration within dopamine-innervated brain structures

    PubMed Central

    Gennatas, E.D.; Cholfin, J.A.; Zhou, J.; Crawford, R.K.; Sasaki, D.A.; Karydas, A.; Boxer, A.L.; Bonasera, S.J.; Rankin, K.P.; Gorno-Tempini, M.L.; Rosen, H.J.; Kramer, J.H.; Weiner, M.; Miller, B.L.

    2012-01-01

    Objective: We sought to determine whether the Val158Met polymorphism in the catechol-O-methyltransferase (COMT) gene influences neurodegeneration within dopamine-innervated brain regions. Methods: A total of 252 subjects, including healthy controls and patients with Alzheimer disease, behavioral variant frontotemporal dementia, and semantic dementia, underwent COMT genotyping and structural MRI. Results: Whole-brain voxel-wise regression analyses revealed that COMT Val158Met Val allele dosage, known to produce a dose-dependent decrease in synaptic dopamine (DA) availability, correlated with decreased gray matter in the region of the ventral tegmental area (VTA), ventromedial prefrontal cortex, bilateral dorsal midinsula, left dorsolateral prefrontal cortex, and right ventral striatum. Unexpectedly, patients carrying a Met allele showed greater VTA volumes than age-matched controls. Gray matter intensities within COMT-related brain regions correlated with cognitive and behavioral deficits. Conclusions: The results are consistent with the hypothesis that increased synaptic DA catabolism promotes neurodegeneration within DA-innervated brain regions. PMID:22573634

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

    PubMed

    Lee, Dongheon; Sung, Eun-Sil; Ahn, Jin-Hyung; An, Sungwon; Huh, Jiwon; You, Weon-Kyoo

    2015-01-01

    Signaling pathways mediated by receptor tyrosine kinases (RTKs) and their ligands play important roles in the development and progression of human cancers, which makes RTK-mediated signaling pathways promising therapeutic targets in the treatment of cancer. Compared with small-molecule compounds, antibody-based therapeutics can more specifically recognize and bind to ligands and RTKs. Several antibody inhibitors of RTK-mediated signaling pathways, such as human epidermal growth factor receptor 2, vascular endothelial growth factor, epidermal growth factor receptor or vascular endothelial growth factor receptor 2, have been developed and are widely used to treat cancer patients. However, since the therapeutic options are still limited in terms of therapeutic efficacy and types of cancers that can be treated, efforts are being made to identify and evaluate novel RTK-mediated signaling pathways as targets for more efficacious cancer treatment. The hepatocyte growth factor/c-Met signaling pathway has come into the spotlight as a promising target for development of potent cancer therapeutic agents. Multiple antibody-based therapeutics targeting hepatocyte growth factor or c-Met are currently in preclinical or clinical development. This review focuses on the development of inhibitors of the hepatocyte growth factor/c-Met signaling pathway for cancer treatment, including critical issues in clinical development and future perspectives for antibody-based therapeutics.

  19. Structure of Met30 variant of transthyretin and its amyloidogenic implications.

    PubMed Central

    Terry, C J; Damas, A M; Oliveira, P; Saraiva, M J; Alves, I L; Costa, P P; Matias, P M; Sakaki, Y; Blake, C C

    1993-01-01

    Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant hereditary type of lethal amyloidosis involving single (or double) amino acid substitutions in the amyloidogenic protein transthyretin (TTR). The most common type of FAP (Type I, or Portuguese) is characterized by a Val-->Met substitution at position 30. The Met30 variant of TTR has been produced by recombinant methods, crystallized in a form isomorphous with native TTR, subjected to X-ray analysis and compared structurally with the wild-type protein. The comparison shows that the effect of the substitution at position 30 is transmitted through the protein core to Cys10, the only thiol group in the TTR subunit, which becomes slightly more exposed. The variant TTR molecule is otherwise in a near-native state. Use of computer graphics has shown that it is possible to model a linear aggregate of TTR molecules, each linked to the next by a pair of disulphide bonds involving Cys10 residues. Formation of these disulphide bonds involves a small number of slightly short molecular contacts with native TTR molecules, most of which are relieved in the Met30 variant. We propose this model as a possible basis for a molecular description of the FAP amyloid fibrils. Images PMID:8382610

  20. BDNF Val66Met Polymorphism Is Associated with Self-Reported Empathy

    PubMed Central

    Taschereau-Dumouchel, Vincent; Hétu, Sébastien; Bagramian, Anaït; Labrecque, Alexandre; Racine, Marion; Chagnon, Yvon C.; Jackson, Philip L.

    2016-01-01

    Empathy is an important driver of human social behaviors and presents genetic roots that have been studied in neuroimaging using the intermediate phenotype approach. Notably, the Val66Met polymorphism of the Brain-derived neurotrophic factor (BDNF) gene has been identified as a potential target in neuroimaging studies based on its influence on emotion perception and social cognition, but its impact on self-reported empathy has never been documented. Using a neurogenetic approach, we investigated the association between the BDNF Val66Met polymorphism and self-reported empathy (Davis’ Interpersonal Reactivity Index; IRI) in a sample of 110 young adults. Our results indicate that the BDNF genotype is significantly associated with the linear combination of the four facets of the IRI, one of the most widely used self-reported empathy questionnaire. Crucially, the effect of BDNF Val66Met goes beyond the variance explained by two polymorphisms of the oxytocin transporter gene previously associated with empathy and its neural underpinnings (OXTR rs53576 and rs2254298). These results represent the first evidence suggesting a link between the BDNF gene and self-reported empathy and warrant further studies of this polymorphism due to its potential clinical significance. PMID:26901829

  1. Catechol-O-methyltransferase val(158)met Polymorphism Interacts with Sex to Affect Face Recognition Ability.

    PubMed

    Lamb, Yvette N; McKay, Nicole S; Singh, Shrimal S; Waldie, Karen E; Kirk, Ian J

    2016-01-01

    The catechol-O-methyltransferase (COMT) val158met polymorphism affects the breakdown of synaptic dopamine. Consequently, this polymorphism has been associated with a variety of neurophysiological and behavioral outcomes. Some of the effects have been found to be sex-specific and it appears estrogen may act to down-regulate the activity of the COMT enzyme. The dopaminergic system has been implicated in face recognition, a form of cognition for which a female advantage has typically been reported. This study aimed to investigate potential joint effects of sex and COMT genotype on face recognition. A sample of 142 university students was genotyped and assessed using the Faces I subtest of the Wechsler Memory Scale - Third Edition (WMS-III). A significant two-way interaction between sex and COMT genotype on face recognition performance was found. Of the male participants, COMT val homozygotes and heterozygotes had significantly lower scores than met homozygotes. Scores did not differ between genotypes for female participants. While male val homozygotes had significantly lower scores than female val homozygotes, no sex differences were observed in the heterozygotes and met homozygotes. This study contributes to the accumulating literature documenting sex-specific effects of the COMT polymorphism by demonstrating a COMT-sex interaction for face recognition, and is consistent with a role for dopamine in face recognition. PMID:27445927

  2. Characterization of the mechanical properties of LTCC ``Green Tape``{trademark} for the MC4352 MET

    SciTech Connect

    Uribe, F.; Garrett, S.; Monroe, S.; Burchett, S.

    1997-03-01

    During the qualification of Low Temperature Cofire Ceramic (LTCC) as an enabling WR packaging technology for manufacturing the MC4352 (MET), issues pertaining to the mechanical performance of the DuPont 951 ``Green Tape{trademark}`` tape were investigated. Understanding the fundamental mechanical performance of the DuPont 951 substrate material, including the effect of surface metallization in STS environments, is required to determine MC4352 survivability. Both fast fracture and slow crack growth behavior were characterized for the MET configuration. A minimum stress threshold of 6.5 Kpsi for slow crack growth was established for substrates containing surface conductors, resistors, and resistor glaze. Finite element analysis was used to optimize the MET substrate thickness and to design the supporting structures to limit mechanical loading of the populated substrate below the slow crack growth threshold. Additionally, test coupons that failed during environmental testing are discussed. The root cause of electrical failures was attributed to solder leaching of the thick film metallization. Changes to solder pad configuration were incorporated to reduce the solder-metallization intermetallic from reaching the substrate interface. Finally, four-point bend tests revealed that the YAG laser approach for sizing LTCC substrates induced flaws, which substantially reduced the overall strength of the test samples as compared to samples sized using a diamond saw.

  3. The regulation mechanism of yitJ and metF riboswitches

    SciTech Connect

    Gong, Sha; Wang, Yujie; Zhang, Wenbing

    2015-07-28

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

  4. JH modulates a cellular immunity of Tribolium castaneum in a Met-independent manner.

    PubMed

    Hepat, Rahul; Kim, Yonggyun

    2014-04-01

    Juvenile hormone (JH) regulates diverse physiological processes in insects during entire developmental stages. Especially, the identification of Methoprene-tolerant (Met), a JH nuclear receptor, allows us to better understand molecular actions of JH to control gene expressions related with metamorphosis. However, several physiological processes including cellular immune response and some molecular actions of JH have been suspected to be mediated via its non-genomic actions. To prove its non-genomic action, JH nuclear signals were suppressed by RNA interference (RNAi) of Met or its downstream gene, Krüppel homolog 1 (Kr-h1), in the red flour beetle, Tribolium castaneum. These RNAi-treated larvae failed to undergo a normal development and suffered precocious metamorphosis. Hemocytes of T. castaneum exhibited their spreading behavior on extracellular matrix and nodule formation in response to bacterial challenge. When the larvae were treated with either RNAi of Met or Kr-h1, the hemocytes of the treated larvae were responsive to JH without any significant difference with those of control larvae. These results suggest that the response of hemocytes to JH is not mediated by its nuclear signal. On the other hand, the JH modulation of hemocyte behaviors of T. castaneum was significantly influenced by membrane and cytosolic protein activities, in which ethoxyzolamide (a specific inhibitor of carbonic anhydrase), calphostin C (a specific inhibitor of protein kinase C) or ouabain (a specific inhibitor of Na(+)-K(+) ATPase) significantly suppressed the responsiveness of hemocytes to JH.

  5. Pulse Pressure Magnifies the Effect of COMT Val(158)Met on 15 Years Episodic Memory Trajectories.

    PubMed

    Persson, Ninni; Lavebratt, Catharina; Sundström, Anna; Fischer, Håkan

    2016-01-01

    We investigated whether a physiological marker of cardiovascular health, pulse pressure (PP), and age magnified the effect of the functional COMT Val(158)Met (rs4680) polymorphism on 15-years cognitive trajectories [episodic memory (EM), visuospatial ability, and semantic memory] using data from 1585 non-demented adults from the Betula study. A multiple-group latent growth curve model was specified to gauge individual differences in change, and average trends therein. The allelic variants showed negligible differences across the cognitive markers in average trends. The older portion of the sample selectively age-magnified the effects of Val(158)Met on EM changes, resulting in greater decline in Val compared to homozygote Met carriers. This effect was attenuated by statistical control for PP. Further, PP moderated the effects of COMT on 15-years EM trajectories, resulting in greater decline in Val carriers, even after accounting for the confounding effects of sex, education, cardiovascular diseases (diabetes, stroke, and hypertension), and chronological age, controlled for practice gains. The effect was still present after excluding individuals with a history of cardiovascular diseases. The effects of cognitive change were not moderated by any other covariates. This report underscores the importance of addressing synergistic effects in normal cognitive aging, as the addition thereof may place healthy individuals at greater risk for memory decline. PMID:26973509

  6. Conformational analysis of the N-terminal sequence Met1 Val60 of the tyrosine hydroxylase

    NASA Astrophysics Data System (ADS)

    Alieva, Irada N.; Mustafayeva, Narmina N.; Gojayev, Niftali M.

    2006-03-01

    Molecular mechanics method and molecular dynamics (MD) simulation techniques are used to study the behavior and the effect of the amino acids substitution on structure and molecular dynamics of the specific portion of Met1-Val60 amino acid residues from N-terminal regulatory domain of the tyrosine hydroxylase (TH) and its mutants in which the positively charged arginine residues at positions 37 and 38 were replaced by electrically neutral Gly and negatively charged Glu, and serine residue at position 40 was replaced by Ala or Asp residue. Our study allowed us to make the following conclusions: (i) the higher conformational flexibility of the Met1-Arg16 sequence is revealed in comparision to other part of the N-terminus; (ii) the stretch of amino acid residues Met30-Ser40 within the N-terminus forms β-turn so that two α-helices (residues 16-29 and residues 41-60) are paralel one another; (ii) the significant differences that are observed for the Arg37→Gly37, Arg37-Arg38→Glu37-Glu38 mutant segments indicates that the positive charge of the Arg37 and Arg38 residues is one of the main factor that maintains the characteristic of the turn; (ii) no major conformational changes are observed between Ser40→Ala40, and Ser40→Asp40 mutant segments.

  7. Extended metAFLP approach in studies of tissue culture induced variation (TCIV) in triticale.

    PubMed

    Machczyńska, Joanna; Orłowska, Renata; Zimny, Janusz; Bednarek, Piotr Tomasz

    2014-01-01

    We present the development of the theoretical background of the metAFLP approach which allows for partition of complex variation into sequence changes, de novo methylation and demethylation of the regenerants derived via in vitro tissue culture methods in the case of triticale. It was demonstrated that, independent of whether andro- or embryogenesis was used for plant regeneration, the level of sequence changes identified between regenerants is about 10 %. Moreover, DNA demethylation prevails over de novo methylation of the regenerants compared to the donor plant. The metAFLP approach allows for the evaluation of numerous quantitative characteristics. For instance, one may quantify the number of sites unaffected by tissue culture approaches, global site DNA methylation etc. It is suggested that the approach could be useful for breeders in order to control plant material uniformity or for the evaluation of modified in vitro tissue culture approaches allowing for control of the (epi)mutation level. The extended metAFLP approach presented here delivers sufficient background for the evaluation of software that could facilitate analyses of the tissue culture induced variation. PMID:25242884

  8. BDNF Val66Met Polymorphism Is Associated with Self-Reported Empathy.

    PubMed

    Taschereau-Dumouchel, Vincent; Hétu, Sébastien; Bagramian, Anaït; Labrecque, Alexandre; Racine, Marion; Chagnon, Yvon C; Jackson, Philip L

    2016-01-01

    Empathy is an important driver of human social behaviors and presents genetic roots that have been studied in neuroimaging using the intermediate phenotype approach. Notably, the Val66Met polymorphism of the Brain-derived neurotrophic factor (BDNF) gene has been identified as a potential target in neuroimaging studies based on its influence on emotion perception and social cognition, but its impact on self-reported empathy has never been documented. Using a neurogenetic approach, we investigated the association between the BDNF Val66Met polymorphism and self-reported empathy (Davis' Interpersonal Reactivity Index; IRI) in a sample of 110 young adults. Our results indicate that the BDNF genotype is significantly associated with the linear combination of the four facets of the IRI, one of the most widely used self-reported empathy questionnaire. Crucially, the effect of BDNF Val66Met goes beyond the variance explained by two polymorphisms of the oxytocin transporter gene previously associated with empathy and its neural underpinnings (OXTR rs53576 and rs2254298). These results represent the first evidence suggesting a link between the BDNF gene and self-reported empathy and warrant further studies of this polymorphism due to its potential clinical significance. PMID:26901829

  9. BDNF Val66Met Polymorphism Is Associated with Self-Reported Empathy.

    PubMed

    Taschereau-Dumouchel, Vincent; Hétu, Sébastien; Bagramian, Anaït; Labrecque, Alexandre; Racine, Marion; Chagnon, Yvon C; Jackson, Philip L

    2016-01-01

    Empathy is an important driver of human social behaviors and presents genetic roots that have been studied in neuroimaging using the intermediate phenotype approach. Notably, the Val66Met polymorphism of the Brain-derived neurotrophic factor (BDNF) gene has been identified as a potential target in neuroimaging studies based on its influence on emotion perception and social cognition, but its impact on self-reported empathy has never been documented. Using a neurogenetic approach, we investigated the association between the BDNF Val66Met polymorphism and self-reported empathy (Davis' Interpersonal Reactivity Index; IRI) in a sample of 110 young adults. Our results indicate that the BDNF genotype is significantly associated with the linear combination of the four facets of the IRI, one of the most widely used self-reported empathy questionnaire. Crucially, the effect of BDNF Val66Met goes beyond the variance explained by two polymorphisms of the oxytocin transporter gene previously associated with empathy and its neural underpinnings (OXTR rs53576 and rs2254298). These results represent the first evidence suggesting a link between the BDNF gene and self-reported empathy and warrant further studies of this polymorphism due to its potential clinical significance.

  10. Catechol-O-methyltransferase val158met Polymorphism Interacts with Sex to Affect Face Recognition Ability

    PubMed Central

    Lamb, Yvette N.; McKay, Nicole S.; Singh, Shrimal S.; Waldie, Karen E.; Kirk, Ian J.

    2016-01-01

    The catechol-O-methyltransferase (COMT) val158met polymorphism affects the breakdown of synaptic dopamine. Consequently, this polymorphism has been associated with a variety of neurophysiological and behavioral outcomes. Some of the effects have been found to be sex-specific and it appears estrogen may act to down-regulate the activity of the COMT enzyme. The dopaminergic system has been implicated in face recognition, a form of cognition for which a female advantage has typically been reported. This study aimed to investigate potential joint effects of sex and COMT genotype on face recognition. A sample of 142 university students was genotyped and assessed using the Faces I subtest of the Wechsler Memory Scale – Third Edition (WMS-III). A significant two-way interaction between sex and COMT genotype on face recognition performance was found. Of the male participants, COMT val homozygotes and heterozygotes had significantly lower scores than met homozygotes. Scores did not differ between genotypes for female participants. While male val homozygotes had significantly lower scores than female val homozygotes, no sex differences were observed in the heterozygotes and met homozygotes. This study contributes to the accumulating literature documenting sex-specific effects of the COMT polymorphism by demonstrating a COMT-sex interaction for face recognition, and is consistent with a role for dopamine in face recognition. PMID:27445927

  11. Post-traumatic stress disorder risk and brain-derived neurotrophic factor Val66Met

    PubMed Central

    Zhang, Lei; Li, Xiao-Xia; Hu, Xian-Zhang

    2016-01-01

    Brain-derived neurotrophic factor (BDNF), which regulates neuronal survival, growth differentiation, and synapse formation, is known to be associated with depression and post-traumatic stress disorder (PTSD). However, the molecular mechanism for those mental disorders remains unknown. Studies have shown that BDNF is associated with PTSD risk and exaggerated startle reaction (a major arousal manifestation of PTSD) in United States military service members who were deployed during the wars in Iraq and Afghanistan. The frequency of the Met/Met in BDNF gene was greater among those with PTSD than those without PTSD. Among individuals who experienced fewer lifetime stressful events, the Met carriers have significantly higher total and startle scores on the PTSD Checklist than the Val/Val carriers. In addition, subjects with PTSD showed higher levels of BDNF in their peripheral blood plasma than the non-probable-PTSD controls. Increased BDNF levels and startle response were observed in both blood plasma and brain hippocampus by inescapable tail shock in rats. In this paper, we reviewed these data to discuss BDNF as a potential biomarker for PTSD risk and its possible roles in the onset of PTSD. PMID:27014593

  12. Endosomal Na+/H+ exchanger NHE5 influences MET recycling and cell migration

    PubMed Central

    Fan, Steven Hung-Yi; Numata, Yuka; Numata, Masayuki

    2016-01-01

    Increased recycling and elevated cell surface expression of receptors serve as a mechanism for persistent receptor-mediated signaling. We show that the neuron-enriched Na+/H+ exchanger NHE5 is abundantly expressed in C6 glioma cells and plays an important part in regulating cell surface expression of the receptor tyrosine kinases MET and EGF receptor. NHE5 is associated with transferrin receptor (TfR)- and Rab11-positive recycling endosomal membranes, and NHE5 knockdown by short hairpin RNA significantly elevates pH of TfR-positive recycling endosomes. We present evidence that NHE5 facilitates MET recycling to the plasma membrane, protects MET from degradation, and modulates HGF-induced phosphatidylinositol-3-kinase and mitogen-activated protein kinase signaling. Moreover, NHE5 depletion abrogates Rac1 and Cdc42 signaling and actin cytoskeletal remodeling. We further show that NHE5 knockdown impairs directed cell migration and causes loss of cell polarity. Our study highlights a possible role of recycling endosomal pH in regulating receptor-mediated signaling through vesicular trafficking. PMID:26700318

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

    SciTech Connect

    Fu, Tian-Min; Zhang, Xiao-Yan; Li, Lan-Fen; Liang, Yu-He Su, Xiao-Dong

    2006-10-01

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

  14. The Aspergillus nidulans metZ gene encodes a transcription factor involved in regulation of sulfur metabolism in this fungus and other Eurotiales.

    PubMed

    Piłsyk, Sebastian; Natorff, Renata; Sieńko, Marzena; Skoneczny, Marek; Paszewski, Andrzej; Brzywczy, Jerzy

    2015-05-01

    In Aspergillus nidulans, expression of sulfur metabolism genes is activated by the MetR transcription factor containing a basic region and leucine zipper domain (bZIP). Here we identified and characterized MetZ, a new transcriptional regulator in A. nidulans and other Eurotiales. It contains a bZIP domain similar to the corresponding region in MetR and this similarity suggests that MetZ could potentially complement the MetR deficiency. The metR and metZ genes are interrupted by unusually long introns. Transcription of metZ, unlike that of metR, is controlled by the sulfur metabolite repression system (SMR) dependent on the MetR protein. Overexpression of metZ from a MetR-independent promoter in a ΔmetR background activates transcription of genes encoding sulfate permease, homocysteine synthase and methionine permease, partially complementing the phenotype of the ΔmetR mutation. Thus, MetZ appears to be a second transcription factor involved in regulation of sulfur metabolism genes.

  15. Clinical impact of c-MET expression and genetic mutational status in colorectal cancer patients after liver resection

    PubMed Central

    Shoji, Hirokazu; Yamada, Yasuhide; Taniguchi, Hirokazu; Nagashima, Kengo; Okita, Natsuko; Takashima, Atsuo; Honma, Yoshitaka; Iwasa, Satoru; Kato, Ken; Hamaguchi, Tetsuya; Shimada, Yasuhiro

    2014-01-01

    c-MET is implicated in the pathogenesis and growth of a wide variety of human malignancies, including colorectal cancer (CRC). The aim of the present study was to clarify the association between c-MET expression and tumor recurrence in CRC patients after curative liver resection, and to evaluate concordance in c-MET expression and various mutations of KRAS, BRAF and PIK3CA between primary CRC and paired liver metastases. A cohort of patients was tested for c-MET immunoreactivity (i.e. immunohistochemistry [IHC]) and KRAS, BRAF and PIK3CA mutations. Analyses were performed both on primary tumors and paired liver metastases, and the association between IHC and mutations results were assessed. A total of 108 patients were eligible. A total of 53% of patients underwent simultaneous resection of primary tumors and metastases, and the others underwent metachronous resection. Levels of concordance between primary tumors and metastases were 65.7%, 87.7%, 100% and 95.2% for c-MET, KRAS, BRAF and PIK3CA, respectively. High levels of c-MET expression (c-MET-high) in the primary tumors were observed in 52% of patients. Relapse-free survival was significantly shorter for patients with c-MET-high primary tumors (9.7 months) than for those with c-MET-low primary tumors (21.1 months) (P = 0.013). These results suggest that a high level of genetic concordance in KRAS, BRAF and PIK3CA between primary tumors and liver metastases, and c-MET-high in the primary tumors were associated with shorter relapse-free survival after hepatic metastasectomy. PMID:24863535

  16. Flight Dynamics Performances of the MetOp A Satellite during the First Months of Operations

    NASA Technical Reports Server (NTRS)

    Righetti, Pier Luigi; Meixner, Hilda; Sancho, Francisco; Damiano, Antimo; Lazaro, David

    2007-01-01

    The 19th of October 2006 at 16:28 UTC the first MetOp satellite (MetOp A) was successfully launched from the Baykonur cosmodrome by a Soyuz/Fregat launcher. After only three days of LEOP operations, performed by ESOC, the satellite was handed over to EUMETSAT, who is since then taking care of all satellite operations. MetOp A is the first European operational satellite for meteorology flying in a Low Earth Orbit (LEO), all previous satellites operated by EUMETSAT, belonging to the METEOSAT family, being located in the Geo-stationary orbit. To ensure safe operations for a LEO satellite accurate and continuous commanding from ground of the on-board AOCS is required. That makes the operational transition at the end of the LEOP quite challenging, as the continuity of the Flight Dynamics operations is to be maintained. That means that the main functions of the Flight Dynamics have to be fully validated on-flight during the LEOP, before taking over the operational responsibility on the spacecraft, and continuously monitored during the entire mission. Due to the nature of a meteorological operational mission, very stringent requirements in terms of overall service availability (99 % of the collected data), timeliness of processing of the observation data (3 hours after sensing) and accuracy of the geo-location of the meteorological products (1 km) are to be fulfilled. That translates in tight requirements imposed to the Flight Dynamics facility (FDF) in terms of accuracy, timeliness and availability of the generated orbit and clock solutions; a detailed monitoring of the quality of these products is thus mandatory. Besides, being the accuracy of the image geo-location strongly related with the pointing performance of the platform and with the on-board timing stability, monitoring from ground of the behaviour of the on-board sensors and clock is needed. This paper presents an overview of the Flight Dynamics operations performed during the different phases of the MetOp A

  17. COMT Val158Met, but not BDNF Val66Met, is associated with white matter abnormalities of the temporal lobe in patients with first-episode, treatment-naïve major depressive disorder: a diffusion tensor imaging study

    PubMed Central

    Hayashi, Kenji; Yoshimura, Reiji; Kakeda, Shingo; Kishi, Taro; Abe, Osamu; Umene-Nakano, Wakako; Katsuki, Asuka; Hori, Hikaru; Ikenouchi-Sugita, Atsuko; Watanabe, Keita; Ide, Satoru; Ueda, Issei; Moriya, Junji; Iwata, Nakao; Korogi, Yukunori; Kubicki, Marek; Nakamura, Jun

    2014-01-01

    We investigated the association between the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene, and white matter changes in patients with major depressive disorder (MDD) and healthy subjects using diffusion tensor imaging (DTI). We studied 30 patients with MDD (17 males and 13 females, with mean age ± standard deviation [SD] =44±12 years) and 30 sex- and age-matched healthy controls (17 males and 13 females, aged 44±13 years). Using DTI analysis with a tract-based spatial statistics (TBSS) approach, we investigated the differences in fractional anisotropy, radial diffusivity, and axial diffusivity distribution among the three groups (patients with the COMT gene Val158Met, those with the BDNF gene Val66Met, and the healthy subjects). In a voxel-wise-based group comparison, we found significant decreases in fractional anisotropy and axial diffusivity within the temporal lobe white matter in the Met-carriers with MDD compared with the controls (P<0.05). No correlations in fractional anisotropy, axial diffusivity, or radial diffusivity were observed between the MDD patients and the controls, either among those with the BDNF Val/Val genotype or among the BDNF Met-carriers. These results suggest an association between the COMT gene Val158Met and the white matter abnormalities found in the temporal lobe of patients with MDD. PMID:25061303

  18. An Association Study of the Brain-Derived Neurotrophic Factor Val66Met Polymorphism and Amphetamine Response

    PubMed Central

    Flanagin, Brody A.; Cook, Edwin H.; de Wit, Harriet

    2008-01-01

    Although genetic factors are known to be important in addiction, no candidate genes have yet been consistently linked to drug use or abuse. Brain-derived neurotrophic factor (BDNF), which has been implicated in the behavioral response to psychomotor stimulants and potentiates neurotransmitters that are strongly linked to addiction, is a logical candidate gene to study. Using a drug challenge approach, we tested for association between BDNF G196A (val66met) genotype and subjective responses to amphetamine (AMPH). Healthy volunteers participated in a double-blind, crossover design in which they received placebo, 10 mg, and 20 mg oral d-amphetamine in random order. Subjective and physical responses to ingestion of AMPH were measured at thirty minute intervals after drug ingestion. Each subject was genotyped for the BDNF G196A polymorphism and grouped and analyzed accordingly. The effects of AMPH on ratings of arousal, energy, and heart rate were compared in subjects with the val/val genotype (N = 67) and the subjects with either the val/met or met/met genotypes (N = 32). AMPH produced less pronounced self-ratings of arousal and energy, yet higher increases in heart rate, in the val/met and met/met compared to the val/val group. These results suggest that BDNF is related to the subjective and physical response to low doses of AMPH. PMID:16823800

  19. Effect of met-enkephalin on chromosomal aberrations in the lymphocytes of the peripheral blood of patients with multiple sclerosis

    PubMed Central

    Rakanović-Todić, Maida; Burnazović-Ristić, Lejla; Ibrulj, Slavka; Mulabegović, Nedžad

    2014-01-01

    Endogenous opiod met-enkephalin throughout previous research manifested cytoprotective and anti-inflammatory effects. Previous research suggests that met-enkephalin has cytogenetic effects. Reducement in the frequency of structural chromosome aberrations as well as a suppressive effect on lymphocyte cell cycle is found. It also reduces apoptosis in the blood samples of the patients with immune-mediated diseases. Met-enkephalin exerts immunomodulatory properties and induces stabilization of the clinical condition in patients with multiple Sclerosis (MS). The goal of the present research was to evaluate met-enkephalin in vitro effects on the number and type of chromosome aberrations in the peripheral blood lymphocytes of patients with MS. Our research detected disappearance of ring chromosomes and chromosome fragmentations in the cultures of the peripheral blood lymphocytes treated with met-enkephalin (1.2 μg/mL). However, this research did not detect any significant effects of met-enkephalin on the reduction of structural chromosome aberrations and disappearance of dicentric chromosomes. Chromosomes with the greatest percent of inclusion in chromosome aberrations were noted as: chromosome 1, chromosome 2 and chromosome 9. Additionally, we confirmed chromosome 14 as the most frequently included in translocations. Furthermore, met-enkephalin effects on the increase of the numerical aberrations in both concentrations applied were detected. Those findings should be interpreted cautiously and more research in this field should be conducted. PMID:24856378

  20. c-Met inhibitor SU11274 enhances the response of the prostate cancer cell line DU145 to ionizing radiation

    SciTech Connect

    Yu, Hongliang; Li, Xiaoying; Sun, Shaoqian; Gao, Xianshu; Zhou, Demin

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer c-Met inhibition could significantly enhance the radiosensitivity of DU145 cells. Black-Right-Pointing-Pointer The mechanisms of the radiosensitization effect of c-Met inhibition on DU145 cells were also presented in this paper. Black-Right-Pointing-Pointer This is the first study demonstrating the effectiveness of c-Met inhibition on treating HRPC cells with radiotherapy. -- Abstract: Hormone-refractory prostate cancer shows substantial resistance to most conventional therapies including radiotherapy, constitutes a key impediment to curing patients with the disease. c-Met overexpression plays a key role in prostate cancer tumorigenesis and disease progression. Here, we demonstrate that c-Met inhibition by SU11274 could significantly suppress cell survival and proliferation as well as enhance the radiosensitivity of DU145 cells. The underlying mechanisms of the effects of SU11274 on DU145 cells may include the inhibition of c-Met signaling, depolarization of the mitochondrial membrane potential, impairment of DNA repair function, abrogation of cell cycle arrest, and enhancement of cell death. Our study is the first to show the effectiveness of combining c-Met inhibition with ionizing radiation to cure hormone-refractory prostate cancer.

  1. Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype

    PubMed Central

    Kaposi-Novak, Pal; Lee, Ju-Seog; Gòmez-Quiroz, Luis; Coulouarn, Cédric; Factor, Valentina M.; Thorgeirsson, Snorri S.

    2006-01-01

    Identification of specific gene expression signatures characteristic of oncogenic pathways is an important step toward molecular classification of human malignancies. Aberrant activation of the Met signaling pathway is frequently associated with tumor progression and metastasis. In this study, we defined the Met-dependent gene expression signature using global gene expression profiling of WT and Met-deficient primary mouse hepatocytes. Newly identified transcriptional targets of the Met pathway included genes involved in the regulation of oxidative stress responses as well as cell motility, cytoskeletal organization, and angiogenesis. To assess the importance of a Met-regulated gene expression signature, a comparative functional genomic approach was applied to 242 human hepatocellular carcinomas (HCCs) and 7 metastatic liver lesions. Cluster analysis revealed that a subset of human HCCs and all liver metastases shared the Met-induced expression signature. Furthermore, the presence of the Met signature showed significant correlation with increased vascular invasion rate and microvessel density as well as with decreased mean survival time of HCC patients. We conclude that the genetically defined gene expression signatures in combination with comparative functional genomics constitute an attractive paradigm for defining both the function of oncogenic pathways and the clinically relevant subgroups of human cancers. PMID:16710476

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

    PubMed

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

    2011-01-01

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

  3. Interplay between VEGF-A and cMET signaling in human vestibular schwannomas and schwann cells.

    PubMed

    Dilwali, Sonam; Roberts, Daniel; Stankovic, Konstantina M

    2015-01-01

    Vestibular schwannoma (VS), the fourth most common intracranial tumor, arises from the Schwann cells of the vestibular nerve. Although several pathways have been independently implicated in VS pathobiology, interactions among these pathways have not been explored in depth. We have investigated the potential cross-talk between hepatocyte growth factor (HGF) and vascular endothelial growth factor-A (VEGF-A) in human VS, an interaction that has been described in other physiological and pathological cell types. We affirmed previous findings that VEGF-A signaling is aberrantly upregulated in VS, and established that expression of HGF and its receptor cMET is also significantly higher in sporadic VS than in healthy nerves. In primary human VS and Schwann cell cultures, we found that VEGF-A and HGF signaling pathways modulate each other. siRNAs targeting cMET decreased both cMET and VEGF-A protein levels, and siRNAs targeting VEGF-A reduced cMET expression. Additionally, siRNA-mediated knockdown of VEGF-A or cMET and pharmacologic inhibition of cMET decreased cellular proliferation in primary human VS cultures. Our data suggest cross-talk between these 2 prominent pathways in VS and highlight the HGF/cMET pathway as an additional important therapeutic target in VS. PMID:25692621

  4. 6-Phosphogluconate dehydrogenase regulates tumor cell migration in vitro by regulating receptor tyrosine kinase c-Met

    SciTech Connect

    Chan, Barden; VanderLaan, Paul A.; Sukhatme, Vikas P.

    2013-09-20

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

  5. Low c-Met expression levels are prognostic for and predict the benefits of temozolomide chemotherapy in malignant gliomas

    PubMed Central

    Li, Ming-Yang; Yang, Pei; Liu, Yan-Wei; Zhang, Chuan-Bao; Wang, Kuan-Yu; Wang, Yin-Yan; Yao, Kun; Zhang, Wei; Qiu, Xiao-Guang; Li, Wen-Bin; Peng, Xiao-Xia; Wang, Yong-Zhi; Jiang, Tao

    2016-01-01

    Aberrant c-Met has been implicated in the development of many cancers. The objective of this study was to identify an unfavorable prognostic marker that might guide decisions regarding clinical treatment strategies for high-grade gliomas. C-Met expression was measured using immunohistochemistry in 783 gliomas, and we further analyzed c-Met mRNA levels using the Agilent Whole Genome mRNA Microarray in 286 frozen samples. In vitro, we performed cell migration and invasion assays. Cell sensitivity to temozolomide (TMZ) chemotherapy was determined using MTT assays. Both mRNA and protein levels of c-Met were significantly associated with tumor grade progression and inversely correlated with overall and progression-free survival in high-grade gliomas (all P < 0.0001). These findings were nearly consistent at the mRNA level across 3 independent cohorts. Multivariable analysis indicated that c-Met was an independent prognostic marker after adjusting for age, preoperative Karnofsky Performance Status (KPS) score, the extent of resection, radiotherapy, TMZ chemotherapy, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Further analysis in vitro revealed that downregulating the expression of c-Met dramatically inhibited cell migration and invasion capacities, enhanced sensitivity to TMZ chemotherapy in H4 and U87 glioma cells. Our results suggest that c-Met may serve as a potential predictive maker for clinical decision making. PMID:26879272

  6. Six habits to enhance MET performance under stress: A discussion paper reviewing team mechanisms for improved patient outcomes.

    PubMed

    Fein, Erich C; Mackie, Benjamin; Chernyak-Hai, Lily; O'Quinn, C Richard V; Ahmed, Ezaz

    2016-05-01

    Effective team decision making has the potential to improve the quality of health care outcomes. Medical Emergency Teams (METs), a specific type of team led by either critical care nurses or physicians, must respond to and improve the outcomes of deteriorating patients. METs routinely make decisions under conditions of uncertainty and suboptimal care outcomes still occur. In response, the development and use of Shared Mental Models (SMMs), which have been shown to promote higher team performance under stress, may enhance patient outcomes. This discussion paper specifically focuses on the development and use of SMMs in the context of METs. Within this process, the psychological mechanisms promoting enhanced team performance are examined and the utility of this model is discussed through the narrative of six habits applied to MET interactions. A two stage, reciprocal model of both nonanalytic decision making within the acute care environment and analytic decision making during reflective action learning was developed. These habits are explored within the context of a MET, illustrating how applying SMMs and action learning processes may enhance team-based problem solving under stress. Based on this model, we make recommendations to enhance MET decision making under stress. It is suggested that the corresponding habits embedded within this model could be imparted to MET members and tested by health care researchers to assess the efficacy of this integrated decision making approach in respect to enhanced team performance and patient outcomes.

  7. The competitive ability and fitness components of the Methoprene-tolerant (Met) Drosophila mutant resistant to juvenile hormone analog insecticides.

    PubMed

    Minkoff, C; Wilson, T G

    1992-05-01

    The Methoprene-tolerant (Met) mutation of Drosophila melanogaster results in a high (100-fold) level of resistance to the insecticide methoprene, a chemical analog of juvenile hormone. Pest species that are under control with methoprene may therefore have the potential to evolve resistance via a mutation homologous to Met. To evaluate the potential of such mutants to persist in wild populations, we must understand the fitness of flies carrying Met. In the absence of methoprene, Met flies were outcompeted by a wild-type strain both in a multigeneration population cage and in single-generation competition experiments. To determine which fitness component(s) is responsible for the competitive disadvantage, the survival, time of development, and fecundity of flies homozygous for each of five Met alleles were compared with wild type. Small but significant differences were found between the pooled Met alleles and wild type for pupal development time, pupal mortality, and early adult fecundity. These differences result in a large competitive disadvantage. Although Met flies were found to have reduced fitness by these measures, the phenotype is not as severe as might be expected from a knowledge of the disruption of juvenile hormone regulation seen in Met flies. It is concluded that (1) although Met flies have a large advantage under methoprene selection, they will quickly become outcompeted upon relaxation of methoprene usage, (2) even a seemingly severe disruption of juvenile hormone regulation has no drastic effect on the vital functions of the insect and (3) small differences in fitness components can translate into a large competitive disadvantage.

  8. Knockdown of c-MET induced apoptosis in ABCB1-overexpressed multidrug-resistance cancer cell lines.

    PubMed

    Hung, T-H; Li, Y-H; Tseng, C-P; Lan, Y-W; Hsu, S-C; Chen, Y-H; Huang, T-T; Lai, H-C; Chen, C-M; Choo, K-B; Chong, K-Y

    2015-05-01

    Inappropriate c-MET signaling in cancer can enhance tumor cell proliferation, survival, motility, and invasion. Inhibition of c-MET signaling induces apoptosis in a variety of cancers. It has also been recognized as a novel anticancer therapy approach. Furthermore, reports have also indicated that constitutive expression of P-glycoprotein (ABCB1) is involved in the HGF/c-MET-related pathway of multidrug resistance ABCB1-positive human hepatocellular carcinoma cell lines. We previously reported that elevated expression levels of PKCδ and AP-1 downstream genes, and HGF receptor (c-MET) and ABCB1, in the drug-resistant MES-SA/Dx5 cells. Moreover, leukemia cell lines overexpressing ABCB1 have also been shown to be more resistant to the tyrosine kinase inhibitor imatinib mesylate. These findings suggest that chemoresistant cancer cells may also develop a similar mechanism against chemotherapy agents. To circumvent clinical complications arising from drug resistance during cancer therapy, the present study was designed to investigate apoptosis induction in ABCB1-overexpressed cancer cells using c-MET-targeted RNA interference technology in vitro and in vivo. The results showed that cell viability decreased and apoptosis rate increased in c-MET shRNA-transfected HGF/c-MET pathway-positive MES-SA/Dx5 and MCF-7/ADR2 cell lines in a dose-dependent manner. In vivo reduction of tumor volume in mice harboring c-MET shRNA-knockdown MES-SA/Dx5 cells was clearly demonstrated. Our study demonstrated that downregulation of c-MET by shRNA-induced apoptosis in a multidrug resistance cell line.

  9. Synthetic lethal screening reveals FGFR as one of the combinatorial targets to overcome resistance to Met-targeted therapy.

    PubMed

    Kim, B; Wang, S; Lee, J M; Jeong, Y; Ahn, T; Son, D-S; Park, H W; Yoo, H-s; Song, Y-J; Lee, E; Oh, Y M; Lee, S B; Choi, J; Murray, J C; Zhou, Y; Song, P H; Kim, K-A; Weiner, L M

    2015-02-26

    Met is a receptor tyrosine kinase that promotes cancer progression. In addition, Met has been implicated in resistance of tumors to various targeted therapies such as epidermal growth factor receptor inhibitors in lung cancers, and has been prioritized as a key molecular target for cancer therapy. However, the underlying mechanism of resistance to Met-targeting drugs is poorly understood. Here, we describe screening of 1310 genes to search for key regulators related to drug resistance to an anti-Met therapeutic antibody (SAIT301) by using a small interfering RNA-based synthetic lethal screening method. We found that knockdown of 69 genes in Met-amplified MKN45 cells sensitized the antitumor activity of SAIT301. Pathway analysis of these 69 genes implicated fibroblast growth factor receptor (FGFR) as a key regulator for antiproliferative effects of Met-targeting drugs. Inhibition of FGFR3 increased target cell apoptosis through the suppression of Bcl-xL expression, followed by reduced cancer cell growth in the presence of Met-targeting drugs. Treatment of cells with the FGFR inhibitors substantially restored the efficacy of SAIT301 in SAIT301-resistant cells and enhanced the efficacy in SAIT301-sensitive cells. In addition to FGFR3, integrin β3 is another potential target for combination treatment with SAIT301. Suppression of integrin β3 decreased AKT phosphorylation in SAIT301-resistant cells and restored SAIT301 responsiveness in HCC1954 cells, which are resistant to SAIT301. Gene expression analysis using CCLE database shows that cancer cells with high levels of FGFR and integrin β3 are resistant to crizotinib treatment, suggesting that FGFR and integrin β3 could be used as predictive markers for Met-targeted therapy and provide a potential therapeutic option to overcome acquired and innate resistance for the Met-targeting drugs. PMID:24662823

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

    PubMed

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

    2016-06-15

    Recent studies confirmed a critical importance of c-Met signaling for liver regeneration by modulating redox balance. Here we used liver-specific conditional knockout mice (MetKO) and a nutritional model of hepatic steatosis to address the role of c-Met in cholesterol-mediated liver toxicity. Liver injury was assessed by histopathology and plasma enzymes levels. Global transcriptomic changes were examined by gene expression microarray, and key molecules involved in liver damage and lipid homeostasis were evaluated by Western blotting. Loss of c-Met signaling amplified the extent of liver injury in MetKO mice fed with high-cholesterol diet for 30days as evidenced by upregulation of liver enzymes and increased synthesis of total bile acids, aggravated inflammatory response and enhanced intrahepatic lipid deposition. Global transcriptomic changes confirmed the enrichment of networks involved in steatosis and cholestasis. In addition, signaling pathways related to glutathione and lipid metabolism, oxidative stress and mitochondria dysfunction were significantly affected by the loss of c-Met function. Mechanistically, exacerbation of oxidative stress in MetKO livers was corroborated by increased lipid and protein oxidation. Western blot analysis further revealed suppression of Erk, NF-kB and Nrf2 survival pathways and downstream target genes (e.g. cyclin D1, SOD1, gamma-GCS), as well as up-regulation of proapoptotic signaling (e.g. p53, caspase 3). Consistent with the observed steatotic and cholestatic phenotype, nuclear receptors RAR, RXR showed increased activation while expression levels of CAR, FXR and PPAR-alpha were decreased in MetKO. Collectively, our data provide evidence for the critical involvement of c-Met signaling in cholesterol and bile acids toxicity. PMID:27394961

  11. Differential modulation of motor cortex excitability in BDNF Met allele carriers following experimentally induced and use-dependent plasticity.

    PubMed

    Cirillo, John; Hughes, James; Ridding, Michael; Thomas, Paul Q; Semmler, John G

    2012-09-01

    The purpose of this study was to investigate how healthy young subjects with one of three variants of the brain-derived neurotrophic factor (BDNF) gene modulate motor cortex excitability following experimentally induced and use-dependent plasticity interventions. Electromyographic recordings were obtained from the right first dorsal interosseous (FDI) muscle of 12 Val/Val, ten Val/Met and seven Met/Met genotypes (aged 18-39 years). Transcranial magnetic stimulation of the left hemisphere was used to assess changes in FDI motor-evoked potentials (MEPs) following three separate interventions involving paired associative stimulation, a simple ballistic task and complex visuomotor tracking task using the index finger. Val/Val subjects increased FDI MEPs following all interventions (≥ 25%, P < 0.01), whereas the Met allele carriers only showed increased MEPs after the simple motor task (≥ 26%, P < 0.01). In contrast to the simple motor task, there was no significant change in MEPs for the Val/Met subjects (7%, P = 0.50) and a reduction in MEPs for the Met/Met group (-38%, P < 0.01) following the complex motor task. Despite these differences in use-dependent plasticity, the performance of both motor tasks was not different between BDNF genotypes. We conclude that modulation of motor cortex excitability is strongly influenced by the BDNF polymorphism, with the greatest differences observed for the complex motor task. We also found unique motor cortex plasticity in the rarest form of the BDNF polymorphism (Met/Met subjects), which may have implications for functional recovery after disease or injury to the nervous system in these individuals. PMID:22694150

  12. Histidine-rich stabilized polyplexes for cMet-directed tumor-targeted gene transfer

    NASA Astrophysics Data System (ADS)

    Kos, Petra; Lächelt, Ulrich; Herrmann, Annika; Mickler, Frauke Martina; Döblinger, Markus; He, Dongsheng; Krhač Levačić, Ana; Morys, Stephan; Bräuchle, Christoph; Wagner, Ernst

    2015-03-01

    Overexpression of the hepatocyte growth factor receptor/c-Met proto oncogene on the surface of a variety of tumor cells gives an opportunity to specifically target cancerous tissues. Herein, we report the first use of c-Met as receptor for non-viral tumor-targeted gene delivery. Sequence-defined oligomers comprising the c-Met binding peptide ligand cMBP2 for targeting, a monodisperse polyethylene glycol (PEG) for polyplex surface shielding, and various cationic (oligoethanamino) amide cores containing terminal cysteines for redox-sensitive polyplex stabilization, were assembled by solid-phase supported syntheses. The resulting oligomers exhibited a greatly enhanced cellular uptake and gene transfer over non-targeted control sequences, confirming the efficacy and target-specificity of the formed polyplexes. Implementation of endosomal escape-promoting histidines in the cationic core was required for gene expression without additional endosomolytic agent. The histidine-enriched polyplexes demonstrated stability in serum as well as receptor-specific gene transfer in vivo upon intratumoral injection. The co-formulation with an analogous PEG-free cationic oligomer led to a further compaction of pDNA polyplexes with an obvious change of shape as demonstrated by transmission electron microscopy. Such compaction was critically required for efficient intravenous gene delivery which resulted in greatly enhanced, cMBP2 ligand-dependent gene expression in the distant tumor.Overexpression of the hepatocyte growth factor receptor/c-Met proto oncogene on the surface of a variety of tumor cells gives an opportunity to specifically target cancerous tissues. Herein, we report the first use of c-Met as receptor for non-viral tumor-targeted gene delivery. Sequence-defined oligomers comprising the c-Met binding peptide ligand cMBP2 for targeting, a monodisperse polyethylene glycol (PEG) for polyplex surface shielding, and various cationic (oligoethanamino) amide cores containing

  13. Circulating [Met]enkephalin and catecholamine responses to acute hypotension and hypertension in anaesthetized greyhounds.

    PubMed Central

    Mason, D. F.; Medbak, S.; Rees, L. H.

    1987-01-01

    The effects of either hypotension induced by sodium nitroprusside or hexamethonium or hypertension produced by angiotensin II or noradrenaline on the circulating levels of methionine enkephalin ([Met]enkephalin)-like immunoreactivity (MLI), adrenaline and noradrenaline in anaesthetized greyhounds were examined. Nitroprusside infusions (200 and 400 micrograms min-1) induced a fall in blood pressure accompanied by significant rises in plasma MLI and catecholamine concentrations. Concomitant administration of a high dose of naloxone did not alter the fall in blood pressure produced by nitroprusside but was associated with greater rises in circulating MLI and catecholamines when compared to nitroprusside alone, suggesting that [Met]enkephalin is not involved in the hypotensive action of nitroprusside. Intravenous hexamethonium (2.5 mg kg-1) provoked a fall in blood pressure which was not associated with any changes in plasma MLI. However, it produced a fall in plasma noradrenaline and a rise in plasma adrenaline. Thus it appears that neural mechanisms are required, at least in part, for the release of MLI. Angiotensin II (1.25 micrograms kg-1 min-1) and noradrenaline (8 micrograms kg-1 min-1) infusions produced an elevation in blood pressure without altering the circulating MLI levels. Study of the molecular forms of circulating MLI, before and during hypotension, revealed that the large molecular weight enkephalin-containing peptides with approximate molecular sizes of 18kD and 8kD were the predominant forms both in the basal and stimulated states. It is concluded that circulating [Met]enkephalin is not involved in the tonic control of blood pressure but it may modulate catecholamine release following hypotension as part of the stress response. PMID:3594068

  14. Delphinidin inhibits cell proliferation and invasion via modulation of Met receptor phosphorylation

    SciTech Connect

    Syed, Deeba N.; Afaq, Farrukh; Sarfaraz, Sami; Khan, Naghma; Kedlaya, Rajendra; Setaluri, Vijayasaradhi; Mukhtar, Hasan

    2008-08-15

    The HGF/Met signaling pathway is deregulated in majority of cancers and is associated with poor prognosis in breast cancer. Delphinidin, present in pigmented fruits and vegetables possesses potent anti-oxidant, anti-inflammatory and anti-angiogenic properties. Here, we assessed the anti-proliferative and anti-invasive effects of delphinidin on HGF-mediated responses in the immortalized MCF-10A breast cell line. Treatment of cells with delphinidin prior to exposure to exogenous HGF resulted in the inhibition of HGF-mediated (i) tyrosyl-phosphorylation and increased expression of Met receptor, (ii) phosphorylation of downstream regulators such as FAK and Src and (iii) induction of adaptor proteins including paxillin, Gab-1 and GRB-2. In addition, delphinidin treatment resulted in significant inhibition of HGF-activated (i) Ras-ERK MAPKs and (ii) PI3K/AKT/mTOR/p70S6K pathways. Delphinidin was found to repress HGF-activated NF{kappa}B transcription with a decrease in (i) phosphorylation of IKK{alpha}/{beta} and I{kappa}B{alpha}, and (ii) activation and nuclear translocation of NF{kappa}B/p65. Inhibition of HGF-mediated membrane translocation of PKC{alpha} as well as decreased phosphorylation of STAT3 was further observed in delphinidin treated cells. Finally, decreased cell viability of Met receptor expressing breast cancer cells treated with delphinidin argues for a potential role of the agent in the prevention of HGF-mediated activation of various signaling pathways implicated in breast cancer.

  15. Biblio-MetReS: A bibliometric network reconstruction application and server

    PubMed Central

    2011-01-01

    Background Reconstruction of genes and/or protein networks from automated analysis of the literature is one of the current targets of text mining in biomedical research. Some user-friendly tools already perform this analysis on precompiled databases of abstracts of scientific papers. Other tools allow expert users to elaborate and analyze the full content of a corpus of scientific documents. However, to our knowledge, no user friendly tool that simultaneously analyzes the latest set of scientific documents available on line and reconstructs the set of genes referenced in those documents is available. Results This article presents such a tool, Biblio-MetReS, and compares its functioning and results to those of other user-friendly applications (iHOP, STRING) that are widely used. Under similar conditions, Biblio-MetReS creates networks that are comparable to those of other user friendly tools. Furthermore, analysis of full text documents provides more complete reconstructions than those that result from using only the abstract of the document. Conclusions Literature-based automated network reconstruction is still far from providing complete reconstructions of molecular networks. However, its value as an auxiliary tool is high and it will increase as standards for reporting biological entities and relationships become more widely accepted and enforced. Biblio-MetReS is an application that can be downloaded from http://metres.udl.cat/. It provides an easy to use environment for researchers to reconstruct their networks of interest from an always up to date set of scientific documents. PMID:21975133

  16. EUV microexposures at the ALS using the 0.3-NA MET projectionoptics

    SciTech Connect

    Naulleau, Patrick; Goldberg, Kenneth A.; Anderson, Erik; Cain,Jason P.; Denham, Paul; Hoef, Brian; Jackson, Keith; Morlens,Anne-Sophie; Rekawa, Seno; Dean, Kim

    2005-09-01

    The recent development of high numerical aperture (NA) EUV optics such as the 0.3-NA Micro Exposure Tool (MET) optic has given rise to a new class of ultra-high resolution microexposure stations. Once such printing station has been developed and implemented at Lawrence Berkeley National Laboratory's Advanced Light Source. This flexible printing station utilizes a programmable coherence illuminator providing real-time pupil-fill control for advanced EUV resist and mask development. The Berkeley exposure system programmable illuminator enables several unique capabilities. Using dipole illumination out to {sigma}=1, the Berkeley tool supports equal-line-space printing down to 12 nm, well beyond the capabilities of similar tools. Using small-sigma illumination combined with the central obscuration of the MET optic enables the system to print feature sizes that are twice as small as those coded on the mask. In this configuration, the effective 10x-demagnification for equal lines and spaces reduces the mask fabrication burden for ultra-high-resolution printing. The illuminator facilitates coherence studies such as the impact of coherence on line-edge roughness (LER) and flare. Finally the illuminator enables novel print-based aberration monitoring techniques as described elsewhere in these proceedings. Here we describe the capabilities of the new MET printing station and present system characterization results. Moreover, we present the latest printing results obtained in experimental resists. Limited by the availability of high-resolution photoresists, equal line-space printing down to 25 nm has been demonstrated as well as isolated line printing down to 29 nm with an LER of approaching 3 nm.

  17. MetRxn: a knowledgebase of metabolites and reactions spanning metabolic models and databases

    PubMed Central

    2012-01-01

    Background Increasingly, metabolite and reaction information is organized in the form of genome-scale metabolic reconstructions that describe the reaction stoichiometry, directionality, and gene to protein to reaction associations. A key bottleneck in the pace of reconstruction of new, high-quality metabolic models is the inability to directly make use of metabolite/reaction information from biological databases or other models due to incompatibilities in content representation (i.e., metabolites with multiple names across databases and models), stoichiometric errors such as elemental or charge imbalances, and incomplete atomistic detail (e.g., use of generic R-group or non-explicit specification of stereo-specificity). Description MetRxn is a knowledgebase that includes standardized metabolite and reaction descriptions by integrating information from BRENDA, KEGG, MetaCyc, Reactome.org and 44 metabolic models into a single unified data set. All metabolite entries have matched synonyms, resolved protonation states, and are linked to unique structures. All reaction entries are elementally and charge balanced. This is accomplished through the use of a workflow of lexicographic, phonetic, and structural comparison algorithms. MetRxn allows for the download of standardized versions of existing genome-scale metabolic models and the use of metabolic information for the rapid reconstruction of new ones. Conclusions The standardization in description allows for the direct comparison of the metabolite and reaction content between metabolic models and databases and the exhaustive prospecting of pathways for biotechnological production. This ever-growing dataset currently consists of over 76,000 metabolites participating in more than 72,000 reactions (including unresolved entries). MetRxn is hosted on a web-based platform that uses relational database models (MySQL). PMID:22233419

  18. Probable precursors of [Leu]enkephalin and [Met]enkephalin in adrenal medulla: peptides of 3-5 kilodaltons.

    PubMed Central

    Kimura, S; Lewis, R V; Stern, A S; Rossier, J; Stein, S; Udenfriend, S

    1980-01-01

    Adrenal chromaffin granules contain at least 10 peptides, ranging in size from 3 to 5 kilodaltons, that yield, upon digestion with trypsin, peptides that show specific binding to opiate receptors. All are distinctly different from beta-endorphin. Two of these peptides have been purified to homogeneity and subjected to chemical analysis. One is apparently a [Met]enkephalin precursor containing two copies of the [Met]enkephalin sequence. The other peptide contains both [Leu]enkephalin and [Met]enkephalin sequences and is presumably a common precursor of the two forms of enkephalin. Images PMID:6246500

  19. Preparations for EUV interferometry of the 0.3 NA MET optic

    SciTech Connect

    Goldberg, Kenneth A.; Naulleau, Patrick P.; Denham, Paul E.; Rekawa, Senajith B.; Jackson, Keith H.; Liddle, J. Alexander; Harteneck, Bruce; Gullikson, Eric; Anderson, Erik H.

    2003-10-30

    An at-wavelength interferometer is being created for the measurement and alignment of the 0.3 numerical aperture Micro Exposure Tool projection optic at EUV wavelengths. The prototype MET system promises to provide early learning from EUV lithographic imaging down to 20-nm feature size. The threefold increase to 0.3 NA in the image-side numerical aperture presents several challenges for the extension of ultra-high-accuracy interferometry, including pinhole fabrication and the calibration and removal of systematic error sources.

  20. Signal to Noise Ratio Estimations for a Volcanic ASH Detection Lidar. Case Study: The Met Office

    NASA Astrophysics Data System (ADS)

    Georgoussis, George; Adam, Mariana; Avdikos, George

    2016-06-01

    In this paper we calculate the Signal-to-Noise (SNR) ratio of a 3-channel commercial (Raymetics) volcanic ash detection system, (LR111-D300), already operating under Met Office organization. The methodology for the accurate estimation is presented for day and nighttime conditions. The results show that SNR values are higher than 10 for ranges up to 13 km for both nighttime and daytime conditions. This is a quite good result compared with other values presented in bibliography and proves that such system is able to detect volcanic ash over a range of 20 km.

  1. Adiabatic shear band formation in explosively driven AerMet-100 alloy cylinders

    SciTech Connect

    Sunwoo, A J; Becker, R; Goto, D M; Orzechowski, T J; Springer, H K; Syn, C K; Zhou, J

    2006-02-08

    Two differently heat-treated AerMet-100 alloy cylinders were explosively driven to fragmentation. Soft-captured fragments were studied to characterize the deformation and damage induced by high explosive loading. The characterization of the fragments reveals that the dominant failure mechanism appears to be dynamic fracture along adiabatic shear bands. These shear bands differ in size and morphology depending on the heat-treated conditions. Nanoindentation measurements of the adiabatic shear bands in either material condition indicate higher hardness in the bands compared to the matrix regions of the fragments.

  2. MetLab: An In Silico Experimental Design, Simulation and Analysis Tool for Viral Metagenomics Studies

    PubMed Central

    Gourlé, Hadrien; Bongcam-Rudloff, Erik; Hayer, Juliette

    2016-01-01

    Metagenomics, the sequence characterization of all genomes within a sample, is widely used as a virus discovery tool as well as a tool to study viral diversity of animals. Metagenomics can be considered to have three main steps; sample collection and preparation, sequencing and finally bioinformatics. Bioinformatic analysis of metagenomic datasets is in itself a complex process, involving few standardized methodologies, thereby hampering comparison of metagenomics studies between research groups. In this publication the new bioinformatics framework MetLab is presented, aimed at providing scientists with an integrated tool for experimental design and analysis of viral metagenomes. MetLab provides support in designing the metagenomics experiment by estimating the sequencing depth needed for the complete coverage of a species. This is achieved by applying a methodology to calculate the probability of coverage using an adaptation of Stevens’ theorem. It also provides scientists with several pipelines aimed at simplifying the analysis of viral metagenomes, including; quality control, assembly and taxonomic binning. We also implement a tool for simulating metagenomics datasets from several sequencing platforms. The overall aim is to provide virologists with an easy to use tool for designing, simulating and analyzing viral metagenomes. The results presented here include a benchmark towards other existing software, with emphasis on detection of viruses as well as speed of applications. This is packaged, as comprehensive software, readily available for Linux and OSX users at https://github.com/norling/metlab. PMID:27479078

  3. Brain-derived neurotrophic factor Val66Met polymorphism, human memory, and synaptic neuroplasticity.

    PubMed

    Lamb, Yvette N; McKay, Nicole S; Thompson, Christopher S; Hamm, Jeffrey P; Waldie, Karen E; Kirk, Ian J

    2015-01-01

    Some people have much better memory than others, and there is compelling evidence that a considerable proportion of this variation in memory ability is genetically inherited. A form of synaptic plasticity known as long-term potentiation (LTP) is the principal candidate mechanism underlying memory formation in neural circuits, and it might be expected, therefore, that a genetic influence on the degree of LTP might in turn influence memory abilities. Of the genetic variations thought to significantly influence mnemonic ability in humans, the most likely to have its effect via LTP is a single nucleotide polymorphism affecting brain-derived neurotrophic factor [BDNF (Val66Met)]. However, although it is likely that BDNF influences memory via a modulation of acute plasticity (i.e., LTP), BDNF also has considerable influence on structural development of neural systems. Thus, the influence of BDNF (Val66Met) on mnemonic performance via influences of brain structure as well as function must also be considered. In this brief review, we will describe the phenomenon of LTP and its study in non-human animals. We will discuss the relatively recent attempts to translate this work to studies in humans. We will describe how this has enabled investigation of the effect of the BDNF polymorphism on LTP, on brain structure, and on memory performance.

  4. Does adult ADHD interact with COMT val (158) met genotype to influence working memory performance?

    PubMed

    Biehl, Stefanie C; Gschwendtner, Kathrin M; Guhn, Anne; Müller, Laura D; Reichert, Susanne; Heupel, Julia; Reif, Andreas; Deckert, Jürgen; Herrmann, Martin J; Jacob, Christian P

    2015-03-01

    Both attention-deficit/hyperactivity disorder (ADHD) and catechol-O-methyltransferase (COMT) genotype have been linked to altered dopaminergic transmission and possible impairment in frontal lobe functioning. This study offers an investigation of a possible interaction between ADHD diagnosis and COMT genotype on measures of working memory and executive function. Thirty-five adults with ADHD, who were recruited from the ADHD outpatient clinic at the Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, and thirty-five matched healthy controls completed the Digit Span test and the Stroop Color Word Test. While there were no main effects of ADHD or COMT, the two factors interacted on both Digit Span subtests with the two groups' met/met carriers showing significantly different performance on the Digit Span Forward subtest and the val/val carriers showing significantly different performance on the Digit Span Backward subtest. Findings provide preliminary support for a differential impact of COMT genotype on working memory measures in adult patients with ADHD compared to healthy controls.

  5. COMT Val158Met Genotype and Individual Differences in Executive Function in Healthy Adults

    PubMed Central

    Wishart, Heather A.; Roth, Robert M.; Saykin, Andrew J.; Rhodes, C. Harker; Tsongalis, Gregory J.; Pattin, Kristine A.; Moore, Jason H.; Mcallister, Thomas W.

    2011-01-01

    The Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene may be related to individual differences in cognition, likely via modulation of prefrontal dopamine catabolism. However, the available studies have yielded mixed results, possibly in part because they do not consistently account for other genes that affect cognition. We hypothesized that COMT Met allele homozygosity, which is associated with higher levels of prefrontal dopamine, would predict better executive function as measured using standard neuropsychological testing, and that other candidate genes might interact with COMT to modulate this effect. Participants were 95 healthy, right-handed adults who underwent genotyping and cognitive testing. COMT genotype predicted executive ability as measured by the Trail-Making Test, even after covarying for demographics and APOE, BDNF and ANKK1 genotype. There was a COMT-ANKK1 interaction in which individuals having both the COMT Val allele and the ANKK1 T allele showed the poorest performance. This study suggests the heterogeneity in COMT effects reported in the literature may be due in part to gene-gene interactions that influence central dopaminergic systems. PMID:21144101

  6. MetLab: An In Silico Experimental Design, Simulation and Analysis Tool for Viral Metagenomics Studies.

    PubMed

    Norling, Martin; Karlsson-Lindsjö, Oskar E; Gourlé, Hadrien; Bongcam-Rudloff, Erik; Hayer, Juliette

    2016-01-01

    Metagenomics, the sequence characterization of all genomes within a sample, is widely used as a virus discovery tool as well as a tool to study viral diversity of animals. Metagenomics can be considered to have three main steps; sample collection and preparation, sequencing and finally bioinformatics. Bioinformatic analysis of metagenomic datasets is in itself a complex process, involving few standardized methodologies, thereby hampering comparison of metagenomics studies between research groups. In this publication the new bioinformatics framework MetLab is presented, aimed at providing scientists with an integrated tool for experimental design and analysis of viral metagenomes. MetLab provides support in designing the metagenomics experiment by estimating the sequencing depth needed for the complete coverage of a species. This is achieved by applying a methodology to calculate the probability of coverage using an adaptation of Stevens' theorem. It also provides scientists with several pipelines aimed at simplifying the analysis of viral metagenomes, including; quality control, assembly and taxonomic binning. We also implement a tool for simulating metagenomics datasets from several sequencing platforms. The overall aim is to provide virologists with an easy to use tool for designing, simulating and analyzing viral metagenomes. The results presented here include a benchmark towards other existing software, with emphasis on detection of viruses as well as speed of applications. This is packaged, as comprehensive software, readily available for Linux and OSX users at https://github.com/norling/metlab. PMID:27479078

  7. Usability of EFBs for Viewing NOTAMs and AIS/MET Data Link Messages

    NASA Technical Reports Server (NTRS)

    Evans, Emory T.; Young, Steven D.; Daniels, Tammi S.; Myer, Robert R.

    2014-01-01

    Electronic Flight Bags (EFB) are increasingly integral to flight deck information management. A piloted simulation study was conducted at NASA Langley Research Center, one aspect of which was to evaluate the usability and acceptability of EFBs for viewing and managing Notices to Airmen (NOTAMs) and data linked aeronautical information services (AIS) and meteorological information (MET). The study simulated approaches and landings at Memphis International Airport (KMEM) using various flight scenarios and weather conditions. Ten two-pilot commercial airline crews participated, utilizing the Cockpit Motion Facility's Research Flight Deck (CMF/RFD) simulator. Each crew completed approximately two dozen flights over a two day period. Two EFBs were installed, one for each pilot. Study data were collected in the form of questionnaire/interview responses, audio/video recordings, oculometer recordings, and aircraft/system state data. Preliminary usability results are reported primarily based on pilot interviews and responses to questions focused on ease of learning, ease of use, usefulness, satisfaction, and acceptability. Analysis of the data from the other objective measures (e.g., oculometer) is ongoing and will be reported in a future publication. This paper covers how the EFB functionality was set up for the study; the NOTAM, AIS/MET data link, and weather messages that were presented; questionnaire results; selected pilot observations; and conclusions.

  8. RNase MRP Cleaves Pre-tRNASer-Met in the tRNA Maturation Pathway

    PubMed Central

    Adachi, Kousuke; Nobe, Yuko; Kobayashi, Junya; Hirota, Kouji; Oliveira, Douglas V.; Taoka, Masato; Isobe, Toshiaki

    2014-01-01

    Ribonuclease mitochondrial RNA processing (RNase MRP) is a multifunctional ribonucleoprotein (RNP) complex that is involved in the maturation of various types of RNA including ribosomal RNA. RNase MRP consists of a potential catalytic RNA and several protein components, all of which are required for cell viability. We show here that the temperature-sensitive mutant of rmp1, the gene for a unique protein component of RNase MRP, accumulates the dimeric tRNA precursor, pre-tRNASer-Met. To examine whether RNase MRP mediates tRNA maturation, we purified the RNase MRP holoenzyme from the fission yeast Schizosaccharomyces pombe and found that the enzyme directly and selectively cleaves pre-tRNASer-Met, suggesting that RNase MRP participates in the maturation of specific tRNA in vivo. In addition, mass spectrometry–based ribonucleoproteomic analysis demonstrated that this RNase MRP consists of one RNA molecule and 11 protein components, including a previously unknown component Rpl701. Notably, limited nucleolysis of RNase MRP generated an active catalytic core consisting of partial mrp1 RNA fragments, which constitute “Domain 1” in the secondary structure of RNase MRP, and 8 proteins. Thus, the present study provides new insight into the structure and function of RNase MRP. PMID:25401760

  9. Mesenchymal-epithelial transition (MET) as a mechanism for metastatic colonisation in breast cancer.

    PubMed

    Gunasinghe, N P A Devika; Wells, Alan; Thompson, Erik W; Hugo, Honor J

    2012-12-01

    As yet, there is no cure for metastatic breast cancer. Historically, considerable research effort has been concentrated on understanding the processes of metastasis, how a primary tumour locally invades and systemically disseminates using the phenotypic switching mechanism of epithelial to mesenchymal transition (EMT); however, much less is understood about how metastases are then formed. Breast cancer metastases often look (and may even function) as 'normal' breast tissue, a bizarre observation against the backdrop of the organ structure of the lung, liver, bone or brain. Mesenchymal to epithelial transition (MET), the opposite of EMT, has been proposed as a mechanism for establishment of the metastatic neoplasm, leading to questions such as: Can MET be clearly demonstrated in vivo? What factors cause this phenotypic switch within the cancer cell? Are these signals/factors derived from the metastatic site (soil) or expressed by the cancer cells themselves (seed)? How do the cancer cells then grow into a detectable secondary tumour and further disseminate? And finally--Can we design and develop therapies that may combat this dissemination switch? This review aims to address these important questions by evaluating long-standing paradigms and novel emerging concepts in the field of epithelial mesencyhmal plasticity.

  10. Brain-derived neurotrophic factor Val66Met polymorphism, human memory, and synaptic neuroplasticity.

    PubMed

    Lamb, Yvette N; McKay, Nicole S; Thompson, Christopher S; Hamm, Jeffrey P; Waldie, Karen E; Kirk, Ian J

    2015-01-01

    Some people have much better memory than others, and there is compelling evidence that a considerable proportion of this variation in memory ability is genetically inherited. A form of synaptic plasticity known as long-term potentiation (LTP) is the principal candidate mechanism underlying memory formation in neural circuits, and it might be expected, therefore, that a genetic influence on the degree of LTP might in turn influence memory abilities. Of the genetic variations thought to significantly influence mnemonic ability in humans, the most likely to have its effect via LTP is a single nucleotide polymorphism affecting brain-derived neurotrophic factor [BDNF (Val66Met)]. However, although it is likely that BDNF influences memory via a modulation of acute plasticity (i.e., LTP), BDNF also has considerable influence on structural development of neural systems. Thus, the influence of BDNF (Val66Met) on mnemonic performance via influences of brain structure as well as function must also be considered. In this brief review, we will describe the phenomenon of LTP and its study in non-human animals. We will discuss the relatively recent attempts to translate this work to studies in humans. We will describe how this has enabled investigation of the effect of the BDNF polymorphism on LTP, on brain structure, and on memory performance. PMID:26263066

  11. The relevance of the TGF-β Paradox to EMT-MET programs.

    PubMed

    Morrison, Chevaun D; Parvani, Jenny G; Schiemann, William P

    2013-11-28

    The role of transforming growth factor-β (TGF-β) during tumorigenesis is complex and paradoxical, reflecting its ability to function as a tumor suppressor in normal and early-stage cancers, and as a tumor promoter in their late-stage counterparts. The switch in TGF-β function is known as the "TGF-β Paradox," whose manifestations are intimately linked to the initiation of epithelial-mesenchymal transition (EMT) programs in developing and progressing carcinomas. Indeed, as carcinoma cells emerge from EMT programs stimulated by TGF-β, they readily display a variety of acquired phenotypes that provide a selective advantage to growing carcinomas, including (i) enhanced cell migration and invasion; (ii) heightened resistance to cytotoxic agents, targeted chemotherapeutic, and radiation treatments; and (iv) boosted expansion of cancer-initiating and stem-like cell populations that underlie tumor metastasis and disease recurrence. At present, the molecular, cellular, and microenvironmental mechanisms that enable post-EMT and metastatic carcinoma cells to hijack the oncogenic activities of TGF-β remain incompletely understood. Additionally, the molecular mechanisms that counter EMT programs and limit the aggressiveness of late-stage carcinomas, events that transpire via mesenchymal-epithelial transition (MET) reactions, also need to be further elucidated. Here we review recent advances that provide new insights into how TGF-β promotes EMT programs in late-stage carcinoma cells, as well as how these events are balanced by MET programs during the development and metastatic progression of human carcinomas.

  12. Plasma BDNF Concentration, Val66Met Genetic Variant, and Depression-Related Personality Traits

    PubMed Central

    Terracciano, Antonio; Martin, Bronwen; Ansari, David; Tanaka, Toshiko; Ferrucci, Luigi; Maudsley, Stuart; Mattson, Mark P.; Costa, Paul T.

    2010-01-01

    Brain derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurogenesis, and BDNF plasma and serum levels have been associated with depression, Alzheimer's disease, and other psychiatric and neurodegenerative disorders. In a relatively large community sample, drawn from the Baltimore Longitudinal Study of Aging (BLSA), we examine whether BDNF plasma concentration is associated with the Val66Met functional polymorphism of the BDNF gene (n = 335) and with depression-related personality traits assessed with the NEO-PI-R (n = 391). Plasma concentration of BDNF was not associated with the Val66Met variant in either men or women. However, in men, but not in women, BDNF plasma level was associated with personality traits linked to depression. Contrary to the notion that low BDNF is associated with negative outcomes, we found lower plasma levels in men who score lower on depression and vulnerability to stress (two facets of Neuroticism) and higher on Conscientiousness and Extraversion. These findings challenge the prevailing hypothesis that lower peripheral levels of BDNF are a marker of depression. PMID:20345896

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

    NASA Astrophysics Data System (ADS)

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

    2010-03-01

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

  14. CoMET: Cost and Mass Evaluation Tool for Spacecraft and Mission Design

    NASA Technical Reports Server (NTRS)

    Bieber, Ben S.

    2005-01-01

    New technology in space exploration is often developed without a complete knowledge of its impact. While the immediate benefits of a new technology are obvious, it is harder to understand its indirect consequences, which ripple through the entire system. COMET is a technology evaluation tool designed to illuminate how specific technology choices affect a mission at each system level. COMET uses simplified models for mass, power, and cost to analyze performance parameters of technologies of interest. The sensitivity analysis that CoMET provides shows whether developing a certain technology will greatly benefit the project or not. CoMET is an ongoing project approaching a web-based implementation phase. This year, development focused on the models for planetary daughter craft, such as atmospheric probes, blimps and balloons, and landers. These models are developed through research into historical data, well established rules of thumb, and engineering judgment of experts at JPL. The model is validated by corroboration with JpL advanced mission studies. Other enhancements to COMET include adding launch vehicle analysis and integrating an updated cost model. When completed, COMET will allow technological development to be focused on areas that will most drastically improve spacecraft performance.

  15. MetLab: An In Silico Experimental Design, Simulation and Analysis Tool for Viral Metagenomics Studies.

    PubMed

    Norling, Martin; Karlsson-Lindsjö, Oskar E; Gourlé, Hadrien; Bongcam-Rudloff, Erik; Hayer, Juliette

    2016-01-01

    Metagenomics, the sequence characterization of all genomes within a sample, is widely used as a virus discovery tool as well as a tool to study viral diversity of animals. Metagenomics can be considered to have three main steps; sample collection and preparation, sequencing and finally bioinformatics. Bioinformatic analysis of metagenomic datasets is in itself a complex process, involving few standardized methodologies, thereby hampering comparison of metagenomics studies between research groups. In this publication the new bioinformatics framework MetLab is presented, aimed at providing scientists with an integrated tool for experimental design and analysis of viral metagenomes. MetLab provides support in designing the metagenomics experiment by estimating the sequencing depth needed for the complete coverage of a species. This is achieved by applying a methodology to calculate the probability of coverage using an adaptation of Stevens' theorem. It also provides scientists with several pipelines aimed at simplifying the analysis of viral metagenomes, including; quality control, assembly and taxonomic binning. We also implement a tool for simulating metagenomics datasets from several sequencing platforms. The overall aim is to provide virologists with an easy to use tool for designing, simulating and analyzing viral metagenomes. The results presented here include a benchmark towards other existing software, with emphasis on detection of viruses as well as speed of applications. This is packaged, as comprehensive software, readily available for Linux and OSX users at https://github.com/norling/metlab.

  16. 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

    ... Regulations Relating to Public Lands BUREAU OF RECLAMATION, DEPARTMENT OF THE INTERIOR RECLAMATION RURAL WATER SUPPLY PROGRAM Overview § 404.19 What requirements must be met before I can request assistance to...

  17. Discovery of Pyrrolopyridine−Pyridone Based Inhibitors of Met Kinase: Synthesis, X-ray Crystallographic Analysis, and Biological Activities

    SciTech Connect

    Kim, Kyoung Soon; Zhang, Liping; Schmidt, Robert; Cai, Zhen-Wei; Wei, Donna; Williams, David K.; Lombardo, Louis J.; Trainor, George L.; Xie, Dianlin; Zhang, Yaquan; An, Yongmi; Sack, John S.; Tokarski, John S.; Darienzo, Celia; Kamath, Amrita; Marathe, Punit; Zhang, Yueping; Lippy, Jonathan; Jeyaseelan, Sr., Robert; Wautlet, Barri; Henley, Benjamin; Gullo-Brown, Johnni; Manne, Veeraswamy; Hunt, John T.; Fargnoli, Joseph; Borzilleri, Robert M.

    2008-10-02

    Conformationally constrained 2-pyridone analogue 2 is a potent Met kinase inhibitor with an IC50 value of 1.8 nM. Further SAR of the 2-pyridone based inhibitors of Met kinase led to potent 4-pyridone and pyridine N-oxide inhibitors such as 3 and 4. The X-ray crystallographic data of the inhibitor 2 bound to the ATP binding site of Met kinase protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues showed potent antiproliferative activities against the Met dependent GTL-16 gastric carcinoma cell line. Compound 2 also inhibited Flt-3 and VEGFR-2 kinases with IC{sub 50} values of 4 and 27 nM, respectively. It possesses a favorable pharmacokinetic profile in mice and demonstrates significant in vivo antitumor activity in the GTL-16 human gastric carcinoma xenograft model.

  18. Chemical shift assignments of zinc finger domain of methionine aminopeptidase 1 (MetAP1) from Homo sapiens.

    PubMed

    Rachineni, Kavitha; Arya, Tarun; Singarapu, Kiran Kumar; Addlagatta, Anthony; Bharatam, Jagadeesh

    2015-10-01

    Methionine aminopeptidase Type I (MetAP1) cleaves the initiator methionine from about 70 % of all newly synthesized proteins in almost every living cell. Human MetAP1 is a two domain protein with a zinc finger on the N-terminus and a catalytic domain on the C-terminus. Here, we report the chemical shift assignments of the amino terminal zinc binding domain (ZBD) (1-83 residues) of the human MetAP1 derived by using advanced NMR spectroscopic methods. We were able to assign the chemical shifts of ZBD of MetAP1 nearly complete, which reveal two helical fragments involving residues P44-L49 (α1) and Q59-K82 (α2). The protein structure unfolds upon complex formation with the addition of 2 M excess EDTA, indicated by the appearance of amide resonances in the random coil chemical shift region of (15)NHSQC spectrum.

  19. Evaluation of c-Met, HGF, and HER-2 expressions in gastric carcinoma and their association with other clinicopathological factors

    PubMed Central

    Yıldız, Yetkin; Sokmensuer, Cenk; Yalcin, Suayib

    2016-01-01

    Background Met and HER-2 are proto-oncogenes encoding receptor tyrosine kinase c-Met and HER-2, respectively. Hepatocyte growth factor (HGF) is a ligand of c-Met. The frequency of c-Met, HGF, and HER-2 expressions in gastric cancer and their association with other clinicopathological factors have not been fully understood. Patients and methods Patients with stage 1–4 disease were analyzed. Expressions of c-Met, HGF, and HER-2 were examined using immunohistochemistry. Results A total of 143 patients, 97 males and 46 females, were included. C-Met scores were 3(+) in 31.5%, 2(+) in 27.3%, and 1(+) in 10.5% of the patients. There was no statistically significant difference in age, sex, tumor location, differentiation, Lauren classification, TNM staging, presence of distant metastasis, depth of tumor invasion (T), lymphovascular invasion, and survival between c-Met subgroups. Overall HGF positivity was 20.6%. HER-2 scores were 3(+) in 9.1%, 2(+) in 9.8%, and 1(+) in 16.1% of the patients. HER-2 overexpression was associated with better differentiation, intestinal subtype, and advanced stage. C-Met overexpressions were 84.6% in the HER-2-overexpression-positive group and 56.2% in the HER-2-overexpression-negative group. There were no statistically significant differences in survival between the high c-Met-expression-positive and -negative stage 3 and stage 4 patients and between the HGF-positive and -negative groups. The mean survival was 11.6±6.3 months in the HER-2-overexpression-positive stage 4 group and 11.9±6.8 months in the HER-2-overexpression-negative stage 4 group. There were no statistically significant differences in survival between the two groups. Conclusion c-Met was not associated with any prognostic factors in gastric cancer. HER-2 was associated with better differentiation, intestinal subtype, advanced stage, and c-Met overexpression. PMID:27703380

  20. Increased sensitivity to thermal pain following a single opiate dose is influenced by the COMT val(158)met polymorphism.

    PubMed

    Jensen, Karin B; Lonsdorf, Tina B; Schalling, Martin; Kosek, Eva; Ingvar, Martin

    2009-01-01

    Increased pain sensitivity after opioid administration (opioid-induced hyperalgesia) and/or repeated painful stimuli is an individually varying and clinically important phenomenon. The functional polymorphism (val(158)met) of the Catechol-O-methyltransferase (COMT) gene regulates the metabolism of dopamine/noradrenaline. Individuals homozygous for the met(158) allele have been reported to have increased pain sensitivity and there are findings of lower micro-opioid system activation during sustained pain. We hypothesized that met/met individuals would exhibit higher pain sensitization and opioid-induced hyperalgesia in response to repeated pain stimuli and an intravenous injection of an opioid drug. Participants were 43 healthy subjects who went through an experiment where five blocks of pain were induced to the hand using a heat probe. After each stimulus subjects rated the pain on a visual analogue scale (VAS) from 0 mm (no pain) to 100 mm (worst possible pain). Before the second stimulus there was an intravenous injection of a rapid and potent opioid drug. At baseline there was no difference in pain ratings between the COMTval(158)met genotypes, F(2, 39)<1. However, a repeated measures ANOVA for all five stimuli revealed a main effect for COMTval(158)met genotype, F(2, 36) = 4.17, p = 0.024. Met/met individuals reported significantly more pain compared to val/val, p = 0.010. A pairwise comparison of baseline and the opioid intervention demonstrated that analgesia was induced in all groups (p = 0.042) without a separating effect for genotype (n.s). We suggest that the initial response of the descending pain system is not influenced by the COMTval(158)met polymorphism but when the system is challenged the difference is revealed. An important clinical implication of this may be that the COMTval(158)met related differences may be more expressed in individuals where the inhibitory system is already challenged and sensitive, e.g. chronic pain patients. This has to be

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

    PubMed

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

    2012-02-01

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

  2. Optical Imaging of Mesenchymal Epithelial Transition Factor (MET) for Enhanced Detection and Characterization of Primary and Metastatic Hepatic Tumors

    PubMed Central

    Esfahani, Shadi A.; Heidari, Pedram; Kim, Sun A.; Ogino, Shuji; Mahmood, Umar

    2016-01-01

    Purpose: To assess optical imaging of Mesenchymal-Epithelial Transition factor (MET) for delineation and characterization of intrahepatic models of human hepatocellular carcinoma (HCC) and metastatic colorectal cancer (CRC), and thereby demonstrate its potential use in precision oncology. Materials and Methods: MET expression in human CRC and HCC was assessed in tissue microarrays. We used GE-137, a modified cyanine 5-tagged peptide for MET targeting. HepG2 and Huh-7 (HCC) and HT-29 (CRC) cells with MET overexpression, and LNCaP cells (negative control) with minimal MET expression were incubated with the probe. Correlation between the relative fluorescence signal intensity and cellular MET expression level was assessed. Flow cytometry was used to assess probe specific binding and dissociation constant (Kd). Orthotopic xenograft models of human HCC and metastatic CRC were generated in nu/nu mice by subcapsular implantation of cells. Epifluorescence imaging was performed to capture the changes in deferential probe accumulation at different time points after injection. Target-to-liver background ratio (TBR) was calculated and the probe biodistribution within different organs was assessed. Histopathologic analysis of extracted xenografts was performed to correlate the tumors MET expression with probe uptake by cancer cells. Results: Approximately 91.5% of HCC and 81% of CRC microarray cores showed MET expression. HCC and CRC cells incubated with the probe showed substantial fluorescence compared to control LNCaP, with strong correlation between fluorescence signal and MET expression (R2 = 0.99, p < 0.001). Probe binding affinity to MET (Kd) was measured to be 2.9 ± 0.36 nM. Epifluorescence imaging showed intense uptake in subcapsular tumors with peak TBR of 5.46 ± 0.46 in Huh-7, 3.55 ± 0.38 in HepG2, and 15.93 ± 0.61 in HT-29 orthotopic xenografts at 4 hours post-injection (mean ± standard deviation). We demonstrated that in vivo probe uptake in xenografts is

  3. Expression and Significance of CD44, CD47 and c-met in Ovarian Clear Cell Carcinoma

    PubMed Central

    Wang, Huimin; Tan, Mingzi; Zhang, Song; Li, Xiao; Gao, Jian; Zhang, Danye; Hao, Yingying; Gao, Song; Liu, Juanjuan; Lin, Bei

    2015-01-01

    Aims: The aim of the present study is to investigate the differential expression of CD44, CD47 and c-met in ovarian clear cell carcinoma (OCCC), the correlation in their expression and their relationship with the biological behavior of OCCC. Methods: We used immunohistochemistry to examine the expression of CD44, CD47 and c-met in OCCC (86 cases) and investigated the effects of the expression and interaction of these molecules on the development of OCCC. Results: CD44, CD47 and c-met expression was significantly high in OCCC. Expression of CD44 and CD47 correlated with patient surgical stage, chemotherapy resistance and prognosis (all p < 0.05), and expression of c-met correlated with chemotherapy resistance and prognosis (all p < 0.05), but did not correlate with lymph node metastasis (all p > 0.05). The surgical stage, CD44, CD47 and c-met expression were independent risk factors for OCCC prognosis (all p < 0.05). Patients with low levels of CD44, CD47 and c-met showed better survival than those with high levels (all p < 0.05). There was a positive correlation between CD44 (or CD47) and c-met, as well as between CD44 and CD47 (the Spearman correlation coefficient rs was 0.783, 0.776 and 0.835, respectively, all p < 0.01). Additionally, pairwise correlation analysis of these three markers shows that the high expression of CD44/CD47, CD44/c-met and CD47/c-met were correlated with patient surgical stage, chemotherapy resistance and prognosis (all p < 0.05), but did not correlate with lymph node metastasis (all p > 0.05). Conclusions: Expression of CD44, CD47 and c-met was upregulated in OCCC and pairwise correlation. CD44, CD47 and c-met may have synergistic effects on the development of OCCC and are prognostic factors for ovarian cancer. PMID:25658794

  4. Optical Imaging of Mesenchymal Epithelial Transition Factor (MET) for Enhanced Detection and Characterization of Primary and Metastatic Hepatic Tumors

    PubMed Central

    Esfahani, Shadi A.; Heidari, Pedram; Kim, Sun A.; Ogino, Shuji; Mahmood, Umar

    2016-01-01

    Purpose: To assess optical imaging of Mesenchymal-Epithelial Transition factor (MET) for delineation and characterization of intrahepatic models of human hepatocellular carcinoma (HCC) and metastatic colorectal cancer (CRC), and thereby demonstrate its potential use in precision oncology. Materials and Methods: MET expression in human CRC and HCC was assessed in tissue microarrays. We used GE-137, a modified cyanine 5-tagged peptide for MET targeting. HepG2 and Huh-7 (HCC) and HT-29 (CRC) cells with MET overexpression, and LNCaP cells (negative control) with minimal MET expression were incubated with the probe. Correlation between the relative fluorescence signal intensity and cellular MET expression level was assessed. Flow cytometry was used to assess probe specific binding and dissociation constant (Kd). Orthotopic xenograft models of human HCC and metastatic CRC were generated in nu/nu mice by subcapsular implantation of cells. Epifluorescence imaging was performed to capture the changes in deferential probe accumulation at different time points after injection. Target-to-liver background ratio (TBR) was calculated and the probe biodistribution within different organs was assessed. Histopathologic analysis of extracted xenografts was performed to correlate the tumors MET expression with probe uptake by cancer cells. Results: Approximately 91.5% of HCC and 81% of CRC microarray cores showed MET expression. HCC and CRC cells incubated with the probe showed substantial fluorescence compared to control LNCaP, with strong correlation between fluorescence signal and MET expression (R2 = 0.99, p < 0.001). Probe binding affinity to MET (Kd) was measured to be 2.9 ± 0.36 nM. Epifluorescence imaging showed intense uptake in subcapsular tumors with peak TBR of 5.46 ± 0.46 in Huh-7, 3.55 ± 0.38 in HepG2, and 15.93 ± 0.61 in HT-29 orthotopic xenografts at 4 hours post-injection (mean ± standard deviation). We demonstrated that in vivo probe uptake in xenografts is

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

    NASA Astrophysics Data System (ADS)

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

    2016-04-01

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

  6. Survival After Transplantation in Patients With Mutations Other Than Val30Met: Extracts From the FAP World Transplant Registry

    PubMed Central

    Suhr, Ole B.; Larsson, Marie; Ericzon, Bo-Göran; Wilczek, Henryk E.

    2016-01-01

    Background Liver transplantation (LTx) has been performed for hereditary transthyretin amyloidosis (ATTR) since 1990. Outcomes for a relatively large series of LTx ATTR patients with the Val30Met (mutation are available, but for non-Val30Met patients, only a few reports with a small number of patients exist. Here, we present outcomes for non-Val30Met ATTR patients after LTx, as reported to the Familial Amyloid Polyneuropathy World Transplant Registry (FAPWTR). Methods Data regarding outcome were extracted for all non-Val30Met patients reported to the registry. Survival rates were analyzed by the Kaplan-Meier method and log-rank test. Results The total number of patients with a non-Val30Met mutation in the registry was 264 (174 men and 90 women), representing 57 mutations. The 10-year survival varied markedly for the 9 most common mutations, ranging from 21% for Ser50Arg to 85% for Val71Ala. Poor survival was noted for all mutations with leptomeningeal complications except for those with the Tyr114Cys mutation. Conclusions Large differences in survival were observed relative to different mutations and between mutations with similar phenotypes. Excellent survival was noted for mutations, such as Leu111Met, Val71Ala, and Leu58His. Patients with mutations other than Val30Met are not a homogeneous group, and the term non-Val30Met should be used with caution or avoided. Moreover, for several mutations, data are too limited to allow evaluation of the efficacy of LTx, and continuous international collaboration is important for obtaining treatment guidance. PMID:26656838

  7. Stabilization of Homoserine-O-Succinyltransferase (MetA) Decreases the Frequency of Persisters in Escherichia coli under Stressful Conditions

    PubMed Central

    Mordukhova, Elena A.; Pan, Jae-Gu

    2014-01-01

    Bacterial persisters are a small subpopulation of cells that exhibit multi-drug tolerance without genetic changes. Generally, persistence is associated with a dormant state in which the microbial cells are metabolically inactive. The bacterial response to unfavorable environmental conditions (heat, oxidative, acidic stress) induces the accumulation of aggregated proteins and enhances formation of persister cells in Escherichia coli cultures. We have found that methionine supplementation reduced the frequency of persisters at mild (37°C) and elevated (42°C) temperatures, as well as in the presence of acetate. Homoserine-o-succinyltransferase (MetA), the first enzyme in the methionine biosynthetic pathway, is prone to aggregation under many stress conditions, resulting in a methionine limitation in E. coli growth. Overexpression of MetA induced the greatest number of persisters at 42°C, which is correlated to an increased level of aggregated MetA. Substitution of the native metA gene on the E. coli K-12 WE chromosome by a mutant gene encoding the stabilized MetA led to reduction in persisters at the elevated temperature and in the presence of acetate, as well as lower aggregation of the mutated MetA. Decreased persister formation at 42°C was confirmed also in E. coli K-12 W3110 and a fast-growing WErph+ mutant harboring the stabilized MetA. Thus, this is the first study to demonstrate manipulation of persister frequency under stressful conditions by stabilization of a single aggregation-prone protein, MetA. PMID:25329174

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

    SciTech Connect

    Husmann, Knut; Ducommun, Pascal; Sabile, Adam A.; Pedersen, Else-Marie; Born, Walter; Fuchs, Bruno

    2015-09-04

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

  9. Prognostic impact of c-MET polymorphism on clinical outcome in loco-regional gastric cancer patients

    PubMed Central

    Sunakawa, Yu; Wakatsuki, Takeru; Yang, Dongyun; Zhang, Wu; Ning, Yan; Stintzing, Sebastian; Stremitzer, Stefan; Yamauchi, Shinichi; Sebio, Ana; El-khoueiry, Rita; Iqbal, Syma; Afsaneh, Barzi; Gerger, Armin; Stotz, Michael; Azuma, Mizutomo; Watanabe, Masahiko; Koizumi, Wasaburo; Lenz, Heinz-Josef

    2014-01-01

    Objective Dysregulation of c-MET signaling pathway results from various molecular mechanisms including mutations, amplification, and overexpression. Overexpression and amplification of c-MET have been correlated with poor clinical outcome in gastric cancer, whereas the associations between c-MET polymorphisms and prognosis have not been well defined. We examined the prognostic impact of functional polymorphisms of MET gene on clinical outcome in gastric cancer. Methods Candidate polymorphisms of MET gene were analyzed by PCR-based direct sequencing for the associations with clinical outcome across three independent cohorts, including 161 Japanese, 101 U.S. and 63 Austrian patients, with loco-regional gastric cancer treated with surgery. Results The univariable analysis showed patients with any G (A/G or G/G genotype) allele of MET rs40239 had significantly longer disease-free survival and overall survival compared to those with the AA genotype in the Japanese cohort (HR: 0.43; P=0.001, HR: 0.47; P=0.006, respectively); this remained significant upon multivariable analysis adjusted for age, sex, stage, and type of adjuvant therapy (HR: 0.48; P=0.009, HR: 0.50; P=0.017, respectively). However, there was no significant association of the polymorphism with clinical outcome in the U.S. and Austrian cohort. When stratified by gender in the Japanese cohort, males, but not females, with the G allele maintained a clinical outcome benefit in both univariable and multivariable analysis. Conclusions The MET rs40239 may serve as a prognostic biomarker in loco-regional gastric cancer. These data also suggest that genetic variants of the c-MET may have a gender-related difference in the impact on clinical outcome. PMID:25203738

  10. The MICA-129Met/Val dimorphism affects plasma membrane expression and shedding of the NKG2D ligand MICA.

    PubMed

    Isernhagen, Antje; Schilling, Daniela; Monecke, Sebastian; Shah, Pranali; Elsner, Leslie; Walter, Lutz; Multhoff, Gabriele; Dressel, Ralf

    2016-02-01

    The MHC class I chain-related molecule A (MICA) is a ligand for the activating natural killer (NK) cell receptor NKG2D. A polymorphism causing a valine to methionine exchange at position 129 affects binding to NKG2D, cytotoxicity, interferon-γ release by NK cells and activation of CD8(+) T cells. It is known that tumors can escape NKG2D-mediated immune surveillance by proteolytic shedding of MICA. Therefore, we investigated whether this polymorphism affects plasma membrane expression (pmMICA) and shedding of MICA. Expression of pmMICA was higher in a panel of tumor (n = 16, P = 0.0699) and melanoma cell lines (n = 13, P = 0.0429) carrying the MICA-129Val/Val genotype. MICA-129Val homozygous melanoma cell lines released more soluble MICA (sMICA) by shedding (P = 0.0015). MICA-129Met or MICA-129Val isoforms differing only in this amino acid were expressed in the MICA-negative melanoma cell line Malme, and clones with similar pmMICA expression intensity were selected. The MICA-129Met clones released more sMICA (P = 0.0006), and a higher proportion of the MICA-129Met than the MICA-129Val variant was retained in intracellular compartments (P = 0.0199). The MICA-129Met clones also expressed more MICA messenger RNA (P = 0.0047). The latter phenotype was also observed in mouse L cells transfected with the MICA expression constructs (P = 0.0212). In conclusion, the MICA-129Met/Val dimorphism affects the expression density of MICA on the plasma membrane. More of the MICA-129Met variants were retained intracellularly. If expressed at the cell surface, the MICA-129Met isoform was more susceptible to shedding. Both processes appear to limit the cell surface expression of MICA-129Met variants that have a high binding avidity to NKG2D.

  11. Stabilization of homoserine-O-succinyltransferase (MetA) decreases the frequency of persisters in Escherichia coli under stressful conditions.

    PubMed

    Mordukhova, Elena A; Pan, Jae-Gu

    2014-01-01

    Bacterial persisters are a small subpopulation of cells that exhibit multi-drug tolerance without genetic changes. Generally, persistence is associated with a dormant state in which the microbial cells are metabolically inactive. The bacterial response to unfavorable environmental conditions (heat, oxidative, acidic stress) induces the accumulation of aggregated proteins and enhances formation of persister cells in Escherichia coli cultures. We have found that methionine supplementation reduced the frequency of persisters at mild (37°C) and elevated (42°C) temperatures, as well as in the presence of acetate. Homoserine-o-succinyltransferase (MetA), the first enzyme in the methionine biosynthetic pathway, is prone to aggregation under many stress conditions, resulting in a methionine limitation in E. coli growth. Overexpression of MetA induced the greatest number of persisters at 42°C, which is correlated to an increased level of aggregated MetA. Substitution of the native metA gene on the E. coli K-12 WE chromosome by a mutant gene encoding the stabilized MetA led to reduction in persisters at the elevated temperature and in the presence of acetate, as well as lower aggregation of the mutated MetA. Decreased persister formation at 42°C was confirmed also in E. coli K-12 W3110 and a fast-growing WErph+ mutant harboring the stabilized MetA. Thus, this is the first study to demonstrate manipulation of persister frequency under stressful conditions by stabilization of a single aggregation-prone protein, MetA. PMID:25329174

  12. Sulfur-Oxygen Chalcogen Bonding Mediates AdoMet Recognition in the Lysine Methyltransferase SET7/9.

    PubMed

    Fick, Robert J; Kroner, Grace M; Nepal, Binod; Magnani, Roberta; Horowitz, Scott; Houtz, Robert L; Scheiner, Steve; Trievel, Raymond C

    2016-03-18

    Recent studies have demonstrated that carbon-oxygen (CH···O) hydrogen bonds have important roles in S-adenosylmethionine (AdoMet) recognition and catalysis in methyltransferases. Here, we investigate noncovalent interactions that occur between the AdoMet sulfur cation and oxygen atoms in methyltransferase active sites. These interactions represent sulfur-oxygen (S···O) chalcogen bonds in which the oxygen atom donates a lone pair of electrons to the σ antibonding orbital of the AdoMet sulfur atom. Structural, biochemical, and computational analyses of an asparagine mutation in the lysine methyltransferase SET7/9 that abolishes AdoMet S···O chalcogen bonding reveal that this interaction enhances substrate binding affinity relative to the product S-adenosylhomocysteine. Corroborative quantum mechanical calculations demonstrate that sulfonium systems form strong S···O chalcogen bonds relative to their neutral thioether counterparts. An inspection of high-resolution crystal structures reveals the presence of AdoMet S···O chalcogen bonding in different classes of methyltransferases, illustrating that these interactions are not limited to SET domain methyltransferases. Together, these results demonstrate that S···O chalcogen bonds contribute to AdoMet recognition and can enable methyltransferases to distinguish between substrate and product.

  13. Absent and abundant MET immunoreactivity is associated with poor prognosis of patients with oral and oropharyngeal squamous cell carcinoma

    PubMed Central

    De Herdt, Maria J.; Willems, Stefan M.; van der Steen, Berdine; Noorlag, Rob; Verhoef, Esther I.; van Leenders, Geert J.L.H.; van Es, Robert J.J.; Koljenović, Senada; de Jong, Robert J. Baatenburg; Looijenga, Leendert H.J.

    2016-01-01

    Although the receptor tyrosine kinase (RTK) MET is widely expressed in head and neck squamous cell carcinoma (HNSCC), its prognostic value remains unclear. This might be due to the use of a variety of antibodies and scoring systems. Here, the reliability of five commercial C-terminal MET antibodies (D1C2, CVD13, SP44, C-12 and C-28) was evaluated before examining the prognostic value of MET immunoreactivity in HNSCC. Using cancer cell lines, it was shown that D1C2 and CVD13 specifically detect MET under reducing, native and formalin-fixed paraffin-embedded (FFPE) conditions. Immunohistochemical staining of routinely FFPE oral SCC with D1C2 and CVD13 demonstrated that D1C2 is most sensitive in the detection of membranous MET. Examination of membranous D1C2 immunoreactivity with 179 FFPE oral and oropharyngeal SCC – represented in a tissue microarray – illustrated that staining is either uniform (negative or positive) across tumors or differs between a tumor's center and periphery. Ultimately, statistical analysis revealed that D1C2 uniform staining is significantly associated with poor 5-year overall and disease free survival of patients lacking vasoinvasive growth (HR = 3.019, p < 0.001; HR = 2.559, p < 0.001). These findings might contribute to reliable stratification of patients eligible for treatment with biologicals directed against MET. PMID:26909606

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

    NASA Astrophysics Data System (ADS)

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

    2016-05-01

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

  15. Dual Constant Domain-Fab: A novel strategy to improve half-life and potency of a Met therapeutic antibody.

    PubMed

    Cignetto, Simona; Modica, Chiara; Chiriaco, Cristina; Fontani, Lara; Milla, Paola; Michieli, Paolo; Comoglio, Paolo M; Vigna, Elisa

    2016-06-01

    The kinase receptor encoded by the Met oncogene is a sensible target for cancer therapy. The chimeric monovalent Fab fragment of the DN30 monoclonal antibody (MvDN30) has an odd mechanism of action, based on cell surface removal of Met via activation of specific plasma membrane proteases. However, the short half-life of the Fab, due to its low molecular weight, is a severe limitation for the deployment in therapy. This issue was addressed by increasing the Fab molecular weight above the glomerular filtration threshold through the duplication of the constant domains, in tandem (DCD-1) or reciprocally swapped (DCD-2). The two newly engineered molecules showed biochemical properties comparable to the original MvDN30 in vitro, acting as full Met antagonists, impairing Met phosphorylation and activation of downstream signaling pathways. As a consequence, Met-mediated biological responses were inhibited, including anchorage-dependent and -independent cell growth. In vivo DCD-1 and DCD-2 showed a pharmacokinetic profile significantly improved over the original MvDN30, doubling the circulating half-life and reducing the clearance. In pre-clinical models of cancer, generated by injection of tumor cells or implant of patient-derived samples, systemic administration of the engineered molecules inhibited the growth of Met-addicted tumors.

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

    NASA Astrophysics Data System (ADS)

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

    2016-05-01

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

  17. Effects of high selenomethionine (L-SeMet) intakes on female long-tailed macaques and their offspring

    SciTech Connect

    Hawkes, W.C.; Craig, K.A.; Omaye, S.T.; Willhite, C.C. Letterman Army Inst. of Research, San Francisco, CA Department of Health Services, Berkeley, CA )

    1991-03-11

    Pregnant females were treated daily for 30 days with 0, 25, 150 or 300 {mu}g Se as L-SeMet per kg body weight. Maternal Se toxicity was evident in the 150 and 300 {mu}g/kg-d groups. There were no effects of L-SeMet on pregnancy outcome, fetal morphology or neonatal development. Erythrocyte (RBC) glutathione peroxidase (GPx), RBC Se, plasma (PL) Se, PL GPx, hair (HR) Se, fecal Se and daily urinary Se excretion (UR Se) in dams were significantly correlated to L-SeMet intake. HR Se and UR Se showed the greatest responses to L-SeMet intake. RBC GPx increased 2.5-fold in the 150 {mu}g/kg-d group, casting doubt on use of RBC GPx saturation as a criterion of nutritional adequacy. Neonatal RBC and PL and fetal RBC, PL, liver, kidney, muscle and placental Se were significantly correlated to L-SeMet intake and maternal Se status, but GPx was not. There was no effect of L-SeMet on milk Se or milk GPx, showing the dominant effect of intrauterine exposure on neonatal Se status. PL Se was 3-fold higher in dams than in fetuses, suggesting a role of the placenta in regulating fetal Se. In control RBC and PL, fetal GPx {gt} neonatal GPx {gt} maternal GPx, suggesting an effect of development on GPx.

  18. HDA6 Directly Interacts with DNA Methyltransferase MET1 and Maintains Transposable Element Silencing in Arabidopsis1[W][OA

    PubMed Central

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

    2012-01-01

    The molecular mechanism of how the histone deacetylase HDA6 participates in maintaining transposable element (TE) silencing in Arabidopsis (Arabidopsis thaliana) is not yet defined. In this study, we show that a subset of TEs was transcriptionally reactivated and that TE reactivation was associated with elevated histone H3 and H4 acetylation as well as increased H3K4Me3 and H3K4Me2 in hda6 mutants. Decreased DNA methylation of the TEs was also detected in hda6 mutants, suggesting that HDA6 silences the TEs by regulating histone acetylation and methylation as well as the DNA methylation status of the TEs. Similarly, transcripts of some of these TEs were also increased in the methyltransferase1 (met1) mutant, with decreased DNA methylation. Furthermore, H4 acetylation, H3K4Me3, H3K4Me2, and H3K36Me2 were enriched at the coregulated TEs in the met1 and hda6 met1 mutants. Protein-protein interaction analysis indicated that HDA6 physically interacts with MET1 in vitro and in vivo, and further deletion analysis demonstrated that the carboxyl-terminal region of HDA6 and the bromo-adjacent homology domain of MET1 were responsible for the interaction. These results suggested that HDA6 and MET1 interact directly and act together to silence TEs by modulating DNA methylation, histone acetylation, and histone methylation status. PMID:21994348

  19. Arabidopsis HDA6 Regulates Locus-Directed Heterochromatin Silencing in Cooperation with MET1

    PubMed Central

    Matsui, Akihiro; Kurihara, Yukio; Morosawa, Taeko; Ishida, Junko; Tanaka, Maho; Endo, Takaho; Kakutani, Tetsuji; Toyoda, Tetsuro; Kimura, Hiroshi; Yokoyama, Shigeyuki; Shinozaki, Kazuo; Seki, Motoaki

    2011-01-01

    Heterochromatin silencing is pivotal for genome stability in eukaryotes. In Arabidopsis, a plant-specific mechanism called RNA–directed DNA methylation (RdDM) is involved in heterochromatin silencing. Histone deacetylase HDA6 has been identified as a component of such machineries; however, its endogenous targets and the silencing mechanisms have not been analyzed globally. In this study, we investigated the silencing mechanism mediated by HDA6. Genome-wide transcript profiling revealed that the loci silenced by HDA6 carried sequences corresponding to the RDR2-dependent 24-nt siRNAs, however their transcript levels were mostly unaffected in the rdr2 mutant. Strikingly, we observed significant overlap of genes silenced by HDA6 to those by the CG DNA methyltransferase MET1. Furthermore, regardless of dependence on RdDM pathway, HDA6 deficiency resulted in loss of heterochromatic epigenetic marks and aberrant enrichment for euchromatic marks at HDA6 direct targets, along with ectopic expression of these loci. Acetylation levels increased significantly in the hda6 mutant at all of the lysine residues in the H3 and H4 N-tails, except H4K16. Interestingly, we observed two different CG methylation statuses in the hda6 mutant. CG methylation was sustained in the hda6 mutant at some HDA6 target loci that were surrounded by flanking DNA–methylated regions. In contrast, complete loss of CG methylation occurred in the hda6 mutant at the HDA6 target loci that were isolated from flanking DNA methylation. Regardless of CG methylation status, CHG and CHH methylation were lost and transcriptional derepression occurred in the hda6 mutant. Furthermore, we show that HDA6 binds only to its target loci, not the flanking methylated DNA, indicating the profound target specificity of HDA6. We propose that HDA6 regulates locus-directed heterochromatin silencing in cooperation with MET1, possibly recruiting MET1 to specific loci, thus forming the foundation of silent chromatin structure

  20. Role of the axial ligand in type 1 Cu centers studied by point mutations of met148 in rusticyanin.

    PubMed

    Hall, J F; Kanbi, L D; Strange, R W; Hasnain, S S

    1999-09-28

    Type 1 Cu centers in cupredoxins, nitrite reductases, and multi-copper oxidases utilize the same trigonal core ligation to His-Cys-His, with a weak axial ligand generally provided by a Met sulfur. In azurin, an additional axial ligand, a carbonyl oxygen from a Gly, is present. The importance of these axial ligands and in particular the Met has been debated extensively in terms of their role in fine-tuning the redox potential, spectroscopic properties, and rack-induced or entatic state properties of the copper sites. Extensive site-directed mutagenesis of the Met ligand has been carried out in azurin, but the presence of an additional carbonyl oxygen axial ligand has made it difficult to interpret the effects of these substitutions. Here, the axial methionine ligand (Met148) in rusticyanin is replaced with Leu, Gln, Lys, and Glu to examine the effect on the redox potential, acid stability, and copper site geometry. The midpoint redox potential varies from 363 (Met148Lys) to 798 mV (Met148Leu). The acid stability of the oxidized proteins is reduced except for the Met148Gln mutant. The Gln mutant remains blue at all pH values between 2.8 and 8, and has a redox potential of 563 mV at pH 3.2. The optical and rhombic EPR properties of this mutant closely resemble those of stellacyanin, which has the lowest redox potential among single-type 1 copper proteins (185 mV). The Met148Lys mutant exhibits type 2 Cu EPR and optical spectra in this pH range. The Met148Glu mutant exhibits a type 2 Cu EPR spectrum above pH 3 and a mixture of type 1 and type 2 Cu spectra at lower pH. The Met148Leu mutant exhibits the highest redox potential ( approximately 800 mV at pH 3.2) which is similar to the values in fungal laccase and in the type 1 Cu site of ceruloplasmin where this axial ligand is also a Leu.

  1. Role of the axial ligand in type 1 Cu centers studied by point mutations of met148 in rusticyanin.

    PubMed

    Hall, J F; Kanbi, L D; Strange, R W; Hasnain, S S

    1999-09-28

    Type 1 Cu centers in cupredoxins, nitrite reductases, and multi-copper oxidases utilize the same trigonal core ligation to His-Cys-His, with a weak axial ligand generally provided by a Met sulfur. In azurin, an additional axial ligand, a carbonyl oxygen from a Gly, is present. The importance of these axial ligands and in particular the Met has been debated extensively in terms of their role in fine-tuning the redox potential, spectroscopic properties, and rack-induced or entatic state properties of the copper sites. Extensive site-directed mutagenesis of the Met ligand has been carried out in azurin, but the presence of an additional carbonyl oxygen axial ligand has made it difficult to interpret the effects of these substitutions. Here, the axial methionine ligand (Met148) in rusticyanin is replaced with Leu, Gln, Lys, and Glu to examine the effect on the redox potential, acid stability, and copper site geometry. The midpoint redox potential varies from 363 (Met148Lys) to 798 mV (Met148Leu). The acid stability of the oxidized proteins is reduced except for the Met148Gln mutant. The Gln mutant remains blue at all pH values between 2.8 and 8, and has a redox potential of 563 mV at pH 3.2. The optical and rhombic EPR properties of this mutant closely resemble those of stellacyanin, which has the lowest redox potential among single-type 1 copper proteins (185 mV). The Met148Lys mutant exhibits type 2 Cu EPR and optical spectra in this pH range. The Met148Glu mutant exhibits a type 2 Cu EPR spectrum above pH 3 and a mixture of type 1 and type 2 Cu spectra at lower pH. The Met148Leu mutant exhibits the highest redox potential ( approximately 800 mV at pH 3.2) which is similar to the values in fungal laccase and in the type 1 Cu site of ceruloplasmin where this axial ligand is also a Leu. PMID:10504237

  2. Observing the atmospheric composition with the IASI/MetOp satellite: emissions, composition and transport

    NASA Astrophysics Data System (ADS)

    Clerbaux, C.; Coheur, P.; George, M.; Clarisse, L.; Hurtmans, D.; Hadji-Lazaro, J.; Razavi, A.

    2010-12-01

    Among the available remote sensing data to monitor the atmospheric composition, IASI, the Infrared Atmospheric Sounding Interferometer flying onboard the MetOp satellite since 2006, offers unprecedented possibilities for sounding the troposphere in near-real time and for capturing sudden changes in the atmosphere with a global coverage. This presentation will review the capabilities of IASI to contribute to several aspects of atmospheric chemistry, such as the identification of local and regional sources to improve emission inventories, the tracking of long-range transport of pollution, and the detection of unexpected events such as large fires or volcanic plumes. Illustrations will be provided for carbon monoxide, methanol, ammonia, and ash/sulfur dioxide from volcanoes. The sensitivity and errors inherent to satellite sounding in the infrared spectral range will also be discussed.

  3. The Mars Pathfinder atmospheric structure investigation/meteorology (ASI/MET) experiment

    NASA Technical Reports Server (NTRS)

    Schofield, J. T.; Barnes, J. R.; Crisp, D.; Haberle, R. M.; Larsen, S.; Magalhaes, J. A.; Murphy, J. R.; Seiff, A.; Wilson, G.

    1997-01-01

    The Mars Pathfinder atmospheric structure investigation/meteorology (ASI/MET) experiment measured the vertical density, pressure, and temperature structure of the martian atmosphere from the surface to 160 km, and monitored surface meteorology and climate for 83 sols (1 sol = 1 martian day = 24.7 hours). The atmospheric structure and the weather record are similar to those observed by the Viking 1 lander (VL-1) at the same latitude, altitude, and season 21 years ago, but there are differences related to diurnal effects and the surface properties of the landing site. These include a cold nighttime upper atmosphere; atmospheric temperatures that are 10 to 12 degrees kelvin warmer near the surface; light slope-controlled winds; and dust devils, identified by their pressure, wind, and temperature signatures. The results are consistent with the warm, moderately dusty atmosphere seen by VL-1.

  4. Children in the criminal justice and secure care systems: how their mental health needs are met.

    PubMed

    Kurtz, Z; Thornes, R; Bailey, S

    1998-10-01

    A study was made of the perceptions among relevant service providers of the mental health needs of young people considered for secure placement. Information was obtained in 1996 from 75% of departments of child and adolescent psychiatry, forensic psychiatry, social services children's services, youth justice, probation, secure units and young offender institutions in England and Wales. The findings confirm that highly disturbed young people, who may be a danger to themselves and others, may present to a wide range of services, and that their mental health needs are neither well recognized, widely understood, nor adequately met. Availability of appropriate levels and types of expertise and resource is patchy and strictly limited, within secure settings and in local community services across all agencies.

  5. Synthesis and biological evaluation of Oblongifolin C derivatives as c-Met inhibitors.

    PubMed

    Wang, Liping; Wu, Rong; Fu, Wenwei; Lao, Yuanzhi; Zheng, Changwu; Tan, Hongsheng; Xu, Hongxi

    2016-09-15

    Oblongifolin C, one of the polyprenylated benzoylphloroglucinol natural products (PPAPs) isolated from the fruits of Garcinia yunnanensis Hu, was recently discovered to be a potent anti-tumor agent. A collection of 12 derivatives with modifications on the benzophenone moieties were synthesized and tested for c-Met kinase inhibition and cytotoxicity against the HepG2, Miapaca-2, HCC827, Hela, A549, AGS, and HT-29 cell lines in vitro. An oxidized derivative, 10, was found to possess strong inhibition and anti-migration properties in the HCC827 cell line and serves as a potential lead compound for the development of new anticancer drugs. In addition, structure-activity relationships (SAR) were also evaluated to provide key information for future anticancer drug development. PMID:27396929

  6. Assimilation Experiments of One-Dimensional Variational Analyses with GPS/MET Refractivity

    NASA Technical Reports Server (NTRS)

    Poli, Paul; Joiner, Joanna; Atlas, Robert (Technical Monitor)

    2002-01-01

    The GPS/MET 1995 experiment demonstrated the feasibility of remote soundings of the Earth's atmosphere using the GPS radio occultation technique. Subsequent studies assessed the information content of such measurements. Several groups have attempted to assimilate the GPS radio occultation measurements into a global Data Assimilation System (DAS). These attempts followed in general the methodology proposed by Eyre, and range from die act four-dimensional variational assimilation of bending angles to assimilation of inverted profiles of temperature and/or humidity. We present here an hybrid approach. We attempted to take advantage of the accuracy of current, weather models to constrain one-dimensional variational analyses using GPS refractivity. Retrieved profiles of atmospheric parameters were then assimilated like other types of observations in a global DAS for issuing the next forecast period.

  7. Transition paths of Met-enkephalin from Markov state modeling of a molecular dynamics trajectory.

    PubMed

    Banerjee, Rahul; Cukier, Robert I

    2014-03-20

    Conformational states and their interconversion pathways of the zwitterionic form of the pentapeptide Met-enkephalin (MetEnk) are identified. An explicit solvent molecular dynamics (MD) trajectory is used to construct a Markov state model (MSM) based on dihedral space clustering of the trajectory, and transition path theory (TPT) is applied to identify pathways between open and closed conformers. In the MD trajectory, only four of the eight backbone dihedrals exhibit bistable behavior. Defining a conformer as the string XXXX with X = "+" or "-" denoting, respectively, positive or negative values of a given dihedral angle and obtaining the populations of these conformers shows that only four conformers are highly populated, implying a strong correlation among these dihedrals. Clustering in dihedral space to construct the MSM finds the same four bistable dihedral angles. These state populations are very similar to those found directly from the MD trajectory. TPT is used to obtain pathways, parametrized by committor values, in dihedral state space that are followed in transitioning from closed to open states. Pathway costs are estimated by introducing a kinetics-based procedure that orders pathways from least (shortest) to greater cost paths. The least costly pathways in dihedral space are found to only involve the same XXXX set of dihedral angles, and the conformers accessed in the closed to open transition pathways are identified. For these major pathways, a correlation between reaction path progress (committors) and the end-to-end distance is identified. A dihedral space principal component analysis of the MD trajectory shows that the first three modes capture most of the overall fluctuation, and pick out the same four dihedrals having essentially all the weight in those modes. A MSM based on root-mean-square backbone clustering was also carried out, with good agreement found with dihedral clustering for the static information, but with results that differ

  8. The interaction of early life experiences with COMT val158met affects anxiety sensitivity.

    PubMed

    Baumann, C; Klauke, B; Weber, H; Domschke, K; Zwanzger, P; Pauli, P; Deckert, J; Reif, A

    2013-11-01

    The pathogenesis of anxiety disorders is considered to be multifactorial with a complex interaction of genetic factors and individual environmental factors. Therefore, the aim of this study was to examine gene-by-environment interactions of the genes coding for catechol-O-methyltransferase (COMT) and monoamine oxidase A (MAOA) with life events on measures related to anxiety. A sample of healthy subjects (N = 782; thereof 531 women; mean age M = 24.79, SD = 6.02) was genotyped for COMT rs4680 and MAOA-uVNTR (upstream variable number of tandem repeats), and was assessed for childhood adversities [Childhood Trauma Questionnaire (CTQ)], anxiety sensitivity [Anxiety Sensitivity Index (ASI)] and anxious apprehension [Penn State Worry Questionnaire (PSWQ)]. Main and interaction effects of genotype, environment and gender on measures related to anxiety were assessed by means of regression analyses. Association analysis showed no main gene effect on either questionnaire score. A significant interactive effect of childhood adversities and COMT genotype was observed: Homozygosity for the low-active met allele and high CTQ scores was associated with a significant increment of explained ASI variance [R(2) = 0.040, false discovery rate (FDR) corrected P = 0.04]. A borderline interactive effect with respect to MAOA-uVNTR was restricted to the male subgroup. Carriers of the low-active MAOA allele who reported more aversive experiences in childhood exhibited a trend for enhanced anxious apprehension (R(2) = 0.077, FDR corrected P = 0.10). Early aversive life experiences therefore might increase the vulnerability to anxiety disorders in the presence of homozygosity for the COMT 158met allele or low-active MAOA-uVNTR alleles. PMID:24118915

  9. The interaction of early life experiences with COMT val158met affects anxiety sensitivity.

    PubMed

    Baumann, C; Klauke, B; Weber, H; Domschke, K; Zwanzger, P; Pauli, P; Deckert, J; Reif, A

    2013-11-01

    The pathogenesis of anxiety disorders is considered to be multifactorial with a complex interaction of genetic factors and individual environmental factors. Therefore, the aim of this study was to examine gene-by-environment interactions of the genes coding for catechol-O-methyltransferase (COMT) and monoamine oxidase A (MAOA) with life events on measures related to anxiety. A sample of healthy subjects (N = 782; thereof 531 women; mean age M = 24.79, SD = 6.02) was genotyped for COMT rs4680 and MAOA-uVNTR (upstream variable number of tandem repeats), and was assessed for childhood adversities [Childhood Trauma Questionnaire (CTQ)], anxiety sensitivity [Anxiety Sensitivity Index (ASI)] and anxious apprehension [Penn State Worry Questionnaire (PSWQ)]. Main and interaction effects of genotype, environment and gender on measures related to anxiety were assessed by means of regression analyses. Association analysis showed no main gene effect on either questionnaire score. A significant interactive effect of childhood adversities and COMT genotype was observed: Homozygosity for the low-active met allele and high CTQ scores was associated with a significant increment of explained ASI variance [R(2) = 0.040, false discovery rate (FDR) corrected P = 0.04]. A borderline interactive effect with respect to MAOA-uVNTR was restricted to the male subgroup. Carriers of the low-active MAOA allele who reported more aversive experiences in childhood exhibited a trend for enhanced anxious apprehension (R(2) = 0.077, FDR corrected P = 0.10). Early aversive life experiences therefore might increase the vulnerability to anxiety disorders in the presence of homozygosity for the COMT 158met allele or low-active MAOA-uVNTR alleles.

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

    SciTech Connect

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

    1985-11-01

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

  11. TLALOCNet: A Continuous GPS-Met Array in Mexico for Seismotectonic and Atmospheric Research

    NASA Astrophysics Data System (ADS)

    Cabral-Cano, E.; Salazar-Tlaczani, L.; Galetzka, J.; DeMets, C.; Serra, Y. L.; Feaux, K.; Mattioli, G. S.; Miller, M. M.

    2015-12-01

    TLALOCNet is a network of continuous Global Positioning System (cGPS) and meteorology stations in Mexico for the interrogation of the earthquake cycle, tectonic processes, land subsidence, and atmospheric processes of Mexico. Once completed, TLALOCNet will span all of Mexico and will link existing GPS infrastructure in North America and the Caribbean aiming towards creating a continuous, federated network of networks in the Americas. Phase 1 (2014-2015), funded by NSF and UNAM, is building and upgrading 30+ cGPS-Met sites to the high standard of the EarthScope Plate Boundary Observatory (PBO). Phase 2 (2016) will add ~25 more cGPS-Met stations to be funded through CONACyT. TLALOCNet provides open and freely available raw GPS data, GPS-PWV, surface meteorology measurements, time series of daily positions, as well as a station velocity field to support a broad range of geoscience investigations. This is accomplished through the development of the TLALOCNet data center (http://tlalocnet.udg.mx) that serves as a collection and distribution point. This data center is based on UNAVCO's Dataworks-GSAC software and can work as part of UNAVCO's seamless archive for discovery, sharing, and access to data.The TLALOCNet data center also contains contributed data from several regional networks in Mexico. By using the same protocols and structure as the UNAVCO and other COCONet regional data centers, the geodetic community has the capability of accessing data from a large number of scientific and academically operated Mexican GPS sites. This archive provides a fully querable and scriptable GPS and Meteorological data retrieval point. Additionally Real-time 1Hz streams from selected TLALOCNet stations are available in BINEX, RTCM 2.3 and RTCM 3.1 formats via the Networked Transport of RTCM via Internet Protocol (NTRIP).

  12. Effect of COMT Val108/158Met genotype on risk for polydipsia in chronic patients with schizophrenia.

    PubMed

    Yamada, Kenji; Shinkai, Takahiro; Chen, Hsin-I; Utsunomiya, Kensuke; Nakamura, Jun

    2014-06-01

    Polydipsia is a serious condition often seen among patients with schizophrenia (SCZ). The cause of polydipsia is unknown; hence, it is hard to treat or manage. Animal studies showed that the drinking behavior is regulated by central dopaminergic neurotransmission at the hypothalamus. Meanwhile, the existence of a genetic predisposition to polydipsia in patients with SCZ has been suggested. The purpose of this study was to assess whether a functional polymorphism, Val(108/158)Met in the gene for catechol-O-methyltransferase (COMT), is associated with susceptibility to polydipsia using a Japanese sample of SCZ. Our sample includes 330 chronic patients with SCZ (83 polydipsic patients and 247 non-polydipsic controls). The common COMT Val(108/158)Met polymorphism was genotyped, and the differences in genotype distribution and allele frequency between cases and controls were evaluated using the χ(2) test. A significant association between the COMT Val(108/158)Met polymorphism and polydipsia was found (genotype distribution: χ(2) = 13.0, df = 2, p = 0.001; allele frequency: χ(2) = 7.50, df = 1, p = 0.006). The high-COMT activity group (Val/Val) was more frequent among patients with polydipsia compared with the low-COMT activity group (Val/Met + Met/Met) [odds ratio (OR) = 2.46]. The association survived after controlling for other possible confounding factors, including gender, age, age of onset, current antipsychotic dose, and smoking status. Our results suggest that the COMT Val(108/158)Met genotype may confer susceptibility to polydipsia in SCZ. To our knowledge, this is the first association study between the COMT gene and polydipsia in SCZ. Further studies with larger sample sizes are warranted to confirm present findings. PMID:24443099

  13. VNTR-DAT1 and COMTVal158Met Genotypes Modulate Mental Flexibility and Adaptive Behavior Skills in Down Syndrome

    PubMed Central

    del Hoyo, Laura; Xicota, Laura; Langohr, Klaus; Sánchez-Benavides, Gonzalo; de Sola, Susana; Cuenca-Royo, Aida; Rodriguez, Joan; Rodríguez-Morató, Jose; Farré, Magí; Dierssen, Mara; de la Torre, Rafael; Cuenca-Royo, Aida

    2016-01-01

    Down syndrome (DS) is an aneuploidy syndrome that is caused by trisomy for human chromosome 21 resulting in a characteristic cognitive and behavioral phenotype, which includes executive functioning and adaptive behavior difficulties possibly due to prefrontal cortex (PFC) deficits. DS also present a high risk for early onset of Alzheimer Disease-like dementia. The dopamine (DA) system plays a neuromodulatory role in the activity of the PFC. Several studies have implicated trait differences in DA signaling on executive functioning based on genetic polymorphisms in the genes encoding for the catechol-O-methyltransferase (COMTVal158Met) and the dopamine transporter (VNTR-DAT1). Since it is known that the phenotypic consequences of genetic variants are modulated by the genetic background in which they occur, we here explore whether these polymorphisms variants interact with the trisomic genetic background to influence gene expression, and how this in turn mediates DS phenotype variability regarding PFC cognition. We genotyped 69 young adults of both genders with DS, and found that VNTR-DAT1 was in Hardy-Weinberg equilibrium but COMTVal158Met had a reduced frequency of Met allele homozygotes. In our population, genotypes conferring higher DA availability, such as Met allele carriers and VNTR-DAT1 10-repeat allele homozygotes, resulted in improved performance in executive function tasks that require mental flexibility. Met allele carriers showed worse adaptive social skills and self-direction, and increased scores in the social subscale of the Dementia Questionnaire for People with Intellectual Disabilities than Val allele homozygotes. The VNTR-DAT1 was not involved in adaptive behavior or early dementia symptoms. Our results suggest that genetic variants of COMTVal158Met and VNTR-DAT1 may contribute to PFC-dependent cognition, while only COMTVal158Met is involved in behavioral phenotypes of DS, similar to euploid population. PMID:27799900

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

    PubMed Central

    Lo, Fu-Sun; Erzurumlu, Reha S.

    2016-01-01

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

  15. Downregulation of c-Met expression does not enhance the sensitivity of gastric cancer cell line MKN-45 to gefitinib.

    PubMed

    Ma, Jin-An; Hu, Chunhong; Li, Wenjuan; Ren, Jing; Zou, Fangwen; Zhou, Dongai; Zou, Wen; Wei, Yajun; Zhou, Ying

    2015-03-01

    The aim of the present study was to investigate the effect of downregulation of the c‑Met gene on signal transduction and apoptosis in gastric cancer MKN‑45 cells; furthermore, the study aimed to determine whether altered c‑Met gene expression affected MKN‑45 sensitivity to gefitinib. Three c‑Met‑specific small interfering RNAs (siRNAs) were synthesized and transfected into MKN‑45 cells. Messenger RNA (mRNA) and protein levels of c‑Met and its downstream signaling molecules [phosphoinositide 3‑kinase (PI3K) and AKT] were examined using reverse transcription polymerase chain reaction and western blot analysis 48 h following transfection. Cell apoptosis was evaluated using Annexin‑V/propidium iodide double staining and fluorescence‑activated cell sorting analysis. An MTT assay was performed in order to measure the 50% inhibitory concentration (IC50) of gefitinib on MKN‑45 cells. The results of the present study demonstrated that 48 h post‑transfection with c‑Met siRNA, MKN‑45 cells showed significantly downregulated expression of c‑Met mRNA and protein as well as an increased rate of apoptosis (P<0.05). In addition, following c‑Met siRNA transfection mRNA and protein levels of PI3K and AKT were not significantly altered in MKN‑45 cells (P>0.05); however, a marked decrease in the expression levels of phosphorylated (p)‑PI3K and p‑AKT was observed (P<0.05). Furthermore, the IC50 of gefitinib in MKN‑45 cells was not significantly decreased. In conclusion, knockdown of the c‑Met gene promoted gastric cancer cell apoptosis and inhibited downstream p‑PI3K and p‑AKT; however, the sensitivity of MKN‑45 cells to gefitinib was not increased. PMID:25395073

  16. Cobalamin-Independent Methionine Synthase (MetE): A Face-to-Face Double Barrel that Evolved by Gene Duplication

    SciTech Connect

    Pejcha, Robert; Ludwig, Martha L.

    2010-03-08

    Cobalamin-independent methionine synthase (MetE) catalyzes the transfer of a methyl group from methyltetrahydrofolate to L-homocysteine (Hcy) without using an intermediate methyl carrier. Although MetE displays no detectable sequence homology with cobalamin-dependent methionine synthase (MetH), both enzymes require zinc for activation and binding of Hcy. Crystallographic analyses of MetE from T. maritima reveal an unusual dual-barrel structure in which the active site lies between the tops of the two ({beta}{alpha}){sub 8} barrels. The fold of the N-terminal barrel confirms that it has evolved from the C-terminal polypeptide by gene duplication; comparisons of the barrels provide an intriguing example of homologous domain evolution in which binding sites are obliterated. The C-terminal barrel incorporates the zinc ion that binds and activates Hcy. The zinc-binding site in MetE is distinguished from the (Cys){sub 3}Zn site in the related enzymes, MetH and betaine-homocysteine methyltransferase, by its position in the barrel and by the metal ligands, which are histidine, cysteine, glutamate, and cysteine in the resting form of MetE. Hcy associates at the face of the metal opposite glutamate, which moves away from the zinc in the binary E {center_dot} Hcy complex. The folate substrate is not intimately associated with the N-terminal barrel; instead, elements from both barrels contribute binding determinants in a binary complex in which the folate substrate is incorrectly oriented for methyl transfer. Atypical locations of the Hcy and folate sites in the C-terminal barrel presumably permit direct interaction of the substrates in a ternary complex. Structures of the binary substrate complexes imply that rearrangement of folate, perhaps accompanied by domain rearrangement, must occur before formation of a ternary complex that is competent for methyl transfer.

  17. Impact of COMT Val158Met-polymorphism on appetitive conditioning and amygdala/prefrontal effective connectivity.

    PubMed

    Klucken, Tim; Kruse, Onno; Wehrum-Osinsky, Sina; Hennig, Juergen; Schweckendiek, Jan; Stark, Rudolf

    2015-03-01

    Appetitive conditioning is an important mechanism for the development, maintenance, and treatment of psychiatric disorders like substance abuse. Therefore, it is important to identify genetic variations, which impact appetitive conditioning. It has been suggested that the Val(158) Met-polymorphism in the Catechol-O-Methyl-Transferase (COMT) is associated with the alteration of neural processes of appetitive conditioning due to the central role of the dopaminergic system in reward processing. However, no study has so far investigated the relationship between variations in the COMT Val(158) Met-polymorphism and appetitive conditioning. In this fMRI study, an appetitive conditioning paradigm was applied, in which one neutral stimulus (CS+) predicted appetitive stimuli (UCS) while a second neutral stimulus (CS-) was never paired with the UCS. As a main result, we observed a significant association between the COMT Val(158) Met-genotype and appetitive conditioning: skin conductance responses (SCRs) revealed a significant difference between CS+ and CS- in Val/Val-allele carriers but not in the other genotype groups. Val/Val-allele carriers showed increased hemodynamic responses in the amygdala compared with the Met/Met-allele group in the contrast CS+ > CS-. In addition, psychophysiological-interaction analysis revealed increased effective amygdala/ventromedial prefrontal cortex connectivity in Met/Met-allele carriers. The increased amygdala activity points to facilitated appetitive conditioning in Val/Val-allele carriers while the amygdala/prefrontal connectivity results could be regarded as a marker for altered emotion regulation during conditioning, which potentially impacts appetitive learning sensitivity. The SCRs finding indicates a stronger conditioned response in the Val/Val-allele group and dovetails with the neural differences between the groups. These findings contribute to the current research on COMT in emotional processing.

  18. Adenovirus expressing dual c-Met-specific shRNA exhibits potent antitumor effect through autophagic cell death accompanied by senescence-like phenotypes in glioblastoma cells

    PubMed Central

    Yoo, Ji Young; Choi, Kyeong Sook; Yoon, Mi Jin; Yun, Chae-Ok

    2015-01-01

    c-Met, a cognate receptor tyrosine kinase of hepatocyte growth factor, is overexpressed and/or mutated in number of tumors. Therefore, abrogation of c-Met signaling may serve as potential therapeutic targets. In this study, we generated Ads expressing single shRNA specific to c-Met (shMet) (dl/shMet4 and dl/shMet5) or dual shRNAs specific to c-Met (dl/shMet4+5); and examined the therapeutic potential of these newly engineered Ads in targeting c-Met, and delineated their mechanism of action in vitro and in vivo. Ads expressing shMet induced knock-down in c-Met, and phenotypically resulted in autophagy-like features including appearance of membranousvacuoles, formation of acidic vesicular organelles, and cleavage and recruitment of microtubule-associated protein1 light chain 3 to autophagosomes. Ads expressing shMet also suppressed Akt phosphorylation and increased number of senescence-related gene products including SM22, TGase II, and PAI-1. These changes resulted in inhibition of cell proliferation and G2/M arrest of U343 cells. In vivo, intratumoral injection with dl/shMet4+5 resulted in a significant reduction of tumor growth with corresponding increasing overall survival. Histopathological analysis of these treated tumors revealed that Atg5 was highly up-regulated, indicating the therapeutic induction of autophagy. In sum, these results reveal that autophagic cell death induced by shMet-expressing Ads provide a novel strategy for targeting c-Met-expressing tumors through non-apoptotic mechanism of cell death. PMID:25726528

  19. Preservation of general intelligence following traumatic brain injury: contributions of the Met66 brain-derived neurotrophic factor.

    PubMed

    Barbey, Aron K; Colom, Roberto; Paul, Erick; Forbes, Chad; Krueger, Frank; Goldman, David; Grafman, Jordan

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) promotes survival and synaptic plasticity in the human brain. The Val66Met polymorphism of the BDNF gene interferes with intracellular trafficking, packaging, and regulated secretion of this neurotrophin. The human prefrontal cortex (PFC) shows lifelong neuroplastic adaption implicating the Val66Met BDNF polymorphism in the recovery of higher-order executive functions after traumatic brain injury (TBI). In this study, we examined the effect of this BDNF polymorphism on the preservation of general intelligence following TBI. We genotyped a sample of male Vietnam combat veterans (n = 156) consisting of a frontal lobe lesion group with focal penetrating head injuries for the Val66Met BDNF polymorphism. Val/Met did not differ from Val/Val genotypes in general cognitive ability before TBI. However, we found substantial average differences between these groups in general intelligence (≈ half a standard deviation or 8 IQ points), verbal comprehension (6 IQ points), perceptual organization (6 IQ points), working memory (8 IQ points), and processing speed (8 IQ points) after TBI. These results support the conclusion that Val/Met genotypes preserve general cognitive functioning, whereas Val/Val genotypes are largely susceptible to TBI. PMID:24586380

  20. MetDIA: Targeted Metabolite Extraction of Multiplexed MS/MS Spectra Generated by Data-Independent Acquisition.

    PubMed

    Li, Hao; Cai, Yuping; Guo, Yuan; Chen, Fangfang; Zhu, Zheng-Jiang

    2016-09-01

    With recent advances in mass spectrometry, there is an increased interest in data-independent acquisition (DIA) techniques for metabolomics. With DIA technique, all metabolite ions are sequentially selected and isolated using a wide window to generate multiplexed MS/MS spectra. Therefore, DIA strategy enables a continuous and unbiased acquisition of all metabolites and increases the data dimensionality, but presents a challenge to data analysis due to the loss of the direct link between precursor ion and fragment ions. However, very few DIA data processing methods are developed for metabolomics application. Here, we developed a new DIA data analysis approach, namely, MetDIA, for targeted extraction of metabolites from multiplexed MS/MS spectra generated using DIA technique. MetDIA approach considers each metabolite in the spectral library as an analysis target. Ion chromatograms for each metabolite (both precursor ion and fragment ions) and MS(2) spectra are readily detected, extracted, and scored for metabolite identification, referred as metabolite-centric identification. A minimum metabolite-centric identification score responsible for 1% false positive rate of identification is determined as 0.8 using fully (13)C labeled biological extracts. Finally, the comparisons of our MetDIA method with data-dependent acquisition (DDA) method demonstrated that MetDIA could significantly detect more metabolites in biological samples, and is more accurate and sensitive for metabolite identifications. The MetDIA program and the metabolite spectral library is freely available on the Internet.

  1. BDNF Val66Met and reward-related brain function in adolescents: role for early alcohol consumption.

    PubMed

    Nees, F; Witt, S H; Dinu-Biringer, R; Lourdusamy, A; Tzschoppe, J; Vollstädt-Klein, S; Millenet, S; Bach, C; Poustka, L; Banaschewski, T; Barker, G J; Bokde, A L W; Bromberg, U; Büchel, C; Conrod, P J; Frank, J; Frouin, V; Gallinat, J; Garavan, H; Gowland, P; Heinz, A; Ittermann, B; Mann, K; Martinot, J-L; Paus, T; Pausova, Z; Robbins, T W; Smolka, M N; Rietschel, M; Schumann, G; Flor, H

    2015-03-01

    Changes in reward processing have been identified as one important pathogenetic mechanism in alcohol addiction. The nonsynonymous single nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene (rs6265/Val66Met) modulates the central nervous system activity of neurotransmitters involved in reward processing such as serotonin, dopamine, and glutamate. It was identified as crucial for alcohol consumption in healthy adults and, in rats, specifically related to the function in the striatum, a region that is commonly involved in reward processing. However, studies in humans on the association of BDNF Val66Met and reward-related brain functions and its role for alcohol consumption, a significant predictor of later alcohol addiction, are missing. Based on an intermediate phenotype approach, we assessed the early orientation toward alcohol and alcohol consumption in 530 healthy adolescents that underwent a monetary incentive delay task during functional magnetic resonance imaging. We found a significantly lower response in the putamen to reward anticipation in adolescent Met carriers with high versus low levels of alcohol consumption. During reward feedback, Met carriers with low putamen reactivity were significantly more likely to orient toward alcohol and to drink alcohol 2 years later. This study indicates a possible effect of BDNF Val66Met on alcohol addiction-related phenotypes in adolescence. PMID:25650137

  2. Enhanced Extinction of Cocaine Seeking in Brain-derived Neurotrophic Factor Val66Met Knock-In Mice

    PubMed Central

    Briand, Lisa A.; Lee, Francis S.; Blendy, Julie A.; Pierce, R. Christopher

    2013-01-01

    The Val66Met polymorphism in the brain-derived neurotropic factor (BDNF) gene results in alterations in fear extinction behavior in both human populations and mouse models. However, it is not clear whether this polymorphism plays a similar role in extinction of appetitive behaviors. Therefore, we examined operant learning and extinction of both food and cocaine self-administration behavior in an inbred genetic knock-in mouse strain expressing the variant Bdnf. These mice provide a unique opportunity to relate alterations in aversive and appetitive extinction learning as well as provide insight into how human genetic variation can lead to differences in behavior. BDNFMet/Met mice exhibited a severe deficit in operant learning as evidenced by an inability to learn the food self-administration task. Therefore, extinction experiments were performed comparing wildtype (BDNFVal/Val) animals to mice heterozygous for the Met allele (BDNFVal/Met), which did not differ in food or cocaine self-administration behavior. In contrast to the deficit in fear extinction previously demonstrated in these mice, we found that BDNFVal/Met mice exhibited more rapid extinction of cocaine responding compared to wildtype mice. No differences were found between the genotypes in the extinction of food self-administration behavior or the reinstatement of cocaine seeking, indicating the effect is specific to extinction of cocaine responding. These results suggest that the molecular mechanisms underlying aversive and appetitive extinction are distinct from one another and BDNF may play opposing roles in the two phenomena. PMID:22394056

  3. Interaction effect between the BDNF Val66Met polymorphism and parental rearing for interpersonal sensitivity in healthy subjects.

    PubMed

    Suzuki, Akihito; Matsumoto, Yoshihiko; Shibuya, Naoshi; Ryoichi, Sadahiro; Kamata, Mitsuhiro; Enokido, Masanori; Goto, Kaoru; Otani, Koichi

    2012-12-30

    Interpersonal sensitivity is defined as undue and excessive awareness of, and sensitivity to, the behaviour and feelings of others and is one of the vulnerable factors to depression. In a twin study, it was suggested that this personality trait was characterised by both genetic and environmental factors. In the present study, we examined the effects of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and parental rearing on interpersonal sensitivity in 725 healthy Japanese subjects. Assessment of interpersonal sensitivity was performed by the Japanese version of the Interpersonal Sensitivity Measure (IPSM). Perceived parental rearing was assessed by the Parental Bonding Instrument (PBI), which consists of the care and protection factors. The BDNF polymorphism was detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. There was no main effect of the BDNF genotype on the IPSM score, while the PBI factors except maternal care had significant main effect on the IPSM score. There was significant interaction effect between the BDNF genotype and maternal care of the PBI on the IPSM score. Post-hoc analysis of simple slopes showed that the negative relationship between the IPSM score and maternal care was strongest and significant in the Met/Met genotype group, intermediate in the Val/Met genotype group and weakest in the Val/Val genotype group. The present study suggests that the interaction between the BDNF Val66Met polymorphism and parental rearing, especially maternal care, influences interpersonal sensitivity in healthy subjects.

  4. Interaction effect between the BDNF Val66Met polymorphism and parental rearing for interpersonal sensitivity in healthy subjects.

    PubMed

    Suzuki, Akihito; Matsumoto, Yoshihiko; Shibuya, Naoshi; Ryoichi, Sadahiro; Kamata, Mitsuhiro; Enokido, Masanori; Goto, Kaoru; Otani, Koichi

    2012-12-30

    Interpersonal sensitivity is defined as undue and excessive awareness of, and sensitivity to, the behaviour and feelings of others and is one of the vulnerable factors to depression. In a twin study, it was suggested that this personality trait was characterised by both genetic and environmental factors. In the present study, we examined the effects of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and parental rearing on interpersonal sensitivity in 725 healthy Japanese subjects. Assessment of interpersonal sensitivity was performed by the Japanese version of the Interpersonal Sensitivity Measure (IPSM). Perceived parental rearing was assessed by the Parental Bonding Instrument (PBI), which consists of the care and protection factors. The BDNF polymorphism was detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. There was no main effect of the BDNF genotype on the IPSM score, while the PBI factors except maternal care had significant main effect on the IPSM score. There was significant interaction effect between the BDNF genotype and maternal care of the PBI on the IPSM score. Post-hoc analysis of simple slopes showed that the negative relationship between the IPSM score and maternal care was strongest and significant in the Met/Met genotype group, intermediate in the Val/Met genotype group and weakest in the Val/Val genotype group. The present study suggests that the interaction between the BDNF Val66Met polymorphism and parental rearing, especially maternal care, influences interpersonal sensitivity in healthy subjects. PMID:22542952

  5. Effect of COMT Val158Met polymorphism on personality traits and educational attainment in a longitudinal population representative study.

    PubMed

    Lehto, K; Akkermann, K; Parik, J; Veidebaum, T; Harro, J

    2013-10-01

    The COMT Val158Met polymorphism has been associated with anxiety and affective disorders, but its effect on anxiety-related personality traits varies between studies. Our purpose was to investigate the effect of COMT Val158Met on personality traits from adolescence to young adulthood in a population representative Caucasian birth cohort. Also its association with educational attainment and anxiety and mood disorders by the age 25 were examined. This analysis is based on the older cohort of the Estonian Children Personality Behavior and Health Study (original number of subjects 593). The personality traits were assessed when the participants were 15, 18 and 25 years old. COMT Val158Met had an effect on Neuroticism in females by age 25 (p=0.001, Bonferroni-corrected for five traits), whereas female Val homozygotes scored the highest. In addition, the Conscientiousness scores of subjects with Val/Val genotype were decreasing in time, being the lowest by the age 25 (p=0.006, Bonferroni-corrected for five traits). By the age 25, males with the Val/Met genotype had mainly secondary or vocational education, whereas female heterozygotes mostly had obtained or were obtaining university education. COMT Val158Met was not associated with anxiety or mood disorders in either gender. These results suggest that genes affecting dopamine system are involved in the development of personality traits and contribute to educational attainment.

  6. AUY922 Effectively Overcomes MET- and AXL-Mediated Resistance to EGFR-TKI in Lung Cancer Cells

    PubMed Central

    Choi, Yun Jung; Kim, Seon Ye; So, Kwang Sup; Baek, In-Jeoung; Kim, Woo Sung; Choi, Se Hoon; Lee, Jae Cheol; Bivona, Trever G.; Rho, Jin Kyung; Choi, Chang-Min

    2015-01-01

    The activation of bypass signals, such as MET and AXL, has been identified as a possible mechanism of EGFR-TKI resistance. Because various oncoproteins depend on HSP90 for maturation and stability, we investigated the effects of AUY922, a newly developed non-geldanamycin class HSP90 inhibitor, in lung cancer cells with MET- and AXL-mediated resistance. We established resistant cell lines with HCC827 cells harboring an exon 19-deletion mutation in of the EGFR gene via long-term exposure to increasing concentrations of gefitinib and erlotinib (HCC827/GR and HCC827/ER, respectively). HCC827/GR resistance was mediated by MET activation, whereas AXL activation caused resistance in HCC827/ER cells. AUY922 treatment effectively suppressed proliferation and induced cell death in both resistant cell lines. Accordingly, the downregulation of EGFR, MET, and AXL led to decreased Akt activation. The inhibitory effects of AUY922 on each receptor were confirmed in gene-transfected LK2 cells. AUY922 also effectively controlled tumor growth in xenograft mouse models containing HCC827/GR and HCC827/ER cells. In addition, AUY922 reduced invasion and migration by both types of resistant cells. Our study findings thus show that AUY922 is a promising therapeutic option for MET- and AXL-mediated resistance to EGFR-TKI in lung cancer. PMID:25780909

  7. A Novel Bispecific Antibody Targeting EGFR and cMet Is Effective against EGFR Inhibitor-Resistant Lung Tumors.

    PubMed

    Moores, Sheri L; Chiu, Mark L; Bushey, Barbara S; Chevalier, Kristen; Luistro, Leopoldo; Dorn, Keri; Brezski, Randall J; Haytko, Peter; Kelly, Thomas; Wu, Sheng-Jiun; Martin, Pauline L; Neijssen, Joost; Parren, Paul W H I; Schuurman, Janine; Attar, Ricardo M; Laquerre, Sylvie; Lorenzi, Matthew V; Anderson, G Mark

    2016-07-01

    Non-small cell lung cancers (NSCLC) with activating EGFR mutations become resistant to tyrosine kinase inhibitors (TKI), often through second-site mutations in EGFR (T790M) and/or activation of the cMet pathway. We engineered a bispecific EGFR-cMet antibody (JNJ-61186372) with multiple mechanisms of action to inhibit primary/secondary EGFR mutations and the cMet pathway. JNJ-61186372 blocked ligand-induced phosphorylation of EGFR and cMet and inhibited phospho-ERK and phospho-AKT more potently than the combination of single receptor-binding antibodies. In NSCLC tumor models driven by EGFR and/or cMet, JNJ-61186372 treatment resulted in tumor regression through inhibition of signaling/receptor downmodulation and Fc-driven effector interactions. Complete and durable regression of human lung xenograft tumors was observed with the combination of JNJ-61186372 and a third-generation EGFR TKI. Interestingly, treatment of cynomolgus monkeys with JNJ-61186372 resulted in no major toxicities, including absence of skin rash observed with other EGFR-directed agents. These results highlight the differentiated potential of JNJ-61186372 to inhibit the spectrum of mutations driving EGFR TKI resistance in NSCLC. Cancer Res; 76(13); 3942-53. ©2016 AACR.

  8. The impact of Val108/158Met polymorphism of catechol-O-methyltransferase on brain oscillations during working memory.

    PubMed

    Altamura, Mario; Elvevåg, Brita; Goldberg, Terry E; Carver, Frederick W; Weinberger, Daniel R; Coppola, Richard

    2016-01-01

    This study investigated whether catechol-O-methyltransferase (COMT) Val/Met polymorphism was associated with variation in event-related desynchronization/synchronization (ERD/ERS) of responses during working memory (WM). 11 Val/Val and 11 Met/Met homozygous participants underwent magnetoencephalography (MEG) while performing a WM task. In contrast to small effects behaviourally, during the delay period Val/Val individuals showed lower ERS in the gamma band (Hz 30-50) in frontal regions, increased ERS in the alpha band (Hz 8-12) in the right frontal and parietal regions and increased ERD in the beta band (Hz 14-30) in the left fronto-temporal regions as compared with Met/Met homozygous individuals. During the response period Val/Val participants showed greater beta ERD in the prefrontal and parietotemporal regions. These results demonstrate that COMT genotype has a strong impact on brain responses (oscillatory activity) during WM performance likely a consequence of compensatory activity during the delay and response periods. PMID:26536074

  9. MET18 Connects the Cytosolic Iron-Sulfur Cluster Assembly Pathway to Active DNA Demethylation in Arabidopsis

    PubMed Central

    Tang, Kai; Zhang, Huiming; Mangrauthia, Satendra K.; Lei, Mingguang; Hsu, Chuan-Chih; Hou, Yueh-Ju; Wang, Chunguo; Li, Yan; Tao, W. Andy; Zhu, Jian-Kang

    2015-01-01

    DNA demethylation mediated by the DNA glycosylase ROS1 helps determine genomic DNA methylation patterns and protects active genes from being silenced. However, little is known about the mechanism of regulation of ROS1 enzymatic activity. Using a forward genetic screen, we identified an anti-silencing (ASI) factor, ASI3, the dysfunction of which causes transgene promoter hyper-methylation and silencing. Map-based cloning identified ASI3 as MET18, a component of the cytosolic iron-sulfur cluster assembly (CIA) pathway. Mutation in MET18 leads to hyper-methylation at thousands of genomic loci, the majority of which overlap with hypermethylated loci identified in ros1 and ros1dml2dml3 mutants. Affinity purification followed by mass spectrometry indicated that ROS1 physically associates with MET18 and other CIA components. Yeast two-hybrid and split luciferase assays showed that ROS1 can directly interact with MET18 and another CIA component, AE7. Site-directed mutagenesis of ROS1 indicated that the conserved iron-sulfur motif is indispensable for ROS1 enzymatic activity. Our results suggest that ROS1-mediated active DNA demethylation requires MET18-dependent transfer of the iron-sulfur cluster, highlighting an important role of the CIA pathway in epigenetic regulation. PMID:26492035

  10. MET18 Connects the Cytosolic Iron-Sulfur Cluster Assembly Pathway to Active DNA Demethylation in Arabidopsis.

    PubMed

    Duan, Cheng-Guo; Wang, Xingang; Tang, Kai; Zhang, Huiming; Mangrauthia, Satendra K; Lei, Mingguang; Hsu, Chuan-Chih; Hou, Yueh-Ju; Wang, Chunguo; Li, Yan; Tao, W Andy; Zhu, Jian-Kang

    2015-10-01

    DNA demethylation mediated by the DNA glycosylase ROS1 helps determine genomic DNA methylation patterns and protects active genes from being silenced. However, little is known about the mechanism of regulation of ROS1 enzymatic activity. Using a forward genetic screen, we identified an anti-silencing (ASI) factor, ASI3, the dysfunction of which causes transgene promoter hyper-methylation and silencing. Map-based cloning identified ASI3 as MET18, a component of the cytosolic iron-sulfur cluster assembly (CIA) pathway. Mutation in MET18 leads to hyper-methylation at thousands of genomic loci, the majority of which overlap with hypermethylated loci identified in ros1 and ros1dml2dml3 mutants. Affinity purification followed by mass spectrometry indicated that ROS1 physically associates with MET18 and other CIA components. Yeast two-hybrid and split luciferase assays showed that ROS1 can directly interact with MET18 and another CIA component, AE7. Site-directed mutagenesis of ROS1 indicated that the conserved iron-sulfur motif is indispensable for ROS1 enzymatic activity. Our results suggest that ROS1-mediated active DNA demethylation requires MET18-dependent transfer of the iron-sulfur cluster, highlighting an important role of the CIA pathway in epigenetic regulation.

  11. Alteration of the substrate specificity of l-amino acid ligase and selective synthesis of Met-Gly as a salt taste enhancer.

    PubMed

    Kino, Haruka; Kino, Kuniki

    2015-01-01

    Dipeptides have unique physiological functions. This study focused on the salt-taste-enhancing dipeptide Met-Gly. BL00235, an l-amino acid ligase from Bacillus licheniformis NBRC12200, synthesizes Met-Gly as a major product as well as Met-Met as a by-product. To alter the substrate specificity of BL00235 and synthesize Met-Gly selectively, we chose to alter Pro85 residue based on the BL00235 crystal structure. We predicted that Met might be not recognized as a C-terminal substrate by occupying the space around C-terminal substrate. Pro85 was replaced with Phe, Tyr, and Trp, which have bulky aromatic side chains, by site-directed mutagenesis. These mutants lost the capacity to synthesize Met-Met, during the synthesis of Met-Gly. Furthermore, they did not synthesize Met-Met, even when methionine was used as a substrate. These results show that the amino acid residue at position 85 has a key role in C-terminal substrate specificity. PMID:26088155

  12. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism influences the association of the methylome with maternal anxiety and neonatal brain volumes.

    PubMed

    Chen, Li; Pan, Hong; Tuan, Ta Anh; Teh, Ai Ling; MacIsaac, Julia L; Mah, Sarah M; McEwen, Lisa M; Li, Yue; Chen, Helen; Broekman, Birit F P; Buschdorf, Jan Paul; Chong, Yap Seng; Kwek, Kenneth; Saw, Seang Mei; Gluckman, Peter D; Fortier, Marielle V; Rifkin-Graboi, Anne; Kobor, Michael S; Qiu, Anqi; Meaney, Michael J; Holbrook, Joanna D

    2015-02-01

    Early life environments interact with genotype to determine stable phenotypic outcomes. Here we examined the influence of a variant in the brain-derived neurotropic factor (BDNF) gene (Val66Met), which underlies synaptic plasticity throughout the central nervous system, on the degree to which antenatal maternal anxiety associated with neonatal DNA methylation. We also examined the association between neonatal DNA methylation and brain substructure volume, as a function of BDNF genotype. Infant, but not maternal, BDNF genotype dramatically influences the association of antenatal anxiety on the epigenome at birth as well as that between the epigenome and neonatal brain structure. There was a greater impact of antenatal maternal anxiety on the DNA methylation of infants with the methionine (Met)/Met compared to both Met/valine (Val) and Val/Val genotypes. There were significantly more cytosine-phosphate-guanine sites where methylation levels covaried with right amygdala volume among Met/Met compared with both Met/Val and Val/Val carriers. In contrast, more cytosine-phosphate-guanine sites covaried with left hippocampus volume in Val/Val infants compared with infants of the Met/Val or Met/Met genotype. Thus, antenatal Maternal Anxiety × BDNF Val66Met Polymorphism interactions at the level of the epigenome are reflected differently in the structure of the amygdala and the hippocampus. These findings suggest that BDNF genotype regulates the sensitivity of the methylome to early environment and that differential susceptibility to specific environmental conditions may be both tissue and function specific.

  13. Radiation test of AMR sensors for MetNet Mars Precursor Mission

    NASA Astrophysics Data System (ADS)

    Sanz, R.; Fernandez, A. B.; Dominguez, J. A.; Martin, B.; Díaz-Michelena, M.

    2012-04-01

    The MetNet Mars Precursor Mission (MMPM) to Mars is supposed to be the first penetrator-based on ground meteorological station of a net over the Martian surface. MMPM will have very limited communications, power, and mass and lander and instrumentation will have to stand a huge mechanical shock, extremely low temperatures with huge temperature excursions and a radiation envelope of 15 krad. One of the instruments on board the MMPM is vector magnetometer, which main goal is to register the thermomangetic curves of the crustal magnetic minerals [1]. The instrument is based on Anisotropic MagnetoResistive (AMR) Commercial Off-The-Shelf (COTS) sensors due to the miniaturization objective and the successful previous experience in geomagnetic surveys [2, 3], achieving a whole mass of 65 g with a good trade off of magnetic performance (resolution levels in the order of the nT). This work reports on the magnetic sensor and the systematic gamma radiation tests performed on the AMR COTS chips. The objective is to study the damage and degradation of these sensors with the total irradiated dose (TID). The sensors were irradiated with gamma rays up to a total irradiation dose of 200 krad following ESCC Basic Specification No. 22900, with limited number of tested sensors. All tests were performed assuring low disturbances of variable magnetic fields, keeping those variations under the error threshold by means of magnetic shielding and registration of magnetic field variations with pT resolution. Parameters like linear response and saturation field, offset and set/reset strips deviations, and power consumption have been monitored for the four different types of sensors during the irradiation. The sensors chosen for the test have been of the HMC series by Honeywell: HMC 1021 S, HMC 1043, HMC 6042 and HMC 6052. HMC 1043 has been chosen for the AOCS of OPTOS picosatellite of INTA and as the magnetic sensor payload for MetNet precursor mission. HMC 1021 S sensors presented low

  14. DRD2 C957T polymorphism interacts with the COMT Val158Met polymorphism in human working memory ability.

    PubMed

    Xu, Haiyan; Kellendonk, Christoph B; Simpson, Eleanor H; Keilp, John G; Bruder, Gerard E; Polan, H Jonathan; Kandel, Eric R; Gilliam, T Conrad

    2007-02-01

    The C957T polymorphism in the dopamine D2 receptor (DRD2) gene and the Val158Met polymorphism in the Catechol-O-Methyl-Transferase (COMT) gene affect dopamine transmission and have been found to be associated with schizophrenia. Since DRD2 in mice and the COMT gene in humans modulate working memory, we examined the relationship and possible interaction of both polymorphisms to working memory performance in 188 healthy adults. Subjects having the DRD2 C/C allele showed the poorest performance in a word serial position test. Moreover, the effect of the C957T genotype was strengthened when interaction with the COMT Val158Met polymorphism was included in the analysis. We propose that an interaction of the DRD2 C957T and COMT Val158Met may be involved in the generation of some working memory deficits in schizophrenia.

  15. RNA polymerase, PurR and MetR interactions at the glyA promoter of Escherichia coli.

    PubMed

    Lorenz, E; Stauffer, G V

    1996-07-01

    In Escherichia coli, the MetR and PurR proteins positively and negatively regulate glyA gene expression, respectively. A DNase I footprint analysis showed that both proteins bind independently to the glyA control region. The PurR protein blocks RNA polymerase (RNAP) from binding to the glyA promoter. The presence of hypoxanthine, the co-repressor of PurR, increases the ability of PurR to prevent RNAP binding, providing a model for repression of the glyA gene by PurR. In contrast, MetR alters the RNAP footprint pattern of the glyA control region. In addition, the MetR footprint is increased in the presence of RNAP, suggesting that the two proteins might interact.

  16. First comes social networking, then comes marriage? Characteristics of Americans married 2005-2012 who met through social networking sites.

    PubMed

    Hall, Jeffrey A

    2014-05-01

    Abstract Although social networking sites (SNS) have become increasingly prevalent and integrated into the lives of users, the role of SNS in courtship is relatively unknown. The present manuscript reports on the characteristics of Americans married between 2005 and 2012 who met through SNS drawn from a weighted national sample (N=18,527). Compared to other online meetings (i.e., dating sites, online communities, one-on-one communication), individuals who met through SNS were younger, married more recently, and were more likely to be African American. Compared with offline meetings, individuals who met through SNS were more likely to be younger, male, African American and Hispanic, married more recently, and frequent Internet users with higher incomes. Trends suggest an increasing proportion of individuals are meeting using SNS, necessitating further research on factors that influence romantic relational development through SNS.

  17. First comes social networking, then comes marriage? Characteristics of Americans married 2005-2012 who met through social networking sites.

    PubMed

    Hall, Jeffrey A

    2014-05-01

    Abstract Although social networking sites (SNS) have become increasingly prevalent and integrated into the lives of users, the role of SNS in courtship is relatively unknown. The present manuscript reports on the characteristics of Americans married between 2005 and 2012 who met through SNS drawn from a weighted national sample (N=18,527). Compared to other online meetings (i.e., dating sites, online communities, one-on-one communication), individuals who met through SNS were younger, married more recently, and were more likely to be African American. Compared with offline meetings, individuals who met through SNS were more likely to be younger, male, African American and Hispanic, married more recently, and frequent Internet users with higher incomes. Trends suggest an increasing proportion of individuals are meeting using SNS, necessitating further research on factors that influence romantic relational development through SNS. PMID:24611755

  18. Long-term pharmacological kindling increases in vitro release of IR-Met and IR-Leu-enkephalin from amygdala.

    PubMed

    Asai, M; Matamoros-Trejo, G; Linares, G

    1998-06-01

    Met-enkephalin release is increased from amygdala and striatum 1 and 15 days after pharmacological kindling with pentylenetetrazol, following potassium-induced depolarization in vitro via a Ca2+ dependent mechanism. Leu-enkephalin release was only enhanced in amygdala and striatum 1 day after the last seizure. IR-Met-enkephalin amygdala tissue content enhanced 1 and 15 days after seizure. In striatum, we found an IR-Met-enkephalin decrease 35 days after the last stimulus. IR-Leu-enkephalin amygdala tissue content enhanced 1 day after the last seizure, and no significant increases were found in striatum 1, 15 and 35 days after the last seizure. In this paper, we show that opioid peptides release is differentially enhanced in rat brain for several days after the last seizure, thus suggesting that opioid peptides may have a protective action against seizure activity.

  19. Impacts of increasing the aerosol complexity in the Met Office global NWP model

    NASA Astrophysics Data System (ADS)

    Mulcahy, Jane; Walters, David; Bellouin, Nicolas; Milton, Sean

    2014-05-01

    Inclusion of the direct and indirect radiative effects of aerosols in high resolution global numerical weather prediction (NWP) models is being increasingly recognised as important for the improved accuracy of short-range weather forecasts. In this study the impacts of increasing the aerosol complexity in the global NWP configuration of the Met Office Unified Model (MetUM) are investigated. A hierarchy of aerosol representations are evaluated including three dimensional monthly mean speciated aerosol climatologies, fully prognostic aerosols modelled using the CLASSIC aerosol scheme and finally, initialised aerosols using assimilated aerosol fields from the GEMS project. The prognostic aerosol schemes are better able to predict the temporal and spatial variation of atmospheric aerosol optical depth, which is particularly important in cases of large sporadic aerosol events such as large dust storms or forest fires. Including the direct effect of aerosols improves model biases in outgoing longwave radiation over West Africa due to a better representation of dust. Inclusion of the indirect aerosol effects has significant impacts on the SW radiation particularly at high latitudes due to lower cloud amounts in high latitude clean air regions. This leads to improved surface radiation biases at the North Slope of Alaska ARM site. Verification of temperature and height forecasts is also improved in this region. Impacts on the global mean model precipitation and large-scale circulation fields were found to be generally small in the short range forecasts. However, the indirect aerosol effect leads to a strengthening of the low level monsoon flow over the Arabian Sea and Bay of Bengal and an increase in precipitation over Southeast Asia. This study highlights the importance of including a more realistic treatment of aerosol-cloud interactions in global NWP models and the potential for improved global environmental prediction systems through the incorporation of more complex

  20. Distribution of Methane in the tropics from MetOp/IASI hyperspectral infrared observations

    NASA Astrophysics Data System (ADS)

    Delphine, Nobileau; Cyril, Crevoisier; Peter, Bergamaschi; Alain, Chedin; Raymond, Armante; Noelle, Scott

    2010-05-01

    The Infrared Atmospheric Sounding Interferometer (IASI) launched onboard the European MetOp platform in October 2006 provides new information on methane (CH4) distribution in the mid-troposphere and gives the opportunity to follow the recent evolution of CH4 concentration. In May 2010, 34 months of IASI observations will have been interpreted in terms of methane distribution. With its high spectral resolution, IASI provides ten channels in the 7.7 μm band highly sensitive to CH4 with reduced sensitivities to other atmospheric variables. We use coupled observations in the thermal infrared from IASI, and in the microwave from the Advanced Microwave Sounding Unit (AMSU), also launched onboard MetOp, to retrieve mid-to-upper tropospheric contents of methane (CH4) in clear-sky conditions, in the tropics. Thermal observations, sensitive to both temperature and CH4, are used in conjunction with microwave observations, only sensitive to temperature, to decorrelate both signals through a non-linear inference scheme based on neural networks. A key point of this approach is that no use is made of prior information in terms of gas seasonality, trend, or geographical patterns. The precision of the IASI retrieval is estimated to be about 1%. Features of the retrieved CH4 space-time distributions include: (1) a CH4 trend of ~10 ppbv.yr-1 in the last couple of years, which confirms the recent increase of methane detected at surface stations; (2) a strong seasonal cycle in the northern tropics, and a lower seasonal cycle in the southern tropics, in agreement with in-situ measurements; (3) a latitudinal decrease from 20 N to 20 S lower than what is observed at the surface but in agreement with tropospheric aircraft measurements; (4) geographical patterns in good agreement with simulations from the TM5 atmospheric transport and chemistry model; (5) signatures of CH4 emissions transported to the troposphere such as a large plume of elevated tropospheric methane south of the Asian

  1. The CFTR Met 470 Allele Is Associated with Lower Birth Rates in Fertile Men from a Population Isolate

    PubMed Central

    Kosova, Gülüm; Pickrell, Joseph K.; Kelley, Joanna L.; McArdle, Patrick F.; Shuldiner, Alan R.; Abney, Mark; Ober, Carole

    2010-01-01

    Although little is known about the role of the cystic fibrosis transmembrane regulator (CFTR) gene in reproductive physiology, numerous variants in this gene have been implicated in etiology of male infertility due to congenital bilateral absence of the vas deferens (CBAVD). Here, we studied the fertility effects of three CBAVD–associated CFTR polymorphisms, the (TG)m and polyT repeat polymorphisms in intron 8 and Met470Val in exon 10, in healthy men of European descent. Homozygosity for the Met470 allele was associated with lower birth rates, defined as the number of births per year of marriage (P = 0.0029). The Met470Val locus explained 4.36% of the phenotypic variance in birth rate, and men homozygous for the Met470 allele had 0.56 fewer children on average compared to Val470 carrier men. The derived Val470 allele occurs at high frequencies in non-African populations (allele frequency  = 0.51 in HapMap CEU), whereas it is very rare in African population (Fst  = 0.43 between HapMap CEU and YRI). In addition, haplotypes bearing Val470 show a lack of genetic diversity and are thus longer than haplotypes bearing Met470 (measured by an integrated haplotype score [iHS] of −1.93 in HapMap CEU). The fraction of SNPs in the HapMap Phase2 data set with more extreme Fst and iHS measures is 0.003, consistent with a selective sweep outside of Africa. The fertility advantage conferred by Val470 relative to Met470 may provide a selective mechanism for these population genetic observations. PMID:20532200

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

    PubMed

    Klauke, Benedikt; Winter, Bernward; Gajewska, Agnes; Zwanzger, Peter; Reif, Andreas; Herrmann, Martin J; Dlugos, Andrea; Warrings, Bodo; Jacob, Christian; Mühlberger, Andreas; Arolt, Volker; Pauli, Paul; Deckert, Jürgen; Domschke, Katharina

    2012-01-01

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

  3. Affect-Modulated Startle: Interactive Influence of Catechol-O-Methyltransferase Val158Met Genotype and Childhood Trauma

    PubMed Central

    Klauke, Benedikt; Winter, Bernward; Gajewska, Agnes; Zwanzger, Peter; Reif, Andreas; Herrmann, Martin J.; Dlugos, Andrea; Warrings, Bodo; Jacob, Christian; Mühlberger, Andreas; Arolt, Volker; Pauli, Paul; Deckert, Jürgen; Domschke, Katharina

    2012-01-01

    The etiology of emotion-related disorders such as anxiety or affective disorders is considered to be complex with an interaction of biological and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic and noradrenergic system – partly conferred by catechol-O-methyltransferase (COMT) gene variation – for the adenosinergic system as well as for early life trauma to constitute risk factors for those conditions. Applying a multi-level approach, in a sample of 95 healthy adults, we investigated effects of the functional COMT Val158Met polymorphism, caffeine as an adenosine A2A receptor antagonist (300 mg in a placebo-controlled intervention design) and childhood maltreatment (CTQ) as well as their interaction on the affect-modulated startle response as a neurobiologically founded defensive reflex potentially related to fear- and distress-related disorders. COMT val/val genotype significantly increased startle magnitude in response to unpleasant stimuli, while met/met homozygotes showed a blunted startle response to aversive pictures. Furthermore, significant gene-environment interaction of COMT Val158Met genotype with CTQ was discerned with more maltreatment being associated with higher startle potentiation in val/val subjects but not in met carriers. No main effect of or interaction effects with caffeine were observed. Results indicate a main as well as a GxE effect of the COMT Val158Met variant and childhood maltreatment on the affect-modulated startle reflex, supporting a complex pathogenetic model of the affect-modulated startle reflex as a basic neurobiological defensive reflex potentially related to anxiety and affective disorders. PMID:22745815

  4. Inhibition of pro-HGF activation by SRI31215, a novel approach to block oncogenic HGF/MET signaling

    PubMed Central

    Owusu, Benjamin Y.; Bansal, Namita; Venukadasula, Phanindra K.M.; Ross, Larry J.; Messick, Troy E.; Goel, Sanjay; Galemmo, Robert A.; Klampfer, Lidija

    2016-01-01

    The binding of hepatocyte growth factor (HGF) to its receptor MET activates a signaling cascade that promotes cell survival, proliferation, cell scattering, migration and invasion of malignant cells. HGF is secreted by cancer cells or by tumor-associated fibroblasts as pro-HGF, an inactive precursor. A key step in the regulation of HGF/MET signaling is proteolytic processing of pro-HGF to its active form by one of the three serine proteases, matriptase, hepsin or HGF activator (HGFA). We developed SRI 31215, a small molecule that acts as a triplex inhibitor of matriptase, hepsin and HGFA and mimics the activity of HAI-1/2, endogenous inhibitors of HGF activation. We demonstrated that SRI 31215 inhibits fibroblast-induced MET activation, epithelial-mesenchymal transition and migration of cancer cells. SRI 31215 overcomes primary resistance to cetuximab and gefitinib in HGF-producing colon cancer cells and prevents fibroblast-mediated resistance to EGFR inhibitors. Thus, SRI 31215 blocks signaling between cancer cells and fibroblasts and inhibits the tumor-promoting activity of cancer-associated fibroblasts. Aberrant HGF/MET signaling supports cell survival, proliferation, angiogenesis, invasion and metastatic spread of cancer cells, establishing HGF and MET as valid therapeutic targets. Our data demonstrate that inhibitors of HGF activation, such as SRI 31215, merit investigation as potential therapeutics in tumors that are addicted to HGF/MET signaling. The findings reported here also indicate that inhibitors of HGF activation overcome primary and acquired resistance to anti-EGFR therapy, providing a rationale for concurrent inhibition of EGFR and HGF to prevent therapeutic resistance and to improve the outcome of cancer patients. PMID:27121052

  5. Comparison of GOME-2/MetOp total ozone data with Brewer spectroradiometer data over the Iberian Peninsula

    NASA Astrophysics Data System (ADS)

    Antón, M.; Loyola, D.; López, M.; Vilaplana, J. M.; Bañón, M.; Zimmer, W.; Serrano, A.

    2009-04-01

    The main objective of this article is to compare the total ozone data from the new Global Ozone Monitoring Experiment instrument (GOME-2/MetOp) with reliable ground-based measurement recorded by five Brewer spectroradiometers in the Iberian Peninsula. In addition, a similar comparison for the predecessor instrument GOME/ERS-2 is described. The period of study is a whole year from May 2007 to April 2008. The results show that GOME-2/MetOp ozone data already has a very good quality, total ozone columns are on average 3.05% lower than Brewer measurements. This underestimation is higher than that obtained for GOME/ERS-2 (1.46%). However, the relative differences between GOME-2/MetOp and Brewer measurements show significantly lower variability than the differences between GOME/ERS-2 and Brewer data. Dependencies of these relative differences with respect to the satellite solar zenith angle (SZA), the satellite scan angle, the satellite cloud cover fraction (CF), and the ground-based total ozone measurements are analyzed. For both GOME instruments, differences show no significant dependence on SZA. However, GOME-2/MetOp data show a significant dependence on the satellite scan angle (+1.5%). In addition, GOME/ERS-2 differences present a clear dependence with respect to the CF and ground-based total ozone; such differences are minimized for GOME-2/MetOp. The comparison between the daily total ozone values provided by both GOME instruments shows that GOME-2/MetOp ozone data are on average 1.46% lower than GOME/ERS-2 data without any seasonal dependence. Finally, deviations of a priori climatological ozone profile used by the satellite retrieval algorithm from the true ozone profile are analyzed. Although excellent agreement between a priori climatological and measured partial ozone values is found for the middle and high stratosphere, relative differences greater than 15% are common for the troposphere and lower stratosphere.

  6. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism affects sympathetic tone in a gender-specific way.

    PubMed

    Chang, Chuan-Chia; Chang, Hsin-An; Chen, Tien-Yu; Fang, Wen-Hui; Huang, San-Yuan

    2014-09-01

    The Val/Val genotype of the brain-derived neurotrophic factor (BDNF) polymorphism (Val66Met) has been reported to affect human anxiety-related phenotypes. Substantial research has demonstrated that anxiety is associated with sympathetic activation, while sex steroid hormones have been shown to exert differential actions in regulating BDNF expression. Thus, we examined whether the BDNF variant modulates autonomic function in a gender-dependent manner. From 708 adults initially screened for medical and psychiatric illnesses, a final cohort of 583 drug-free healthy Han Chinese (355 males, 228 females; age 34.43±8.42 years) was recruited for BDNF genotyping (Val/Val: 136, 23.3%, Val/Met: 294, 50.4%, and Met/Met: 153, 26.2%). Time- and frequency-domain analyses of heart rate variability (HRV) were used to assess autonomic outflow to the heart. Significant genotype-by-gender interaction effects were found on HRV indices. Even after adjusting for possible confounders, male participants bearing the Val/Val genotype had significant increases in low frequency (LF), LF% and LF/high frequency (HF) ratio, indicating altered sympathovagal balance with increased sympathetic modulation, compared to male Met/Met homozygotes. Females, however, showed an opposite but non-significant pattern. These results suggest that the studied BDNF polymorphism is associated with sympathetic control in a gender-specific way. The findings here support the view that male subjects with the Val/Val genotype have increased risk of anxiety by association with sympathetic activation.

  7. Brain met-enkephalin immunostaining after subacute and subchronic exposure to benzene

    SciTech Connect

    Gandarias, J.M. de; Echevarria, E.; Martinez-Millan, L.; Casis, L.; Martinez-Garcia, F.

    1994-01-01

    Benzene is used in a wide variety of domestic and occupational activities, and due to its lipophilic nature, it accumulates in lipid-rich tissues like the brain. In this sense, neurotoxic action has long been associated with organic solvent exposure and it has been shown that benzene, injected in a single dose or during a prolongued administration, modifies the content of dopamine, noradrenaline, serotonin and its main metabolite 5-hydroxy indolacetic acid, in several brain regions of the rat, then revealing a stimulating action on brain monoamine synthesis and turnover. However, information concerning neurotoxic action of benzene exposure in vivo on peptidergic neuromodulatory systems is still lacking. Nevertheless, it has been recently described that subacute benzene exposure in rats generates regional changes in brain aminopeptidase activity. These proteolytic enzymes have been widely associated with metabolic control of neuropeptides and it has been suggested that they could play a role in benzene neurotoxic mechanism by hypothetically changing regional neuropeptide levels. This being the case, we focused on analyzing met-enkephalin immunostaining in different brain regions of the rat after subacute and subchronic administration of benzene. 12 refs., 3 figs.

  8. A joint data record of tropospheric ozone from Aura-TES and MetOp-IASI

    NASA Astrophysics Data System (ADS)

    Oetjen, Hilke; Payne, Vivienne H.; Neu, Jessica L.; Kulawik, Susan S.; Edwards, David P.; Eldering, Annmarie; Worden, Helen M.; Worden, John R.

    2016-08-01

    The Tropospheric Emission Spectrometer (TES) on Aura and Infrared Atmospheric Sounding Interferometer (IASI) on MetOp-A together provide a time series of 10 years of free-tropospheric ozone with an overlap of 3 years. We characterise the differences between TES and IASI ozone measurements and find that IASI's coarser vertical sensitivity leads to a small (< 5 ppb) low bias relative to TES for the free troposphere. The TES-IASI differences are not dependent on season or any other factor and hence the measurements from the two instruments can be merged, after correcting for the offset, in order to study decadal-scale changes in tropospheric ozone. We calculate time series of regional monthly mean ozone in the free troposphere over eastern Asia, the western United States (US), and Europe, carefully accounting for differences in spatial sampling between the instruments. We show that free-tropospheric ozone over Europe and the western US has remained relatively constant over the past decade but that, contrary to expectations, ozone over Asia in recent years does not continue the rapid rate of increase observed from 2004 to 2010.

  9. A seamless approach to assessing monsoon simulations in the Met Office Unified Model

    NASA Astrophysics Data System (ADS)

    Levine, R. C.; Boo, K. O.; Martin, G. M.; Milton, S. F.; Mitra, A.; Sellar, A. A.; Willett, M. R.

    2009-04-01

    We present an assessment of monsoons as simulated by the latest configurations of the Met Office Unified Model. These consist of models of varying complexity that are used for Numerical Weather Prediction (NWP), climate, and seasonal prediction. A comparison is made between the model biases in different monsoon regions for the different configurations, giving an insight into the nature of the main systematic errors, and also of the time-scales involved in their development. Both the mean state and the variability are assessed using a metric-based approach. The main model bias in the Indian monsoon region is the relatively low precipitation over Indian land. This has been significantly improved in the latest atmospheric component of the climate model, mainly due to changes in the CAPE closure in the convection scheme, which are aimed at reducing the tendency for strong intermittent deep convection. A more detailed comparison of the model with ERA re-analysis data is made for the onset and the pre-monsoon period of the Indian summer monsoon, giving an insight into the impact of various changes to the model. The emphasis is placed on the impacts of the timing of convection, the development of the monsoon jet, the impact of cyclonic vortices, and the moistening rates over India. The interannual variability is further examined through analysis of the ENSO-monsoon teleconnection, the link between El Nino/La Nina events and below/above average rainfall over India, which is assessed using a metric-based approach.

  10. Investigating the genetic basis of altruism: the role of the COMT Val158Met polymorphism

    PubMed Central

    Frenzel, Clemens; Walter, Nora T.; Markett, Sebastian; Montag, Christian

    2011-01-01

    Findings from twin studies yield heritability estimates of 0.50 for prosocial behaviours like empathy, cooperativeness and altruism. First molecular genetic studies underline the influence of polymorphisms located on genes coding for the receptors of the neuropeptides, oxytocin and vasopressin. However, the proportion of variance explained by these gene loci is rather low indicating that additional genetic variants must be involved. Pharmacological studies show that the dopaminergic system interacts with oxytocin and vasopressin. The present experimental study tests a dopaminergic candidate polymorphism for altruistic behaviour, the functional COMT Val158Met SNP. N = 101 healthy Caucasian subjects participated in the study. Altruism was assessed by the amount of money donated to a poor child in a developing country, after having earned money by participating in two straining computer experiments. Construct validity of the experimental data was given: the highest correlation between the amount of donations and personality was observed for cooperativeness (r = 0.32, P ≤ 0.001). Carriers of at least one Val allele donated about twice as much money as compared with those participants without a Val allele (P = 0.01). Cooperativeness and the Val allele of COMT additively explained 14.6% of the variance in donation behaviour. Results indicate that the Val allele representing strong catabolism of dopamine is related to altruism. PMID:21030481

  11. Impacts of Increased Vertical Resolution in the Met Office UK Model

    NASA Astrophysics Data System (ADS)

    Finnenkoetter, Anke; Van Weverberg, Kwinten; Morcrette, Cyril

    2016-04-01

    As computing resources increase, NWP models continue to move to finer grid resolutions in order to improve the representation of small scale atmospheric processes. While improvements resulting from increasing horizontal resolution are often obviously linked to the better orographic representation and finer scale land use data, the benefits seen from an increased vertical resolution can be more subtle and the underlying mechanisms complex to understand. Increasing the number of vertical levels from 70 to 120, we performed a number of case studies with the Met Office's 1.5km horizontal resolution UK model (UKV). Statistical analyses show a slight, but systematic decrease in low rain rates and high-level cloud amount. The most significant impact can be seen in the representation of widespread low-level cloud. While there is little change to cloud top heights, the cloud base lifts in runs with the new vertical level set. The resulting thinned cloud layers are more prone to break up, offering a better agreement with low cloud cover seen in satellite imagery. Ongoing work aims to fully understand the mechanisms leading to the changes in the vertical humidity distribution and the enhanced decoupling seen within the boundary layer.

  12. The Met pathway: master switch and drug target in cancer progression.

    PubMed

    Mazzone, Massimiliano; Comoglio, Paolo M

    2006-08-01

    It has been recognized for more than a century that most tumors tend to become more aggressive in clinical behavior over time, although this time course may be variable. This phenomenon has been termed "cancer progression," a process that appears to develop in a stepwise fashion through qualitatively different stages. Cancer progression relies on the ability of neoplastic cells to abandon their primary site of accretion, trespass tissue boundaries, and penetrate into the vasculature to colonize and repopulate distant sites. Among the various properties associated with cancer progression, the acquisition by neoplastic cells of the capacity to invade locally and to metastasize is of great clinical significance, and is still the fundamental definition of malignancy. This process represents the aberrant counterpart of a physiological morphogenetic program, known as invasive growth, occurring during embryo development and, in some instances, in adulthood for the generation and maintenance of normal organ complexity and architecture. Here we summarize some of the strategies adopted to inhibit cancer cell growth and spreading. We also review the current findings about cancer and metastasis inhibitors. As we suggest possible directions for drug development, we propose the receptor for the hepatocyte growth factor, Met, as an ideal target for tackling cancer progression.

  13. The Met Office's new operational analysis system for diurnally varying skin-SST

    NASA Astrophysics Data System (ADS)

    While, James; Mao, Chongyuan; Martin, Matthew; Good, Simon; Sykes, Peter

    2016-04-01

    Diurnal variations in skin Sea Surface Temperature (skin SST), which can be as large as several degrees, play an important role in determining the heat flux between the ocean and atmosphere. As such, since February 2015 the Met Office, as part of the Copernicus Marine Environment Monitoring Service (CMEMS), has been producing an operational analysis of the diurnal cycle of skin SST. This product consists of three components: an underlying 'foundation' SST (based on the OSTIA analysis), a warm layer where solar heating is important, and a cool skin where cooling due to long wave radiation dominates. A major development in this system is the use of a 4D-Var data assimilation technique with multiple outer-loops to improve estimates of the warm layer. Observations assimilated come from the SEVIRI, GOES-W, MTSAT2, and NOAA-AVHRR infra-red satellite instruments. Through their assimilation, the observations act to update the applied heat and wind flux such that the diurnal cycle in the warm layer is improved. In this presentation we describe the analysis system and how it produces a skin SST product. Particular attention is paid to the data assimilation aspects and on the observation processing. We also present results from a three month validation period showing that the system is well able to reproduce a drifter based climatology of the diurnal cycle in SST. A direct validation of our diurnal SST output against near surface Argo data is also given.

  14. Comparison of quantitative sensory testing and heart rate variability in Swedish Val30Met ATTR.

    PubMed

    Heldestad, Victoria; Wiklund, Urban; Hörnsten, Rolf; Obayashi, Konen; Suhr, Ole B; Nordh, Erik

    2011-12-01

    Patients with transthyretin amyloidosis (ATTR) polyneuropathy, a hereditary fatal disease, often report defects in both thermal perception and autonomic nervous system function as their first clinical symptoms. While elevated thermal perception thresholds (TPT) for cold and warmth only recently have been shown as an early marker of small nerve fiber dysfunction in these patients, heart rate variability (HRV) has frequently been used to quantify autonomic neuropathy. The main purpose with this report was to elucidate a possible relationship between estimates of HRV and TPT in a selected group of early and late-onset Swedish Val30Met ATTR patients. The results show significantly more pronounced elevation of TPT in early compared to late-onset patients. Significant correlations between HRV and TPT were found among late-onset cases, indicating a possible relationship between loss of thin nerve fibers in somatic and autonomic nerves, while generally no such relationships were found among early-onset cases. This observation emphasizes the importance of testing both HRV and TPT to ensure optimal early detection of neuropathic changes in an as wide as possible range of small nerve fibers in suspected ATTR patients. This is of particular importance as the phenotype of the ATTR disease varies between groups with different age of onset. PMID:22035563

  15. Multi-frequency solar observations at Metsähovi Radio Observatory and KAIRA

    NASA Astrophysics Data System (ADS)

    Kallunki, J.; Uunila, M.; McKay-Bukowski, D.

    2015-08-01

    We describe solar observations carried out for the first time jointly with Kilpisjärvi Atmospheric Imaging Receiver Array (KAIRA) and Aalto University Metsähovi Radio Observatory (MRO). KAIRA is new radio antenna array observing the decimeter and meter wavelength range. It is located near Kilpisjärvi, Finland, and operated by the Sodankylä Geophysical Observatory, University of Oulu. We investigate the feasibility of KAIRA for solar observations, and the additional benefits of carrying out multi-instrument solar observations with KAIRA and the MRO facilities, which are already used for regular solar observations. The data measured with three instruments at MRO, and with KAIRA during time period 2014 April-October were analyzed. One solar radio event, measured on 2014 April 18, was studied in detail. Seven solar flares were recorded with at least two of the three instruments at MRO, and with KAIRA during the chosen time period. KAIRA is a great versatile asset as a new Finnish instrument that can also be used for solar observations. Collaboration observations with MRO instruments and KAIRA enable detailed multi-frequency solar flare analysis. Flare pulsations, flare statistics and radio spectra of single flares can be investigated due to the broad frequency range observations. The Northern locations of both MRO and KAIRA make as long as 15-hour unique solar observations possible during summer time.

  16. Influence of catechol-o-methyltransferase genotype (Val158Met) on endocrine, sympathetic nervous and mucosal immune systems in breast cancer survivors.

    PubMed

    Fernández-de-Las-Peñas, César; Cantarero-Villanueva, Irene; Fernández-Lao, Carolina; Ambite-Quesada, Silvia; Díaz-Rodríguez, Lourdes; Rivas-Martínez, Inés; del Moral-Avila, Rosario; Arroyo-Morales, Manuel

    2012-04-01

    Stress can play an important role in development of cancer-related fatigue (CRF) by activating the hypothalamic-pituitary-adrenal (HPA) axis, the sympathetic nervous system (SNS), and altering the immune system. This study examined the influence of catechol-O-methyltransferase (COMT) Val158Met genotypes on salivary markers of HPA axis (cortisol), SNS (α-amylase) and immune (IgA) systems, as well as on CRF in breast cancer survivors (BCS). One-hundred BCS participated. After amplifying Val158Met COMT polymorphisms by polymerase chain reaction, three COMT genotypes were considered: Val/Val, Val/Met, Met/Met. Salivary cortisol, α-amylase activity, salivary flow rate, and IgA concentration were collected from non-stimulated saliva. CRF was assessed with the fatigue subscale of the Profile of Mood State (POMS) questionnaire. We found that BCS carrying Met/Met genotype reported higher cortisol concentration, α-amylase activity and greater CRF than those with Val/Met (P < 0.05) and Val/Val (P < 0.001) genotypes. No differences in salivary flow rate or IgA concentration (P > 0.20) were found. The results suggest that BCS carrying Met/Met genotype exhibit greater dysfunction of the HPA axis and SNS system associated with severe CRF. This study is important because it strives to understand biological factors that predispose some BCS to higher levels of CRF. PMID:21974969

  17. Co-activation of AKT and c-Met triggers rapid hepatocellular carcinoma development via the mTORC1/FASN pathway in mice

    PubMed Central

    Hu, Junjie; Che, Li; Li, Lei; Pilo, Maria G.; Cigliano, Antonio; Ribback, Silvia; Li, Xiaolei; Latte, Gavinella; Mela, Marta; Evert, Matthias; Dombrowski, Frank; Zheng, Guohua; Chen, Xin; Calvisi, Diego F.

    2016-01-01

    Activation of the AKT/mTOR cascade and overexpression of c-Met have been implicated in the development of human hepatocellular carcinoma (HCC). To elucidate the functional crosstalk between the two pathways, we generated a model characterized by the combined expression of activated AKT and c-Met in the mouse liver. Co-expression of AKT and c-Met triggered rapid liver tumor development and mice required to be euthanized within 8 weeks after hydrodynamic injection. At the molecular level, liver tumors induced by AKT/c-Met display activation of AKT/mTOR and Ras/MAPK cascades as well as increased lipogenesis and glycolysis. Since a remarkable lipogenic phenotype characterizes liver lesions from AKT/c-Met mice, we determined the requirement of lipogenesis in AKT/c-Met driven hepatocarcinogenesis using conditional Fatty Acid Synthase (FASN) knockout mice. Of note, hepatocarcinogenesis induced by AKT/c-Met was fully inhibited by FASN ablation. In human HCC samples, coordinated expression of FASN, activated AKT, and c-Met proteins was detected in a subgroup of biologically aggressive tumors. Altogether, our study demonstrates that co-activation of AKT and c-Met induces HCC development that depends on the mTORC1/FASN pathway. Suppression of mTORC1 and/or FASN might be highly detrimental for the growth of human HCC subsets characterized by concomitant induction of the AKT and c-Met cascades. PMID:26857837

  18. Meta-analysis reveals a lack of association between a common catechol-O-methyltransferase (COMT) polymorphism val¹⁵⁸met and fibromyalgia.

    PubMed

    Zhang, Lei; Zhu, Junwei; Chen, Yong; Zhao, Jianning

    2014-01-01

    This study is to evaluate the association between the catechol-O-methyltransferase (COMT) gene val(158)met polymorphism and FM risk. We performed a meta-analysis of 8 case-control studies that included 589 FM cases and 527 case-free controls. We assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). Overall, this meta-analysis showed that the COMT gene val(158)met polymorphism was not associated with FM risk in all genetic models, i.e., allele (met vs. val: OR=1.46, 95% CI=0.80-2.66, P heterpgeneity<0.001), homozygous (met/met vs. val/val: OR=1.72, 95% CI=0.61-4.87, P heterpgeneity<0.001), heterozygous (val/met vs. val/val: OR=1.25, 95% CI=0.82-1.92, P heterpgeneity=0.050), recessive (met/met vs. val/val+val/met: OR=1.52, 95% CI=0.60-3.86, P heterpgeneity<0.001) and dominant model (met/met+val/met vs. val/val: OR=1.52, 95% CI=0.80-2.90, P heterpgeneity<0.001). Similarly, there were no significant associations in the subgroup analyses by ethnicity and HWE. No publication bias was found in the present study. This meta-analysis suggests that the COMT gene val(158)met polymorphism is not associated with FM risk. Further large and well-designed studies are needed to confirm this association.

  19. Meta-analysis reveals a lack of association between a common catechol-O-methyltransferase (COMT) polymorphism val¹⁵⁸met and fibromyalgia.

    PubMed

    Zhang, Lei; Zhu, Junwei; Chen, Yong; Zhao, Jianning

    2014-01-01

    This study is to evaluate the association between the catechol-O-methyltransferase (COMT) gene val(158)met polymorphism and FM risk. We performed a meta-analysis of 8 case-control studies that included 589 FM cases and 527 case-free controls. We assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). Overall, this meta-analysis showed that the COMT gene val(158)met polymorphism was not associated with FM risk in all genetic models, i.e., allele (met vs. val: OR=1.46, 95% CI=0.80-2.66, P heterpgeneity<0.001), homozygous (met/met vs. val/val: OR=1.72, 95% CI=0.61-4.87, P heterpgeneity<0.001), heterozygous (val/met vs. val/val: OR=1.25, 95% CI=0.82-1.92, P heterpgeneity=0.050), recessive (met/met vs. val/val+val/met: OR=1.52, 95% CI=0.60-3.86, P heterpgeneity<0.001) and dominant model (met/met+val/met vs. val/val: OR=1.52, 95% CI=0.80-2.90, P heterpgeneity<0.001). Similarly, there were no significant associations in the subgroup analyses by ethnicity and HWE. No publication bias was found in the present study. This meta-analysis suggests that the COMT gene val(158)met polymorphism is not associated with FM risk. Further large and well-designed studies are needed to confirm this association. PMID:25674213

  20. Meta-analysis reveals a lack of association between a common catechol-O-methyltransferase (COMT) polymorphism val158met and fibromyalgia

    PubMed Central

    Zhang, Lei; Zhu, Junwei; Chen, Yong; Zhao, Jianning

    2014-01-01

    This study is to evaluate the association between the catechol-O-methyltransferase (COMT) gene val158met polymorphism and FM risk. We performed a meta-analysis of 8 case-control studies that included 589 FM cases and 527 case-free controls. We assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). Overall, this meta-analysis showed that the COMT gene val158met polymorphism was not associated with FM risk in all genetic models, i.e., allele (met vs. val: OR=1.46, 95% CI=0.80-2.66, P heterpgeneity<0.001), homozygous (met/met vs. val/val: OR=1.72, 95% CI=0.61-4.87, P heterpgeneity<0.001), heterozygous (val/met vs. val/val: OR=1.25, 95% CI=0.82-1.92, P heterpgeneity=0.050), recessive (met/met vs. val/val+val/met: OR=1.52, 95% CI=0.60-3.86, P heterpgeneity<0.001) and dominant model (met/met+val/met vs. val/val: OR=1.52, 95% CI=0.80-2.90, P heterpgeneity<0.001). Similarly, there were no significant associations in the subgroup analyses by ethnicity and HWE. No publication bias was found in the present study. This meta-analysis suggests that the COMT gene val158met polymorphism is not associated with FM risk. Further large and well-designed studies are needed to confirm this association. PMID:25674213

  1. 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

    ... Federal Aviation Administration 21st Meeting: RTCA Special Committee 206: EUROCAE WG 76 Plenary: AIS and... Special Committee 206: EUROCAE WG 76 Plenary: AIS and MET Data Link Services meeting. SUMMARY: The FAA is issuing this notice to advise the public of a meeting of RTCA Special Committee 206: EUROCAE WG 76...

  2. 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

    ... Federal Aviation Administration 24th Meeting: RTCA Special Committee 206: EUROCAE WG 76 Plenary: AIS and... Special Committee 206: EUROCAE WG 76 Plenary: AIS and MET Data Link Services meeting. SUMMARY: The FAA is issuing this notice to advise the public of a meeting of RTCA Special Committee 206: EUROCAE WG 76...

  3. 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

    ... Federal Aviation Administration 22nd Meeting: RTCA Special Committee 206: EUROCAE WG 76 Plenary: AIS and... Special Committee 206: EUROCAE WG 76 Plenary: AIS and MET Data Link Services meeting. SUMMARY: The FAA is issuing this notice to advise the public of a meeting of RTCA Special Committee 206: EUROCAE WG 76...

  4. Have We Identified Effective Teachers? Validating Measures of Effective Teaching Using Random Assignment. Research Paper. MET Project

    ERIC Educational Resources Information Center

    Kane, Thomas J.; McCaffrey, Daniel F.; Miller, Trey; Staiger, Douglas O.

    2013-01-01

    To develop, reward, and retain great teachers, school systems first must know how to identify them. The authors designed the Measures of Effective Teaching (MET) project to test replicable methods for identifying effective teachers. In past reports, the authors described three approaches to measuring different aspects of teaching: student surveys,…

  5. Afterschool: A Strategy for Addressing and Preventing Middle School Bullying. MetLife Foundation Afterschool Alert. Issue Brief No. 51

    ERIC Educational Resources Information Center

    Afterschool Alliance, 2011

    2011-01-01

    The Afterschool Alliance, in partnership with MetLife Foundation, is proud to present the second in a 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 focuses on bullying awareness and prevention. Bullying is a dangerous behavior…

  6. Olive Phenolics as c-Met Inhibitors: (-)-Oleocanthal Attenuates Cell Proliferation, Invasiveness, and Tumor Growth in Breast Cancer Models

    PubMed Central

    Akl, Mohamed R.; Ayoub, Nehad M.; Mohyeldin, Mohamed M.; Busnena, Belnaser A.; Foudah, Ahmed I.; Liu, Yong-Yu; Sayed, Khalid A. EI

    2014-01-01

    Dysregulation of the Hepatocyte growth factor (HGF)/c-Met signaling axis upregulates diverse tumor cell functions, including cell proliferation, survival, scattering and motility, epithelial-to-mesenchymal transition (EMT), angiogenesis, invasion, and metastasis. (-)-Oleocanthal is a naturally occurring secoiridoid from extra-virgin olive oil, which showed antiproliferative and antimigratory activity against different cancer cell lines. The aim of this study was to characterize the intracellular mechanisms involved in mediating the anticancer effects of (-)-oleocanthal treatment and the potential involvement of c-Met receptor signaling components in breast cancer. Results showed that (-)-oleocanthal inhibits the growth of human breast cancer cell lines MDA-MB-231, MCF-7 and BT-474 while similar treatment doses were found to have no effect on normal human MCF10A cell growth. In addition, (-)-oleocanthal treatment caused a dose-dependent inhibition of HGF-induced cell migration, invasion and G1/S cell cycle progression in breast cancer cell lines. Moreover, (-)-oleocanthal treatment effects were found to be mediated via inhibition of HGF-induced c-Met activation and its downstream mitogenic signaling pathways. This growth inhibitory effect is associated with blockade of EMT and reduction in cellular motility. Further results from in vivo studies showed that (-)-oleocanthal treatment suppressed tumor cell growth in an orthotopic model of breast cancer in athymic nude mice. Collectively, the findings of this study suggest that (-)-oleocanthal is a promising dietary supplement lead with potential for therapeutic use to control malignancies with aberrant c-Met activity. PMID:24849787

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

    PubMed

    Akl, Mohamed R; Ayoub, Nehad M; Mohyeldin, Mohamed M; Busnena, Belnaser A; Foudah, Ahmed I; Liu, Yong-Yu; Sayed, Khalid A Ei

    2014-01-01

    Dysregulation of the Hepatocyte growth factor (HGF)/c-Met signaling axis upregulates diverse tumor cell functions, including cell proliferation, survival, scattering and motility, epithelial-to-mesenchymal transition (EMT), angiogenesis, invasion, and metastasis. (-)-Oleocanthal is a naturally occurring secoiridoid from extra-virgin olive oil, which showed antiproliferative and antimigratory activity against different cancer cell lines. The aim of this study was to characterize the intracellular mechanisms involved in mediating the anticancer effects of (-)-oleocanthal treatment and the potential involvement of c-Met receptor signaling components in breast cancer. Results showed that (-)-oleocanthal inhibits the growth of human breast cancer cell lines MDA-MB-231, MCF-7 and BT-474 while similar treatment doses were found to have no effect on normal human MCF10A cell growth. In addition, (-)-oleocanthal treatment caused a dose-dependent inhibition of HGF-induced cell migration, invasion and G1/S cell cycle progression in breast cancer cell lines. Moreover, (-)-oleocanthal treatment effects were found to be mediated via inhibition of HGF-induced c-Met activation and its downstream mitogenic signaling pathways. This growth inhibitory effect is associated with blockade of EMT and reduction in cellular motility. Further results from in vivo studies showed that (-)-oleocanthal treatment suppressed tumor cell growth in an orthotopic model of breast cancer in athymic nude mice. Collectively, the findings of this study suggest that (-)-oleocanthal is a promising dietary supplement lead with potential for therapeutic use to control malignancies with aberrant c-Met activity. PMID:24849787

  8. Beta 1-integrin-c-Met cooperation reveals an inside-in survival signalling on autophagy-related endomembranes.

    PubMed

    Barrow-McGee, Rachel; Kishi, Naoki; Joffre, Carine; Ménard, Ludovic; Hervieu, Alexia; Bakhouche, Bakhouche A; Noval, Alejandro J; Mai, Anja; Guzmán, Camilo; Robert-Masson, Luisa; Iturrioz, Xavier; Hulit, James; Brennan, Caroline H; Hart, Ian R; Parker, Peter J; Ivaska, Johanna; Kermorgant, Stéphanie

    2016-01-01

    Receptor tyrosine kinases (RTKs) and integrins cooperate to stimulate cell migration and tumour metastasis. Here we report that an integrin influences signalling of an RTK, c-Met, from inside the cell, to promote anchorage-independent cell survival. Thus, c-Met and β1-integrin co-internalize and become progressively recruited on LC3B-positive 'autophagy-related endomembranes' (ARE). In cells growing in suspension, β1-integrin promotes sustained c-Met-dependent ERK1/2 phosphorylation on ARE. This signalling is dependent on ATG5 and Beclin1 but not on ATG13, suggesting ARE belong to a non-canonical autophagy pathway. This β1-integrin-dependent c-Met-sustained signalling on ARE supports anchorage-independent cell survival and growth, tumorigenesis, invasion and lung colonization in vivo. RTK-integrin cooperation has been assumed to occur at the plasma membrane requiring integrin 'inside-out' or 'outside-in' signalling. Our results report a novel mode of integrin-RTK cooperation, which we term 'inside-in signalling'. Targeting integrin signalling in addition to adhesion may have relevance for cancer therapy. PMID:27336951

  9. Keeping Kids Safe and Supported in the Hours After School. MetLife Foundation Afterschool Alert. Issue Brief No. 65

    ERIC Educational Resources Information Center

    Afterschool Alliance, 2014

    2014-01-01

    The Afterschool Alliance, in partnership with MetLife Foundation, is proud to present the third issue brief in their 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 series explores afterschool and: the Common Core State Standards,…

  10. Norstictic Acid Inhibits Breast Cancer Cell Proliferation, Migration, Invasion, and In Vivo Invasive Growth Through Targeting C-Met.

    PubMed

    Ebrahim, Hassan Y; Elsayed, Heba E; Mohyeldin, Mohamed M; Akl, Mohamed R; Bhattacharjee, Joydeep; Egbert, Susan; El Sayed, Khalid A

    2016-04-01

    Breast cancer is a major health problem affecting the female population worldwide. The triple-negative breast cancers (TNBCs) are characterized by malignant phenotypes, worse patient outcomes, poorest prognosis, and highest mortality rates. The proto-oncogenic receptor tyrosine kinase c-Met is usually dysregulated in TNBCs, contributing to their oncogenesis, tumor progression, and aggressive cellular invasiveness that is strongly linked to tumor metastasis. Therefore, c-Met is proposed as a promising candidate target for the control of TNBCs. Lichens-derived metabolites are characterized by their structural diversity, complexity, and novelty. The chemical space of lichen-derived metabolites has been extensively investigated, albeit their biological space is still not fully explored. The anticancer-guided fractionation of Usnea strigosa (Ach.) lichen extract led to the identification of the depsidone-derived norstictic acid as a novel bioactive hit against breast cancer cell lines. Norstictic acid significantly suppressed the TNBC MDA-MB-231 cell proliferation, migration, and invasion, with minimal toxicity to non-tumorigenic MCF-10A mammary epithelial cells. Molecular modeling, Z'-LYTE biochemical kinase assay and Western blot analysis identified c-Met as a potential macromolecular target. Norstictic acid treatment significantly suppressed MDA-MB-231/GFP tumor growth of a breast cancer xenograft model in athymic nude mice. Lichen-derived natural products are promising resources to discover novel c-Met inhibitors useful to control TNBCs. PMID:26744260

  11. 77 FR 16562 - Solicitation for a Cooperative Agreement-Curriculum Development for MET, ECCP, and ICMS Training...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-21

    ... to follow. The MET approach differs from cognitive-behavioral treatment strategies that teach... cover letter that identifies the audit agency responsible for the applicant's financial accounts as well as the audit period or fiscal year that the applicant operates under (e.g., July 1 through June...

  12. 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

    ... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false How and when we determine whether the performance accuracy standard is met. 404.1645 Section 404.1645 Employees' Benefits SOCIAL SECURITY ADMINISTRATION FEDERAL OLD-AGE, SURVIVORS AND DISABILITY INSURANCE (1950- ) Determinations of...

  13. Norstictic Acid Inhibits Breast Cancer Cell Proliferation, Migration, Invasion, and In Vivo Invasive Growth Through Targeting C-Met

    PubMed Central

    Ebrahim, Hassan Y.; Elsayed, Heba E.; Mohyeldin, Mohamed M.; Akl, Mohamed R.; Bhattacharjee, Joydeep; Egbert, Susan; El Sayed, Khalid A.

    2016-01-01

    Breast cancer is a major health problem affecting the female population worldwide. The triple-negative breast cancers (TNBCs) are characterized by malignant phenotypes, worse patient outcomes, poorest prognosis, and highest mortality rates. The proto-oncogenic receptor tyrosine kinase c-Met is usually dysregulated in TNBCs, contributing to their oncogenesis, tumor progression, and aggressive cellular invasiveness that is strongly linked to tumor metastasis. Therefore, c-Met is proposed as a promising candidate target for the control of TNBCs. Lichens-derived metabolites are characterized by their structural diversity, complexity, and novelty. The chemical space of lichen-derived metabolites has been extensively investigated, albeit their biological space is still not fully explored. The anticancer-guided fractionation of Usnea strigosa (Ach.) lichen extract led to the identification of the depsidone-derived norstictic acid as a novel bioactive hit against breast cancer cell lines. Norstictic acid significantly suppressed the TNBC MDA-MB-231 cell proliferation, migration, and invasion, with minimal toxicity to non-tumorigenic MCF-10A mammary epithelial cells. Molecular modeling, Z′-LYTE biochemical kinase assay and Western blot analysis identified c-Met as a potential macromolecular target. Norstictic acid treatment significantly suppressed MDA-MB-231/GFP tumor growth of a breast cancer xenograft model in athymic nude mice. Lichen-derived natural products are promising resources to discover novel c-Met inhibitors useful to control TNBCs. PMID:26744260

  14. Met.3D - a new open-source tool for interactive 3D visualization of ensemble weather forecasts

    NASA Astrophysics Data System (ADS)

    Rautenhaus, Marc; Kern, Michael; Schäfler, Andreas; Westermann, Rüdiger

    2015-04-01

    We introduce Met.3D, a new open-source tool for the interactive 3D visualization of numerical ensemble weather predictions. The tool has been developed to support weather forecasting during aircraft-based atmospheric field campaigns, however, is applicable to further forecasting, research and teaching activities. Our work approaches challenging topics related to the visual analysis of numerical atmospheric model output -- 3D visualisation, ensemble visualization, and how both can be used in a meaningful way suited to weather forecasting. Met.3D builds a bridge from proven 2D visualization methods commonly used in meteorology to 3D visualization by combining both visualization types in a 3D context. It implements methods that address the issue of spatial perception in the 3D view as well as approaches to using the ensemble in order to assess forecast uncertainty. Interactivity is key to the Met.3D approach. The tool uses modern graphics hardware technology to achieve interactive visualization of present-day numerical weather prediction datasets on standard consumer hardware. Met.3D supports forecast data from the European Centre for Medium Range Weather Forecasts and operates directly on ECMWF hybrid sigma-pressure level grids. In this presentation, we provide an overview of the software --illustrated with short video examples--, and give information on its availability.

  15. Modification of Depression by COMT val[superscript 158]Met Polymorphism in Children Exposed to Early Severe Psychosocial Deprivation

    ERIC Educational Resources Information Center

    Drury, Stacy S.; Theall, Katherine P.; Smyke, Anna T.; Keats, Bronya J. B.; Egger, Helen L.; Nelson, Charles A.; Fox, Nathan A.; Marshall, Peter J.; Zeanah, Charles H.

    2010-01-01

    Objective: To examine the impact of the catechol-O-methyltransferase (COMT) val[superscript 158]met allele on depressive symptoms in young children exposed to early severe social deprivation as a result of being raised in institutions. Methods: One hundred thirty six children from the Bucharest Early Intervention Project (BEIP) were randomized…

  16. Multiple Endocrine Disruption by the MET/ALK Inhibitor Crizotinib in Patients With Non–Small Cell Lung Cancer

    PubMed Central

    Sargis, Robert M.; Salgia, Ravi

    2014-01-01

    Objectives Non–small cell lung cancer (NSCLC) is a heterogenous group of disorders that can be subclassified based upon molecular characterization. Anaplastic lymphoma kinase translocation and MET aberrations occur in a subset of NSCLC. Anaplastic lymphoma kinase/ MET have been shown to be inhibited by the small molecule tyrosine kinase inhibitor crizotinib. Recently, crizotinib was shown to decrease testosterone in males. Herein, we describe the effects of crizotinib on multiple hormonal axes. Materials and Methods Seven consecutive patients with NSCLC who were receiving crizotinib as part of their standard care were evaluated for hormonal disruptions. Results Primary hypogonadism was detected in 4/5 of males, whereas mildly elevated prolactin was observed in 4/7 patients. Hypocalcemia was observed in 3/7 patients. Interestingly, 5/7 patients had elevated levels of insulin-like growth factor-1 (IGF-1) levels, and the remaining 2 individuals had levels that were near the upper limits of the normal range. Conclusions Because of cellular cross-talk between MET and IGF-1 signaling, elevated IGF-1 levels induced by crizotinib treatment may have implications for long-term drug efficacy. Furthermore, this finding suggests a potential avenue of therapeutic synergy, namely coordinate inhibition of the MET and IGF-1 signaling pathways. Finally, as crizotinib has been recently approved, it is prudent to check hormone and calcium biomarkers and correct noted deficiencies for improved outcomes and quality of life. PMID:23934135

  17. Afterschool: An Ally in Promoting Middle School Improvement. MetLife Foundation Afterschool Alert. Issue Brief No. 55

    ERIC Educational Resources Information Center

    Afterschool Alliance, 2012

    2012-01-01

    The Afterschool Alliance, in partnership with MetLife Foundation, is proud to present the first 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 school improvement. In communities across the…

  18. Afterschool Supporting Students with Disabilities and Other Special Needs. MetLife Foundation Afterschool Alert. Issue Brief No. 64

    ERIC Educational Resources Information Center

    Afterschool Alliance, 2014

    2014-01-01

    The Afterschool Alliance, in partnership with MetLife Foundation, is proud to present the second in their 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 series explores afterschool and: the Common Core State Standards, students…

  19. Afterschool: A Key to Successful Parent Engagement. MetLife Foundation Afterschool Alert. Issue Brief No. 57

    ERIC Educational Resources Information Center

    Afterschool Alliance, 2012

    2012-01-01

    The Afterschool Alliance, in partnership with MetLife Foundation, is proud to present the third 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 parent engagement. There is little dispute…

  20. Tyrosine residues 654 and 670 in {beta}-cat enin are crucial in regulation of Met-{beta}-catenin interactions

    SciTech Connect

    Zeng, Gang; Apte, Udayan; Micsenyi, Amanda; Bell, Aaron; Monga, Satdarshan P.S. . E-mail: smonga@pitt.edu

    2006-11-01

    {beta}-catenin, a key component of the canonical Wnt pathway, is also regulated by tyrosine phosphorylation that regulates its association to E-cadherin. Previously, we reported its association with the hepatocyte growth factor (HGF) receptor Met at the membrane. HGF induced Met-{beta}-catenin dissociation and nuclear translocation of {beta}-catenin, which was tyrosine-phosphorylation-dependent. Here, we further investigate the Met-{beta}-catenin interaction by selectively mutating several tyrosine residues, alone or in combination, in {beta}-catenin. The mutants were subcloned into FLAG-CMV vector and stably transfected into rat hepatoma cells, which were treated with HGF. All single or double-mutant-transfected cells continued to show HGF-induced nuclear translocation of FLAG-{beta}-catenin except the mutations affecting 654 and 670 simultaneously (Y654/670F), which coincided with the lack of formation of {beta}-catenin-TCF complex and DNA synthesis, in response to the HGF treatment. In addition, the Y654/670F-transfected cells also showed no phosphorylation of {beta}-catenin or dissociation from Met in response to HGF. Thus, intact 654 and 670 tyrosine residues in {beta}-catenin are crucial in HGF-mediated {beta}-catenin translocation, activation and mitogenesis.

  1. Biphasic Regulation of the NADPH Oxidase by HGF/c-Met Signaling Pathway in Primary Mouse Hepatocytes

    PubMed Central

    Clavijo-Cornejo, Denise; Enriquez-Cortina, Cristina; López-Reyes, Alberto; Domínguez-Pérez, Mayra; Nuño, Natalia; Domínguez-Meraz, Marcela; Bucio, Leticia; Souza, Verónica; Factor, Valentina M.; Thorgeirsson, Snorri S.; Gutiérrez-Ruiz, María Concepción; Gómez-Quiroz, Luis E.

    2013-01-01

    Redox signaling is emerging as an essential mechanism in the regulation of biological activities of the cell. The HGF/c-Met signaling pathway has been implicated as a key regulator of the cellular redox homeostasis and oxidative stress. We previously demonstrated that genetic deletion of c-met in hepatocytes disrupts redox homeostasis by a mechanism involving NADPH oxidase. Here, we were focused to address the mechanism of NADPH oxidase regulation by HGF/c-Met signaling in primary mouse hepatocytes and its relevance. HGF induced a biphasic mechanism of NADPH oxidase regulation. The first phase employed the rapid increase in production of ROS as signaling effectors to activate the Nrf2-mediated protective response resulting in up-regulation of the antioxidant proteins, such as NAD(P)H quinone oxidoreductase and γ-glutamylcysteine synthetase. The second phase operated under a prolonged HGF exposure, caused a suppression of the NADPH oxidase components, including NOX2, NOX4, p22 and p67, and was able to abrogate the TGFβ-induced ROS production and improve cell viability. In conclusion, HGF/c-Met induces a Nrf2-mediated protective response by a double mechanism driven by NADPH oxidase. PMID:23333744

  2. Beta 1-integrin–c-Met cooperation reveals an inside-in survival signalling on autophagy-related endomembranes

    PubMed Central

    Barrow-McGee, Rachel; Kishi, Naoki; Joffre, Carine; Ménard, Ludovic; Hervieu, Alexia; Bakhouche, Bakhouche A.; Noval, Alejandro J.; Mai, Anja; Guzmán, Camilo; Robert-Masson, Luisa; Iturrioz, Xavier; Hulit, James; Brennan, Caroline H.; Hart, Ian R.; Parker, Peter J.; Ivaska, Johanna; Kermorgant, Stéphanie

    2016-01-01

    Receptor tyrosine kinases (RTKs) and integrins cooperate to stimulate cell migration and tumour metastasis. Here we report that an integrin influences signalling of an RTK, c-Met, from inside the cell, to promote anchorage-independent cell survival. Thus, c-Met and β1-integrin co-internalize and become progressively recruited on LC3B-positive ‘autophagy-related endomembranes' (ARE). In cells growing in suspension, β1-integrin promotes sustained c-Met-dependent ERK1/2 phosphorylation on ARE. This signalling is dependent on ATG5 and Beclin1 but not on ATG13, suggesting ARE belong to a non-canonical autophagy pathway. This β1-integrin-dependent c-Met-sustained signalling on ARE supports anchorage-independent cell survival and growth, tumorigenesis, invasion and lung colonization in vivo. RTK–integrin cooperation has been assumed to occur at the plasma membrane requiring integrin ‘inside-out' or ‘outside-in' signalling. Our results report a novel mode of integrin–RTK cooperation, which we term ‘inside-in signalling'. Targeting integrin signalling in addition to adhesion may have relevance for cancer therapy. PMID:27336951

  3. Redesigning of anti-c-Met single chain Fv antibody for the cytoplasmic folding and its structural analysis.

    PubMed

    Edwardraja, Selvakumar; Neelamegam, Rameshkumar; Ramadoss, Vijayaraj; Venkatesan, Subramanian; Lee, Sun-Gu

    2010-06-15

    Typically, single chain Fv antibodies are unable to fold properly under a reducing cytoplasm because of the reduction of disulfide bonds. The inability to fold limits both the production of the functional scFvs and their targeting against antigens, which are generally executed in a reducing cytoplasm. In this study, the target scFv CDR was grafted with stable human consensus framework sequences, which enabled the generation of a foldable scFv in a reducing cytoplasm of Escherichia coli. Additionally, the structural features affecting the folding efficiency of the engineered scFv were identified by analyzing the predicted structure. An anti-c-Met scFv, which was a cytoplasmic non-foldable protein, was redesigned as the model system. This study confirmed that the engineered anti-c-Met scFv was folded into its native form in the cytoplasm of E. coli BL21(DE3) without a significant loss in the specific binding activity against c-Met antigen. The structures of the wild-type anti-c-Met scFv and the engineered scFv were predicted using homology modeling. A comparative analysis based on the sequence and structure showed that the hydrophobicity of 12 solvent exposed residues decreased, and two newly formed salt bridges might have improved the folding efficiency of the engineered scFv under the reducing condition.

  4. Afterschool and the Common Core State Standards. MetLife Foundation Afterschool Alert. Issue Brief No. 63

    ERIC Educational Resources Information Center

    Afterschool Alliance, 2014

    2014-01-01

    The Afterschool Alliance, in partnership with MetLife Foundation, is proud to present the first in their 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 series explores afterschool and: the Common Core State Standards, students…

  5. 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

    ... Services and a revised Terms of Reference (TOR) for SC-206 has been approved by the RTCA Program Management Committee. A brief description of the document deliverables called out in the revised SC-206 TOR is provided... Architecture Recommendations are included in the TOR deliverables. The Concept of Use for AIS and MET Data...

  6. Grandparents: Generous with Money, Not with Advice. A MetLife QuickPOLL of American Grandparents

    ERIC Educational Resources Information Center

    Metropolitan Life Insurance Company, 2009

    2009-01-01

    In May 2009, the MetLife Mature Market Institute conducted a nationwide survey of grandparents age 45 and older with grandchildren under the age of 25. This survey examined their attitudes and behaviors toward providing financial assistance and advice to their grandchildren and what effect the current economy is having on the assistance they are…

  7. 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

    ... background check, which includes a fingerprint check through the Criminal Justice Information Services... considered met only after the individual has been the subject of a satisfactory background investigation. The background investigation shall include a review of: (a) The individual's trustworthiness, through...

  8. 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

    ... background check, which includes a fingerprint check through the Criminal Justice Information Services... considered met only after the individual has been the subject of a satisfactory background investigation. The background investigation shall include a review of: (a) The individual's trustworthiness, through...

  9. The BDNF Val66Met Polymorphism Interacts with Maternal Parenting Influencing Adolescent Depressive Symptoms: Evidence of Differential Susceptibility Model.

    PubMed

    Zhang, Leilei; Li, Zhi; Chen, Jie; Li, Xinying; Zhang, Jianxin; Belsky, Jay

    2016-03-01

    Although depressive symptoms are common during adolescence, little research has examined gene-environment interaction on youth depression. This study chose the brain-derived neurotrophic factor (BDNF) gene, tested the interaction between a functional polymorphism resulting amino acid substitution of valine (Val) to methionine (Met) in the proBDNF protein at codon 66 (Val66Met), and maternal parenting on youth depressive symptoms in a sample of 780 community adolescents of Chinese Han ethnicity (aged 11-17, M = 13.6, 51.3 % females). Participants reported their depressive symptoms and perceived maternal parenting. Results indicated the BDNF Val66Met polymorphism significantly moderated the influence of maternal warmth-reasoning, but not harshness-hostility, on youth depressive symptoms. Confirmatory model evaluation indicated that the interaction effect involving warmth-reasoning conformed to the differential-susceptibility rather than diathesis-stress model of person-X-environment interaction. Thus, Val carriers experienced less depressive symptoms than Met homozygotes when mothering was more positive but more symptoms when mothering was less positive. The findings provided evidence in support of the differential susceptibility hypothesis of youth depressive symptoms and shed light on the importance of examining the gene-environment interaction from a developmental perspective.

  10. 34 CFR 461.46 - What requirements for program reviews and evaluations must be met by a State?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 34 Education 3 2014-07-01 2014-07-01 false What requirements for program reviews and evaluations... requirements for program reviews and evaluations must be met by a State? (a) An SEA shall provide for program reviews and evaluations of all State-administered adult education programs, services, and activities...

  11. 34 CFR 461.46 - What requirements for program reviews and evaluations must be met by a State?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 34 Education 3 2013-07-01 2013-07-01 false What requirements for program reviews and evaluations... requirements for program reviews and evaluations must be met by a State? (a) An SEA shall provide for program reviews and evaluations of all State-administered adult education programs, services, and activities...

  12. 34 CFR 461.46 - What requirements for program reviews and evaluations must be met by a State?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 34 Education 3 2012-07-01 2012-07-01 false What requirements for program reviews and evaluations... requirements for program reviews and evaluations must be met by a State? (a) An SEA shall provide for program reviews and evaluations of all State-administered adult education programs, services, and activities...

  13. OECD MCCI project Melt Eruption Test (MET) design report, Rev. 2. April 15, 2003.

    SciTech Connect

    Farmer, M. T.; Lomperski, S.; Kilsdonk, D. J.; Aeschlimann, R. W.; Basu, S.

    2011-05-23

    The Melt Attack and Coolability Experiments (MACE) program at Argonne National Laboratory addressed the issue of the ability of water to cool and thermally stabilize a molten core-concrete interaction when the reactants are flooded from above. These tests provided data regarding the nature of corium interactions with concrete, the heat transfer rates from the melt to the overlying water pool, and the role of noncondensable gases in the mixing processes that contribute to melt quenching. The Melt Coolability and Concrete Interaction (MCCI) program is pursuing separate effect tests to examine the viability of the melt coolability mechanisms identified as part of the MACE program. These mechanisms include bulk cooling, water ingression, volcanic eruptions, and crust breach. At the second PRG meeting held at ANL on 22-23 October 2002, a preliminary design1 for a separate effects test to investigate the melt eruption cooling mechanism was presented for PRG review. At this meeting, NUPEC made several recommendations on the experiment approach aimed at optimizing the chances of achieving a floating crust boundary condition in this test. The principal recommendation was to incorporate a mortar sidewall liner into the test design, since data from the COTELS experiment program indicates that corium does not form a strong mechanical bond with this material. Other recommendations included: (i) reduction of the electrode elevation to well below the melt upper surface elevation (since the crust may bond to these solid surfaces), and (ii) favorably taper the mortar liner to facilitate crust detachment and relocation during the experiment. Finally, as a precursor to implementing these modifications, the PRG recommended the development of a design for a small-scale scoping test intended to verify the ability of the mortar liner to preclude formation of an anchored bridge crust under core-concrete interaction conditions. This revised Melt Eruption Test (MET) plan is intended to

  14. In vitro and in vivo metabolism of (Met)enkephalin in rabbit plasma

    SciTech Connect

    Gaddis, R.R.; Schadt, J.C.; McKown, M.; Garrett, L.

    1986-03-05

    During the discovery of enkephalins by Hughes it was observed that these peptides were susceptible to rapid enzymatic inactivation. Since that time considerable work has been done to characterize the route of catabolism of (Met)enkephalin (ME) in brain and selected peripheral tissues. However, little has been done to characterize the metabolic disposition of the enkephalins in the peripheral circulation. The purpose of this study was to identify the mode of deactivation of ME in rabbit plasma. In vitro plasma half life (t1/2) of /sup 3/H-ME was determined following incubation of freshly isolated rabbit plasma at 37/sup 0/C. In vivo 1/2 was determined following a bolus injection of /sup 3/H-ME. /sup 3/H-ME was extracted from plasma by chromatographic separation using Amberlite XAD-2 columns. Degradation was temperature dependent with a t1/2 of 1.5 +/- 0.3 min at 37/sup 0/C. In vitro catabolism was dose dependently inhibited in the presence of either bacitracin, bestatin, puromycin or thiorpan. The t1/2 in the presence of 20 ..mu..M of each inhibitor was 2.4 +/- 0.3, 7.1 +/- 0.6, 2.4 +/- 0.3 and 3.2 +/- 0.2 min, respectively. The in vivo t1/2 was 0.5 +/- 0.1 min. Pretreatment of rabbits with a combination of 50 mg/kg bacitracin, 1 mg/kg thiorphan and 1.5 mg/kg puromycin produced a 1.6 fold increase in the in vivo t1/2 (0.8 +/- 0.1 min). Thus, circulating levels of ME are rapidly inactivated primarily by an aminopeptidase.

  15. A novel homozygous LMNA mutation (p.Met540Ile) causes mandibuloacral dysplasia type A.

    PubMed

    Yassaee, Vahid Reza; Khojaste, Arash; Hashemi-Gorji, Feyzollah; Ravesh, Zeinab; Toosi, Parviz

    2016-02-10

    Mandibuloacral dysplasia with type A lipodystrophy (MADA) is a rare genetic disorder inherited in an autosomal recessive fashion characterized by hypoplasia of the mandible and clavicles, acroosteolysis and lipodystrophy due to mutations in the LMNA or ZMPSTE24 genes. In the current study, we have investigated a consanguineous family clinically diagnosed with mandibuloacral dysplasia type A having an affected child for the LMNA gene alteration(s). Mother is now 15weeks pregnant, seeking advice on the health of her fetus. Peripheral blood was obtained from all family members after informed consent was achieved. Genomic DNA was isolated. The sequence of the LMNA gene, including all exons and intron boundaries was analyzed by PCR and Sanger sequencing. Chorionic villus was collected from the placenta to reveal the condition of the fetus. Molecular analysis ascertained a homozygous mutation c.1620G>A (p.M540I) in the proband and heterozygous alteration in the family. Genomic DNA isolated from the CVS was amplified using specific primers for identified deleterious mutation and analyzed by Sanger sequencing. Two pathogenic mutations c.1620G>A and c.1698C>T were identified in the fetus. Genetic counseling as well as justified rapid and sensitive genetic testing can provide reassurance for the families to prevent the high burden of genetic disorders. We have also applied several online tools including PolyPhen2, MUpro, SIFT, PoPMuSiC, Project HOPE and Mutation Taster to predict the impact of p.Met540Ile substitution as a hotspot region within LMNA. All tools showed reduction in the stability of the protein structure. We conclude that p.M540I mutation may causes disease in the homozygous state. PMID:26602028

  16. New dye-decolorizing peroxidases from Bacillus subtilis and Pseudomonas putida MET94: towards biotechnological applications.

    PubMed

    Santos, Ana; Mendes, Sónia; Brissos, Vânia; Martins, Lígia O

    2014-03-01

    This work provides spectroscopic, catalytic, and stability fingerprints of two new bacterial dye-decolorizing peroxidases (DyPs) from Bacillus subtilis (BsDyP) and Pseudomonas putida MET94 (PpDyP). DyPs are a family of microbial heme-containing peroxidases with wide substrate specificity, including high redox potential aromatic compounds such as synthetic dyes or phenolic and nonphenolic lignin units. The genes encoding BsDyP and PpDyP, belonging to subfamilies A and B, respectively, were cloned and heterologously expressed in Escherichia coli. The recombinant PpDyP is a 120-kDa homotetramer while BsDyP enzyme consists of a single 48-kDa monomer. The optimal pH of both enzymes is in the acidic range (pH 4-5). BsDyP has a bell-shape profile with optimum between 20 and 30 °C whereas PpDyP shows a peculiar flat and broad (10-30 °C) temperature profile. Anthraquinonic or azo dyes, phenolics, methoxylated aromatics, and also manganese and ferrous ions are substrates used by the enzymes. In general, PpDyP exhibits higher activities and accepts a wider scope of substrates than BsDyP; the spectroscopic data suggest distinct heme microenvironments in the two enzymes that might account for the distinctive catalytic behavior. However, the Bs enzyme with activity lasting for up to 53 h at 40 °C is more stable towards temperature or chemical denaturation than the PpDyP. The results of this work will guide future optimization of the biocatalytis towards their utilization in the fields of environmental or industrial biotechnology. PMID:23820555

  17. New dye-decolorizing peroxidases from Bacillus subtilis and Pseudomonas putida MET94: towards biotechnological applications.

    PubMed

    Santos, Ana; Mendes, Sónia; Brissos, Vânia; Martins, Lígia O

    2014-03-01

    This work provides spectroscopic, catalytic, and stability fingerprints of two new bacterial dye-decolorizing peroxidases (DyPs) from Bacillus subtilis (BsDyP) and Pseudomonas putida MET94 (PpDyP). DyPs are a family of microbial heme-containing peroxidases with wide substrate specificity, including high redox potential aromatic compounds such as synthetic dyes or phenolic and nonphenolic lignin units. The genes encoding BsDyP and PpDyP, belonging to subfamilies A and B, respectively, were cloned and heterologously expressed in Escherichia coli. The recombinant PpDyP is a 120-kDa homotetramer while BsDyP enzyme consists of a single 48-kDa monomer. The optimal pH of both enzymes is in the acidic range (pH 4-5). BsDyP has a bell-shape profile with optimum between 20 and 30 °C whereas PpDyP shows a peculiar flat and broad (10-30 °C) temperature profile. Anthraquinonic or azo dyes, phenolics, methoxylated aromatics, and also manganese and ferrous ions are substrates used by the enzymes. In general, PpDyP exhibits higher activities and accepts a wider scope of substrates than BsDyP; the spectroscopic data suggest distinct heme microenvironments in the two enzymes that might account for the distinctive catalytic behavior. However, the Bs enzyme with activity lasting for up to 53 h at 40 °C is more stable towards temperature or chemical denaturation than the PpDyP. The results of this work will guide future optimization of the biocatalytis towards their utilization in the fields of environmental or industrial biotechnology.