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  1. Geluidsexpositie bij Gebruik van Otoplastieken met Communicatie (Sound Exposure Level of F-16 Crew Chiefs Using Custom Molded Communications Earplugs)

    DTIC Science & Technology

    2008-10-01

    energetische som over alle banden van dit spectrum worden gegeven in tabel 6 (’onbeschermd’). De niveaus hebben we uitgedrukt in ASEL , A-weighted...Invloed van de gehoorbescherming op de geluidbelasting in de praktijk. Alle niveaus /.ijn in ASEL De onbeschermde situatie is het gemiddelde A-gewogen...seconden aanwezig was, kan het gemiddelde A-gewogen niveau in dB SPL verkregen worden door de ASELs te verminderen met 10 * 10log(750) = 28,8 dB

  2. Kompressionstherapie bei Patienten mit Ulcus cruris venosum.

    PubMed

    Dissemond, Joachim; Assenheimer, Bernd; Bültemann, Anke; Gerber, Veronika; Gretener, Silvia; Kohler-von Siebenthal, Elisabeth; Koller, Sonja; Kröger, Knut; Kurz, Peter; Läuchli, Severin; Münter, Christian; Panfil, Eva-Maria; Probst, Sebastian; Protz, Kerstin; Riepe, Gunnar; Strohal, Robert; Traber, Jürg; Partsch, Hugo

    2016-11-01

    Wund-D.A.CH. ist der Dachverband deutschsprachiger Fachgesellschaften, die sich mit den Thematiken der Wundbehandlung beschäftigen. Experten verschiedener Fachgesellschaften aus Deutschland, Österreich und der Schweiz haben nun einen aktuellen Konsens der Kompressionstherapie für Patienten mit Ulcus cruris venosum erstellt. In Europa ist das Ulcus cruris venosum eine der häufigsten Ursachen für chronische Wunden. Neben der konservativen und interventionellen Wund- und Venentherapie, ist die Kompressionstherapie die Basis der Behandlungsstrategien. Die Kompressionstherapie kann heute mit sehr unterschiedlichen Materialien und Systemen durchgeführt werden. Während in der Entstauungsphase insbesondere Verbände mit Kurzzugbinden oder Mehrkomponentensysteme zur Anwendung kommen, sind es anschließend überwiegend Ulkus-Strumpfsysteme. Eine weitere, bislang wenig verbreitete Alternative sind adaptive Kompressionsbandagen. Insbesondere für die Rezidivprophylaxe werden medizinische Kompressionsstrümpfe empfohlen. Durch die Vielzahl der heute zur Verfügung stehenden Behandlungsoptionen, kann für nahezu alle Patienten ein Konzept entwickelt werden, dass sich an den individuellen Bedürfnissen und Fähigkeiten orientiert und daher auch akzeptiert und durchgeführt wird. Die Kompressionstherapie ist für die Behandlung von Patienten mit Ulcus cruris venosum essentiell. In den letzten Jahren sind viele verschiedene Therapieoptionen verfügbar, die in den deutschsprachigen Ländern unterschiedlich angewendet oder durchgeführt werden. Daher soll dieser Expertenkonsens dazu beitragen, konkrete Empfehlungen für die praktische Durchführung der Kompressionstherapie von Patienten mit Ulcus cruris venosum darzustellen. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  3. Nagelbefall kann bei Patienten mit Psoriasis auf eine Enthesiopathie hinweisen.

    PubMed

    Castellanos-González, Maria; Joven, Beatriz Esther; Sánchez, Julio; Andrés-Esteban, Eva María; Vanaclocha-Sebastián, Francisco; Romero, Pablo Ortiz; Díaz, Raquel Rivera

    2016-11-01

    Obwohl subklinische Enthesiopathie ein gut etabliertes diagnostisches Merkmal der Psoriasisarthritis (PsA) ist, wird sie häufig übersehen, da viele Patienten asymptomatisch sind. Gäbe es klinische Hinweise auf das Vorliegen einer Enthesiopathie, würde dies den Klinikern die Möglichkeit eröffnen, eine PsA frühzeitig zu diagnostizieren. Es wurde eine monozentrische prospektive Studie mit insgesamt 90 Psoriasis-Patienten durchgeführt, um mittels Ultraschall das Vorliegen von Enthesenanomalien zu untersuchen und eine Korrelation mit dem Befall der Nägel festzustellen. Enthesenanomalien wurden bei 23 Patienten (25,5 %) gefunden, von denen 19 (82,6 %) Nagelbefall aufwiesen. Bei 4 Patienten waren die Nägel nicht betroffen. Enthesiopathie lag bei 31,1 % (19/61) der Patienten mit Onychopathie vor, von den Patienten ohne Nagelbefall litten nur 13,8 % (4/29) an Enthesiopathie (p = 0,07). Zwischen dem Target-NAPSI-Score und dem Vorliegen einer Enthesiopathie bestand eine signifikante Korrelation. Eine signifikante Korrelation bestand darüber hinaus auch zwischen dem Vorliegen einer Enthesiopathie und der Anzahl der betroffenen Nägel (p = 0,035). Klinische Belege für eine Onychopathie können der Schlüssel für die frühe Diagnose einer Enthesiopathie bei Psoriasis-Patienten sein. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  4. Kompressionstherapie - Versorgungspraxis: Informationsstand von Patienten mit Ulcus cruris venosum.

    PubMed

    Protz, Kerstin; Heyer, Kristina; Dissemond, Joachim; Temme, Barbara; Münter, Karl-Christian; Verheyen-Cronau, Ida; Klose, Katharina; Hampel-Kalthoff, Carsten; Augustin, Matthias

    2016-12-01

    Eine Säule der kausalen Therapie bei Patienten mit Ulcus cruris venosum ist die Kompressionstherapie. Sie unterstützt die Abheilung, reduziert Schmerzen und Rezidive und steigert die Lebensqualität. Bislang existieren kaum wissenschaftliche Daten zu dem Versorgungsstand und fachspezifischem Wissen von Patienten mit Ulcus cruris venosum. Standardisierte Fragebögen wurden bundesweit in 55 Pflegediensten, 32 Arztpraxen, vier Wundzentren und -sprechstunden sowie einem Pflegetherapiestützpunkt von Patienten mit Ulcus cruris venosum bei Erstvorstellung anonym ausgefüllt. Insgesamt nahmen 177 Patienten (Durchschnittsalter 69,4 Jahre; 75,1 % Frauen) teil. Ein florides Ulcus cruris venosum bestand im Mittel 17 Monate. 31,1 % hatten keine Kompressionstherapie, 40,1 % Binden und 28,8 % Strümpfe. Bei der Bestrumpfung hatten 13,7 % Kompressionsklasse III, 64,7 % Kompressionsklasse II und 19,6 % Kompressionsklasse I. 70,6 % legten die Strümpfe nach dem Aufstehen an, 21,1 % trugen sie Tag und Nacht. 39,2 % bereiteten die Strümpfe Beschwerden. Lediglich 11,7 % hatten eine An- und Ausziehhilfe. Die Binden wurden im Mittel 40,7 Wochen getragen und bei 69 % nicht unterpolstert. Bei 2,8 % wurde der Knöchel- und Waden-Umfang zur Erfolgskontrolle gemessen. Venensport machten 45,9 %. Ein Drittel hatte keine Kompressionsversorgung, obwohl diese eine Basismaßnahme der Therapie des Ulcus cruris venosum ist. Zudem ist deren korrekte Auswahl und Anwendung angesichts der langen Bestandsdauer der Ulzerationen zu hinterfragen. Weiterführende Fachkenntnisse bei Anwendern und Verordnern sowie Patientenschulungen sind erforderlich. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  5. Prä- und perioperative Aspekte der Versorgung dermatochirurgischer Patienten.

    PubMed

    Müller, Cornelia S L; Hubner, Wakiko; Thieme-Ruffing, Sigrid; Pföhler, Claudia; Vogt, Thomas; Volk, Thomas; Gärtner, Barbara C; Bialas, Patric

    2017-02-01

    Die Dermatochirurgie nimmt hinsichtlich vieler Punkte eine Sonderstellung unter den operativen Fächern ein. Hierzu gehört in erster Linie die Tatsache, dass bis auf wenige Ausnahmen fast alle Eingriffe traditionell in Lokal- bzw. Regionalanästhesie und oft auch in räumlich-infrastruktureller Trennung von den großen Zentral-Operationssälen stattfinden können. Die peri- und postoperative Überwachung obliegt dabei dem dermatochirurgischen Operationsteam. Das sui generis kleinere OP-Team hat somit eine ganze Reihe perioperativer Notwendigkeiten zu beachten, um die sich in den "großen" chirurgischen Fächern eine Vielzahl verschiedener beteiligter Fachgruppen gemeinsam kümmern. Hierzu gehören neben Hygieneaspekten, Kenntnissen in der Überwachung der Patienten sowie dem Aspekt der surgical site infections auch Fragen zur postoperativen Schmerztherapie sowie detailliertes pharmakologisches Wissen über die zur Anwendung kommenden Lokalanästhetika und das Handling der damit assoziierten toxischen und allergischen Reaktionen. Eine interdisziplinäre Zusammenarbeit und Verantwortung für den Patienten ist notwendig und erfordert die Erarbeitung und Umsetzung qualitätsorientierter und evidenzbasierter Handlungsanweisungen, die im dermatochirurgischen OP-Setting meist weit über das eigentliche Fach hinausgehen. Ziel dieses Weiterbildungsartikels soll die komprimierte Darstellung der genannten fachübergreifenden Standpunkte bezüglich der wichtigsten perioperativen Aspekte sein. © 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

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

    DTIC Science & Technology

    1990-01-22

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

  7. Ustekinumab in der Therapie der Pustulosis palmoplantaris - Eine Fallserie mit neun Patienten.

    PubMed

    Buder, Valeska; Herberger, Katharina; Jacobi, Arnd; Augustin, Matthias; Radtke, Marc Alexander

    2016-11-01

    Die Pustulosis palmoplantaris ist eine chronisch entzündliche Hauterkrankung, die mit bedeutenden Einschränkungen der Lebensqualität und der Belastbarkeit einhergeht. Aufgrund von Zulassungsbeschränkungen und einem häufig therapierefraktären Verlauf sind die Behandlungsmöglichkeiten limitiert. Nach zuvor frustranen Therapien erhielten 9 Patienten mit Pustulosis palmoplantaris nach Ausschluss einer latenten Tuberkulose Ustekinumab (45 mg Ustekinumab bei < 100 kg Körpergewicht [KG], 90 mg Ustekinumab > 100 kg KG) in Woche 0, 4, 12 und 24. Reguläre Visiten erfolgten nach 4 und 12 Wochen, im weiteren Verlauf alle 12 Wochen. Das Durchschnittsalter bei Therapiebeginn betrug 48 Jahre. Drei Patienten waren männlich. Bei n  =  4 Patienten (44,4 %) wurde eine Verbesserung um 75 % des Palmoplantar-Psoriasis-Area-Severity-Index (PPPASI) erreicht. Insgesamt verbesserte sich der PPPASI nach 24 Wochen durchschnittlich um 71,6 %. Eine komplette Abheilung zeigte sich bei n  =  2 Patienten nach 24 Wochen. Bis auf lokale Injektionsreaktionen und leichte Infekte wurden keine unerwünschten Wirkungen beobachtet. Die Fallserie ist ein weiterer Beleg für die Wirksamkeit und Verträglichkeit von Ustekinumab in der Therapie der Pustulosis palmoplantaris. Zur Beurteilung der Langzeitwirkung und -sicherheit sowie der Wirksamkeit einer intermittierenden Therapie sind kontrollierte Studiendaten sowie Beobachtungen im Rahmen von Patientenregistern notwendig. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  8. [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. © 2016 S. Karger GmbH, Freiburg.

  9. 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...

  10. 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...

  11. Zeitlicher Verlauf der avaskulären Nekrose des Hüftkopfes bei Patienten mit Pemphigus vulgaris.

    PubMed

    Balighi, Kamran; Daneshpazhooh, Maryam; Aghazadeh, Nessa; Saeidi, Vahide; Shahpouri, Farzam; Hejazi, Pardis; Chams-Davatchi, Cheyda

    2016-10-01

    Pemphigus vulgaris (PV) wird in der Regel mit systemischen Corticosteroiden und Immunsuppressiva behandelt. Avaskuläre Nekrose (AVN) des Hüftkopfes ist eine gut bekannte schwerere Komplikation einer Corticosteroid-Therapie. Die Charakteristika dieser schweren Komplikation bei PV sind nach wie vor unbekannt. Nicht kontrollierte, retrospektive Untersuchung aller PV-bedingten AVN-Fälle, die in einer iranischen Klinik für bullöse Autoimmunerkrankungen zwischen 1985 und 2013 diagnostiziert wurden. Anhand der Krankenakten von 2321 untersuchten PV-Patienten wurden 45 Fälle (1,93 %) von femoraler AVN identifiziert. Dreißig davon waren Männer. Das mittlere Alter bei der Diagnose der AVN betrug 47,4 ± 14,2 Jahre. Der mittlere Zeitraum zwischen der Diagnose des PV und dem Einsetzen der AVN lag bei 25,3 ± 18,3 Monaten. Mit Ausnahme von acht Fällen (17,8 %) setzte die AVN bei der Mehrheit der Patienten innerhalb von drei Jahren nach Diagnose des PV ein. Die mittlere kumulative Dosis von Prednisolon bei Patienten mit AVN betrug 13.115,8 ± 7041,1 mg. Zwischen der Prednisolon-Gesamtdosis und dem Zeitraum bis zum Einsetzen der AVN bestand eine starke Korrelation (p = 0,001). Bei Patienten mit Alendronateinnahme in der Vorgeschichte war dieser Zeitraum signifikant kürzer (p = 0,01). Die AVN ist eine schwere Komplikation einer Corticosteroid-Behandlung bei Patienten mit PV. Sie wird bei 2 % der Patienten beobachtet und tritt vor allem in den ersten drei Behandlungsjahren auf. Bei Patienten, die höhere Dosen von Prednisolon erhalten, setzt die AVN tendenziell früher ein. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  12. Retrospektive Analyse von Zufallsbefunden, die bei Patienten mit kutanem malignen Malignom durch (18) F-Fluordeoxyglucose-PET/CT erhoben wurden.

    PubMed

    Conrad, Franziska; Winkens, Thomas; Kaatz, Martin; Goetze, Steven; Freesmeyer, Martin

    2016-08-01

    Bei der (18) F-Fluordeoxyglucose-Positronenemissionstomographie/Computertomographie (FDG-PET/CT) ergeben sich häufig Zufallsbefunde. In der vorliegenden Studie konzentrierten wir uns auf mittels FDG-PET/CT erhaltene Zufallsbefunde bei Patienten mit kutanem Melanom und überprüften deren Relevanz hinsichtlich weiterer diagnostischer Maßnahmen und Interventionen. Die Krankenakten von 181 konsekutiven Melanom-Patienten wurden retrospektiv ausgewertet, um das Management von Zufallsbefunden zu dokumentieren. Der Schwerpunkt lag dabei auf den histologischen Befunden. Bei 33 von 181 (18 %) Patienten lagen 39 relevante Zufallsbefunde vor, und zwar im Kolorektalbereich (n = 15 Patienten), in der Schilddrüse (n = 8), der Prostata (n = 2), dem Bewegungsapparat (n = 2), in Lymphknoten (n = 2), der Parotis (n = 1), den Mandeln (n = 1), den Nieren (n = 1) und der Gallenblase (n = 1). Bei 25 Patienten schlossen sich weitere diagnostische Verfahren an, wobei in 21 Fällen ein klinisches Korrelat nachgewiesen wurde. Bei 16 von 21 Patienten ergab sich eine Neoplasie, darunter fünf maligne Läsionen (vier Kolonkarzinome und ein Prostatakarzinom). Die Malignome wurden frühzeitig diagnostiziert und in der Mehrzahl der Fälle erfolgreich entfernt. Der Einsatz der FDG-PET/CT als Routine-Diagnostik wird in den Leitlinien empfohlen und ist indiziert bei malignem Melanom ab Stadium IIC. In dieser Studie wurden auf effektive Weise ansonsten nicht erkannte Krebserkrankungen, insbesondere Kolonkarzinome, detektiert. In den meisten Fällen war eine frühe Intervention möglich. Zufallsbefunde durch FDG-PET/CT sollten, unter Berücksichtigung des Zustands und der Wünsche des Patienten, mit den geeigneten diagnostischen Maßnahmen abgeklärt werden. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  13. [Cardiodoron® bei Patienten mit Schlafstörungen - Ergebnisse einer prospektiven Beobachtungsstudie].

    PubMed

    Rother, Claudia; Schnelle, Martin

    2017-01-01

    Hintergrund: Schlafstörungen gehören zu den häufigsten gesundheitlichen Problemen der heutigen Zeit. Stress und die dadurch bedingte innere Anspannung sowie eine unrhythmische Lebensführung z.B. durch Schichtarbeit sind bekannte auslösende Faktoren. Weniger bekannt ist, dass auch funktionelle Herz-Kreislauf-Beschwerden zu Störungen des Schlafs führen können und dass deren Behandlung zu einer Verbesserung der Schlafqualität beiträgt. Ganzheitlich betrachtet geht es daher um die Wiederherstellung einer gesunden Rhythmik, insbesondere des Herz-/Atem- sowie des Schlaf-Wach-Rhythmus, die Cardiodoron®, eine Heilpflanzenkomposition aus Primula veris, Hyoscyamus niger und Onopordum acanthium, unterstützt. Patienten und Methoden: Mittels einer prospektiven, multizentrischen Beobachtungsstudie sollte ermittelt werden, wie sich funktionelle Herz-Kreislauf-Beschwerden und/oder Schlafstörungen unter der Behandlung mit Cardiodoron® (Dilution) über 3-6 Monate entwickeln. Im Zeitraum von September 2009 bis März 2012 dokumentierten 92 Ärzte 501 Patienten, von denen 380 über Schlafstörungen klagten und deren Daten in dieser Publikation näher betrachtet werden. Nach einer Aufnahmeuntersuchung erfolgte nach 90 Tagen eine Abschlussuntersuchung und bei Fortführung der Therapie nach nochmals 90 Tagen eine Follow-up-Untersuchung. Neben 30 ärztlicherseits bewerteten Symptomen beurteilten die Patienten ihr Befinden mittels Pittsburgh Sleep Quality Index (PSQI) nach Buysse und der Beschwerden-Liste nach von Zerssen (B-L und B-L'). Ergebnisse: Unter der Cardiodoron®-Therapie gingen bei guter Verträglichkeit sowohl die Ausprägung der Schlafstörungen (um 65% von 2,0 auf 0,7 Punkte) als auch die erfassten 30 Symptome (um 59% von 24,3 auf 9,9 Punkte) deutlich zurück (p < 0,01). Weiterhin reduzierten sich der PSQI und der Gesamtwert der Beschwerden-Liste signifikant (p < 0,0001) um 60% bzw. 56% (von 12,2 auf 4,8 bzw. von 25,6 auf 11,4 Punkte). Schlussfolgerungen: Bei

  14. Der Einfluss von Alitretinoin auf die Lebensqualität bei Patienten mit schwerem chronischen Handekzem: FUGETTA - Beobachtungsstudie unter Praxisbedingungen.

    PubMed

    Augustin, Matthias; Thaçi, Diamant; Kamps, Anja

    2016-12-01

    Alitretinoin ist die einzige zugelassene Behandlung für schweres chronisches Handekzem (CHE), das refraktär gegenüber potenten topischen Corticosteroiden ist. Bei dieser Studie (FUGETTA) wurde die Wirksamkeit von leitliniengerecht angewendetem oralem Alitretinoin sowie dessen Einfluss auf die Lebensqualität (LQ) bei Patienten mit schwerem refraktärem CHE beurteilt. Multizentrische, offene, nichtinterventionelle Beobachtungsstudie, durchgeführt in Deutschland. Die Patienten wurden nach Ermessen ihres behandelnden Arztes mit Alitretinoin 10 mg oder 30 mg einmal täglich über maximal 24 Wochen behandelt. Die Wirksamkeit wurde anhand des Physician Global Assessment (PGA) und des Dermatology Life Quality Index (DLQI) bewertet. Zudem wurden unerwünschte Ereignisse (UE) erfasst. Die Studienpopulation bestand aus 658 Patienten (30 mg: n = 581; 10 mg: n = 77). Bei Beobachtungsbeginn litten die meisten Patienten (83 %) gemäß PGA an einem schweren CHE. Bei Beobachtungsende war das Handekzem bei 48 % der Patienten gemäß PGA vollständig oder fast vollständig abgeheilt (30 mg: 49 %; 10 mg: 43 %). Die mittlere Verbesserung des DLQI-Scores in Woche 24 betrug 58 % (30 mg: mittlere [SD] Veränderung gegenüber dem Ausgangswert -10,4 [8,04]) und 70 % (10 mg: mittlere [SD] Veränderung gegenüber dem Ausgangswert -10,8 [7,29]). Die Gesamtinzidenz von NW war niedrig und in den beiden Gruppen ähnlich. Alitretinoin führte zu einer schnellen, deutlichen Verbesserung der LQ bei Patienten mit schwerem CHE. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  15. Gebrauch von Komplementärmedizin bei Patienten mit metastasierendem Melanom unter Therapie mit Ipilimumab innerhalb einer klinischen Studie.

    PubMed

    Huebner, Jutta; Mohr, Peter; Simon, Jan-Christoph; Fluck, Michael; Berking, Carola; Zimmer, Lisa; Loquai, Carmen

    2016-05-01

    In Deutschland wenden 40-90 % aller Krebspatienten Methoden der komplementären and alternativen Medizin (KAM) an. Bis dato gibt es kein Datenmaterial zum Einsatz der KAM bei Melanompatienten. Das Ziel unserer Studie war es, Daten über den Gebrauch, die Informationsquellen und Ziele von Patienten mit metastasierendem Melanom zu erfassen. Einhundertsechsundfünfzig Patienten aus 25 Studienzentren nahmen an der DecOG-MM-PAL Multibasket Studie teil. Die beteiligten Personen wurden auch gebeten, an einer Nebenstudie teilzunehmen, die ihren Gebrauch von KAM erfassen sollte. Dazu wurde während der Behandlung ein standardisierter Fragebogen zu genau festgelegten Zeitpunkten ausgeteilt. Insgesamt gingen 55 Fragebögen von 32 (21 %) Melanompatienten ein. Von diesen gaben 17 (53 %) ein Interesse an KAM an, und sieben (22 %) machten von KAM Gebrauch. Die Hauptinformationsquellen (31 %) waren Familienmitglieder und Freunde, gefolgt von Ärzten (19 %). Die Hauptgründe für die Anwendung von KAM waren die Stärkung des Immunsystems (41 %) und des Körpers (34 %). Nahrungsergänzungsmittel (Vitamine und Spurenelemente) wurden am häufigsten angewendet (28 %). Eine relativ hohe Anzahl an Patienten mit metastasierendem Melanom machte trotz Teilnahme an einer klinischen Studie von KAM Gebrauch. Wechselwirkungen könnten durch biologisch basierte KAM auftreten, und hier besonders bei immunmodulierenden KAM- Strategien. Um Risiken zu vermeiden, sollte die Kommunikation zwischen den Ärzten und den Patienten verbessert werden. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  16. 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

  17. Characterizing the roles of Met31 and Met32 in coordinating Met4-activated transcription in the absence of Met30

    PubMed Central

    Carrillo, Emilio; Ben-Ari, Giora; Wildenhain, Jan; Tyers, Mike; Grammentz, Dilon; Lee, Traci A.

    2012-01-01

    Yeast sulfur metabolism is transcriptionally regulated by the activator Met4. Met4 lacks DNA-binding ability and relies on interactions with Met31 and Met32, paralogous proteins that bind the same cis-regulatory element, to activate its targets. Although Met31 and Met32 are redundant for growth in the absence of methionine, studies indicate that Met32 has a prominent role over Met31 when Met30, a negative regulator of Met4 and Met32, is inactive. To characterize different roles of Met31 and Met32 in coordinating Met4-activated transcription, we examined transcription in strains lacking either Met31 or Met32 upon Met4 induction in the absence of Met30. Microarray analysis revealed that transcripts involved in sulfate assimilation and sulfonate metabolism were dramatically decreased in met32Δ cells compared to its wild-type and met31Δ counterparts. Despite this difference, both met31Δ and met32Δ cells used inorganic sulfur compounds and sulfonates as sole sulfur sources in minimal media when Met30 was present. This discrepancy may be explained by differential binding of Met31 to Cbf1-dependent promoters between these two conditions. In the absence of Met30, genome-wide chromatin immunoprecipitation analyses found that Met32 bound all Met4-bound targets, supporting Met32 as the main platform for Met4 recruitment. Finally, Met31 and Met32 levels were differentially regulated, with Met32 levels mimicking the profile for active Met4. These different properties of Met32 likely contribute to its prominent role in Met4-activated transcription when Met30 is absent. PMID:22438580

  18. ASI/MET - 3-D

    NASA Image and Video Library

    1997-07-13

    The Atmospheric Structure Instrument/Meteorology Package ASI/MET is the mast and windsocks at the center of this stereo image from NASA Mars Pathfinder. 3D glasses are necessary to identify surface detail.

  19. 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.

  20. MET — EDRN Public Portal

    Cancer.gov

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

  1. Wirksamkeit und Sicherheit von Fumarsäureestern in Kombination mit Phototherapie bei Patienten mit moderater bis schwerer Plaque-Psoriasis (FAST).

    PubMed

    Weisenseel, Peter; Reich, Kristian; Griemberg, Wiebke; Merten, Katharina; Gröschel, Christine; Gomez, Natalie Nunez; Taipale, Kirsi; Bräu, Beate; Zschocke, Ina

    2017-02-01

    Die Behandlung von Psoriasis-Patienten mit einer Kombination aus Fumarsäureestern (FSE, Fumaderm(®) ) und Phototherapie (UV) ist verbreitet, wurde aber im Rahmen von Studien wenig untersucht. Bisher liegen lediglich Daten aus einer kleinen Pilotstudie vor. Intention dieser Studie war, eine FSE/UV-Kombinationsbehandlung an einem größeren Patientenkollektiv mit mittelschwerer bis schwerer Psoriasis zu untersuchen. In dieser prospektiven, multizentrischen, nichtinterventionellen Studie wurden Daten von Patienten mit FSE/UV-Kombinationstherapie hinsichtlich der Wirksamkeit (PGA' PASI, DLQI, EQ-5D), Sicherheit und Dosierung über einen Zeitraum von zwölf Monaten erfasst und mit Daten einer retrospektiven Studie mit FSE-Monotherapie verglichen. Es wurden Daten von 363 Patienten ausgewertet. Unter der Kombinationstherapie verbesserten sich alle Wirksamkeitsparameter deutlich. Im Vergleich zur Monotherapie mit FSE konnte durch die Kombination mit UV ein schnellerer Wirkeintritt erzielt werden, wobei nach zwölf Monaten kein Unterschied in der Wirksamkeit bestand. Die Dauer und Art der Phototherapie zeigte keinen Einfluss auf die Wirksamkeitsparameter. Allgemein wurde die Kombinationstherapie gut vertragen. Unerwünschte Ereignisse wurden bei 7 % der Patienten berichtet. Die FSE/UV Kombinationstherapie zeigt eine gute Wirksamkeit und Verträglichkeit und kann zu einem schnelleren Wirkeintritt führen. Eine Kombinationstherapie erscheint vor allem in den ersten drei Monaten der FSE Behandlung sinnvoll. © 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  2. Ionospheric Profiling using GPS/MET Data

    NASA Technical Reports Server (NTRS)

    Hajj, George; Romans, Larry

    1996-01-01

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

  3. Krankheitsverlauf, medizinische Versorgung und Lebensqualität von Patienten mit kongenitalen melanozytären Nävi - Auswertung des deutschsprachigen KMN-Registers.

    PubMed

    Elisabeth Wramp, Maria; Langenbruch, Anna; Augustin, Matthias; Zillikens, Detlef; Krengel, Sven

    2017-02-01

    Kongenitale melanozytäre Nävi (KMN) bedeuten für Patienten und Familien eine psychologische Belastung und bergen zudem medizinische Risiken. Das 2005 gegründete deutschsprachige KMN-Register wurde nun einer Zwischenauswertung bezüglich des Krankheitsverlaufes, der medizinischen Versorgung und der Lebensqualität unterzogen. 100 Patienten, die sich in den Jahren 2005 bis 2012 mit einem Erstmeldebogen registriert hatten, wurde im Rahmen einer prospektiven Kohortenstudie Anfang 2013 ein Folgemeldebogen zugesandt. Außerdem wurden mithilfe standardisierter Fragebögen Daten zu Lebensqualität (dermatology life quality index, DLQI) und Stigmatisierungserfahrungen (perceived stigmatization questionnaire, PSQ; social comfort questionnaire, SCQ) erhoben. 83 % der Patienten oder deren Eltern antworteten (Altersdurchschnitt 11,2 Jahre, Median 6 Jahre; mittleres Follow-up 4,4 Jahre). Im Gesamtkollektiv wurden vier Melanome diagnostiziert, davon zwei zerebrale Melanome im Kindesalter, ein kutanes Melanom im Erwachsenenalter und eines, das sich als proliferierender Knoten erwies. Bei vier Kindern wurde eine neurokutane Melanozytose festgestellt, drei davon mit neurologischer Symptomatik. Chirurgisch behandelt wurden 88 % (73/83). Achtundsiebzig Prozent der Befragten berichteten eine geringe oder keine Beeinträchtigung der Lebensqualität. Die wahrgenommene Stigmatisierung beziehungsweise Beeinträchtigung des sozialen Wohlbefindens war generell ebenfalls gering. Die Ergebnisse geben einen Überblick über die Situation von Patienten mit KMN in Deutschland, Österreich und der Schweiz. Ein Melanom entwickelte sich in 3 %, eine ZNS-Beteiligung bestand in 4 % der Fälle. © 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  4. Reactions of Met-Cars

    SciTech Connect

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

    1993-12-31

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

  5. Transcriptional start and MetR binding sites on the Escherichia coli metH gene.

    PubMed

    Marconi, R; Wigboldus, J; Weissbach, H; Brot, N

    1991-03-29

    The 5' upstream region of the Escherichia coli metH gene has been sequenced. Primer extension analysis revealed a transcription start site at 324 bases upstream of the initiator codon. An 8 base sequence homologous to the MetR binding region on the E. coli metE gene is present 217 bp downstream of the transcription start site. Gel retardation experiments showed that purified MetR protein could bind to a 30 base oligonucleotide containing the putative MetR binding region. No "met box" was present which explains the relative lack of regulation of the expression of the metH gene by methionine.

  6. 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...

  7. NARSTO EPA SS BALTIMORE JHU MET DATA

    Atmospheric Science Data Center

    2014-04-25

    NARSTO EPA SS BALTIMORE JHU MET DATA Project Title:  NARSTO ... Pyranometer Barometer Location:  Baltimore, Maryland Spatial Resolution:  Point Measurements ...   Order Data Guide Documents:  Baltimore JHU Met Guide Baltimore Project Plan  (PDF) ...

  8. 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

  9. Prevalence, components, and correlates of metabolic syndrome (MetS) among elderly Muscovites.

    PubMed

    Metelskaya, Victoria A; Shkolnikova, Maria A; Shalnova, Svetlana A; Andreev, Evgeny M; Deev, Alexander D; Jdanov, Dmitri A; Shkolnikov, Vladimir M; Vaupel, James W

    2012-01-01

    The goal of this study is to estimate the prevalence of MetS, together with its components and correlates, among elderly Russians. Our population-based sample included randomly selected residents of Moscow aged 55 and older: 955 women with an average age of 67.6, and 833 men with an average age of 68.9. MetS was defined according to National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII). The prevalence of MetS was found to be 41.7% in women and 26.8% in men. It tended to decrease with age in men, but not in women. MetS was inversely related to education in women, but not in men. The most prevalent individual components of MetS were as follows: hypertension (64.4%), abdominal obesity (55%), and decreased high density lipoprotein cholesterol (HDL C) (46%) for women; and hypertension (71%) and fasting hyperglycemia (35.2%) for men. An elevated level of triglycerides (TG) was the rarest MetS component, affecting 23.5% of women and 22.1% of men. The higher female prevalence of MetS was attributable to abdominal obesity. MetS was found to be associated with markers of insulin resistance (IR), low-grade inflammation, and insufficient fibrinolysis. Although the metabolic burden is an important contributor to high levels of ill-health and cardiovascular mortality among elderly Russians (especially women), it does not explain why cardiovascular mortality is much higher in Russia than in other industrialized countries.

  10. Arabidopsis MET1 cytosine methyltransferase mutants.

    PubMed Central

    Kankel, Mark W; Ramsey, Douglas E; Stokes, Trevor L; Flowers, Susan K; Haag, Jeremy R; Jeddeloh, Jeffrey A; Riddle, Nicole C; Verbsky, Michelle L; Richards, Eric J

    2003-01-01

    We describe the isolation and characterization of two missense mutations in the cytosine-DNA-methyltransferase gene, MET1, from the flowering plant Arabidopsis thaliana. Both missense mutations, which affect the catalytic domain of the protein, led to a global reduction of cytosine methylation throughout the genome. Surprisingly, the met1-2 allele, with the weaker DNA hypomethylation phenotype, alters a well-conserved residue in methyltransferase signature motif I. The stronger met1-1 allele caused late flowering and a heterochronic delay in the juvenile-to-adult rosette leaf transition. The distribution of late-flowering phenotypes in a mapping population segregating met1-1 indicates that the flowering-time phenotype is caused by the accumulation of inherited defects at loci unlinked to the met1 mutation. The delay in flowering time is due in part to the formation and inheritance of hypomethylated fwa epialleles, but inherited defects at other loci are likely to contribute as well. Centromeric repeat arrays hypomethylated in met1-1 mutants are partially remethylated when introduced into a wild-type background, in contrast to genomic sequences hypomethylated in ddm1 mutants. ddm1 met1 double mutants were constructed to further our understanding of the mechanism of DDM1 action and the interaction between two major genetic loci affecting global cytosine methylation levels in Arabidopsis. PMID:12663548

  11. Mars MetNet Mission Payload Overview

    NASA Astrophysics Data System (ADS)

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

    2012-09-01

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

  12. 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

  13. Mars MetNet Precursor Mission Status

    NASA Astrophysics Data System (ADS)

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

    2013-09-01

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

  14. 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.

  15. MMPM - Mars MetNet Precursor Mission

    NASA Astrophysics Data System (ADS)

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

    2008-09-01

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

  16. MetNet - Martian Network Mission

    NASA Astrophysics Data System (ADS)

    Harri, A.-M.

    2009-04-01

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

  17. 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

  18. 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

  19. Everolimus induces Met inactivation by disrupting the FKBP12/Met complex

    PubMed Central

    Raimondo, Lucia; D'Amato, Valentina; Servetto, Alberto; Rosa, Roberta; Marciano, Roberta; Formisano, Luigi; Mauro, Concetta Di; Orsini, Roberta Clara; Cascetta, Priscilla; Ciciola, Paola; De Maio, Ana Paula; Di Renzo, Maria Flavia; Cosconati, Sandro; Bruno, Agostino; Randazzo, Antonio; Napolitano, Filomena; Montuori, Nunzia; Veneziani, Bianca Maria; Placido, Sabino De; Bianco, Roberto

    2016-01-01

    Inhibition of the mechanistic target of rapamycin (mTOR) is a promising treatment strategy for several cancer types. Rapamycin derivatives such as everolimus are allosteric mTOR inhibitors acting through interaction with the intracellular immunophilin FKBP12, a prolyl isomerase with different cellular functions. Although mTOR inhibitors have significantly improved survival of different cancer patients, resistance and lack of predictive factors of response remain unsolved issues. To elucidate the mechanisms of resistance to everolimus, we evaluated Met activation in everolimus-sensitive/resistant human cancer cells, in vitro and in vivo. Biochemical and computational analyses were performed. Everolimus-resistant cells were xenografted into mice (10/group) and studied for their response to everolimus and Met inhibitors. The statistical significance of the in vitro results was evaluated by Student's t test. Everolimus reduced Met phosphorylation in everolimus-sensitive cells. This event was mediated by the formation of a Met-FKBP12 complex, which in turn is disrupted by everolimus. Aberrant Met activation in everolimus-resistant cells and overexpression of wild-type/mutant Met caused everolimus resistance. Pharmacological inhibition and RNA silencing of Met are effective in condition of everolimus resistance (P<0.01). In mice xenografted with everolimus-resistant cells, the combination of everolimus with the Met inhibitor PHA665752 reduced tumor growth and induced a statistically significant survival advantage (combination vs control P=0.0005). FKBP12 binding is required for full Met activation and everolimus can inhibit Met. Persistent Met activation might sustain everolimus resistance. These results identify a novel everolimus mechanism of action and suggest the development of clinical strategies based on Met inhibitors in everolimus-resistant cancers. PMID:27223077

  20. Methionine synthesis in Escherichia coli: effect of the MetR protein on metE and metH expression.

    PubMed

    Cai, X Y; Maxon, M E; Redfield, B; Glass, R; Brot, N; Weissbach, H

    1989-06-01

    Studies by Urbanowski et al. [Urbanowski, M. L., Stauffer, L. T., Plamann, L. S. & Stauffer, G. V. (1987) J. Bacteriol. 169, 1391-1397] have identified a regulatory locus, called metR, required for the expression of the metE and metH genes. We recently purified the MetR protein from Escherichia coli and showed that it could stimulate the in vitro expression of the metE gene and autoregulate its own synthesis. In the present study, the purified MetR protein has been shown to stimulate the in vitro expression of the metH gene. Also, the in vitro synthesized MetE, MetH, and MetR proteins were shown to be biologically active. The transcription start sites for the metE and metR genes have been determined, and DNA footprinting experiments have identified regions in the metE-metR intergenic sequence that are protected by either the MetR or MetJ proteins.

  1. Prototype of the Modular Equipment Transporter (MET)

    NASA Image and Video Library

    1970-02-13

    S70-29505 (13-18 Feb. 1970) --- A prototype of the modular equipment transporter (MET), nicknamed the "Rickshaw" after its shape and method of propulsion. This equipment was used by the Apollo 14 astronauts during their geological and lunar surface simulation training in the Pinacate volcanic area of northwestern Sonora, Mexico. The Apollo 14 crew will be the first one to use the MET. It will be a portable workbench with a place for the lunar hand tools and their carrier, three cameras, two sample container bags, a special environmental sample container, spare film magazines, and a lunar surface Penetrometer.

  2. Functional AdoMet Isosteres Resistant to Classical AdoMet Degradation Pathways.

    PubMed

    Huber, Tyler D; Wang, Fengbin; Singh, Shanteri; Johnson, Brooke R; Zhang, Jianjun; Sunkara, Manjula; Van Lanen, Steven G; Morris, Andrew J; Phillips, George N; Thorson, Jon S

    2016-09-16

    S-adenosyl-l-methionine (AdoMet) is an essential enzyme cosubstrate in fundamental biology with an expanding range of biocatalytic and therapeutic applications. We report the design, synthesis, and evaluation of stable, functional AdoMet isosteres that are resistant to the primary contributors to AdoMet degradation (depurination, intramolecular cyclization, and sulfonium epimerization). Corresponding biochemical and structural studies demonstrate the AdoMet surrogates to serve as competent enzyme cosubstrates and to bind a prototypical class I model methyltransferase (DnrK) in a manner nearly identical to AdoMet. Given this conservation in function and molecular recognition, the isosteres presented are anticipated to serve as useful surrogates in other AdoMet-dependent processes and may also be resistant to, and/or potentially even inhibit, other therapeutically relevant AdoMet-dependent metabolic transformations (such as the validated drug target AdoMet decarboxylase). This work also highlights the ability of the prototypical class I model methyltransferase DnrK to accept non-native surrogate acceptors as an enabling feature of a new high-throughput methyltransferase assay.

  3. MET Senior Projects at an Urban University.

    ERIC Educational Resources Information Center

    Neff, Gregory; And Others

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

  4. 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.

  5. Angular MET sensor for precise azimuth determination

    NASA Astrophysics Data System (ADS)

    Zaitsev, Dmitry; Antonov, Alexander; Krishtop, Vladimir

    2016-12-01

    This paper describes using a MET-based low-noise angular motion sensor to precisely determine azimuth direction in a dynamic-scheme method of measuring Earth's rotation velocity vector. The scheme includes installing a sensor on a rotating platform so that it could scan a space and seek for the position of highest Earth's rotation vector projection on its axis. This method is very efficient provided a low-noise sensor is used. We take a low-cost angular sensor based on MET (molecular electronic transduction) technology. Sensors of this kind were originally developed for the seismic activity monitoring and are well-known for very good noise performance and high sensitivity. This approach, combined with use of special signal processing algorithms, allowed for reaching the accuracy of 0.07° for a measurement time of 200 seconds.

  6. nMET, A New Target in Recurrent Cancer.

    PubMed

    Xie, Yingqiu; Istayeva, Sholpan; Chen, Zhanlin; Tokay, Tursonjan; Zhumadilov, Zhaxybay; Wu, Denglong; Hortelano, Gonzalo; Zhang, Jinfu

    2016-01-01

    Membranous Met is classically identified with its role in cancer metastases, while nuclear Met is associated with a more invasive, aggressive and proliferative form of cancer. Full-length Met or N-terminal transmembrane domain cleaved Met can translocate into nucleus in a cell growth and pH dependent but both ligand-dependent (full length Met) and -independent (cleaved Met) manner. nMET may play greater essential roles in cancer recurrence than membranous Met. For example, in prostate cancer, it has been found that androgen receptor (AR) may inhibit the expression of membranous Met so anti-androgen based prostate cancer therapy may promote the expression of nuclear Met (nMET). We recently found a novel nMET/SOX9/ β-Catenin/AR pathway in relapsed prostate cancer which may contribute to the formation of the feedback loop of AR reactivation via MET/nMET. Emerging evidence suggests the possibility of nMET as a prognostic marker in relapsed cancer. This review summarizes recent findings about nMET and its unique role in recurrent cancer.

  7. Could the organ shortage ever be met?

    PubMed

    Levitt, Mairi

    2015-01-01

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

  8. Smart Polymeric Nanocarriers of Met-enkephalin.

    PubMed

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

    2016-08-08

    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.

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

    PubMed

    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.

  10. 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

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

    SciTech Connect

    Ritsche, M. T.; Environmental Science Division

    2006-04-01

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

  12. Performance Measures: Search Performance for Different Fields-of Regard (prestatiemeting se: zoekprstatie bij geinstrumenteerd zien)

    DTIC Science & Technology

    2006-07-01

    FOV) grootte, resolutie, en opvallendheid van het doel. Proefpersonen moesten in een experiment zoeken naar doelen in geprojecteerde digitale foto’s. De...Zoekplaten De zoekplaten bestonden uit geprojecteerde digitale foto’s van landschappen en stadssc~nes met daarin een doel (zie figuur 2, 3 & 4). Dit...De resolutie Het beeldmateriaal werd opgenomen met een digitale camera van het type Sony DSC- P 12. De resolutie van de oorspron~ketijke beelden was

  13. 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.

  14. 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.

  15. Targeting of the MET receptor tyrosine kinase by small molecule inhibitors leads to MET accumulation by impairing the receptor downregulation.

    PubMed

    Leiser, Dominic; Pochon, Benoît; Blank-Liss, Wieslawa; Francica, Paola; Glück, Astrid A; Aebersold, Daniel M; Zimmer, Yitzhak; Medová, Michaela

    2014-03-03

    The MET receptor tyrosine kinase is deregulated primarily via overexpression or point mutations in various human cancers and different strategies for MET inhibition are currently evaluated in clinical trials. We observed by Western blot analysis and by Flow cytometry that MET inhibition by different MET small molecule inhibitors surprisingly increases in a dose-dependent manner total MET levels in treated cells. Mechanistically, this inhibition-related MET accumulation was associated with reduced Tyr1003 phosphorylation and MET physical association with the CBL ubiquitin ligase with concomitant decrease in MET ubiquitination. These data may suggest careful consideration for design of anti-MET clinical protocols. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  16. The control region of the metH gene of Salmonella typhimurium LT2: an atypical met promoter.

    PubMed

    Urbanowski, M L; Stauffer, G V

    1988-12-15

    The control region of the Salmonella typhimurium metH gene was sequenced and the transcription start point was determined by S1 nuclease mapping experiments. Activation of the metH gene by the metR gene product was shown to occur at the level of transcription. The translation start site was determined by amino acid sequence analysis of the amino terminus of a chimeric Met-Lac fusion protein encoded by a metH-lacZ gene fusion. Analysis of the nucleotide sequence of the metH promoter region showed that two sequence elements, present in the promoters of all other met biosynthetic genes thus far examined, are not present in the metH promoter region, namely, the repeated MetJ repressor recognition sequence 5'-AGACGTCT-3' and a highly conserved sequence 5'-TGGA----TAAAC-3' of unknown function.

  17. c-Met in chromophobe renal cell carcinoma.

    PubMed

    Erlmeier, Franziska; Ivanyi, Philipp; Hartmann, Arndt; Autenrieth, Michael; Wiedemann, Max; Weichert, Wilko; Steffens, Sandra

    2017-02-01

    c-Met plays a role as a prognostic marker in clear cell renal cell carcinoma. In addition, recently the tyrosine kinase inhibitor cabozantinib targeting c-Met was approved for the treatment of advanced renal cell carcinoma (RCC). In contrast to clear cell RCC, little is known about c-Met expression patterns in rarer RCC subtypes. The aim of this study was to evaluate the prevalence, distribution and prognostic impact of c-Met expression on chromophobe (ch)RCC. Patients who underwent renal surgery due to chRCC were retrospectively evaluated. Tumor specimens were analyzed for c-Met expression by immunohistochemistry. Expression data were associated with clinicopathological parameters including patient survival. Eighty-one chRCC patients were eligible for analysis. Twenty-four (29.6%) patients showed a high c-Met expression (c-Met(high), staining intensity higher than median). Our results showed an association between c-Met(high) expression and the existence of lymph node metastasis (p = 0.007). No further significant clinicopathological associations with c-Met were identified, also regarding c-Met expression and overall survival. In conclusion, to our knowledge this is the first study evaluating the prognostic impact of c-Met in a considerably large cohort of chRCC. High c-Met expression is associated with the occurrence of lymph node metastasis. This indicates that c-Met might be implicated into metastatic progression in chRCC.

  18. The Mars Pathfinder ASI/MET Investigation

    NASA Astrophysics Data System (ADS)

    Schofield, J.; Crisp, D.; Labaw, C.; Mahoney, C.; Seiff, A.; Murphy, J.; Mihalov, J.; Wilson, G.; Haberle, R.; Tillman, J.; Barnes, J.

    1996-09-01

    On July 4th 1997, the Mars Pathfinder spacecraft will enter the martian atmosphere, land in the Ares Vallis region, and obtain the first in-situ measurements of the atmosphere and surface since the Viking mission more than 20 years ago. In addition to a Stereo Imager and an Alpha Proton X-Ray spectrometer, the Pathfinder Lander will carry an Atmospheric Structure and Meteorology (ASI/MET) experiment designed to study the atmosphere during the entry, descent, and landed phases of the mission. The ASI/MET package consists of 3 accelerometers, 4 thermocouple temperature sensors, a Tavis pressure sensor, and a 6-sector hot-wire wind sensor. The sensitivity limits of these instruments are respectively 2 micro g, 0.01 K, 0.25 micro bars, and 0.04 K. Measurements of deceleration in 3-orthogonal axes during entry will be used to determine a density, pressure, temperature profile for the upper atmosphere from 15-150 km, and direct measurements of temperature and pressure in the lower atmosphere will be made as the lander descends on its parachute. After landing, surface pressure measurements will continue and a meteorological mast will deploy. From this mast, atmospheric temperature will be measured 0.25, 0.5, & 1.0 m above the surface, and wind speed and direction will be determined at 1.1 m. Landed data will be acquired continuously for 1 year. Pathfinder is expected to make a significant contribution to Mars atmospheric science. It will provide a third in-situ atmospheric profile at a different season and local time to the earlier Viking profiles, and its surface observations will generate a climate record at the landing site with an order of magnitude better resolution than Viking. Because measurements will be made at different altitudes, they will also allow superior characterization of the martian surface boundary layer.

  19. Gastrointestinal malignancies harbor actionable MET exon 14 deletions

    PubMed Central

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

    2015-01-01

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

  20. [MET receptor inhibition: Hope against resistance to targeted therapies?

    PubMed

    Hochart, Audrey; Leblond, Pierre; Le Bourhis, Xuefen; Meignan, Samuel; Tulasne, David

    2017-02-01

    Overcoming the drug resistance remains a crucial issue in cancer treatment. For refractory patients, the use of MET receptor tyrosine kinase inhibitors seems to be hopeful. Indeed, important mechanisms underlying drug resistance argue for association of MET inhibitors with targeted therapies, both on first-line to prevent a primary resistance and on the second line to overcoming acquired resistance. Indeed, met gene amplification is the second most common alteration involved in acquired resistance to anti-epidermal growth factor receptor (EGFR) therapies in non-small cells lung cancer (NSCLC). Hypoxia, for its part, can activate MET transcription and amplifies HGF signaling resulting in MET activation, which could be involved in vascular endothelial growth factor (VEGF) inhibitors escape. In HER2 positive breast cancers, MET amplification may also induce tumor cells a hatch escape, resulting in secondary resistance. Finally, some patients with BRAF mutated melanoma exhibit primary resistance to BRAF inhibition by stromal HGF (ligand of MET) secretion resulting in MET receptor activation. Experimental data highlight the role of MET in primary and secondary resistance and encourage combined treatments including MET inhibitors. In this context, several promising clinical trials are in progress in numerous cancers (NSCLC, melanoma, breast cancer, glioblastoma…) using combination of anti-MET and other specific therapies targeting EGFR, BRAF, VEGF or HER2. This review summarizes the potential benefits that MET inhibition should provide to patients with cancer refractory to targeted therapies.

  1. 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.

  2. MET: roles in epithelial-mesenchymal transition and cancer stemness

    PubMed Central

    Jeon, Hye-Min

    2017-01-01

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

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

    PubMed

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

    2015-12-01

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

  4. 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. Copyright 2001 John Wiley & Sons, Ltd.

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

    PubMed

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

    2015-08-15

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

  6. 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.

  7. 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.

  8. Responsie van Verschillende Munitieartikelen bij Opwarming en Brand (Response of Munitions Items Due to Heating or a Fire)

    DTIC Science & Technology

    2007-09-01

    werkzaamheden thermische responsie van artikelen. (met KS32) valt binnen deze normen net als Het project is gestart met bet ontwikkelen De kritische temperatuur...RDX, HMX of TNT en bindersystemnen als HTPB. Ook bijvoorbeeld de moderne 155 munitie van Rheinmetall (met KS32) valt binnen deze normen , net als

  9. 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

  10. Training with Simulated Team Members (Trainen met Gesimuleerde Teamieden).

    DTIC Science & Technology

    2007-11-02

    can only be integrated when team members are training together. And this improves the transfer of knowledge and skills. Practising with simulated team...And this improves the transfer of knowledge and skills. Practising with simulated team members offers the advantages of training apart and training...respectievelijke taken perfect uitvoeren. In dat geval is trainen met gesimuleerde teamleden vergelijkbaar met trainen met ervaren teamleden (vgl

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

    PubMed Central

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

    2017-01-01

    MET tyrosine kinase (TK) dysregulation is significantly implicated in many types of cancer. Despite over 20 years of drug development to target MET in cancers, a pure anti-MET therapeutic has not yet received market approval. The failure of two recently concluded phase III trials point to a major weakness in biomarker strategies to identify patients who will benefit most from MET therapies. The capability to interrogate oncogenic mutations in MET via circulating tumor DNA (ctDNA) provides an important advancement in identification and stratification of patients for MET therapy. However, a wide range in type and frequency of these mutations suggest there is a need to carefully link these mutations to MET dysregulation, at least in proof-of-concept studies. In this review, we elaborate how we can utilize recently developed and validated pharmacodynamic biomarkers of MET not only to show target engagement, but more importantly to quantitatively measure MET dysregulation in tumor tissues. The MET assay endpoints provide evidence of both canonical and non-canonical MET signaling, can be used as “effect markers” to define biologically effective doses (BEDs) for molecularly targeted drugs, confirm mechanism-of-action in testing combination of drugs, and establish whether a diagnostic test is reporting MET dysregulation. We have established standard operating procedures for tumor biopsy collections to control pre-analytical variables that have produced valid results in proof-of-concept studies. The reagents and procedures are made available to the research community for potential implementation on multiple platforms such as ELISA, quantitative immunofluorescence assay (qIFA), and immuno-MRM assays. PMID:28164088

  12. HGF-MET in cancer progression and biomarker discovery.

    PubMed

    Matsumoto, Kunio; Umitsu, Masataka; De Silva, Dinuka M; Roy, Arpita; Bottaro, Donald P

    2017-01-08

    Signaling driven by hepatocyte growth factor (HGF) and MET receptor facilitates conspicuous biological responses such as epithelial cell migration, 3-D morphogenesis, and survival. The dynamic migration and promotion of cell survival induced by MET activation are bases respectively for invasion-metastasis and resistance against targeted drugs in cancers. Recent studies indicated that MET in tumor-derived exosomes facilitates metastatic niche formation and metastasis in malignant melanoma. In lung cancer, gene amplification-induced MET activation and ligand-dependent MET activation in autocrine/paracrine manner are causes for resistance to EGF receptor tyrosine kinase inhibitors and ALK inhibitors. HGF secreted in the tumor microenvironment contributes to the innate and acquired resistance to RAF inhibitors. Changes in serum/plasma HGF, soluble MET, and phosphor-MET have been confirmed to be associated with disease progression, metastasis, therapy response, and survival. Higher serum/plasma HGF levels are associated with therapy resistance and/or metastasis, while lower HGF levels are associated with progression-free survival and overall survival after treatment with targeted drugs in lung cancer, gastric cancer, colon cancer, and malignant melanoma. Urinary soluble MET levels in patients with bladder cancer are higher than those in patients without bladder cancer and associated with disease progression. Some of the multi-kinase inhibitors that target MET have received regulatory approval, whereas none of the selective HGF-MET inhibitors have shown efficacy in phase III clinical trials. Validation of the HGF-MET pathway as a critical driver in cancer development/progression and utilization of appropriate biomarkers are key to development and approval of HGF-MET inhibitors for clinical use. This article is protected by copyright. All rights reserved.

  13. Mars MetNet Mission Pressure and Humidity Devices

    NASA Astrophysics Data System (ADS)

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

    2012-09-01

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

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

    PubMed Central

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

    2015-01-01

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

  15. Reversal of c-MET-mediated Resistance to Cytotoxic Anticancer Drugs by a Novel c-MET Inhibitor TAS-115.

    PubMed

    Kunii, Eiji; Ozasa, Hiroaki; Oguri, Tetsuya; Maeno, Ken; Fukuda, Satoshi; Uemura, Takehiro; Takakuwa, Osamu; Ohkubo, Hirotsugu; Takemura, Masaya; Niimi, Akio

    2015-10-01

    The cellular N-methyl-N'-nitroso-guanidine human osteosarcoma transforming gene (c-MET) protein is the receptor tyrosine kinase for hepatocyte growth factor. We recently found that c-MET protein expression and activation were enhanced in the majority of small cell lung cancer cell lines with cytotoxic anticancer drug resistance, and that down-regulation of c-MET reduced resistance to these drugs. Expression of c-MET was studied in three non-small cell lung cancer (NSCLC) cell lines, including six resistant cell strains to cytotoxic anticancer drugs. To assess the effect of c-MET activation on drug resistance, we studied drug sensitivity in the presence of a novel c-MET inhibitor TAS-115. c-MET expression and activation are also enhanced in some cytotoxic anticancer drug-resistant NSCLC cell lines, and inhibition of c-MET activation by TAS-115 reduced resistance of these cell lines to anticancer drugs. The mechanism of cellular resistance to anticancer drugs via hepatocyte growth factor/c-MET signal activation is not restricted to small cell lung cancer cell lines, and TAS-115 might be able to reverse the drug resistance of these cancer cells. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  16. 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…

  17. 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…

  18. Impact of MET targeting on tumor-associated angiogenesis and growth of MET mutations-driven models of liver cancer

    PubMed Central

    Keogh, Adrian; Glück, Astrid A.; Aebersold, Daniel M.; Dufour, Jean-François; Zimmer, Yitzhak

    2015-01-01

    Deregulated expression of the MET receptor tyrosine kinase has been reported in up to 50% of patients with hepatocellular carcinoma, the most abundant form of liver cancers, and is associated with decreased survival. Consequently, MET is considered as a molecular target in this malignancy, whose progression is highly dependent on extensive angiogenesis. Here we studied the impact of MET small molecule inhibitors on angiogenesis-associated parameters and growth of xenograft liver models consisting of cells expressing MET-mutated variants M1268T and Y1248H, which exhibit constitutive kinase activity. We demonstrate that MET mutations expression is associated with significantly increased production of vascular endothelial growth factor, which is blocked by MET targeting only in cells expressing the M1268T inhibitor-sensitive but not in the Y1248H inhibitor-resistant variant. Decrease in vascular endothelial growth factor production is also associated with reduction of tyrosine phopshorylation of the vascular endothelial growth factor receptor 2 expressed on primary liver sinusoidal endothelial cells and with inhibition of vessel formation. Furthermore, MET inhibition demonstrated an efficient anti-tumor activity and considerable reduction in microvessel density only against the M1268T-derived intrahepatic tumors. Collectively, our data support the role of targeting MET-associated angiogenesis as a major biological determinant for liver tumor growth control. PMID:26413215

  19. MET-EGFR dimerization in lung adenocarcinoma is dependent on EGFR mtations and altered by MET kinase inhibition

    PubMed Central

    Owen, William; Weitsman, Gregory; Fruhwirth, Gilbert; Dunn, Robert G.; Neat, Michael J.; McCaughan, Frank; Parker, Peter; Ng, Tony; Santis, George

    2017-01-01

    Advanced lung cancer has poor survival with few therapies. EGFR tyrosine kinase inhibitors (TKIs) have high response rates in patients with activating EGFR mutations, but acquired resistance is inevitable. Acquisition of the EGFR T790M mutation causes over 50% of resistance; MET amplification is also common. Preclinical data suggest synergy between MET and EGFR inhibitors. We hypothesized that EGFR-MET dimerization determines response to MET inhibition, depending on EGFR mutation status, independently of MET copy number. We tested this hypothesis by generating isogenic cell lines from NCI-H1975 cells, which co-express L858R and T790M EGFR mutations, namely H1975L858R/T790M (EGFR TKI resistant); H1975L858R (sensitized) and H1975WT (wild-type). We assessed cell proliferation in vitro and tumor growth/stroma formation in derived xenograft models in response to a MET TKI (SGX523) and correlated with EGFR-MET dimerization assessed by Förster Resonance Energy Transfer (FRET). SGX523 significantly reduced H1975L858R/T790M cell proliferation, xenograft tumor growth and decreased ERK phosphorylation. The same was not seen in H1975L858R or H1975WT cells. SGX523 only reduced stroma formation in H1975L858R. SGX523 reduced EGFR-MET dimerization in H1975L858R/T790M but induced dimer formation in H1975L858R with no effect in H1975WT. Our data suggests that MET inhibition by SGX523 and EGFR-MET heterodimerisation are determined by EGFR genotype. As tumor behaviour is modulated by this interaction, this could determine treatment efficacy. PMID:28141869

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

    PubMed

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

    2012-01-01

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

  1. MET-EGFR dimerization in lung adenocarcinoma is dependent on EGFR mtations and altered by MET kinase inhibition.

    PubMed

    Ortiz-Zapater, Elena; Lee, Richard W; Owen, William; Weitsman, Gregory; Fruhwirth, Gilbert; Dunn, Robert G; Neat, Michael J; McCaughan, Frank; Parker, Peter; Ng, Tony; Santis, George

    2017-01-01

    Advanced lung cancer has poor survival with few therapies. EGFR tyrosine kinase inhibitors (TKIs) have high response rates in patients with activating EGFR mutations, but acquired resistance is inevitable. Acquisition of the EGFR T790M mutation causes over 50% of resistance; MET amplification is also common. Preclinical data suggest synergy between MET and EGFR inhibitors. We hypothesized that EGFR-MET dimerization determines response to MET inhibition, depending on EGFR mutation status, independently of MET copy number. We tested this hypothesis by generating isogenic cell lines from NCI-H1975 cells, which co-express L858R and T790M EGFR mutations, namely H1975L858R/T790M (EGFR TKI resistant); H1975L858R (sensitized) and H1975WT (wild-type). We assessed cell proliferation in vitro and tumor growth/stroma formation in derived xenograft models in response to a MET TKI (SGX523) and correlated with EGFR-MET dimerization assessed by Förster Resonance Energy Transfer (FRET). SGX523 significantly reduced H1975L858R/T790M cell proliferation, xenograft tumor growth and decreased ERK phosphorylation. The same was not seen in H1975L858R or H1975WT cells. SGX523 only reduced stroma formation in H1975L858R. SGX523 reduced EGFR-MET dimerization in H1975L858R/T790M but induced dimer formation in H1975L858R with no effect in H1975WT. Our data suggests that MET inhibition by SGX523 and EGFR-MET heterodimerisation are determined by EGFR genotype. As tumor behaviour is modulated by this interaction, this could determine treatment efficacy.

  2. Structural Diversity in the AdoMet Radical Enzyme Superfamily

    PubMed Central

    Dowling, Daniel P.; Vey, Jessica L.; Croft, Anna K.; Drennan, Catherine L.

    2012-01-01

    AdoMet radical enzymes are involved in processes such as cofactor biosynthesis, anaerobic metabolism, and natural product biosynthesis. These enzymes utilize the reductive cleavage of S-adenosylmethionine (AdoMet) to afford L-methionine and a transient 5'-deoxyadenosyl radical, which subsequently generates a substrate radical species. By harnessing radical reactivity, the AdoMet radical enzyme superfamily is responsible for an incredible diversity of chemical transformations. Structural analysis reveals that family members adopt a full or partial Triose-phosphate Isomerase Mutase (TIM) barrel protein fold, containing core motifs responsible for binding a catalytic [4Fe-4S] cluster and AdoMet. Here we evaluate over twenty structures of AdoMet radical enzymes and classify them into two categories: traditional and ThiC-like (named for the structure of 4-amino-5-hydroxymethyl-2-methylpyrimidine phosphate synthase (ThiC)). In light of new structural data, we reexamine the traditional structural motifs responsible for binding the [4Fe-4S] cluster and AdoMet, and compare and contrast these motifs with the ThiC case. We also review how structural data combine with biochemical, spectroscopic, and computational data to help us understand key features of this enzyme superfamily, such as the energetics, the triggering, and the molecular mechanisms of AdoMet reductive cleavage. PMID:22579873

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

    PubMed Central

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

    2015-01-01

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

  4. MET2 affects production of hydrogen sulfide during wine fermentation.

    PubMed

    Huang, Chien; Roncoroni, Miguel; Gardner, Richard C

    2014-08-01

    The production of hydrogen sulfide (H2S) during yeast fermentation contributes negatively to wine aroma. We have mapped naturally occurring mutations in commercial wine strains that affect production of H2S. A dominant R310G mutant allele of MET2, which encodes homoserine O-acetyltransferase, is present in several wine yeast strains as well as in the main lab strain S288c. Reciprocal hemizygosity and allele swap experiments demonstrated that the MET2 R310G allele confers reduced H2S production. Mutations were also identified in genes encoding the two subunits of sulfite reductase, MET5 and MET10, which were associated with reduced H2S production. The most severe of these, an allele of MET10, showed five additional phenotypes: reduced growth rate on sulfate, elevated secretion of sulfite, and reduced production in wine of three volatile sulfur compounds: methionol, carbon disulfide and methylthioacetate. Alleles of MET5 and MET10, but not MET2, affected H2S production measured by colour assays on BiGGY indicator agar, but MET2 effects were seen when bismuth was added to agar plates made with Sauvignon blanc grape juice. Collectively, the data are consistent with the hypothesis that H2S production during wine fermentation results predominantly from enzyme activity in the sulfur assimilation pathway. Lower H2S production results from mutations that reduce the activity of sulfite reductase, the enzyme that produces H2S, or that increase the activity of L-homoserine-O-acetyltransferase, which produces substrate for the next step in the sulfur assimilation pathway.

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

    PubMed

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

    2015-08-13

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

  6. MetNet Precursor - Network Mission to Mars

    NASA Astrophysics Data System (ADS)

    Harri, Arri-Matti

    2010-05-01

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

  7. Reduced hippocampus volume and memory performance in bipolar disorder patients carrying the BDNF val66met met allele.

    PubMed

    Cao, Bo; Bauer, Isabelle E; Sharma, Ajaykumar N; Mwangi, Benson; Frazier, Thomas; Lavagnino, Luca; Zunta-Soares, Giovana B; Walss-Bass, Consuelo; Glahn, David C; Kapczinski, Flavio; Nielsen, David A; Soares, Jair C

    2016-07-01

    Previous studies investigated the impact of brain-derived neurotrophic factor (BDNF) val66met (rs6265) on hippocampus volumes and neurocognition in bipolar disorders (BD), but the results were not consistent. This study aimed to investigate the effect of BDNF polymorphism on hippocampus volumes and memory performance in well-characterized adult populations diagnosed with type I BD (BD-I) and major depressive disorder (MDD) compared with healthy controls (HC). 48 BD-I patients, 33 MDD patients and 60 HC were genotyped for BDNF rs6265 using DNA isolated from white blood cells. Individuals with val/met and met/met genotypes were grouped as met carriers and compared to those with the val/val. Brain segmentations were obtained from structural magnetic resonance imaging (MRI) using the Freesurfer. Memory performance was assessed with the California Verbal Learning Task (CVLT). We found a significant diagnosis effect and marginal interaction between diagnosis and BDNF genotype group for both hippocampus volumes and memory performance. BDNF met allele carrier BD patients had smaller hippocampus volumes and reduced performance on multiple CVLT scores compared to MDD patients and HC. We provide strong evidence for the BDNF val66met polymorphism as a putative biological signature for the neuroanatomical and cognitive abnormalities commonly observed in BD patients. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. 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.

  9. Loss of embryonic MET signaling alters profiles of hippocampal interneurons.

    PubMed

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

    2007-01-01

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

  10. 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

  11. Mars MetNet Mission - Martian Atmospheric Observational Post Network

    NASA Astrophysics Data System (ADS)

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

    2017-04-01

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

  12. Design and Implementation of Image Research for the Columbia Mets

    DTIC Science & Technology

    1992-01-01

    respondents have at least attended college or are college graduates. This figure is almost 30% higher than the Major League Baseball average of 52...appreciation to the staff of the Columbia Mets. I thank Dr. Eric Margenau, Owner/President of the Mets and president of United Baseball , Inc., for...most important and special person in my life, my wife Diane. God blessed you with an abundance of patience in putting up with my love baseball

  13. MMPM - Mission implementation of Mars MetNet Precursor

    NASA Astrophysics Data System (ADS)

    Harri, A.-M.

    2009-04-01

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

  14. MONIM: the new Met Office Night Illumination Model

    NASA Astrophysics Data System (ADS)

    Revell, S. J.; Hignett, P.

    2004-09-01

    This paper describes a new model developed by the Met Office to predict night-time light levels. The Met Office Night Illumination Model (MONIM) predicts light levels both in the visible (photopic) range and in the waveband to which night vision goggles (NVGs) are sensitive. The model will be used operationally for support of night-time flying operations. The model is described in detail and its light-level forecasts are compared with observations.

  15. 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. © 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

  16. Effect of individual Fc methionine oxidation on FcRn binding: Met252 oxidation impairs FcRn binding more profoundly than Met428 oxidation.

    PubMed

    Gao, Xuan; Ji, Junyan A; Veeravalli, Karthik; Wang, Y John; Zhang, Taylor; Mcgreevy, William; Zheng, Kai; Kelley, Robert F; Laird, Michael W; Liu, Jun; Cromwell, Mary

    2015-02-01

    The long serum half-lives of mAbs are conferred by pH-dependent binding of IgG-Fc to the neonatal Fc receptor (FcRn). The Fc region of human IgG1 has three conserved methionine residues, Met252, Met358, and Met428. Recent studies showed oxidation of these Met residues impairs FcRn binding and consequently affects pharmacokinetics of therapeutic antibodies. However, the quantitative effect of individual Met oxidation on Fc-FcRn binding has not been addressed. This information is valuable for defining critical quality attributes. In the present study, two sets of homodimeric site-directed IgG1 mutations were generated to understand how individual Fc Met oxidation affects FcRn binding. The first approach used Met to Leu mutants to block site-specific Met oxidation. In the other approach, Met to Gln mutants were designed to mimic site-specific Met oxidation. Both mutagenesis approaches show that either Met252 or Met428 oxidation alone significantly impairs Fc-FcRn binding. Met252 oxidation has a more deleterious effect on FcRn binding than M428 oxidation, whereas Met428 oxidation has a bigger destabilization effect on the thermal stability. Our results also show that Met358 oxidation does not affect FcRn binding. In addition, our study suggests that Met to Gln mutation may serve as an important tool to understand Met oxidation. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  17. 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

  18. Disruption of the gene for Met-tRNA(fMet) formyltransferase severely impairs growth of Escherichia coli.

    PubMed Central

    Guillon, J M; Mechulam, Y; Schmitter, J M; Blanquet, S; Fayat, G

    1992-01-01

    In bacteria, as well as in chloroplasts and mitochondria, the free amino group of the methionylated initiator tRNA(fMet) is specifically modified by the addition of a formyl group. The importance of this modification remains unclear. With the availability of pure Escherichia coli 10-formyltetrahydrofolate:L-methionyl-tRNA(fMet) N-formyltransferase, the enzyme catalyzing Met-tRNA(fMet) formylation, the corresponding fmt gene and its flanking regions were cloned and sequenced. The chromosomal fmt gene was disrupted, and strains modified in their formylation activity were constructed. A depletion of the cellular formylation activity was accompanied by a decrease in the growth rate of the bacteria. At 37 degrees C, in a rich medium, the absence of a functional fmt gene reduced the growth rate to 0.28 doubling per h, from 2.3 for the control strain. At 42 degrees C, the studied fmt mutant strain did not grow further. PMID:1624424

  19. 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.

  20. 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

  1. MET and AKT Genetic Influence on Facial Emotion Perception

    PubMed Central

    Huang, Chieh-Liang; Huang, Yu-Jhen; Tsai, Guochuan E.; Lane, Hsien-Yuan

    2012-01-01

    Background Facial emotion perception is a major social skill, but its molecular signal pathway remains unclear. The MET/AKT cascade affects neurodevelopment in general populations and face recognition in patients with autism. This study explores the possible role of MET/AKT cascade in facial emotion perception. Methods One hundred and eighty two unrelated healthy volunteers (82 men and 100 women) were recruited. Four single nucleotide polymorphisms (SNP) of MET (rs2237717, rs41735, rs42336, and rs1858830) and AKT rs1130233 were genotyped and tested for their effects on facial emotion perception. Facial emotion perception was assessed by the face task of Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). Thorough neurocognitive functions were also assessed. Results Regarding MET rs2237717, individuals with the CT genotype performed better in facial emotion perception than those with TT (p = 0.016 by ANOVA, 0.018 by general linear regression model [GLM] to control for age, gender, and education duration), and showed no difference with those with CC. Carriers with the most common MET CGA haplotype (frequency = 50.5%) performed better than non-carriers of CGA in facial emotion perception (p = 0.018, df = 1, F = 5.69, p = 0.009 by GLM). In MET rs2237717/AKT rs1130233 interaction, the C carrier/G carrier group showed better facial emotion perception than those with the TT/AA genotype (p = 0.035 by ANOVA, 0.015 by GLM), even when neurocognitive functions were controlled (p = 0.046 by GLM). Conclusions To our knowledge, this is the first study to suggest that genetic factors can affect performance of facial emotion perception. The findings indicate that MET variances and MET/AKT interaction may affect facial emotion perception, implicating that the MET/AKT cascade plays a significant role in facial emotion perception. Further replication studies are needed. PMID:22558359

  2. Photodissociation of metallo-carbohedrene (met-cars) cluster cations

    SciTech Connect

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

    1993-05-19

    Castleman and co-workers have recently reported the formation of especially stable metal-carbon clusters designated [open quotes]metallo-carbohedrenes[close quotes], or [open quotes]met-cars[close quotes]. In their work, metal-carbon mixed clusters having the formula M[sub 8]C[sub 12] form preferentially from plasmas containing a carbon precursor and transition metals (e.g., Ti[sub 8]C[sub 12]). We report here the first mass-selected photo-dissociation experiments on met-cars clusters. These experiments reveal the decomposition mechanism of these species and provide new insight into their bonding and stabilities. These photodissociation experiments indicate that there are at least two general mechanisms important in met-cars cluster decomposition, metal atom elimination and M-C[sub 2] elimination. Chromium and iron met-cars clusters are suggested to be less stable overall than titanium and vanadium systems, while the M-C[sub 2] interactions are suggested to be especially strong for zirconium met-cars cluster. 10 refs., 1 fig.

  3. 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

  4. Sequential EMT-MET induces neuronal conversion through Sox2.

    PubMed

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

    2017-01-01

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

  5. "Active" cancer immunotherapy by anti-Met antibody gene transfer.

    PubMed

    Vigna, Elisa; Pacchiana, Giovanni; Mazzone, Massimiliano; Chiriaco, Cristina; Fontani, Lara; Basilico, Cristina; Pennacchietti, Selma; Comoglio, Paolo M

    2008-11-15

    Gene therapy provides a still poorly explored opportunity to treat cancer by "active" immunotherapy as it enables the transfer of genes encoding antibodies directed against specific oncogenic proteins. By a bidirectional lentiviral vector, we transferred the cDNA encoding the heavy and light chains of a monoclonal anti-Met antibody (DN-30) to epithelial cancer cells. In vitro, the transduced cells synthesized and secreted correctly assembled antibodies with the expected high affinity, inducing down-regulation of the Met receptor and strong inhibition of the invasive growth response. The inhibitory activity resulted (a) from the interference of the antibody with the Met receptor intracellular processing ("cell autonomous activity," in cis) and (b) from the antibody-induced cleavage of Met expressed at the cell surface ("bystander effect," in trans). The monoclonal antibody gene transferred into live animals by systemic administration or by local intratumor delivery resulted in substantial inhibition of tumor growth. These data provide proof of concept both for targeting the Met receptor and for a gene transfer-based immunotherapy strategy.

  6. 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.

  7. Adsorption of methane molecules on neutral titanium Met-Cars

    SciTech Connect

    Sakurai, H.; Castleman, A.W. Jr.

    1999-07-01

    Titanium metallocarbohedrenes (Met-Cars) are observed to adsorb methane molecules at low temperatures. The observed formation of the methane-Ti{sub 8}C{sub 12} cluster complexes provides further direct evidence establishing that stable {ital neutral} titanium Met-Cars are present in copious amounts in the cluster beam. At sufficiently low temperatures, a dominant peak is observed for Ti{sub 8}C{sub 12}(CH{sub 4}){sub 4} along with less intense peaks of other methane-Ti{sub 8}C{sub 12} clusters, which suggests the geometry of titanium Met-Cars may be the tetrahedral cage structure with T{sub d} symmetry. By studying the photoionization efficiency of the methane-Ti{sub 8}C{sub 12} complexes near ionization threshold, their ionization potentials are found to be lower than that of Ti{sub 8}C{sub 12}. {copyright} {ital 1999 American Institute of Physics.}

  8. BacMet: antibacterial biocide and metal resistance genes database

    PubMed Central

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

    2014-01-01

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

  9. 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.

  10. EMT and MET as paradigms for cell fate switching.

    PubMed

    Chen, Jiekai; Han, Qingkai; Pei, Duanqing

    2012-04-01

    Cell fate determination is a major unsolved problem in cell and developmental biology. The discovery of reprogramming by pluripotent factors offers a rational system to investigate the molecular mechanisms associated with cell fate decisions. The idea that reprogramming of fibroblasts starts with a mesenchymal-epithelial transition (MET) suggests that the process is perhaps a reversal of epithelial to mesenchymal transition (EMT) found frequently during early embryogenesis. As such, we believe that investigations into MET-EMT may yield detailed molecular insights into cell fate decisions, not only for the switching between epithelial and mesenchymal cells, but also other cell types.

  11. The MetOp satellite - Weather information from polar orbit

    NASA Astrophysics Data System (ADS)

    Edwards, Peter G.; Berutti, Bruno; Blythe, Paul; Callies, Joerg; Carlier, Stefane; Fransen, Cees; Krutsch, Rainer; Lefebvre, Alain-Robert; Loiselet, Marc; Stricker, Nico

    2006-08-01

    MetOp-A is Europe's first polar-orbiting satellite dedicated to operational meteorology. With its array of advanced instruments, it will provide data of unprecedented accuracy and resolution on temperature and humidity, wind speed and direction over the ocean, and ozone and other trace gases, making a huge contribution to global weather forecasting and climate monitoring. In addition, MetOp-A will observe land and ocean surfaces and its search-and-rescue service will help ships and aircraft in distress.

  12. 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.

  13. 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…

  14. 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,…

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

    Atmospheric Science Data Center

    2014-05-07

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

  16. Altered White Matter Architecture in BDNF Met Carriers

    PubMed Central

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

    2013-01-01

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

  17. Early Field Experience: How Well Are Students' Expectations Met?

    ERIC Educational Resources Information Center

    Rekkas, Alexandria J.

    This study examined preservice teachers' expectations of their field experiences and how those expectations were met. The study population included primarily college sophomores who were either elementary or secondary education majors at a medium-sized university. An expectation checklist was given to 110 students prior to the field experience at…

  18. 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…

  19. 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…

  20. 17 CFR 230.502 - General conditions to be met.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... advertising, including, but not limited to, the following: (1) Any advertisement, article, notice or other... 17 Commodity and Securities Exchanges 2 2010-04-01 2010-04-01 false General conditions to be met. 230.502 Section 230.502 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION...

  1. Viewpoint: We Have Met the Enemy and He Is Us.

    ERIC Educational Resources Information Center

    Reinert, Harry

    1981-01-01

    Points out that services to the foreign language profession, ranging from work on local committees to national leadership, are performed almost exclusively by volunteers and criticizes the attitudes of some members of the profession toward their visiting colleagues. Cites several incidents where visitors met with shocking lack of assistance and…

  2. 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…

  3. Viewpoint: We Have Met the Enemy and He Is Us.

    ERIC Educational Resources Information Center

    Reinert, Harry

    1981-01-01

    Points out that services to the foreign language profession, ranging from work on local committees to national leadership, are performed almost exclusively by volunteers and criticizes the attitudes of some members of the profession toward their visiting colleagues. Cites several incidents where visitors met with shocking lack of assistance and…

  4. 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

  5. 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

  6. 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.

  7. 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.

  8. Technology evaluation: MetXia-P450, Oxford Biomedica.

    PubMed

    Hunt, S

    2001-12-01

    Oxford BioMedica is developing gene therapies for treating various forms of cancer. The therapies comprise the transfer of several anticancer genes at a time using a recombinant retrovirus approach based on the company's proprietary LTR Deleted Vector and Accelerated Vector Evolution technologies [238147]. MetXia-P450 is a gene therapy construct containing the cytochrome P450 gene CYP2B6, and is designed to be injected directly into tumors to convert them into 'drug factories'. This is achieved because CYP2B6 converts the inactive produg form cyclophosphamide into the active cytotoxic drug. MetXia-P450 is in phase I/II trials for breast cancer [339582].

  9. 75 FR 44289 - MET Laboratories, Inc.; Application for Expansion of Recognition

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-28

    ... Occupational Safety and Health Administration MET Laboratories, Inc.; Application for Expansion of Recognition... announces the application of MET Laboratories, Inc., (MET) for expansion of its recognition, and presents... Expansion Application The Occupational Safety and Health Administration (OSHA) is providing notice that MET...

  10. 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

  11. The MetOp second generation 3MI instrument

    NASA Astrophysics Data System (ADS)

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

    2013-10-01

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

  12. Met as a therapeutic target in HCC: facts and hopes.

    PubMed

    Giordano, Silvia; Columbano, Amedeo

    2014-02-01

    Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and its burden is expected to increase further in the next years. In spite of the advances of classical therapies, such as surgery, transplantation, use of radiofrequency and transarterial embolization, the prognosis of this neoplasm has not considerably improved over the past few years. The advent of targeted therapies and the approval of the systemic treatment of advanced HCC with the kinase inhibitor sorafenib have provided some hope for the future. Even if the molecular mechanisms responsible for the onset and progression of HCC are still largely unknown, new therapeutic targets have recently come to the spotlight. One of these targets is the tyrosine kinase receptor for the Hepatocyte Growth Factor, encoded by the MET gene, known to promote tumor growth and metastasis in many human organs. In this review we will summarize the contrasting results obtained in vitro (in HCC cell lines) and in animal experimental models and we will also try to analyze the reasons for the opposite findings, suggesting that the HGF/MET axis can have either a promoting or a suppressive role in the development of HCC. We will also reconsider the evidence of activation of this pathway in human HCCs and discuss the results of the clinical trials performed with MET inhibitors. The final purpose is to better clarify which can be the role of MET as a therapeutic target in HCC. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  13. COMT Val158Met Polymorphism Modulates Huntington's Disease Progression.

    PubMed

    de Diego-Balaguer, Ruth; Schramm, Catherine; 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

    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.

  14. 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

  15. Application of MET for the validation of satellite precipitation estimates

    NASA Astrophysics Data System (ADS)

    Kucera, P.; Brown, B.; Bullock, R.; Ahijevych, D.

    2009-04-01

    The goal of this study is to demonstrate the usefulness of the NCAR Model Evaluation Tools (MET) applied to the validation of high-resolution satellite rainfall estimates. MET provides grid-to-point, grid-to-grid, and advanced spatial validation techniques in one unified, modular toolkit that can be applied to a variety of spatial fields (e.g., satellite precipitation estimates). Most validation studies rely on the use of standard validation measures (mean error, bias, mean absolute error, and root mean squared error, etc.) to quantify the quality of the precipitation estimates. Often these measures indicate poorer performance because, among other things, they are unable to account for small-scale variability or discriminate types of errors such as displacement in time and/or space (location, intensity, and orientation errors, etc.) in the precipitation estimates. This issue has motivated recent research and development of many new techniques such as, but not limited to, scale decomposition, fuzzy neighborhood, and object orientated methods for evaluating spatial precipitation estimates. This study will compute statistics for high resolution satellite estimates of precipitation using standard validation measures for the comparison with object orientated measures using the MET built-in Method for Object-based Diagnostic Evaluation (MODE) algorithm using the radar-rainfall estimates as the reference. Rainfall estimates generated by the TRMM Multi-satellite precipitation analysis (TMPA) and CPC Morphing technique (CMORPH) will be used demonstrate the new validation techniques.

  16. Acquired METD1228V Mutation and Resistance to MET Inhibition in Lung Cancer.

    PubMed

    Bahcall, Magda; Sim, Taebo; Paweletz, Cloud P; Patel, Jyoti D; Alden, Ryan S; Kuang, Yanan; Sacher, Adrian G; Kim, Nam Doo; Lydon, Christine A; Awad, Mark M; Jaklitsch, Michael T; Sholl, Lynette M; Jänne, Pasi A; Oxnard, Geoffrey R

    2016-12-01

    Amplified and/or mutated MET can act as both a primary oncogenic driver and as a promoter of tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC). However, the landscape of MET-specific targeting agents remains underdeveloped, and understanding of mechanisms of resistance to MET TKIs is limited. Here, we present a case of a patient with lung adenocarcinoma harboring both a mutation in EGFR and an amplification of MET, who after progression on erlotinib responded dramatically to combined MET and EGFR inhibition with savolitinib and osimertinib. When resistance developed to this combination, a new MET kinase domain mutation, D1228V, was detected. Our in vitro findings demonstrate that MET(D1228V) induces resistance to type I MET TKIs through impaired drug binding, while sensitivity to type II MET TKIs is maintained. Based on these findings, the patient was treated with erlotinib combined with cabozantinib, a type II MET inhibitor, and exhibited a response.

  17. [Construction of a recombinant stable Ba/F3 cell strain containing Tpr-Met].

    PubMed

    Shu, Ling-fei; Li, Wei; Zhan, Yi-qun; Xu, Wang-xiang; Yang, Xiao-ming; Li, Chang-yan

    2012-11-01

    To construct a stable cell strain encoding tumor-associated fused gene which expresses oncoprotein Tpr-Met. We transfected Tpr-Met vector into Ba/F3 cells and screened the cell strain stably expressing Tpr-Met. The interleukin 3 (IL-3) independent proliferation of the cells was measured using the MTS assay. The expression of Tpr-Met, the activity of downstream signal transduction pathway and SU11274-induced inhibition of the signal pathway were investigated by Western blotting. We obtained a Ba/F3 cell strain stably expressing Tpr-Met. The cells presented IL-3 independent proliferation, suggesting a malignant transformation of the cell line. In Tpr-Met transformed Ba/F3 cells, the phosphorylation of Met and ERK were enhanced; however, specific c-Met inhibitor SU11274 suppressed the cell proliferation and c-Met phosphorylation. Tpr-Met transformed Ba/F3 strain has been successfully constructed.

  18. MetMAb, the one-armed 5D5 anti-c-Met antibody, inhibits orthotopic pancreatic tumor growth and improves survival.

    PubMed

    Jin, Hongkui; Yang, Renhui; Zheng, Zhong; Romero, Mally; Ross, Jed; Bou-Reslan, Hani; Carano, Richard A D; Kasman, Ian; Mai, Elaine; Young, Judy; Zha, Jiping; Zhang, Zemin; Ross, Sarajane; Schwall, Ralph; Colbern, Gail; Merchant, Mark

    2008-06-01

    The hepatocyte growth factor (HGF) and its receptor, c-Met, have been implicated in driving proliferation, invasion, and poor prognosis in pancreatic cancer. Here, we investigated the expression of HGF and c-Met in primary pancreatic cancers and described in vitro and in vivo models in which MetMAb, a monovalent antibody against c-Met, was evaluated. First, expression of HGF and MET mRNA was analyzed in 59 primary pancreatic cancers and 51 normal samples, showing that both factors are highly expressed in pancreatic cancer. We next examined HGF responsiveness in pancreatic cancer lines to select lines that proliferate in response to HGF. Based on these studies, two lines were selected for further in vivo model development: BxPC-3 (c-Met(+), HGF(-)) and KP4 (c-Met(+), HGF(+)) cells. As BxPC-3 cells are responsive to exogenous HGF, s.c. tumor xenografts were grown in a paracrine manner with purified human HGF provided by osmotic pumps, wherein MetMAb treatment significantly inhibited tumor growth. KP4 cells are autocrine for HGF and c-Met, and MetMAb strongly inhibited s.c. tumor growth. To better model pancreatic cancer and to enable long-term survival studies, an orthotopic model of KP4 was established. MetMAb significantly inhibited orthotopic KP4 tumor growth in 4-week studies monitored by ultrasound and also improved survival in 90-day studies. MetMAb significantly reduced c-Met phosphorylation in orthotopic KP4 tumors with a concomitant decrease in Ki-67 staining. These data suggest that the HGF/c-Met axis plays an important role in the progression of pancreatic cancer and that targeting c-Met therein may have therapeutic value.

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

    PubMed

    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; Knudsen, Beatrice S

    2016-10-01

    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 (MET4(EC), SP44_MET(IC), D1C2_MET(IC)), 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, MET4(EC) correlated more strongly with pMET (r = 0.47) than SP44_MET(IC) (r = 0.21) or D1C2_MET(IC) (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 MET4(EC), SP44_MET(IC) 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.

  20. Absolute quantitation of Met using mass spectrometry for clinical application: assay precision, stability, and correlation with MET gene amplification in FFPE tumor tissue.

    PubMed

    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

    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. 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). 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. 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 tumors. These results demonstrate a novel clinical

  1. The Met allele of BDNF Val66Met polymorphism is associated with increased BDNF levels in generalized anxiety disorder.

    PubMed

    Moreira, Fernanda P; Fabião, Júlia D; Bittencourt, Guilherme; Wiener, Carolina D; Jansen, Karen; Oses, Jean P; Quevedo, Luciana de Ávila; Souza, Luciano D M; Crispim, Daisy; Portela, Luiz V; Pinheiro, Ricardo T; Lara, Diogo R; Kaster, Manuella P; da Silva, Ricardo A; Ghisleni, Gabriele

    2015-10-01

    Generalized anxiety disorder (GAD) is a common psychiatric disorder characterized by long-term worry, tension, nervousness, fidgeting, and symptoms of autonomic system hyperactivity. The neurobiology of this disorder is still unclear, although it has been shown consistently that the environment and the genetic profile could increase its risk. We examined whether a polymorphism in the brain-derived neurotrophic factor (BDNF) gene, which plays a role in neuroplasticity and memory, could increase the vulnerability to this disorder. In our study, 816 participants from a population-based study were genotyped by qPCR for the BDNF functional variant rs6265 (Val66Met) and the BDNF serum levels were measured by ELISA. Our results showed a significant association between the Met allele and risk for GAD (P=0.014), but no differences were observed in the serum levels of BDNF according to diagnosis (P=0.531) or genotype distribution (P=0.197). However, after stratification according to the GAD diagnosis, the Met allele was associated significantly with an increase in serum BDNF levels compared with the Val/Val genotype in GAD participants (F=3.93; P=0.048). The logistic regression analysis confirmed the independent association of Met allele as a risk factor for development of GAD after adjusting for confounder variables (β=0.528; 95% confidence interval: 0.320-0.871; P=0.012). These results suggest that BDNF could be involved in the neurobiology of GAD and might represent a useful marker associated with the disease.

  2. MetAP1 and MetAP2 drive cell selectivity for a potent anti-cancer agent in synergy, by controlling glutathione redox state

    PubMed Central

    Frottin, Frédéric; Bienvenut, Willy V.; Bignon, Jérôme; Jacquet, Eric; Jacome, Alvaro Sebastian Vaca; Van Dorsselaer, Alain; Cianferani, Sarah; Carapito, Christine; Meinnel, Thierry; Giglione, Carmela

    2016-01-01

    Fumagillin and its derivatives are therapeutically useful because they can decrease cancer progression. The specific molecular target of fumagillin is methionine aminopeptidase 2 (MetAP2), one of the two MetAPs present in the cytosol. MetAPs catalyze N-terminal methionine excision (NME), an essential pathway of cotranslational protein maturation. To date, it remains unclear the respective contribution of MetAP1 and MetAP2 to the NME process in vivo and why MetAP2 inhibition causes cell cycle arrest only in a subset of cells. Here, we performed a global characterization of the N-terminal methionine excision pathway and the inhibition of MetAP2 by fumagillin in a number of lines, including cancer cell lines. Large-scale N-terminus profiling in cells responsive and unresponsive to fumagillin treatment revealed that both MetAPs were required in vivo for M[VT]X-targets and, possibly, for lower-level M[G]X-targets. Interestingly, we found that the responsiveness of the cell lines to fumagillin was correlated with the ability of the cells to modulate their glutathione homeostasis. Indeed, alterations to glutathione status were observed in fumagillin-sensitive cells but not in cells unresponsive to this agent. Proteo-transcriptomic analyses revealed that both MetAP1 and MetAP2 accumulated in a cell-specific manner and that cell sensitivity to fumagillin was related to the levels of these MetAPs, particularly MetAP1. We suggest that MetAP1 levels could be routinely checked in several types of tumor and used as a prognostic marker for predicting the response to treatments inhibiting MetAP2. PMID:27542228

  3. LY2875358, a neutralizing and internalizing anti-MET bivalent antibody, inhibits HGF-dependent and HGF-independent MET activation and tumor growth.

    PubMed

    Liu, Ling; Zeng, Wei; Wortinger, Mark A; Yan, S Betty; Cornwell, Paul; Peek, Victoria L; Stephens, Jennifer R; Tetreault, Jonathan W; Xia, Jinqi; Manro, Jason R; Credille, Kelly M; Ballard, Darryl W; Brown-Augsburger, Patricia; Wacheck, Volker; Chow, Chi-Kin; Huang, Lihua; Wang, Yong; Denning, Irene; Davies, Julian; Tang, Ying; Vaillancourt, Peter; Lu, Jirong

    2014-12-01

    MET, the receptor for hepatocyte growth factor (HGF), has been implicated in driving tumor proliferation and metastasis. High MET expression is correlated with poor prognosis in multiple cancers. Activation of MET can be induced either by HGF-independent mechanisms such as gene amplification, specific genetic mutations, and transcriptional upregulation or by HGF-dependent autocrine or paracrine mechanisms. Here, we report on LY2875358, a novel humanized bivalent anti-MET antibody that has high neutralization and internalization activities, resulting in inhibition of both HGF-dependent and HGF-independent MET pathway activation and tumor growth. In contrast to other bivalent MET antibodies, LY2875358 exhibits no functional agonist activity and does not stimulate biologic activities such as cell proliferation, scattering, invasion, tubulogenesis, or apoptosis protection in various HGF-responsive cells and no evidence of inducing proliferation in vivo in a monkey toxicity study. LY2875358 blocks HGF binding to MET and HGF-induced MET phosphorylation and cell proliferation. In contrast to the humanized one-armed 5D5 anti-MET antibody, LY2875358 induces internalization and degradation of MET that inhibits cell proliferation and tumor growth in models where MET is constitutively activated. Moreover, LY2875358 has potent antitumor activity in both HGF-dependent and HGF-independent (MET-amplified) xenograft tumor models. Together, these findings indicate that the mechanism of action of LY2875358 is different from that of the one-armed MET antibody. LY2875358 may provide a promising therapeutic strategy for patients whose tumors are driven by both HGF-dependent and HGF-independent MET activation. LY2875358 is currently being investigated in multiple clinical studies. ©2014 American Association for Cancer Research.

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

    PubMed Central

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

    2015-01-01

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

  5. HGF/Met and FOXM1 form a positive feedback loop and render pancreatic cancer cells resistance to Met inhibition and aggressive phenotypes.

    PubMed

    Cui, J; Xia, T; Xie, D; Gao, Y; Jia, Z; Wei, D; Wang, L; Huang, S; Quan, M; Xie, K

    2016-09-08

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

  6. 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

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

    NASA Astrophysics Data System (ADS)

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

    2017-04-01

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

  8. Seasonal to decadal climate services at the Met Office

    NASA Astrophysics Data System (ADS)

    Brookshaw, A.; Arribas, A.; Graham, R.; Vellinga, M.; Fereday, D.

    2012-12-01

    For several years the Met Office, the UK's National Met service, has been providing climate services to a large range of users - from government organisations, both national and international, to commercial customers. This presentation will describe our current activities and future plans for development of user-relevant climate science and new products and services for monthly to decadal timescales, which build on our current role as a Global Producing Centre of long-range forecasts and key contributor to a number of operational multi-model ensembles and Regional Climate Outlook Forums. Already, much of the recent research has been geared towards applications: from making the monthly, seasonal and decadal predictability at regional scales the focus of development for the coupled climate model and the operational forecasting systems, to investigating methodologies for predicting seasonal and decadal tropical storm activity and climate and weather extremes. An example of such a development towards user-relevant applications and services will be presented in detail: the Climate Science Research Partnership (CSRP). This is a partnership between the Met Office Hadley Centre and the UK Department for International Development, aimed at advancing the quality, relevance and uptake of climate services in Africa. It has been running for almost three years, and during this period activities have ranged from fundamental climate research - focused on improving the understanding, modelling and prediction of African climate - to development of user-relevant products and activities to strengthen uptake of such science and services. The presentation will highlight key scientific results, new experimental products driven by user needs identified by consultation, as well as some of the limitations and challenges encountered along the way.

  9. 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.

  10. Correlation between plasma calcium, parathyroid hormone (PTH) and the metabolic syndrome (MetS) in a community-based cohort of men and women.

    PubMed

    Ahlström, Tommy; Hagström, Emil; Larsson, Anders; Rudberg, Claes; Lind, Lars; Hellman, Per

    2009-11-01

    In recent years, an association has been noted between several abnormalities that characterize the metabolic syndrome (MetS) and primary hyperparathyroidism (pHPT). These abnormalities include dyslipidaemia, obesity, insulin resistance and hypertension. The correlations between plasma calcium, parathyroid hormone (PTH) and the variables in the MetS in a normal population are still unclear. To describe correlations between plasma calcium and PTH and the various abnormalities present in the MetS in a healthy population. We studied 1016 healthy individuals from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) population of 70 years old, by means of plasma analyses of calcium, PTH, creatinine, lipids, insulin and glucose, as well as by standardized blood pressure measurements. Further, body mass index (BMI) and waist circumference were determined. The more National Cholesterol Education Program (NCEP) criteria for the MetS that were met, the higher the s-PTH and albumin-corrected s-calcium. Further, positive correlations between plasma calcium and BMI (P = 0.0003), waist circumference (P = 0.0009) and insulin resistance (P = 0.079) were found. PTH and BMI (P < 0.0001), waist circumference (P < 0.0001), systolic blood pressure (P = 0.0034), diastolic blood pressure (P = 0.0008), serum triglycerides (P = 0.0003) and insulin resistance (P = 0.0003) were positively correlated, whereas serum high density lipoproteins (HDL) (P = 0.036) and PTH were negatively correlated. We conclude that PTH correlates with several of the metabolic factors included in the MetS within a normocalcaemic population. In addition, individuals with mild pHPT present significantly more NCEP criteria for MetS. We postulate that increased levels of PTH in pHPT may be associated with the increased cardiovascular morbidity and mortality seen in pHPT.

  11. Additional Value from Road Mapping in Defense Policy Making (meerwaarde van roadmapping bij beleidsontwikkeling van de koninklijke landmacht)

    DTIC Science & Technology

    2006-05-01

    diplomaat, woordvoerder ( media ) en manager zijn. Kuj dient in elke faso van eon oporatie met do media to kunnen communicoron an Commandant van do aan to...doel te richten. Hierbij kan gedacht worden aan politieke-, sociale -, humanitaire-, economische-, militaire- en financiele instrumenten. Door de...Hierbij kan gedacht worden aan politieke-, sociale -, humanitaire-, economisvhe-, militaire- en financi~le instrumenten. Door de ontwikkeling van NEC

  12. MET tyrosine kinase receptor expression and amplification as prognostic biomarkers of survival in gastroesophageal adenocarcinoma

    PubMed Central

    Ang, Agnes; Liao, Wei‐Li; Shen, Jing; O'Day, Emily; Loberg, Robert D.; Cecchi, Fabiola; Hembrough, Todd; Ruzzo, Annamaria; Graziano, Francesco

    2016-01-01

    BACKGROUND MET gene amplification and Met protein overexpression may be associated with a poor prognosis. The MET/Met status is typically determined with fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), respectively. Targeted proteomics uses mass spectrometry–based selected reaction monitoring (SRM) to accurately quantitate Met expression. FISH, IHC, and SRM analyses were compared to characterize the prognostic value of MET/Met in gastroesophageal adenocarcinoma (GEC). METHODS Samples from 447 GEC patients were analyzed for MET gene amplification (FISH) and Met protein expression (IHC and SRM). Cox proportional hazards models and Kaplan‐Meier estimates were applied to explore relations between Met, overall survival (OS), and clinical/pathological characteristics. Spearman's rank coefficient was used to assess the correlation between parameters. RESULTS Patients with MET‐amplified tumors had worse OS when: the MET/centromere enumeration probe for chromosome 7 FISH ratio was ≥ 2 (hazard ratio [HR], 3.13; 95% confidence interval [CI], 1.84‐5.33), the MET gene copy number was ≥5 (HR, 2.51; 95% CI, 1.45‐4.34), or ≥ 10% of the cells had ≥15 copies (HR, 4.28; 95% CI, 2.18‐8.39). Similar observations were made with Met protein overexpression by IHC (≥1 + intensity in ≥ 25% of the tumor cell membrane: HR, 1.39; 95% CI, 1.04‐1.86) or SRM (≥400 amol/μg: HR, 1.76; 95% CI, 1.06‐2.90). A significant correlation was observed between MET FISH/Met IHC, MET FISH/Met SRM, and Met IHC/Met SRM; only MET FISH and Met SRM were independent negative prognostic biomarkers in multivariate analyses. CONCLUSIONS MET amplification and overexpression, assessed by multiple methods, were associated with a worse prognosis in univariate analyses. However, only MET amplification by FISH and Met expression by SRM were independent prognostic biomarkers. Compared with IHC, SRM may provide an added benefit for informed decisions

  13. 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.

  14. 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

  15. 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.

  16. Association between XRCC3 Thr241Met polymorphism and risk of osteosarcoma in a Chinese population.

    PubMed

    Guo, J; Lv, H C; Shi, R H; Liu, W L

    2015-12-09

    Osteosarcoma is one of the most common bone malignancies in adolescents, and hereditary factors may influence its susceptibility. We assessed the association between XRCC3 Thr241Met polymorphism and susceptibility to osteosarcoma in a Chinese population. Between May 2012 and May 2014, a total of 136 osteosarcoma patients and 136 healthy control subjects were included in our study. The XRCC3 Thr241Met polymorphism was analyzed using a polymerase chain reaction restriction fragment length polymorphism assay. By multiple logistic regression analysis, individuals carrying the Met/Met genotype of XRCC3 Thr241Met were at significantly increased risk of osteosarcoma when compared with the Thr/Thr (OR = 2.50, 95%CI = 1.13-5.66). The Thr/Met+Met/Met genotype of XRCC3 Thr241Met was furthermore found to be correlated with an elevated increased risk of osteosarcoma when compared with the Thr/Thr genotype (OR = 1.71, 95%CI = 1.03-2.87), and Met/Met genotype of XRCC3 Thr241Met was associated with an increased risk of osteosarcoma compared to the Thr/Thr (OR = 3.50, 95%CI = 1.51-8.79). In conclusion, our study firstly reports that XRCC3 Thr241Met gene polymorphism is associated with an elavated risk of osteosarcoma.

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

    PubMed

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

    2016-05-01

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

  18. Point prevalence of patients fulfilling MET criteria in ten MET equipped hospitals. The methodology of the RESCUE study.

    PubMed

    Bucknall, Tracey K; Jones, Daryl; Barrett, Jonathon; Bellomo, Rinaldo; Botti, Mari; Considine, Julie; Currey, Judy; Dunning, Trisha L; Green, David; Levinson, Michele; Livingston, Patricia M; O'Connell, Bev; Ruseckaite, Rasa; Staples, Margaret

    2011-05-01

    The RESCUE study examined the prevalence of patients at risk of a medical emergency in acute care settings by assessing the prevalence of cases where patients fulfil the hospital-specific criteria for MET activation. This article will detail the study methodology including the ethics applications and approvals process, organisational preparation, research staff training, tools for data collection, as well as barriers encountered during the conduct of the study. A point prevalence design conducted at 10 hospitals, comprising of private and public, secondary and tertiary referral, ICU equipped, metropolitan and regional settings. All inpatients were eligible except intensive care and psychiatric patients. On a single day consenting inpatients in each hospital had a single set of vital signs obtained, their observation chart reviewed and followed up for MET activations, unplanned ICU admissions, cardiac arrests and 30 and 60 day mortality. Of 2199 eligible patients, 1688 (76.76%) were assessed, 175 (7.95%) refused consent and 336 (15.28%) were unavailable. Access to patients was refused in some wards despite ethics approval. Data collection required 2 student nurses approximately 14 min per patient assessment. In conducting a large multi-site point prevalence study, critical organisational processes were shown to influence the access to patients. This study demonstrated the impact of variation in Human Research Ethics Committee interpretations of protocols on consenting processes and the importance of communication and leadership at ward level to promote access to patients. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

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

    PubMed

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

    2016-03-01

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

  20. Identification of short-form RON as a novel intrinsic resistance mechanism for anti-MET therapy in MET-positive gastric cancer

    PubMed Central

    Ge, Xiaoxiao; Lin, Ying; Dai, Congqi; Chang, Jinjia; Liu, Xinyang; Geng, Ruixuan; Wang, Chenchen; Chen, Huan; Sun, Menghong; Guo, Weijian; Li, Jin

    2015-01-01

    Despite the promising results from initial studies, there are significant limitations in the application of MET-targeted therapy in gastric cancer. Intrinsic resistance is one of the major obstacles. The aim of this study is to identify the responsible receptor tyrosine kinases (RTKs) that determine the unresponsiveness of MET inhibitor in MET-positive gastric cancer. through an RNA-interference-based functional screen targeting most human RTKs, we identified that activation of the fibroblast growth factor receptor 2 (FGFR2) and recepteur d'origine nantais (RON) pathways attenuated MET inhibitor-induced suppression of cell proliferation and migration. Notably, in the two forms of RON pathway activation, only upregulation of short-form RON (sf-RON), but not stimulation of full length RON with macrophage stimulating protein, conferred MET inhibitor resistance in vitro and in vivo. Furthermore, the profile of the gastric cancer samples observed that sf-RON was frequently upregulated in MET-positive gastric cancer. Our findings indicate that activation of the sf-RON signaling pathway represents a novel mechanism underlying MET inhibitor unresponsiveness. A combination strategy with drugs targeting both RON and MET pathways is believed to improve the efficacy of MET-targeted therapy. PMID:26528757

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

    SciTech Connect

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

    2010-09-03

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

  2. Alteration status and prognostic value of MET in head and neck squamous cell carcinoma

    PubMed Central

    Cho, Yoon Ah; Kim, Eun Kyung; Heo, Su Jin; Cho, Byoung Chul; Kim, Hye Ryun; Chung, Ji Myung; Yoon, Sun Och

    2016-01-01

    The MET pathway plays a key role in various cancers, and its inhibition represents a potential treatment target. However, appropriate biomarkers are needed to facilitate the selection of patients who would benefit from MET inhibiting therapy. We herein conducted a robust confirmatory evaluation of the MET copy number alteration status and prognostic significance of c-Met expression in a large series of patients (n = 396) who underwent standard surgical resection and adjuvant chemoradiotherapy for head and neck squamous cell carcinoma (HNSCC). Surgically resected HNSCC samples were subjected to immunohistochemical and H-score analysis of c-Met expression and silver in situ hybridization analysis of MET amplification and copy number gains. c-Met expression varied, with mean and median H-scores (scale: 0-300 scale) of 61.2 and 60.0, respectively. The lowest and highest expression levels were observed in SCC of the larynx and oral cavity, respectively. MET copy number gains were observed in 16.9% of cases (67/339) and were associated with c-Met protein expression. High c-Met expression, determined according to MET gain status, was associated with an inferior overall survival rate, especially among completely resected cases. In conclusion, our robust analysis revealed that c-Met expression in HNSCCs varied according to anatomical site, correlated with MET copy number gains, and was associated with poor prognosis. This c-Met expression analysis method, which is based on the MET gain status, appears to appropriately predict high-risk HNSCC patients in the context of anti-MET therapeutic decisions. PMID:27994655

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

    PubMed

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

    2010-05-01

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

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

    PubMed

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

    2014-11-15

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

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

    NASA Technical Reports Server (NTRS)

    1997-01-01

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

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

  6. Aerosol impacts in the Met Office global NWP model

    NASA Astrophysics Data System (ADS)

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

    2010-05-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2017-04-01

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

  8. 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.

  9. 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.

  10. Conformational analysis of [Met5]-enkephalin: Solvation and ionization considerations

    NASA Astrophysics Data System (ADS)

    Carlacci, Louis

    1998-03-01

    [Met5]-Enkephalin has the sequence Tyr-Gly-Gly-Phe-Met. Only the extended conformation of the peptide has been observed by X-ray crystallography. Nuclear magnetic resonance spectroscopy supports the presence of a turn at Gly 3 and Phe 4 in dimethyl sulfoxide. In this study, the peptide conformational states and thermodynamic properties are understood in terms of ionization state and solvent environment. In the calculation, final conformations obtained from multiple independent Monte Carlo simulated annealing conformational searches are starting points for molecular dynamics simulations. In an aqueous environment given by the use of solvation free energy and the zwitterionic state, dominant structural motifs computed are G-P Type II' bend, G-G Type II' bend, and G-G Type I' bend motifs, in order of increasing free energy. In the calculation of the peptide with neutral N- and C-termini and solvation free energy, the extended conformer dominates (by at least a factor of 2.5), and the conformation of another low free energy conformer superimposes well on the pharmacophoric groups of morphine. Neutralization of charge and solvation induce and stabilize the extended conformation, respectively. A mechanism of inter-conversion between the extended conformer and three bent conformers is supported by φ/ψ-scatter plots, and by the conformer relative free energies. An estimate of the entropy change of receptor unbinding is 8.3 cal K-1 mol-1, which gives rise to a -2.5 kcal/mol entropy contribution to the free energy of unbinding at 25 °C. The conformational analysis methodology described here should be useful in studies on short peptides and flexible protein surface loops that have important biological implications.

  11. Are energy and protein requirements met in hospital?

    PubMed

    Pullen, K; Collins, R; Stone, T; Carter, H; Sadler, H; Collinson, A

    2017-06-06

    Malnutrition is a problem within hospitals, which impacts upon clinical outcomes. The present audit assesses whether a hospital menu meets the energy and protein standards recommended by the British Dietetic Association's (BDA) Nutrition and Hydration Digest and determines the contribution of oral nutrition supplements (ONS) and additional snacks. Patients in a UK South West hospital were categorised as 'nutritionally well' or 'nutritionally vulnerable' in accordance with their Malnutrition Universal Screening Tool score. Energy and protein content of food selected from the menu ('menu choice'), menu food consumed ('hospital intake') and total food consumed including snacks ('overall intake') were calculated and compared with the standards. In total, 93 patients were included. For 'nutritionally well' patients (n = 81), energy and protein standards were met by 11.1% and 33.3% ('menu choice'); 7.4% and 22.2% ('hospital intake'); and 14.8% and 28.4% ('overall intake'). For 'nutritionally vulnerable' patients (n = 12), energy and protein standards were met by 0% and 8.3% ('menu choice'); 0% and 8.3% ('hospital intake'); and 8.3% and 16.7% ('overall intake'). Ten percent of patients consumed ONS. Patients who consumed hospital snacks (34%) were more likely to meet the nutrient standards (P ≤ 0.001). The present audit demonstrated that most patients are not meeting the nutrient standards recommended by the BDA Nutrition and Hydration Digest. Recommendations include the provision of energy/protein-dense snacks, as well as menu, offering ONS where clinically indicated, in addition to training for staff. A food services dietitian is ideally placed to lead this, forming a vital link between patients, caterers and clinical teams. © 2017 The British Dietetic Association Ltd.

  12. 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…

  13. 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…

  14. MET receptor juxtamembrane exon 14 alternative spliced variant: novel cancer genomic predictive biomarker.

    PubMed

    Ma, Patrick C

    2015-08-01

    Clinical studies on MET-targeting cancer therapeutics have yielded mixed results in recent years, and MET-relevant predictive biomarkers remain elusive. New studies now reveal METex14 alternative splicing aberrations to represent potential predictive cancer genomic biomarker, hence renewing optimism and directions in the quest for optimized MET-targeting personalized cancer therapy.

  15. 77 FR 25080 - Safety Zones; TriMet Bridge Project, Willamette River, Portland, OR

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-27

    ... SECURITY Coast Guard 33 CFR Part 165 RIN 1625-AA00 Safety Zones; TriMet Bridge Project, Willamette River... of the TriMet Bridge on the Willamette River, in Portland, OR. This action is necessary to ensure the... established for the TriMet Bridge construction site and are more focused in nature than the previous safety...

  16. 76 FR 53054 - Safety Zone; TriMet Bridge Project, Willamette River; Portland, OR

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-25

    ... SECURITY Coast Guard 33 CFR Part 165 RIN 1625-AA00 Safety Zone; TriMet Bridge Project, Willamette River... safety zone during the construction of the TriMet Bridge on the Willamette River, in Portland, OR. This... proposed rulemaking (NPRM) entitled Safety Zone: TriMet Bridge Project, Willamette River; Portland, OR in...

  17. Recent Developments of c-Met as a Therapeutic Target in Hepatocellular Carcinoma.

    PubMed

    Bouattour, Mohamed; Raymond, Eric; Qin, Shukui; Cheng, Ann-Lii; Stammberger, Uz; Locatelli, Giuseppe; Faivre, Sandrine

    2017-09-01

    Aberrant c-Met activity is implicated in the development of hepatocellular carcinoma (HCC), suggesting that c-Met inhibition may have therapeutic potential. However, clinical trials of nonselective kinase inhibitors with c-Met activity (tivantinib, cabozantinib, foretinib, and golvatinib) in patients with HCC have failed so far to demonstrate significant efficacy. This is likely due to several factors, including trial design, lack of patient selection according to tumor c-Met status, and the prevalent off-target activity of these agents, which may mean that c-Met inhibition is incomplete. In contrast, selective c-Met inhibitors (tepotinib, capmatinib) can be dosed at a level predicted to achieve a complete inhibition of tumor c-Met activity. Moreover, results from early trials can be used to optimize the design of clinical trials of these agents. Preliminary results suggest that selective c-Met inhibitors have antitumor activity in HCC, with acceptable safety and tolerability in patients with Child-Pugh A liver function. Ongoing trials have been designed to assess the efficacy and safety of selective c-Met inhibition compared with standard therapy in patients with HCC selected based on tumor c-Met status. Thus, c-Met inhibition continues to be an active area of research in HCC, with well-designed trials in progress to investigate the benefit of selective c-Met inhibitors. This article is protected by copyright. All rights reserved. © 2017 by the American Association for the Study of Liver Diseases.

  18. Met and its ligand HGF are associated with clinical outcome in breast cancer.

    PubMed

    Veenstra, Cynthia; Pérez-Tenorio, Gizeh; Stelling, Anna; Karlsson, Elin; Mirwani, Sanam Mirwani; Nordensköljd, Bo; Fornander, Tommy; Stål, Olle

    2016-06-14

    Few biomarkers exist to predict radiotherapy response in breast cancer. In vitro studies suggest a role for Met and its ligand HGF. To study this suggested role, MET and HGF gene copy numbers were determined by droplet digital PCR in tumours from 205 pre-menopausal and 184 post-menopausal patients, both cohorts randomised to receive either chemo- or radiotherapy. MET amplification was found in 8% of the patients in both cohorts and HGF amplification in 7% and 6% of the patients in the pre- and post-menopausal cohort, respectively. Met, phosphorylated Met (pMet), and HGF protein expression was determined by immunohistochemistry in the pre-menopausal cohort. Met, pMet, and HGF was expressed in 33%, 53%, and 49% of the tumours, respectively. MET amplification was associated with increased risk of distant recurrence for patients receiving chemotherapy. For the pre-menopausal patients, expression of cytoplasmic pMet and HGF significantly predicted benefit from radiotherapy in terms of loco-regional recurrence. Similar trends were seen for MET and HGF copy gain. In the post-menopausal cohort, no significant association of benefit from radiotherapy with neither genes nor proteins was found. The present results do not support that inhibition of Met prior to radiotherapy would be favourable for pre-menopausal breast cancer, as previously suggested.

  19. The potential roles of hepatocyte growth factor (HGF)-MET pathway inhibitors in cancer treatment.

    PubMed

    Parikh, Rahul A; Wang, Peng; Beumer, Jan H; Chu, Edward; Appleman, Leonard J

    2014-01-01

    MET is located on chromosome 7q31 and is a proto-oncogene that encodes for hepatocyte growth factor (HGF) receptor, a member of the receptor tyrosine kinase (RTK) family. HGF, also known as scatter factor (SF), is the only known ligand for MET. MET is a master regulator of cell growth and division (mitogenesis), mobility (motogenesis), and differentiation (morphogenesis); it plays an important role in normal development and tissue regeneration. The HGF-MET axis is frequently dysregulated in cancer by MET gene amplification, translocation, and mutation, or by MET or HGF protein overexpression. MET dysregulation is associated with an increased propensity for metastatic disease and poor overall prognosis across multiple tumor types. Targeting the dysregulated HGF-MET pathway is an area of active research; a number of monoclonal antibodies to HGF and MET, as well as small molecule inhibitors of MET, are under development. This review summarizes the key biological features of the HGF-MET axis, its dysregulation in cancer, and the therapeutic agents targeting the HGF-MET axis, which are in development.

  20. Met and its ligand HGF are associated with clinical outcome in breast cancer

    PubMed Central

    Veenstra, Cynthia; Pérez-Tenorio, Gizeh; Stelling, Anna; Karlsson, Elin; Mirwani, Sanam Mirwani; Nordensköljd, Bo; Fornander, Tommy; Stål, Olle

    2016-01-01

    Few biomarkers exist to predict radiotherapy response in breast cancer. In vitro studies suggest a role for Met and its ligand HGF. To study this suggested role, MET and HGF gene copy numbers were determined by droplet digital PCR in tumours from 205 pre-menopausal and 184 post-menopausal patients, both cohorts randomised to receive either chemo- or radiotherapy. MET amplification was found in 8% of the patients in both cohorts and HGF amplification in 7% and 6% of the patients in the pre- and post-menopausal cohort, respectively. Met, phosphorylated Met (pMet), and HGF protein expression was determined by immunohistochemistry in the pre-menopausal cohort. Met, pMet, and HGF was expressed in 33%, 53%, and 49% of the tumours, respectively. MET amplification was associated with increased risk of distant recurrence for patients receiving chemotherapy. For the pre-menopausal patients, expression of cytoplasmic pMet and HGF significantly predicted benefit from radiotherapy in terms of loco-regional recurrence. Similar trends were seen for MET and HGF copy gain. In the post-menopausal cohort, no significant association of benefit from radiotherapy with neither genes nor proteins was found. The present results do not support that inhibition of Met prior to radiotherapy would be favourable for pre-menopausal breast cancer, as previously suggested. PMID:27175600

  1. The novel ATP-competitive inhibitor of the MET hepatocyte growth factor receptor EMD1214063 displays inhibitory activity against selected MET-mutated variants.

    PubMed

    Medová, Michaela; Pochon, Benoît; Streit, Bruno; Blank-Liss, Wieslawa; Francica, Paola; Stroka, Deborah; Keogh, Adrian; Aebersold, Daniel M; Blaukat, Andree; Bladt, Friedhelm; Zimmer, Yitzhak

    2013-11-01

    The receptor tyrosine kinase MET is a prime target in clinical oncology due to its aberrant activation and involvement in the pathogenesis of a broad spectrum of malignancies. Similar to other targeted kinases, primary and secondary mutations seem to represent an important resistance mechanism to MET inhibitors. Here, we report the biologic activity of a novel MET inhibitor, EMD1214063, on cells that ectopically express the mutated MET variants M1268T, Y1248H, H1112Y, L1213V, H1112L, V1110I, V1206L, and V1238I. Our results show a dose-dependent decrease in MET autophosphorylation in response to EMD1214063 in five of the eight cell lines (IC50 2-43 nmol/L). Blockade of MET by EMD1214063 was accompanied by a reduced activation of downstream effectors in cells expressing EMD1214063-sensitive mutants. In all sensitive mutant-expressing lines, EMD1214063 altered cell-cycle distribution, primarily with an increase in G1 phase. EMD1214063 strongly influenced MET-driven biologic functions, such as cellular morphology, MET-dependent cell motility, and anchorage-independent growth. To assess the in vivo efficacy of EMD1214063, we used a xenograft tumor model in immunocompromised mice bearing NIH3T3 cells expressing sensitive and resistant MET-mutated variants. Animals were randomized for the treatment with EMD1214063 (50 mg/kg/d) or vehicle only. Remarkably, five days of EMD1214063 treatment resulted in a complete regression of the sensitive H1112L-derived tumors, whereas tumor growth remained unaffected in mice with L1213V tumors and in vehicle-treated animals. Collectively, the current data identifies EMD1214063 as a potent MET small-molecule inhibitor with selective activity towards mutated MET variants. ©2013 AACR.

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

    PubMed

    Sucaet, Yves; Wurtele, Eve Syrkin

    2010-11-18

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

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

    PubMed Central

    2010-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  5. Cytotoxic activity of tivantinib (ARQ 197) is not due solely to c-MET inhibition.

    PubMed

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

    2013-05-15

    The receptor tyrosine kinase c-MET is the high-affinity receptor for the hepatocyte growth factor (HGF). The HGF/c-MET axis is often dysregulated in tumors. c-MET activation can be caused by MET gene amplification, activating mutations, and auto- or paracrine mechanisms. Thus, c-MET inhibitors are under development as anticancer drugs. Tivantinib (ARQ 197) was reported as a small-molecule c-MET inhibitor and early clinical studies suggest antitumor activity. To assess whether the antitumor activity of tivantinib was due to inhibition of c-MET, we compared the activity of tivantinib with other c-MET inhibitors in both c-MET-addicted and nonaddicted cancer cells. As expected, other c-MET inhibitors, crizotinib and PHA-665752, suppressed the growth of c-MET-addicted cancers, but not the growth of cancers that are not addicted to c-MET. In contrast, tivantinib inhibited cell viability with similar potency in both c-MET-addicted and nonaddicted cells. These results suggest that tivantinib exhibits its antitumor activity in a manner independent of c-MET status. Tivantinib treatment induced a G(2)-M cell-cycle arrest in EBC1 cells similarly to vincristine treatment, whereas PHA-665752 or crizotinib treatment markedly induced G(0)-G(1) cell-cycle arrest. To identify the additional molecular target of tivantinib, we conducted COMPARE analysis, an in silico screening of a database of drug sensitivities across 39 cancer cell lines (JFCR39), and identified microtubule as a target of tivantinib. Tivantinib-treated cells showed typical microtubule disruption similar to vincristine and inhibited microtubule assembly in vitro. These results suggest that tivantinib inhibits microtubule polymerization in addition to inhibiting c-MET. ©2013 AACR.

  6. Ethnic Differences and Functional Analysis of MET Mutations in Lung Cancer

    PubMed Central

    Krishnaswamy, Soundararajan; Kanteti, Rajani; Duke-Cohan, Jonathan S.; Loganathan, Sivakumar; Liu, Wanqing; Ma, Patrick C.; Sattler, Martin; Singleton, Patrick A.; Ramnath, Nithya; Innocenti, Federico; Nicolae, Dan L.; Ouyang, Zheng; Liang, Jie; Minna, John; Kozloff, Mark F.; Ferguson, Mark K.; Natarajan, Viswanathan; Wang, Yi-Ching; Garcia, Joe G. N.; Vokes, Everett E.; Salgia, Ravi

    2009-01-01

    Purpose African Americans have higher incidence and poorer response to lung cancer treatment compared with Caucasians. However, the underlying molecular mechanisms for the significant ethnic difference are not known. The present study examines the ethnic differences in the type and frequency of MET proto-oncogene (MET) mutation in lung cancer and correlated them with other frequently mutated genes such as epidermal growth factor receptor (EGFR), KRAS2, and TP53. Experimental Design Using tumor tissue genomic DNA from 141 Asian, 76 Caucasian, and 66 African American lung cancer patients, exons coding for MET and EGFR were PCR amplified, and mutations were detected by sequencing. Mutation carriers were further screened for KRAS2 and TP53 mutations. Functional implications of important MET mutations were explored by molecular modeling and hepatocyte growth factor binding studies. Results Unlike the frequently encountered somatic mutations in EGFR, MET mutations in lung tumors were germline. MET-N375S, the most frequent mutation of MET, occurred in 13% of East Asians compared with none in African Americans. The frequency of MET mutations was highest among male smokers and squamous cell carcinoma. The MET-N375S mutation seems to confer resistance to MET inhibition based on hepatocyte growth factor ligand binding, molecular modeling, and apoptotic susceptibility to MET inhibitor studies. Conclusions MET in lung cancer tissues contained nonsynonymous mutations in the semaphorin and juxtamembrane domains but not in the tyrosine kinase domain. All the MET mutations were germline. East Asians, African-Americans, and Caucasians had different MET genotypes and haplotypes. MET mutations in the semaphorin domain affected ligand binding. PMID:19723643

  7. The Role of MET Receptor Tyrosine Kinase in Non-Small Cell Lung Cancer and Clinical Development of Targeted Anti-MET Agents

    PubMed Central

    Robinson, Kyle W.

    2013-01-01

    A better understanding of the pathophysiology and evolution of non-small cell lung cancer (NSCLC) has identified a number of molecular targets and spurred development of novel targeted therapeutic agents. The MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) are implicated in tumor cell proliferation, migration, invasion, and angiogenesis in a broad spectrum of human cancers, including NSCLC. Amplification of MET has been reported in approximately 5%–22% of lung tumors with acquired resistance to small-molecule inhibitors of the epidermal growth factor receptor (EGFR). Resistance to EGFR inhibitors is likely mediated through downstream activation of the phosphoinositide 3-kinase /AKT pathway. Simultaneous treatment of resistant tumors with a MET inhibitor plus an EGFR inhibitor can abrogate activation of downstream effectors of cell growth, proliferation, and survival, thereby overcoming acquired resistance to EGFR inhibitors. Development and preclinical testing of multiple agents targeting the HGF–MET pathway, including monoclonal antibodies targeting HGF or the MET receptor and small-molecule inhibitors of the MET tyrosine kinase, have confirmed the crucial role of this pathway in NSCLC. Several agents are now in phase III clinical development for the treatment of NSCLC. This review summarizes the role of MET in the pathophysiology of NSCLC and in acquired resistance to EGFR inhibitors and provides an update on progress in the clinical development of inhibitors of MET for treatment of NSCLC. PMID:23345546

  8. Initiation factor eIF2γ promotes eIF2-GTP-Met-tRNAi(Met) ternary complex binding to the 40S ribosome.

    PubMed

    Shin, Byung-Sik; Kim, Joo-Ran; Walker, Sarah E; Dong, Jinsheng; Lorsch, Jon R; Dever, Thomas E

    2011-10-16

    In contrast to prokaryotic elongation factor EF-Tu, which delivers aminoacyl-tRNAs to the ribosomal A-site, eukaryotic initiation factor eIF2 binds methionyl initiator transfer RNA (Met-tRNA(i)(Met)) to the P-site of the 40S ribosomal subunit. The results of directed hydroxyl radical probing experiments to map binding of Saccharomyces cerevisiae eIF2 on the ribosome and on Met-tRNA(i)(Met) revealed that eIF2γ primarily contacts the acceptor stem of Met-tRNA(i)(Met) and identified a key binding interface between domain III of eIF2γ and 18S rRNA helix h44 on the 40S subunit. Whereas the analogous domain III of EF-Tu contacts the T stem of tRNAs, biochemical analyses demonstrated that eIF2γ domain III is important for ribosome, not Met-tRNA(i)(Met). Thus, despite their structural similarity, eIF2 and EF-Tu bind tRNAs in substantially different manners, and we propose that the tRNA-binding domain III of EF-Tu has acquired a new ribosome-binding function in eIF2γ.

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

    PubMed Central

    2013-01-01

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

  10. Monovalency unleashes the full therapeutic potential of the DN-30 anti-Met antibody.

    PubMed

    Pacchiana, Giovanni; Chiriaco, Cristina; Stella, Maria C; Petronzelli, Fiorella; De Santis, Rita; Galluzzo, Maria; Carminati, Paolo; Comoglio, Paolo M; Michieli, Paolo; Vigna, Elisa

    2010-11-12

    Met, the high affinity receptor for hepatocyte growth factor, is one of the most frequently activated tyrosine kinases in human cancer and a validated target for cancer therapy. We previously developed a mouse monoclonal antibody directed against the extracellular portion of Met (DN-30) that induces Met proteolytic cleavage (receptor "shedding") followed by proteasome-mediated receptor degradation. This translates into inhibition of hepatocyte growth factor/Met-mediated biological activities. However, DN-30 binding to Met also results in partial activation of the Met kinase due to antibody-mediated receptor homodimerization. To safely harness the therapeutic potential of DN-30, its shedding activity must be disassociated from its agonistic activity. Here we show that the DN-30 Fab fragment maintains high affinity Met binding, elicits efficient receptor shedding and down-regulation, and does not promote kinase activation. In Met-addicted tumor cell lines, DN-30 Fab displays potent cytostatic and cytotoxic activity in a dose-dependent fashion. DN-30 Fab also inhibits anchorage-independent growth of several tumor cell lines. In mouse tumorigenesis assays using Met-addicted carcinoma cells, intratumor administration of DN-30 Fab or systemic delivery of a chemically stabilized form of the same molecule results in reduction of Met phosphorylation and inhibition of tumor growth. These data provide proof of concept that monovalency unleashes the full therapeutic potential of the DN-30 antibody and point at DN-30 Fab as a promising tool for Met-targeted therapy.

  11. Monovalency Unleashes the Full Therapeutic Potential of the DN-30 Anti-Met Antibody*

    PubMed Central

    Pacchiana, Giovanni; Chiriaco, Cristina; Stella, Maria C.; Petronzelli, Fiorella; De Santis, Rita; Galluzzo, Maria; Carminati, Paolo; Comoglio, Paolo M.; Michieli, Paolo; Vigna, Elisa

    2010-01-01

    Met, the high affinity receptor for hepatocyte growth factor, is one of the most frequently activated tyrosine kinases in human cancer and a validated target for cancer therapy. We previously developed a mouse monoclonal antibody directed against the extracellular portion of Met (DN-30) that induces Met proteolytic cleavage (receptor “shedding”) followed by proteasome-mediated receptor degradation. This translates into inhibition of hepatocyte growth factor/Met-mediated biological activities. However, DN-30 binding to Met also results in partial activation of the Met kinase due to antibody-mediated receptor homodimerization. To safely harness the therapeutic potential of DN-30, its shedding activity must be disassociated from its agonistic activity. Here we show that the DN-30 Fab fragment maintains high affinity Met binding, elicits efficient receptor shedding and down-regulation, and does not promote kinase activation. In Met-addicted tumor cell lines, DN-30 Fab displays potent cytostatic and cytotoxic activity in a dose-dependent fashion. DN-30 Fab also inhibits anchorage-independent growth of several tumor cell lines. In mouse tumorigenesis assays using Met-addicted carcinoma cells, intratumor administration of DN-30 Fab or systemic delivery of a chemically stabilized form of the same molecule results in reduction of Met phosphorylation and inhibition of tumor growth. These data provide proof of concept that monovalency unleashes the full therapeutic potential of the DN-30 antibody and point at DN-30 Fab as a promising tool for Met-targeted therapy. PMID:20833723

  12. Transcriptional upregulation of c-MET is associated with invasion and tumor budding in colorectal cancer

    PubMed Central

    Bradley, Conor A.; Dunne, Philip D.; Bingham, Victoria; McQuaid, Stephen; Khawaja, Hajrah; Craig, Stephanie; James, Jackie; Moore, Wendy L.; McArt, Darragh G.; Lawler, Mark; Dasgupta, Sonali; Johnston, Patrick G.; Van Schaeybroeck, Sandra

    2016-01-01

    c-MET and its ligand HGF are frequently overexpressed in colorectal cancer (CRC) and increased c-MET levels are found in CRC liver metastases. This study investigated the role of the HGF/c-MET axis in regulating migration/invasion in CRC, using pre-clinical models and clinical samples. Pre-clinically, we found marked upregulation of c-MET at both protein and mRNA levels in several invasive CRC cells. Down-regulation of c-MET using RNAi suppressed migration/invasion of parental and invasive CRC cells. Stimulation of CRC cells with rh-HGF or co-culture with HGF-expressing colonic myofibroblasts, resulted in significant increases in their migratory/invasive capacity. Importantly, HGF-induced c-MET activation promoted rapid downregulation of c-MET protein levels, while the MET transcript remained unaltered. Using RNA in situ hybridization (RNA ISH), we further showed that MET mRNA, but not protein levels, were significantly upregulated in tumor budding foci at the invasive front of a cohort of stage III CRC tumors (p < 0.001). Taken together, we show for the first time that transcriptional upregulation of MET is a key molecular event associated with CRC invasion and tumor budding. This data also indicates that RNA ISH, but not immunohistochemistry, provides a robust methodology to assess MET levels as a potential driving force of CRC tumor invasion and metastasis. PMID:27793046

  13. Impact of MET inhibition on small-cell lung cancer cells showing aberrant activation of the hepatocyte growth factor/MET pathway.

    PubMed

    Taniguchi, Hirokazu; Yamada, Tadaaki; Takeuchi, Shinji; Arai, Sachiko; Fukuda, Koji; Sakamoto, Shuichi; Kawada, Manabu; Yamaguchi, Hiroyuki; Mukae, Hiroshi; Yano, Seiji

    2017-07-01

    Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers, and is characterized as extremely aggressive, often displaying rapid tumor growth and multiple organ metastases. In addition, the clinical outcome of SCLC patients is poor due to early relapse and acquired resistance to standard chemotherapy treatments. Hence, novel therapeutic strategies for the treatment of SCLC are urgently required. Accordingly, several molecular targeted therapies were evaluated in SCLC; however, they failed to improve the clinical outcome. The receptor tyrosine kinase MET is a receptor for hepatocyte growth factor (HGF), and aberrant activation of HGF/MET signaling is known as one of the crucial mechanisms enabling cancer progression and invasion. Here, we found that the HGF/MET signaling was aberrantly activated in chemoresistant or chemorelapsed SCLC cell lines (SBC-5, DMS273, and DMS273-G3H) by the secretion of HGF and/or MET copy number gain. A cell-based in vitro assay revealed that HGF/MET inhibition, induced either by MET inhibitors (crizotinib and golvatinib), or by siRNA-mediated knockdown of HGF or MET, constrained growth of chemoresistant SCLC cells through the inhibition of ERK and AKT signals. Furthermore, treatment with either crizotinib or golvatinib suppressed the systemic metastasis of SBC-5 cell tumors in natural killer cell-depleted SCID mice, predominantly through cell cycle arrest. These findings reveal the therapeutic potential of targeting the HGF/MET pathway for inhibition, to constrain tumor progression of SCLC cells showing aberrant activation of HGF/MET signaling. We suggest that it would be clinically valuable to further investigate HGF/MET-mediated signaling in SCLC cells. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  14. MetPetDB: New Directions for Metamorphic Studies

    NASA Astrophysics Data System (ADS)

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

    2008-12-01

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

  15. MetPetDB: A database for metamorphic geochemistry

    NASA Astrophysics Data System (ADS)

    Spear, Frank S.; Hallett, Benjamin; Pyle, Joseph M.; Adalı, Sibel; Szymanski, Boleslaw K.; Waters, Anthony; Linder, Zak; Pearce, Shawn O.; Fyffe, Matthew; Goldfarb, Dennis; Glickenhouse, Nickolas; Buletti, Heather

    2009-12-01

    We present a data model for the initial implementation of MetPetDB, a geochemical database specific to metamorphic rock samples. The database is designed around the concept of preservation of spatial relationships, at all scales, of chemical analyses and their textural setting. Objects in the database (samples) represent physical rock samples; each sample may contain one or more subsamples with associated geochemical and image data. Samples, subsamples, geochemical data, and images are described with attributes (some required, some optional); these attributes also serve as search delimiters. All data in the database are classified as published (i.e., archived or published data), public or private. Public and published data may be freely searched and downloaded. All private data is owned; permission to view, edit, download and otherwise manipulate private data may be granted only by the data owner; all such editing operations are recorded by the database to create a data version log. The sharing of data permissions among a group of collaborators researching a common sample is done by the sample owner through the project manager. User interaction with MetPetDB is hosted by a web-based platform based upon the Java servlet application programming interface, with the PostgreSQL relational database. The database web portal includes modules that allow the user to interact with the database: registered users may save and download public and published data, upload private data, create projects, and assign permission levels to project collaborators. An Image Viewer module provides for spatial integration of image and geochemical data. A toolkit consisting of plotting and geochemical calculation software for data analysis and a mobile application for viewing the public and published data is being developed. Future issues to address include population of the database, integration with other geochemical databases, development of the analysis toolkit, creation of data models for

  16. Epimorphin-Induced MET Sensitizes Ovarian Cancer Cells to Platinum

    PubMed Central

    Yew, Kok-Hooi; Crow, Jennifer; Hirst, Jeff; Pressetto, Ziyan; Godwin, Andrew K.

    2013-01-01

    Distinctive genotypic and phenotypic features of ovarian cancer via epithelial-mesenchymal transition (EMT) have been correlated with drug resistance and disease recurrence. We investigated whether therapeutic reversal of EMT could re-sensitize ovarian cancer cells (OCCs) to existing chemotherapy. We report that epimorphin, a morphogenic protein, has pivotal control over mesenchymal versus epithelial cell lineage decision of the putative OCCs. Exposure to epimorphin induced morphological changes reminiscent of mesenchymal-to-epithelial transition (MET), but in a dose dependent manner, i.e., at 10 µg/mL of epimorphin cells obtain a more mesenchymal-like morphology while at 20 µg/mL of epimorphin cells display an epithelial morphology. The latter changes were accompanied by suppression of mesenchymal markers, such as vimentin (∼8-fold↓, p<0.02), Twist1 (∼7-fold↓, p<0.03), dystroglycan (∼4-fold↓, p<0.01) and palladin (∼3-fold↓, p<0.01). Conversely, significant elevations of KLF4 (∼28-fold↑, p<0.002), β-catenin (∼6-fold↑, p<0.004), EpCAM (∼6-fold↑, p<0.0002) and occludin (∼15-fold↑, p<0.004) mRNAs as part of the commitment to the epithelial cell lineage were detected in response to 20 µg/mL of exogenous epimorphin. Changes in occludin mRNA levels were accompanied by a parallel, albeit weaker expression at the protein level (∼5-fold↑, p<0.001). Likewise, acquisition of epithelial-like properties, including mucin1, CK19, and β-catenin gene expression, was also obtained following epimorphin treatment. Further, MMP3 production was found to be reduced whereas laminin secretion was strongly amplified upon epimorphin-induced MET. These results suggest there is a dosage window for actions of epimorphin on cellular differentiation, wherein it can either suppress or enhance epithelial differentiation of OCCs. Importantly, induction of epithelial-like phenotypes by epimorphin led to an enhanced sensitivity to carboplatin. Overall, we

  17. 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

  18. c-MET expression in primary and liver metastases in uveal melanoma.

    PubMed

    Gardner, Faithlore P; Serie, Daniel J; Salomao, Diva R; Wu, Kevin J; Markovic, Svetomir N; Pulido, Jose S; Joseph, Richard W

    2014-12-01

    There is a pressing need for effective therapies to treat uveal melanoma. Agents that inhibit the c-MET pathway have shown promise in multiple malignancies that overexpress c-MET. Herein, we assess c-MET expression in both primary uveal melanoma and liver metastases of uveal melanoma and evaluate the association of c-MET expression with clinical and pathologic variables. We have retrospectively identified tumor samples from primary and liver metastases of uveal melanoma from 1 January 1990 to 1 January 2012. We utilized immunohistochemistry to assess c-MET expression, and two pathologists quantified c-MET expression using an H-score (product of the intensity of staining and percentage of positive cells). The Mann-Whitney U-test, Pearson's correlation, and Cox model were used as appropriate. Thirty-nine of 40 (98%) primary tumors and nine of 10 (90%) metastatic liver lesions expressed c-MET (H-score range 0-300). There was a strong association between the percentage of positive cells and the intensity of c-MET expression (P=0.007). We found no association between c-MET H-score and clinicopathologic variables such as age, sex, or stage. c-MET expression was significantly higher in metastatic compared with primary tumors (median H-score 190 vs. 30, P=0.022). c-MET is expressed in the vast majority of primary and liver metastases of uveal melanomas; however, c-MET expression did not associate with pathologic features in our cohort. Metastatic lesions have higher expression of c-MET expression than primary tumors. Clinical trials involving c-MET inhibitors deserve further study in patients with uveal melanoma in both the adjuvant and metastatic setting.

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

    PubMed

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

    2016-08-01

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

  20. Overview of multilayer ceramic actuator program at C-MET

    NASA Astrophysics Data System (ADS)

    Raghu, N.; Kumar, V.; Dayas, K. R.; Rao, I. C.

    2003-10-01

    One of the major programs being undertaken in our unit is, development of actuator materials and conversion of these materials into multilayer actuator devices. In order to achieve this objective, development of piezoelectric and electrostrictive materials are also being attempted. A simple and novel chemical precipitation route has been adopted for the synthesis of nano-actuator materials. Lead Zirconate Titanate (PZT) powder, free of agglomerates, phase pure, good chemical homogeneity and of 50 - 75 nm size has been synthesized. Synthesis of nano Ba(Sn,Ti)O3 which shows linear, nearly hysteresis free strain curve is also discussed. Phase pure electrostrictive Lead Magnesium Niobate-Lead Titanate (PMN-PT) powder with a dielectric constant of 25,000 and a Tc of 38°C was prepared through double-step process. C-MET has state of the art facility for multilayer (ML) ceramic processing. These Nano-PZT powders have been converted into 50 micron green tapes through tape casting technique. Characteristics of these synthesized materials and the fabrication of ML actuators there from are presented.

  1. AKT-ions with a TWIST between EMT and MET

    PubMed Central

    Tang, Huifang; Massi, Daniela; Hemmings, Brian A.; Mandalà, Mario; Hu, Zhengqiang; Wicki, Andreas; Xue, Gongda

    2016-01-01

    The transcription factor Twist is an important regulator of cranial suture during embryogenesis. Closure of the neural tube is achieved via Twist-triggered cellular transition from an epithelial to mesenchymal phenotype, a process known as epithelial-mesenchymal transition (EMT), characterized by a remarkable increase in cell motility. In the absence of Twist activity, EMT and associated phenotypic changes in cell morphology and motility can also be induced, albeit moderately, by other transcription factor families, including Snail and Zeb. Aberrant EMT triggered by Twist in human mammary tumour cells was first reported to drive metastasis to the lung in a metastatic breast cancer model. Subsequent analysis of many types of carcinoma demonstrated overexpression of these unique EMT transcription factors, which statistically correlated with worse outcome, indicating their potential as biomarkers in the clinic. However, the mechanisms underlying their activation remain unclear. Interestingly, increasing evidence indicates they are selectively activated by distinct intracellular kinases, thereby acting as downstream effectors facilitating transduction of cytoplasmic signals into nucleus and reprogramming EMT and mesenchymal-epithelial transition (MET) transcription to control cell plasticity. Understanding these relationships and emerging data indicating differential phosphorylation of Twist leads to complex and even paradoxical functionalities, will be vital to unlocking their potential in clinical settings. PMID:27623213

  2. Biomarkers for EMT and MET in breast cancer: An update

    PubMed Central

    Liu, Fei; Gu, Li-Na; Shan, Bao-En; Geng, Cui-Zhi; Sang, Mei-Xiang

    2016-01-01

    Metastasis and recurrence are the leading cause of mortality due to breast cancer, but the underlying mechanisms are still poorly understood. Understanding the breast cancer metastasis mechanism is important for early diagnosis and treatment of breast cancer. The seeding and growth of breast cancer cells at sites distinct from the primary tumor is a complex and multistage process. Recently, it has been reported that the epithelial-mesenchymal transition (EMT) and the mesenchymal-epithelial transition (MET) are the main mechanisms for breast cancer metastasis. During EMT, carcinoma cells shed their differentiated epithelial characteristics, including cell-cell adhesion, polarity and lack of motility, and acquire mesenchymal traits, including motility and invasiveness. This review has summarized the studies of known EMT biomarkers in the context of breast cancer progression. These biomarkers include EMT-related genes, proteins, microRNAs and kinases. In general, the findings of these studies suggest that EMT markers are associated with the invasion and metastasis of breast cancer. Further studies on the link between EMT markers and breast cancer will contribute to identify biomarkers for predicting early breast cancer metastasis as well as to provide new ideas for the treatment of breast cancer. PMID:28105194

  3. Biomarkers for EMT and MET in breast cancer: An update.

    PubMed

    Liu, Fei; Gu, Li-Na; Shan, Bao-En; Geng, Cui-Zhi; Sang, Mei-Xiang

    2016-12-01

    Metastasis and recurrence are the leading cause of mortality due to breast cancer, but the underlying mechanisms are still poorly understood. Understanding the breast cancer metastasis mechanism is important for early diagnosis and treatment of breast cancer. The seeding and growth of breast cancer cells at sites distinct from the primary tumor is a complex and multistage process. Recently, it has been reported that the epithelial-mesenchymal transition (EMT) and the mesenchymal-epithelial transition (MET) are the main mechanisms for breast cancer metastasis. During EMT, carcinoma cells shed their differentiated epithelial characteristics, including cell-cell adhesion, polarity and lack of motility, and acquire mesenchymal traits, including motility and invasiveness. This review has summarized the studies of known EMT biomarkers in the context of breast cancer progression. These biomarkers include EMT-related genes, proteins, microRNAs and kinases. In general, the findings of these studies suggest that EMT markers are associated with the invasion and metastasis of breast cancer. Further studies on the link between EMT markers and breast cancer will contribute to identify biomarkers for predicting early breast cancer metastasis as well as to provide new ideas for the treatment of breast cancer.

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

    PubMed

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

    2012-01-01

    Metabolic syndrome (MetS) which is a multifaceted syndrome, has been demonstrated as a common precursor for developing cardiovascular diseases and/or type 2 diabetes mellitus. Different diagnostic definitions for MetS have been proposed and recommended. We set up to evaluate the reliabilities of the National Cholesterol Education Program's Adult Treatment Panel III (NCEP/ATP III) and the International Diabetes Federation (IDF) definitions in diagnosing MetS among Gaza Strip Palestinians. This cross sectional study involved a randomly selected two hundred and thirty apparently healthy adults from the Gaza Strip. Anthropometric measurements, blood pressure, fasting plasma glucose, lipid profile, and questionnaire interviews were performed. The overall prevalence of MetS in our Gaza Strip cohort was 23.0% and 39.5% according to NCEP/ATP III and IDF definitions respectively (p<0.001). No significant differences were seen in the number of MetS components in individuals having MetS by either definition (mean 3.42 ± 0.63 vs 3.52 ± 0.69 respectively, p=0.865). Both IDF and NCEP/ATP III showed an increased prevalence of MetS with age, and body mass index (BMI), however they revealed different prevalence trends with sex. Except for BMI, there were no significant differences in the general and metabolic related characteristics between subjects with MetS of IDF and NCEP/ATP III definitions. Independently of the definition used, MetS is highly prevalent in Gaza Strip population, with a steady increase in MetS prevalence through age and BMI. The IDF definition tends to give higher values for MetS prevalence, and therefore could be more appropriate for diagnosing MetS in Gaza Strip cohort. Copyright © 2012 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  5. 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

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

    PubMed

    Liu, Kai; Song, Xilin; Zhu, Meirong; Ma, Heng

    2015-10-01

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

  7. Vraagstukken besmettingsbeheersing prio 3 (Questions Regarding Contamination Control, Priority 3)

    DTIC Science & Technology

    2008-11-01

    samenvatting • Gevaren bij inhalatie: Pijnlijke keel, hoesten, adem tekort, dufheid. • Gevaren bij huidcontact: Wordt door huid opgenomen; roodheid. • Het...aangetast met pijnlijke keel, hoesten, adem tekort. • Huidcontact: Corrosief voor huid en ogen. Wordt door huid opgenomen onder vorming van roodheid of...samenvatting • Gevaren bij inhalatie: Mond en keel worden aangetast met pijnlijke keel, hoesten, adem tekort. • Gevaren bij huidcontact: Sterk oog

  8. Breast cancer-derived bone metastasis can be effectively reduced through specific c-MET inhibitor tivantinib (ARQ 197) and shRNA c-MET knockdown.

    PubMed

    Previdi, Sara; Abbadessa, Giovanni; Dalò, Francesca; France, Dennis S; Broggini, Massimo

    2012-01-01

    Breast cancer exhibits a propensity to metastasize to bone, resulting in debilitating skeletal complications associated with significant morbidity and poor prognosis. The cross-talk between metastatic cancer cells and bone is critical to the development and progression of bone metastases. We have shown the involvement of the HGF/c-MET system in tumor-bone interaction contributing to human breast cancer metastasis. Therefore, disruption of HGF/c-MET signaling is a potential targeted approach to treating metastatic bone disease. In this study, we evaluated the effects of c-MET inhibition by both an oral, selective, small-molecule c-MET inhibitor, tivantinib, and a specific short hairpin RNA (shRNA) against c-MET in a mouse model of human breast cancer. Tivantinib exhibited dose-dependent antimetastatic activity in vivo, and the 120 mg/kg dose, proven to be suboptimal in reducing subcutaneous tumor growth, induced significant inhibition of metastatic growth of breast cancer cells in bone and a noteworthy reduction of tumor-induced osteolysis. shRNA-mediated c-MET silencing did not affect in vitro proliferation of bone metastatic cells, but significantly reduced their migration, and this effect was further enhanced by tivantinib. Both observations were confirmed in vivo. Indeed, more pronounced tumor growth suppression with concomitant marked decreases of lytic lesions and prolongation of survival were achieved by dual c-MET inhibition using both tivantinib and RNA interference strategies. Overall, our findings highlighted the effectiveness of c-MET inhibition in delaying the onset and progression of bone metastases and strongly suggest that targeting c-MET may have promising therapeutic value in the treatment of bone metastases from breast cancer. ©2011 AACR.

  9. Elements involved in S-adenosylmethionine-mediated regulation of the Saccharomyces cerevisiae MET25 gene.

    PubMed Central

    Thomas, D; Cherest, H; Surdin-Kerjan, Y

    1989-01-01

    In Saccharomyces cerevisiae, the MET25 gene encodes O-acetylhomoserine sulfhydrylase. Synthesis of this enzyme is repressed by the presence of S-adenosylmethionine (AdoMet) in the growth medium. We identified cis elements required for MET25 expression by analyzing small deletions in the MET25 promoter region. The results revealed a regulatory region, acting as an upstream activation site, that activated transcription of MET25 in the absence of methionine or AdoMet. We found that, for the most part, repression of MET25 expression was due to a lack of activation at this site, reinforced by an independent repression mechanism. The activation region contained a repeated dyad sequence that is also found in the promoter regions of other unlinked but coordinately regulated genes (MET3, MET2, and SAM2). We show that the presence of the two dyads is necessary for maximal gene expression. Moreover, we demonstrate that in addition to this transcriptional regulation, a posttranscriptional regulation, probably targeted at the 5' region of mRNA, is involved in MET25 expression. Images PMID:2552290

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

    PubMed

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

    2017-01-01

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

  11. 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.

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

    PubMed Central

    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. PMID:25674220

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

    PubMed

    Feng, Yan; Ma, Patrick C

    2012-01-01

    MET, the receptor for hepatocyte growth factor, has been identified as a novel promising target in various human malignancies, including lung cancer. Research studies have demonstrated that MET signaling plays important physiologic roles in embryogenesis and early development, whereas its deregulation from an otherwise quiescent signaling state in mature adult tissues can lead to upregulated cell proliferation, survival, scattering, motility and migration, angiogenesis, invasion, and metastasis in tumorigenesis and tumor progression. The MET pathway can be activated through ligand (hepatocyte growth factor, HGF) or MET receptor overexpression, genomic amplification, MET mutations, and alternative splicing. A number of novel therapeutic agents that target the MET/hepatocyte growth factor pathway have been tested in early-phase clinical studies with promising results. Phase III studies of MET targeting agents have recently been initiated. This paper will review the MET signaling pathway and biology in lung cancer, and the recent clinical development and advances of MET/hepatocyte growth factor targeting agents. Emphasis will be placed on discussing various unanswered issues and key strategies needed to optimize further clinical development of MET targeting personalized lung cancer therapy.

  14. 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

  15. The BDNF Val66Met polymorphism impairs NMDA receptor-dependent synaptic plasticity in the hippocampus.

    PubMed

    Ninan, Ipe; Bath, Kevin G; Dagar, Karishma; Perez-Castro, Rosalia; Plummer, Mark R; Lee, Francis S; Chao, Moses V

    2010-06-30

    The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene results in a defect in regulated release of BDNF and affects episodic memory and affective behaviors. However, the precise role of the BDNF Val66Met polymorphism in hippocampal synaptic transmission and plasticity has not yet been studied. Therefore, we examined synaptic properties in the hippocampal CA3-CA1 synapses of BDNF(Met/Met) mice and matched wild-type mice. Although basal glutamatergic neurotransmission was normal, both young and adult mice showed a significant reduction in NMDA receptor-dependent long-term potentiation. We also found that NMDA receptor-dependent long-term depression was decreased in BDNF(Met/Met) mice. However, mGluR-dependent long-term depression was not affected by the BDNF Val66Met polymorphism. Consistent with the NMDA receptor-dependent synaptic plasticity impairment, we observed a significant decrease in NMDA receptor neurotransmission in the CA1 pyramidal neurons of BDNF(Met/Met) mice. Thus, these results show that the BDNF Val66Met polymorphism has a direct effect on NMDA receptor transmission, which may account for changes in synaptic plasticity in the hippocampus.

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

    PubMed Central

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

    2017-01-01

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

  17. 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.

  18. 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

  19. Profiling of Oncogenic Driver Events in Lung Adenocarcinoma Revealed MET Mutation as Independent Prognostic Factor.

    PubMed

    Yeung, Sai F; Tong, Joanna H M; Law, Peggy P W; Chung, Lau Y; Lung, Raymond W M; Tong, Carol Y K; Chow, Chit; Chan, Anthony W H; Wan, Innes Y P; Mok, Tony S K; To, Ka F

    2015-09-01

    Oncogenic driver mutations activating receptor tyrosine kinase pathways are promising predictive markers for targeted treatment. We investigated the mutation profile of an updated driver events list on receptor tyrosine kinase/RAS/PI3K axis and the clinicopathologic implications in a cohort of never-smoker predominated Chinese lung adenocarcinoma. We tested 154 lung adenocarcinomas and adenosquamous carcinomas for EGFR, KRAS, HER2, BRAF, PIK3CA, MET, NRAS, MAP2K1, and RIT1 mutations by polymerase chain reaction-direct sequencing. MET amplification and ALK and ROS1 translocations were assessed by fluorescent in situ hybridizations. MET and thyroid transcription factor-1 protein expressions were investigated by immunohistochemistry. Seventy percent of lung adenocarcinomas carried actionable driver events. Alterations on EGFR (43%), KRAS (11.4%), ALK (6%), and MET (5.4%) were frequently found. ROS1 translocation and mutations involving BRAF, HER2, NRAS, and PIK3CA were also detected. No mutation was observed in RIT1 and MAP2K1. Patients with EGFR mutations had a favorable prognosis, whereas those with MET mutations had poorer overall survival. Multivariate analysis further demonstrated that MET mutation was an independent prognostic factor. Although MET protein expression was detected in 65% of lung adenocarcinoma, only 10% of the MET-immunohistochemistry positive tumors harbor MET DNA alterations that drove protein overexpression. Appropriate predictive biomarker is essential for selecting patients who might benefit from specific targeted therapy. Actionable driver events can be detected in two thirds of lung adenocarcinoma. MET DNA alterations define a subset of patients with aggressive diseases that might potentially benefit from anti-MET targeted therapy. High negative predictive values of thyroid transcription factor-1 and MET expression suggest potential roles as surrogate markers for EGFR and/or MET mutations.

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

    PubMed Central

    2012-01-01

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

  1. 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.

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

    PubMed Central

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

    2009-01-01

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

  3. MET/HGF pathway activation as a paradigm of resistance to targeted therapies.

    PubMed

    Ko, Brian; He, Tianfang; Gadgeel, Shirish; Halmos, Balazs

    2017-01-01

    Resistance to targeted therapeutics is a key issue limiting the long-term utility of these medications in the management of molecularly selected subsets of cancer patients, including patients with non-small cell lung cancer harboring oncogenic alterations affecting EGFR, ALK and other genes. Bypass resistance mediated by activation of MET kinase has emerged as a frequent, validated and pivotal resistance mechanism in multiple types of cancers. Biochemical understanding is accumulating to explain the unique role of MET in such bypass pathways, providing alternate downstream activation opportunities and intricate interactions during epithelial-mesenchymal transitions. Multiple diagnostic testing platforms have become available for selecting appropriate patients for MET targeting in a variety of settings. Importantly, in light of the failures of several earlier clinical studies of MET targeting agents, a large array of recent and current MET-focused trials are incorporating stricter patient selection and more robust predictive biomarkers providing hope for validation of MET targeting as a clinically impactful strategy.

  4. MET/HGF pathway in multiple myeloma: from diagnosis to targeted therapy?

    PubMed

    Gambella, Manuela; Palumbo, Antonio; Rocci, Alberto

    2015-01-01

    The interaction between neoplastic cells and the microenvironment is critical in several cancers and plays a central role in multiple myeloma. Microenvironmental stimuli support plasma cell proliferation, survival, motility and can determine drug resistance. The network between plasma cells and surrounding cells is also responsible for increasing angiogenesis, unbalancing bone formation and bony lesions. The MET/HGF pathway is a key player in this interaction and has been found to be abnormally active in both malignant plasma cells and surrounding cells. Patients with abnormal MET and/or HGF levels usually have a poor outcome even when treated with novel drugs. This review addresses the role of MET/HGF in the pathogenesis of myeloma and describes the role of MET/HGF signaling as a prognostic factor. The different techniques to detect MET/HGF abnormalities are examined and a description of compounds targeting MET/HGF is also provided.

  5. 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.

  6. MET4 Expression Predicts Poor Prognosis of Gastric Cancers with Helicobacter pylori Infection.

    PubMed

    Sakamoto, Naoko; Tsujimoto, Hironori; Takahata, Risa; Brian, Cao; Ping, Zhao; Ito, Nozomi; Shimazaki, Hideyuki; Ichikura, Takashi; Hase, Kazuo; Vande Woude, George F; Shinomiya, Nariyoshi

    2016-12-23

    Role of HGF/SF-MET signaling is important in cancer progression, but its relation with Helicobacter pylori-positive gastric cancers remains to be elucidated. In total, 201 patients with primary gastric carcinoma who underwent curative or debulking resection without preoperative chemotherapy were studied. MET4 and anti-HGF/SF mAbs were used for immunohistochemical analysis. Survival of gastric cancer patients was estimated by Kaplan-Meier method and compared with log-rank. Cox proportional hazards models were fit to determine the independent association of MET-staining status with outcome. The effect of live H. pylori bacteria on cell signaling and biological behaviors was evaluated using gastric cancer cell lines. MET4-positive gastric cancers showed poorer prognosis than MET4-negative cases (overall survival, P = 0.02; relapse-free survival, P = 0.06). Positive staining for MET4 was also a statistically significant factor to predict poor prognosis in H. pylori-positive cases (overall survival, P < 0.01; relapse-free survival, P = 0.01) but not in H. pylori-negative cases. Gastric cancers positively stained with both HGF/SF and MET4 showed a tendency of worst prognosis. Stimulation of MET-positive gastric cancer cells with live H. pylori bacteria directly up-regulated MET phosphorylation and activated MET downstream signals such as p44/42MAPK and Akt, conferring cell proliferation and anti-apoptotic activity. In conclusion, positive staining for MET4 was useful for predicting poor prognosis of gastric cancers with H. pylori infection. H. pylori stimulated MET-positive gastric cancers and activated downstream signaling, thereby promoting cancer proliferation and anti-apoptotic activity. These results support the importance of H. pylori elimination from gastric epithelial surface in clinical therapy. This article is protected by copyright. All rights reserved.

  7. MET and MST1R as prognostic factors for classical Hodgkin's lymphoma.

    PubMed

    Wha Koh, Young; Park, Chansik; Hyun Yoon, Dok; Suh, Cheolwon; Huh, Jooryung

    2013-09-01

    MST1R (RON) and MET are receptor tyrosine kinase gene family members that form a noncovalent complex on the cell surface, a critical step in tumor progression. A recent study suggested a prognostic role of MET expression in Hodgkin/Reed-Sternberg (HRS) cells in classical Hodgkin's lymphoma (cHL). The purpose of this study was to examine the prognostic significance of MET and MST1R expression in cHL. The prognostic impact of MET and MST1R was examined in 100 patients with cHL (median age: 32 years) by immunohistochemistry and mRNA in situ hybridization. The median follow-up time was 95 months (interquartile range: 42-126 months). MET or MST1R protein expression was associated with high MET or MST1R mRNA expression, respectively. Thirty-eight patients (38%) expressed MET protein in HRS cell, which was associated with better overall survival (P=0.004). Twenty-six patients (26%) expressed MST1R protein, which was associated with better overall survival (P=0.022) and event-free survival (P=0.021). Multivariate analysis identified MET protein as an independent prognostic factor for overall survival and MST1R protein as an independent prognostic factor for event-free survival. Subgroup analysis according to Ann Arbor stage showed that expressions of MET and MST1R protein have prognostic impact in the advanced stage only. In particular, coexpression of MST1R and MET protein was associated with a better survival outcome than MET or MST1R expression alone or no expression. This study suggests that MET and MST1R are independent prognostic factors in classical cHL, and may allow the identification of a subgroup of cHL patients who require more intensive therapy.

  8. Negative Suppressors of Oncogenic Activation of the Met Receptor Tyrosine Kinase

    DTIC Science & Technology

    2007-03-01

    that activate the Met receptor in human cancer , I have previously shown that the specific uncoupling of Met from ubiquitination results in its...INTRODUCTION The Met receptor tyrosine kinase (RTK) and its ligand, Hepatocyte growth factor (HGF) are deregulated in human breast cancer , through over...invasive tumour margins. We have shown that HGF stimulates the dissociation, motility and invasion of human breast cancer cell lines in culture. These

  9. 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

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

    PubMed Central

    2012-01-01

    Background Hepatocyte growth factor (HGF) induced c-Met activation is known as the main stimulus for hepatocyte proliferation and is essential for liver development and regeneration. Activation of HGF/c-Met signaling has been correlated with aggressive phenotype and poor prognosis in hepatocellular carcinoma (HCC). MUC1 is a transmembrane mucin, whose over-expression is reported in most cancers. Many of the oncogenic effects of MUC1 are believed to occur through the interaction of MUC1 with signaling molecules. To clarify the role of MUC1 in HGF/c-Met signaling, we determined whether MUC1 and c-Met interact cooperatively and what their role(s) is in hepatocarcinogenesis. Results MUC1 and c-Met over-expression levels were determined in highly motile and invasive, mesenchymal-like HCC cell lines, and in serial sections of cirrhotic and HCC tissues, and these levels were compared to those in normal liver tissues. Co-expression of both c-Met and MUC1 was found to be associated with the differentiation status of HCC. We further demonstrated an interaction between c-Met and MUC1 in HCC cells. HGF-induced c-Met phosphorylation decreased this interaction, and down-regulated MUC1 expression. Inhibition of c-Met activation restored HGF-mediated MUC1 down-regulation, and decreased the migratory and invasive abilities of HCC cells via inhibition of β-catenin activation and c-Myc expression. In contrast, siRNA silencing of MUC1 increased HGF-induced c-Met activation and HGF-induced cell motility and invasion. Conclusions These findings indicate that the crosstalk between MUC1 and c-Met in HCC could provide an advantage for invasion to HCC cells through the β-catenin/c-Myc pathway. Thus, MUC1 and c-Met could serve as potential therapeutic targets in HCC. PMID:22962849

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

    NASA Technical Reports Server (NTRS)

    Herman, Benjamin M.

    2003-01-01

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

  12. Met/HGF receptor modulates bcl-w expression and inhibits apoptosis in human colorectal cancers

    PubMed Central

    Kitamura, S; Kondo, S; Shinomura, Y; Kanayama, S; Miyazaki, Y; Kiyohara, T; Hiraoka, S; Matsuzawa, Y

    2000-01-01

    The met proto-oncogene is the tyrosine kinase growth factor receptor for hepatocyte growth factor. In the present study, we investigated the role of met expression on the modulation of apoptosis in colorectal tumours. The gene expressions of c- met and the anti-apoptotic bcl -2 family, including bcl -2, bcl -x L and bcl-w, were analysed in human colorectal adenomas and adenocarcinomas by using a quantitative polymerase chain-reaction combined with reverse transcription. In seven of 12 adenomas and seven of 11 carcinomas, the c- met gene was overexpressed. The bcl -w, bcl -2 and bcl -x L genes were over-expressed in nine, five and six of 12 adenomas and in five, two and seven of 11 carcinomas, respectively. The c- met mRNA level in human colorectal adenomas and carcinomas was correlated with bcl -w but not with bcl -2 or with bcl -x L mRNA level. The administration of c- met -antisense oligonucleotides decreased Met protein levels in the LoVo human colon cancer cell line. In the case of c- met -antisense-treated cells, apoptotic cell death induced by serum deprivation was more prominent, compared to control or c- met -nonsense-treated cells. Treatment with c- met -antisense oligonucleotides inhibits the gene expression of bcl -w in LoVo cells. On the other hand, the gene expression of bcl -2 or bcl -x L was not affected by treatment with c- met -antisense oligonucleotides. These findings suggest that Met expression modulates apoptosis through bcl -w expression in colorectal tumours. © 2000 Cancer Research Campaign PMID:10944610

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

    NASA Technical Reports Server (NTRS)

    Herman, Benjamin M.

    2003-01-01

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

  14. Necrosis- and apoptosis-related Met cleavages have divergent functional consequences

    PubMed Central

    Montagne, R; Berbon, M; Doublet, L; Debreuck, N; Baranzelli, A; Drobecq, H; Leroy, C; Delhem, N; Porte, H; Copin, M-C; Dansin, E; Furlan, A; Tulasne, D

    2015-01-01

    Upon activation by its ligand hepatocyte growth factor/scatter factor, the receptor tyrosine kinase Met promotes survival, proliferation, and migration of epithelial cells during embryogenesis. Deregulated Met signaling can also promote cancer progression and metastasis. Met belongs to the functional family of dependence receptors whose activity switches from pro-survival to pro-apoptotic during apoptosis upon caspase cleavage. Although apoptosis resistance is a hallmark of cancer cells, some remain sensitive to other cell death processes, including necrosis induced by calcium stress. The role and fate of Met during necrotic cell death are unknown. Following treatment with calcium ionophores, cell lines and primary cells undergo necrosis, and the full-length Met receptor is efficiently degraded. This degradation is achieved by double cleavage of Met in its extracellular domain by a metalloprotease of the A disintegrin and metalloproteinase (ADAM) family and in its intracellular domain by calpains (calcium-dependent proteases). These cleavages separate the Met extracellular region from its kinase domain, thus preventing Met activity and its potential pro-survival activity. Although the intracellular fragment is very similar to the fragment generated by caspases, it displays no pro-apoptotic property, likely because of the presence of the last few amino acids of Met, known to inhibit this pro-apoptotic function. The fragments identified here are observed in lung tumors overexpressing the Met receptor, along with fragments previously identified, suggesting that proteolytic cleavages of Met are involved in its degradation in tumor tissues. Thus, Met is a modulator of necrosis, able to protect cells when activated by its ligand but efficiently degraded by proteolysis when this process is engaged. PMID:25996296

  15. MDA-MET-conditioned-medium augments the chemoattractant-dependent migration of MDA-MET cells towards hFOB-conditioned medium and increases collagenase activity.

    PubMed

    Chin-Quee, Karis; Donahue, Henry J

    2017-05-11

    Metastasis of breast cancer displays site-specificity towards bone. Recently, studies have emerged indicating that primary tumors may remotely influence creation of a pre-metastatic niche. In this study, we used human fetal osteoblastic cells and MDA-MET, a metastatic and preferentially bone homing derivative of the breast cancer cell line MDA-MB-231. We examined 1) whether secreted factors from MDA-MET cells increase generation of chemoattractants by human foetal osteoblastic cells 2) whether MDA-MET cells were responsive to these chemoattractants and 3) the identity of these chemoattractants. Human foetal osteoblastic cells were treated with conditioned medium of MDA-MET cells for 24 hours and then washed with phosphate-buffered saline. Serum-free replacement medium was conditioned by treated hFOB cells for 18 hours, before its use in in vitro quantification of MDA-MET migration. We also quantified collagen levels and collagenase activity in conditioned medium from human foetal osteoblastic cells. Conditioned medium from human foetal osteoblastic cells that had been treated with MDA-MET-conditioned medium attracted more MDA-MET cells than hFOB cells pre-exposed to their own medium. This conditioned medium had increased collagenase activity. The addition of bacterial collagenase removed the ability of conditioned medium from human foetal osteoblastic cells to attract MDA-MET cells. Our data suggest that an increase in collagenase activity in osteoblastic cells induced by their exposure to breast cancer cell-secreted factors may increase their ability to attract breast cancer cells.

  16. Met degradation by SAIT301, a Met monoclonal antibody, reduces the invasion and migration of nasopharyngeal cancer cells via inhibition of EGR-1 expression

    PubMed Central

    Lee, B-S; Kang, S; Kim, K-A; Song, Y-J; Cheong, K H; Cha, H-Y; Kim, C-H

    2014-01-01

    Nasopharyngeal carcinoma (NPC) is a common malignant tumor with high invasive and metastatic potential. The hepatocyte growth factor (HGF)-Met signaling pathway has a critical role in mediating the invasive growth of many different types of cancer, including head and neck squamous cell carcinoma. HGF also stimulates NPC cell growth and invasion in the cell line model. In this study, we determined the inhibitory effect of Met, using a Met-targeting monoclonal antibody (SAIT301), on the invasive and growth potential of NPC cell lines. Met inhibition by SAIT301 resulted in highly significant inhibition of cell migration and invasion in both the HONE1 and HNE1 cell lines. In addition, we also found that co-treatment of SAIT301 and HGF decreased the anchorage-independent growth induced by HGF in HNE1 cell lines. After SAIT301 treatment, Met, together with its downstream signaling proteins, showed downregulation of p-Met and p-ERK, but not p-AKT, in both HONE1 and HNE1 cell lines. Interestingly, we found that HGF treatment of NPC cell lines induced early growth response protein (EGR-1) expression, which is involved in cell migration and invasion. In addition, co-treatment with SAIT301 and HGF inhibited the HGF-induced expression of EGR-1. Next, knockdown of EGR-1 using small-interfering RNA inhibited HGF-induced cell invasion in NPC cell lines, suggesting that the expression level of EGR-1 is important in HGF-induced cell invasion of NPC cells. Therefore, the results support that SAIT301 inhibited Met activation as well as the downstream EGR-1 expression and could have therapeutic potential in NPC. Taken together, we suggest that Met is an anticancer therapeutic target for NPC that warrants further investigation and clinical trials and SAIT301 may be a promising tool for NPC therapy. PMID:24722284

  17. Activation of MET pathway predicts poor outcome to cetuximab in patients with recurrent or metastatic head and neck cancer.

    PubMed

    Madoz-Gúrpide, Juan; Zazo, Sandra; Chamizo, Cristina; Casado, Victoria; Caramés, Cristina; Gavín, Eduardo; Cristóbal, Ion; García-Foncillas, Jesús; Rojo, Federico

    2015-08-29

    Activation of the MET oncogene promotes tumor growth, invasion and metastasis in several tumor types. Additionally, MET is activated as a compensatory pathway in the presence of EGFR blockade, thus resulting in a mechanism of resistance to EGFR inhibitors. We have investigated the impact of HGF and MET expression, MET activation (phosphorylation), MET gene status, and MET-activating mutations on cetuximab sensitivity in recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC) patients. A single-institution retrospective analysis was performed in 57 patients. MET overexpression was detected in 58% patients, MET amplification in 39% and MET activation (p-MET) in 30%. Amplification was associated with MET overexpression. Log-rank testing showed significantly worse outcomes in recurrent/metastatic, MET overexpressing patients for progression-free survival and overall survival. Activation of MET was correlated with worse PFS and OS. In multivariate logistic regression analysis, p-MET was an independent prognostic factor for PFS. HGF overexpression was observed in 58% patients and was associated with MET phosphorylation, suggesting a paracrine activation of the receptor. HGF/MET pathway activation correlated with worse outcome in recurrent/metastatic HNSCC patients. When treated with a cetuximab-based regimen, these patients correlated with worse outcome. This supports a dual blocking strategy of HGF/MET and EGFR pathways for the treatment of patients with recurrent/metastatic HNSCC.

  18. Chemical inhibitors of c-Met receptor tyrosine kinase stimulate osteoblast differentiation and bone regeneration.

    PubMed

    Kim, Jung-Woo; Nam Lee, Mi; Jeong, Byung-Chul; Oh, Sin-Hye; Kook, Min-Suk; Koh, Jeong-Tae

    2017-03-16

    The c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been recently introduced to negatively regulate bone morphogenetic protein (BMP)-induced osteogenesis. However, the effect of chemical inhibitors of c-Met receptor on osteoblast differentiation process has not been examined, especially the applicability of c-Met chemical inhibitors on in vivo bone regeneration. In this study, we demonstrated that chemical inhibitors of c-Met receptor tyrosine kinase, SYN1143 and SGX523, could potentiate the differentiation of precursor cells to osteoblasts and stimulate regeneration in calvarial bone defects of mice. Treatment with SYN1143 or SGX523 inhibited HGF-induced c-Met phosphorylation in MC3T3-E1 and C3H10T1/2 cells. Cell proliferation of MC3T3-E1 or C3H10T1/2 was not significantly affected by the concentrations of these inhibitors. Co-treatment with chemical inhibitor of c-Met and osteogenic inducing media enhanced osteoblast-specific genes expression and calcium nodule formation accompanied by increased Runx2 expression via c-Met receptor-dependent but Erk-Smad signaling independent pathway. Notably, the administration of these c-Met inhibitors significantly repaired critical-sized calvarial bone defects. Collectively, our results suggest that chemical inhibitors of c-Met receptor tyrosine kinase might be used as novel therapeutics to induce bone regeneration.

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

    PubMed Central

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

    2016-01-01

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

  20. Activation of Pim Kinases Is Sufficient to Promote Resistance to MET Small Molecule Inhibitors

    PubMed Central

    An, Ningfei; Xiong, Ying; LaRue, Amanda C.; Kraft, Andrew S.; Cen, Bo

    2015-01-01

    MET blockade offers a new targeted therapy particularly in those cancers with MET amplification. However, the efficacy and the duration of the response to MET inhibitors are limited by the emergence of drug resistance. Here we report that resistance to small molecule inhibitors of MET can arise from increased expression of the pro-survival Pim protein kinases. This resistance mechanism was documented in non-small cell lung cancer and gastric cancer cells with MET amplification. Inhibition of Pim kinases enhanced cell death triggered by short-term treatment with MET inhibitors. Pim kinases control the translation of anti-apoptotic protein Bcl-2 at an internal ribosome entry site and this mechanism was identified as the basis for Pim-mediated resistance to MET inhibitors. Protein synthesis was increased in drug-resistant cells, secondary to a Pim-mediated increase in cap-independent translation. In cells rendered drug resistant by chronic treatment with MET inhibitors, genetic or pharmacological inhibition of Pim kinases was sufficient to restore sensitivity in vitro and in vivo. Taken together, our results rationalize Pim inhibition as a strategy to augment responses and blunt acquired resistance to MET inhibitors in cancer. PMID:26670562

  1. 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.

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2014-01-01

    c-Met, the receptor for Hepatocyte Growth Factor (HGF), overexpressed and deregulated in Hepatocellular Carcinoma (HCC). Caveolin 1 (CAV1), a plasma membrane protein that modulates signal transduction molecules, is also overexpressed in HCC. The aim of this study was to investigate biological and clinical significance of co-expression and activation of c-Met and CAV1 in HCC. We showed that c-Met and CAV1 were co-localized in HCC cells and HGF treatment increased this association. HGF-triggered c-Met activation caused a concurrent rise in both phosphorylation and expression of CAV1. Ectopic expression of CAV1 accelerated c-Met signaling, resulted in enhanced migration, invasion, and branching-morphogenesis. Silencing of CAV1 downregulated c-Met signaling, and decreased migratory/invasive capability of cells and attenuated branching morphogenesis. In addition, activation and co-localization of c-Met and CAV1 were elevated during hepatocarcinogenesis. In conclusion reciprocal activating crosstalk between c-Met and CAV1 promoted oncogenic signaling of c-Met contributed to the initiation and progression of HCC. PMID:25148256

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

    PubMed

    Lozano, Jesus; Belles, Xavier

    2014-01-01

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

  5. Definition of a direct extracellular interaction between Met and E-cadherin.

    PubMed

    Reshetnikova, Galina; Troyanovsky, Sergei; Rimm, David L

    2007-04-01

    High levels of the Met tyrosine kinase receptor expression are associated with metastatic disease. Met activation by hepatocyte growth factor (HGF) is associated with decreased E-cadherin-dependent cell-cell contacts. The molecular mechanism underlying this process remains unclear. To better understand the relationship between E-cadherin and Met, we assessed Met localization in cells which form mature E-cadherin-dependent adhesion HT-29 and cells which have lost E-cadherin expression BT-549. Met colocalized with E-cadherin at the site of cell-cell adhesion in HT-29 cells, but Met was distributed in an intracellular compartment in BT-549 cells. Forced expression of E-cadherin in BT-549 cells recruited Met to the membrane. Cross-linking studies suggested that Met and E-cadherin interact in the extracellular domain in HT-29 cells. This is the first evidence of a physical interaction between Met and E-cadherin. We suggest that this receptor/cadherin pairing may be a mechanism for cellular presentation of receptors in a manner that localizes them optimally for interaction with ligand.

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

    PubMed

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

    2016-03-01

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

  7. Proteomic insights into metabolic adaptation to deletion of metE in Saccharopolyspora spinosa.

    PubMed

    Yang, Qi; Li, Yunlong; Yang, Huijun; Rang, Jie; Tang, Sijia; He, Lian; Li, Li; Ding, Xuezhi; Xia, Liqiu

    2015-10-01

    Saccharopolyspora spinosa can produce spinosad as a major secondary metabolite, which is an environmentally friendly agent for insect control. Cobalamin-independent methionine synthase (MetE) is an important enzyme in methionine biosynthesis, and this enzyme is probably closely related to spinosad production. In this study, its corresponding gene metE was inactivated, which resulted in a rapid growth and glucose utilisation rate and almost loss of spinosad production. A label-free quantitative proteomics-based approach was employed to obtain insights into the mechanism by which the metabolic network adapts to the absence of MetE. A total of 1440 proteins were detected from wild-type and ΔmetE mutant strains at three time points: stationary phase of ΔmetE mutant strain (S1ΔmetE , 67 h), first stationary phase of wild-type strain (S1WT, 67 h) and second stationary phase of wild-type strain (S2WT, 100 h). Protein expression patterns were determined using an exponentially modified protein abundance index (emPAI) and analysed by comparing S1ΔmetE /S1WT and S1ΔmetE /S2WT. Results showed that differentially expressed enzymes were mainly involved in primary metabolism and genetic information processing. This study demonstrated that the role of MetE is not restricted to methionine biosynthesis but rather is involved in global metabolic regulation in S. spinosa.

  8. Tracking MET de-addiction in lung cancer: A road towards the oncogenic target.

    PubMed

    Pilotto, S; Carbognin, L; Karachaliou, N; Ma, P C; Rosell, R; Tortora, G; Bria, E

    2017-08-20

    The discovery of druggable oncogenic drivers (i.e. EGFR and ALK), along with the introduction of comprehensive tumor genotyping techniques into the daily clinical practice define non-small-cell lung cancer (NSCLC) asa group of heterogeneous diseases, requiring a context-personalized clinico-therapeutical approach. Among the most investigated biomarkers, the MET proto-oncogene has been extensively demonstrated to play a crucial role throughout the lung oncogenesis, unbalancing the proliferation/apoptosis signaling and influencing the epithelial-mesenchymal transition and the invasive phenotype. Nevertheless, although different mechanisms eliciting the aberrant MET-associated oncogenic stimulus have been detected in lung cancer (such as gene amplification, increased gene copy number, mutations and MET/HGF overexpression), to date no clinically impactful results have been achieved with anti-MET tyrosine kinase inhibitors and monoclonal antibodies in the context of an unselected or MET enriched population. Recently, MET exon 14 splicing abnormalities have been identified asa potential oncogenic target in lung cancer, able to drive the activity of MET inhibitors in molecularly selected patients. In this paper, the major advancement and drawbacks of MET history in lung cancer are reviewed, underlying the renewed scientific euphoria related to the recent identification of MET exon 14 splicing variants asan actionable oncogenic target. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Effect of COMT val158met genotype on cognition and personality.

    PubMed

    Sheldrick, A J; Krug, A; Markov, V; Leube, D; Michel, T M; Zerres, K; Eggermann, T; Kircher, T

    2008-09-01

    The gene encoding catechol-O-methyltransferase (COMT), an enzyme which regulates prefrontal cortex dopamine, contains a common functional single nucleotide polymorphism (val158met, rs4680G/A), which accounts for part of the interindividual variance in performance during working memory tasks and also predicts personality traits. We examined the relationship between the val158met polymorphism and cognitive function as well as personality traits in 522 healthy individuals (mean age: 24.75 years, SD=5.84, mean years of education: 15.59, SD=2.65). COMT val158met genotype was related in allele dosage fashion to performance in an executive function test, with the met/met carriers scoring highest. Subjects carrying the met/met genotype also scored higher in the disorganization domain of the SPQ-B personality inventory. Consistent with evidence from previous studies, higher dopamine availability of the met/met genotype enhances prefrontally mediated executive function in healthy individuals. Furthermore, we replicated findings from a recent study whereby the COMT genotype also predicts disorganized personality features.

  10. 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.

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

    PubMed

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

    2014-06-14

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

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

    PubMed Central

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

    2014-01-01

    Aberrant activation of the HGF/MET signaling axis has been strongly implicated in the malignant transformation and progression of gastroesophageal cancer (GEC). MET receptor overexpression in tumor samples from GEC patients has been consistently correlated with an aggressive metastatic phenotype and poor prognosis. In preclinical GEC models, abrogation of HGF/MET signaling has been shown to induce tumor regression as well as inhibition of metastatic dissemination. Promising clinical results in patient subsets in which MET is overexpressed have spurned several randomized studies of HGF/MET-directed agents, including two pivotal global Phase III trials. Available data highlight the need for predictive biomarkers in order to select patients most likely to benefit from HGF/MET inhibition. In this review, we discuss the current knowledge of mechanisms of MET activation in GEC, the current status of the clinical evaluation of MET-targeted therapies in GEC, characteristics of ongoing randomized GEC trials and the associated efforts to identify and validate biomarkers. We also discuss the considerations and challenges for HGF/MET inhibitor drug development in the GEC setting. PMID:24930887

  13. Progress of antibody-based inhibitors of the HGF–cMET axis in cancer therapy

    PubMed Central

    Kim, Ki-Hyun; Kim, Hyori

    2017-01-01

    Dysregulated receptor tyrosine kinase signaling in human cancer cells leads to tumor progression, invasion and metastasis. The receptor tyrosine kinase cMET is frequently overexpressed in cancer tissue, and activation of cMET signaling is related to drug resistance and the processes of carcinogenesis, invasion and metastasis. For that reason, cMET and its ligand, hepatocyte growth factor (HGF), are considered prime targets for the development of anticancer drugs. At least eight anti-cMET and four anti-HGF antibodies have been tested or are being tested in clinical trials. However, to date none of these HGF/cMET inhibitors have shown significant efficacy in clinical trials. Furthermore, no receptor tyrosine kinase inhibitors primarily targeting cMET have been approved. Given that neutralization of HGF or cMET does not cause significant adverse effects, inhibition of the HGF/cMET signaling pathway appears to be safe. In this review, we summarized the completed and ongoing clinical trials testing antibody- or protein-based anticancer drugs targeting cMET and HGF. PMID:28336955

  14. Progress of antibody-based inhibitors of the HGF-cMET axis in cancer therapy.

    PubMed

    Kim, Ki-Hyun; Kim, Hyori

    2017-03-24

    Dysregulated receptor tyrosine kinase signaling in human cancer cells leads to tumor progression, invasion and metastasis. The receptor tyrosine kinase cMET is frequently overexpressed in cancer tissue, and activation of cMET signaling is related to drug resistance and the processes of carcinogenesis, invasion and metastasis. For that reason, cMET and its ligand, hepatocyte growth factor (HGF), are considered prime targets for the development of anticancer drugs. At least eight anti-cMET and four anti-HGF antibodies have been tested or are being tested in clinical trials. However, to date none of these HGF/cMET inhibitors have shown significant efficacy in clinical trials. Furthermore, no receptor tyrosine kinase inhibitors primarily targeting cMET have been approved. Given that neutralization of HGF or cMET does not cause significant adverse effects, inhibition of the HGF/cMET signaling pathway appears to be safe. In this review, we summarized the completed and ongoing clinical trials testing antibody- or protein-based anticancer drugs targeting cMET and HGF.

  15. 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

  16. 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

    2008-12-02

    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.

  17. Putative PPAR target genes express highly in skeletal muscle of insulin-resistant MetS model SHR/NDmc-cp rats.

    PubMed

    Hariya, Natsuyo; Miyake, Kunio; Kubota, Takeo; Goda, Toshinao; Mochizuki, Kazuki

    2015-01-01

    It is known that insulin resistance in skeletal muscle induces subsequent metabolic diseases such as metabolic syndrome (MetS). However, which genes are altered in the skeletal muscle by development of insulin resistance in animal models has not been examined. In this study, we performed microarray and subsequent real-time RT-PCR analyses using total RNA extracted from the gastrocnemius muscle of the MetS model, spontaneously hypertensive corpulent congenic (SHR/NDmc-cp) rats, and control Wistar Kyoto (WKY) rats. SHR/NDmc-cp rats displayed overt insulin resistance relative to WKY rats. The expression of many genes related to fatty acid oxidation was higher in SHR/NDmc-cp rats than in WKY rats. Among 18 upregulated genes, putative peroxisome proliferator responsive elements were found in the upstream region of 15 genes. The protein expression of ACOX2, an upregulated gene, and peroxisome proliferator-activated receptor (PPAR) G1, but not of PPARG2, PPARA or PPARD, was higher in the gastrocnemius muscle of SHR/NDmc-cp rats than that in WKY rats. These results suggest that insulin resistance in the MetS model, SHR/NDmc-cp rats, is positively associated with the expression of fatty acid oxidation-related genes, which are presumably PPARs’ targets, in skeletal muscle.

  18. 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

  19. Plexin B1 inhibits MET through direct association and regulates Shp2 expression in melanocytes.

    PubMed

    Soong, Joanne; Scott, Glynis

    2013-01-15

    Plexin B1, the receptor for Semaphorin 4D (Sema4D), is expressed by melanocytes in the skin. We recently showed that Sema4D suppresses activation of the hepatocyte growth factor receptor, MET, in melanocytes, and that knockdown of Plexin B1 results in activation of MET. MET signaling mediates proliferation, survival and migration in melanocytes, and its activation is associated with transformation of melanocytes to melanoma. In this report we investigated the mechanism by which Plexin B1 inhibits MET activation. Our results show that Plexin B1 and MET exist as an oligomeric receptor-receptor complex in melanocytes, and that receptor association is increased by Sema4D. MET and Plexin B1 receptor complexes were identified along the cell body of melanocytes, and Sema4D increased receptor association on dendrites, suggesting that Sema4D regulates MET-dependent processes at precise locations on the melanocyte. Despite activation of MET, Plexin B1 knockdowns proliferated slowly and showed increased apoptosis compared with controls. Shp2, a non-receptor protein tyrosine phosphatase, translates growth and survival signals from MET and other receptor tyrosine kinases. Plexin B1 knockdowns had markedly lower levels of Shp2 compared with controls, and Sema4D upregulated Shp2 expression at the protein and message level in normal melanocytes. Functional studies showed that blockade of Shp2 activity abrogated MET-dependent activation of Erk1/Erk2 and Akt in melanocytes. These results suggest a complex role for Sema4D and Plexin B1 in orchestrating signaling from the MET receptor in melanocytes. Because Shp2 is a downstream adaptor protein for multiple receptors, Sema4D may control the effects of several growth factors on melanocytes through regulation of Shp2.

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

    PubMed Central

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

    2005-01-01

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

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

    PubMed

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

    2005-03-28

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

  2. XRCC3 Thr241Met polymorphism and risk of acute myeloid leukemia in a Romanian population.

    PubMed

    Bănescu, Claudia; Tilinca, Mariana; Benedek, Erzsebeth Lazar; Demian, Smaranda; Macarie, Ioan; Duicu, Carmen; Dobreanu, Minodora

    2013-09-10

    DNA repair systems have a critical role in maintaining the genome integrity and stability. DNA repair gene polymorphisms may influence the capacity to repair DNA damage, and thus lead to an increased cancer susceptibility. X-ray repair cross-complementing groups 3 (XRCC3), a DNA repair gene, may be involved in acute myeloid leukemia susceptibility. The objective of the current study was to investigate the association of Thr241Met polymorphism of XRCC3 gene with the risk of acute myeloid leukemia (AML). This study included 78 AML patients and 121 healthy individuals without cancer. We used polymerase chain reaction-restriction fragment length polymorphism assay to determine XRCC3 genotypes. The XRCC3 variant genotype (Thr/Met+Met/Met) was more frequent in AML patients than in healthy controls (OR=2.76, 95% CI: 1.52-4.98, P=0.001). Our study revealed a statistically significant association between variant genotype (Thr/Met+Met/Met) and AML de novo compared to secondary AML (P=0.007). No significant associations were found between any genotype and age at diagnosis, number of white blood cells and subtype of AML. Overall survival of patients with Thr/Thr genotype was better than those of variant Thr/Met and Met/Met genotypes. Our findings indicate that the XRCC3 Thr241Met polymorphism may be a genetic risk factor for AML, particularly in male patients with de novo AML from the central part of Romania. Copyright © 2013 Elsevier B.V. All rights reserved.

  3. 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.

  4. The Prognostic Significance of c-MET and EGFR Overexpression in Resected Gastric Adenocarcinomas.

    PubMed

    Paliga, Aleksandra; Marginean, Horia; Tessier-Cloutier, Basile; Purgina, Bibianna; Jonker, Derek; Marginean, Esmeralda C

    2015-06-29

    Epidermal growth factor receptor (EGFR) and c-MET are tyrosine kinase growth factor receptors implicated in gastric cancer (GC), and their pathways appear to be interdependent. The aim of this study was to investigate the prognostic value of EGFR and c-MET protein overexpression by immunohistochemistry in Canadian patients with resected GC and correlate it with clinicopathologic characteristics and overall survival (OS). Tissue microarray blocks were constructed from 120 resected GCs stained with EGFR and c-MET and scored semiquantitatively (0 to 3+). Each receptor's expression was compared with clinicopathologic characteristics and survival. Descriptive statistics, Kaplan-Meyer, and Cox regression were used for statistical analyses. Of the 113 interpretable cases, overexpression of EGFR and c-MET was noted in 17 (15%) and 65 (57%), respectively; coexpression of EGFR and c-MET was observed in 12 (10%) of GC. EGFR and c-MET overexpression correlated with poor OS: median 13 versus 30 months in EGFR positive versus negative GC (hazard ratio [HR]=1.67, P=0.11); 27 versus 49 months in c-MET positive versus negative GC (HR=1.17, P=0.49), respectively. GC coexpressing EGFR and c-MET was significantly correlated with poor survival: 12 versus 29 months in double-positive versus rest of tumors both in univariate (HR=2.62, P=0.003) and multivariate analyses (HR=2.58, P=0.01). This study describes the prevalence and prognostic value of EGFR and c-MET in a Canadian population of patients undergoing curative intent resection for GC. Both c-MET and EGFR overexpression trended toward poor OS, but only the group with EGFR+/c-MET+ GC reached statistical significance on multivariate analysis.

  5. Quantification of serum MET in non-small-cell lung cancer and its clinical significance.

    PubMed

    Li, Detao; Li, Fengzeng; Wu, Yanfeng; Zhou, Dandan; Chen, Hui

    2015-02-01

    Mesenchymal-epithelial transition factor (MET) plays a critical role in the development and progression of lung cancer. We aimed to quantify the level of serum MET DNA, analyze its diagnostic value, and provide a novel biomarker for lung cancer. Serum MET DNA was extracted from 95 patients with lung cancer, 10 with benign lung diseases, and 34 healthy volunteers. MET DNA was quantified using real-time fluorescent quantitative polymerase chain reaction (FQ-PCR). Data were analyzed using statistical software SPSS 17.0. Serum MET DNA level in the lung cancer group was higher than in the healthy group and benign lung diseases group. Serum MET DNA level was higher in lung cancers patients with smoking, squamous cell carcinoma, advanced TNM stage, and increased tumor size. The difference in serum MET DNA level was not related to sex, age, and lymph node metastasis among the lung cancer patients. The receiver operating characteristic curve showed a sensitivity of 72.6% and specificity of 90.9% for the ability of serum MET DNA to detect lung cancer at the cutoff value of 1.30 × 10(4) copies/μL. The association of serum MET DNA level with existing clinical lung tumor markers was analyzed, including neuron-specific enolase, squamous cell carcinoma antigen, and cytokeratin fragment 21-1. With the combination of serum MET DNA, the sensitivity was raised from 39.1%, 24.9%, 66.1% to 83.3%, 79.4% and 90.7%, respectively. Quantification of serum MET DNA by FQ-PCR may serve as a novel accessible diagnostic tool for the clinical screening and detection of lung cancer. Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  6. DNA repair gene XRCC3 Thr241Met polymorphism and hepatocellular carcinoma risk.

    PubMed

    Duan, Chenyang; Zhang, Wanli; Lu, Jiangfeng; Wu, Huawen; Liu, Mengying; Zhu, Wentao

    2013-10-01

    The DNA repair genes have been indicated as candidates in the risk of hepatocellular carcinoma (HCC). Published data on the association between X-ray repair cross-complementing group 3 (XRCC3), a critical member of the DNA repair genes, and HCC risk were contradictory. The aim of this meta-analysis was to assess the effect of XRCC3 Thr241Met polymorphism on HCC risk by pooling available data from published case-control studies. We calculated the pooled odds ratio (OR) with the corresponding 95 % confidence interval (95 % CI) to estimate the effect. Based on the inclusion criteria, six individual studies with 2,288 cases and 3,170 controls were included into our study. Overall, significant association between the XRCC3 Thr241Met variant and HCC risk was observed under the following contrast models (OR Met vs. Thr = 1.68, 95 %CI 1.08-2.62; OR MetMet vs. ThrThr = 5.54, 95 %CI 3.09-9.94; OR MetMet vs. ThrThr + ThrMet = 5.70, 95 % CI 4.24-7.64). Besides, the pooled ORs indicated that the XRCC3 Thr241Met polymorphism exerted risk effect on the HCC pathogenesis among Asians. Additionally, when stratifying by the status of smoking and hepatitis B virus infection, the XRCC3 Thr241Met variant was significantly associated with HCC risk among the HBsAg (+) individuals but not the HBsAg (-) individuals, smokers, and non-smokers. The present meta-analysis suggests that the XRCC3 Thr241Met polymorphism is an independent risk factor for HCC, particularly among Asians and the HBsAg (+) individuals.

  7. Different growth and metastatic phenotypes associated with a cell-intrinsic change of Met in metastatic melanoma

    PubMed Central

    Adachi, Eri; Sakai, Katsuya; Nishiuchi, Takumi; Imamura, Ryu; Sato, Hiroki; Matsumoto, Kunio

    2016-01-01

    A dynamic phenotypic change contributes to the metastatic progression and drug resistance in malignant melanoma. Nevertheless, mechanisms for a phenotypic change have remained to be addressed. Here, we show that Met receptor expression changes in a cell-autonomous manner and can distinguish phenotypical differences in growth, as well as in metastatic and drug-resistant characteristics. In metastatic melanoma, the cells are composed of Met-low and Met-high populations. Met-low populations have stem-like gene expression profiles, are resistant to chemotherapeutic agents, and have shown abundant angiogenesis and rapid tumor growth in subcutaneous inoculation. Met-high populations have a differentiated phenotype, are relatively resistant to B-RAF inhibitor, and are highly metastatic to the lungs. Met plays a definitive role in lung metastasis because the lung metastasis of Met-high cells requires Met, and treatment of mice with the Met-containing exosomes from Met-high cells facilitates lung metastasis by Met-low cells. Clonal cell fate analysis showed the hierarchical phenotypical changes from Met-low to Met-high populations. Met-low cells either showed self-renewal or changed into Met-high cells, whereas Met-high cells remained Met-high. Clonal transition from Met-low to Met-high cells accompanied changes in the gene expression profile, in tumor growth, and in metastasis that were similar to those in Met-high cells. These findings indicate that malignant melanoma has the ability to undergo phenotypic change by a cell-intrinsic/autonomous mechanism that can be characterized by Met expression. PMID:27683122

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

    PubMed

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

    2011-10-01

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

  9. Down-Regulation of the Met Receptor Tyrosine Kinase by Presenilin-dependent Regulated Intramembrane Proteolysis

    PubMed Central

    Foveau, Bénédicte; Ancot, Frédéric; Leroy, Catherine; Petrelli, Annalisa; Reiss, Karina; Vingtdeux, Valérie; Giordano, Silvia; Fafeur, Véronique

    2009-01-01

    Hepatocyte growth factor/scatter factor (HGF/SF) acts through the membrane-anchored Met receptor tyrosine kinase to induce invasive growth. Deregulation of this signaling is associated with tumorigenesis and involves, in most cases, overexpression of the receptor. We demonstrate that Met is processed in epithelial cells by presenilin-dependent regulated intramembrane proteolysis (PS-RIP) independently of ligand stimulation. The proteolytic process involves sequential cleavage by metalloproteases and the γ-secretase complex, leading to generation of labile fragments. In normal epithelial cells, although expression of cleavable Met by PS-RIP is down-regulated, uncleavable Met displayed membrane accumulation and induced ligand-independent motility and morphogenesis. Inversely, in transformed cells, the Met inhibitory antibody DN30 is able to promote Met PS-RIP, resulting in down-regulation of the receptor and inhibition of the Met-dependent invasive growth. This demonstrates the original involvement of a proteolytic process in degradation of the Met receptor implicated in negative regulation of invasive growth. PMID:19297528

  10. 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…

  11. PRIMA-1(MET) induces death in soft-tissue sarcomas cell independent of p53.

    PubMed

    Grellety, Thomas; Laroche-Clary, Audrey; Chaire, Vanessa; Lagarde, Pauline; Chibon, Frédéric; Neuville, Agnes; Italiano, Antoine

    2015-10-13

    The aim of this study was to explore the efficacy and define mechanisms of action of PRIMA-1(MET) as a TP53 targeted therapy in soft-tissue sarcoma (STS) cells. We investigated effects of PRIMA-1(MET) on apoptosis, cell cycle, and induction of oxidative stress and autophagy in a panel of 6 STS cell lines with different TP53 status. Cell viability reduction by PRIMA-1(MET) was significantly observed in 5 out of 6 STS cell lines. We found that PRIMA-1(MET) was capable to induce cell death not only in STS cells harboring mutated TP53 but also in TP53-null STS cells demonstrating that PRIMA-1(MET) can induce cell death independently of TP53 in STS cells. We identified an important role of reactive oxygen species (ROS), involved in PRIMA-1(MET) toxicity in STS cells leading to a caspase-independent cell death. ROS toxicity was associated with autophagy induction or JNK pathway activation which represented potential mechanisms of cell death induced by PRIMA-1(MET) in STS. PRIMA-1(MET) anti-tumor activity in STS partly results from off-target effects involving ROS toxicity and do not deserve further development as a TP53-targeted therapy in this setting.

  12. 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…

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

    ERIC Educational Resources Information Center

    Valladares, Maya

    2017-01-01

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

  14. Learning about Teaching: Initial Findings from the Measures of Effective Teaching Project. Research Paper. MET Project

    ERIC Educational Resources Information Center

    Bill & Melinda Gates Foundation, 2010

    2010-01-01

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

  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. 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.

  17. 76 FR 25278 - Safety Zone; TriMet Bridge Project, Willamette River; Portland, OR

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-04

    ... SECURITY Coast Guard 33 CFR Part 165 RIN 1625-AA00 Safety Zone; TriMet Bridge Project, Willamette River... is proposing the establishment of a safety zone during the construction of the TriMet Bridge on the..., will be starting construction of the new Portland-Milwaukie Light Rail Bridge on July 1, 2011 (with in...

  18. 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

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

    DTIC Science & Technology

    2012-07-01

    bromopalmitate (2BP) at time points prior to loss of significant c-Met protein which supports the specificity of labeling (Fig. 1B). I was further...palmitate. Here we provide evidence that inhibition of palmitoylation, using the palmitate analog 2- bromopalmitate , lowers total c-Met levels. This

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

    PubMed

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

    2015-10-01

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

  1. 34 CFR 650.34 - What conditions must be met by fellows?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 34 Education 3 2013-07-01 2013-07-01 false What conditions must be met by fellows? 650.34 Section 650.34 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF... By Fellows? § 650.34 What conditions must be met by fellows? In order to continue to receive...

  2. 34 CFR 650.34 - What conditions must be met by fellows?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 34 Education 3 2014-07-01 2014-07-01 false What conditions must be met by fellows? 650.34 Section 650.34 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF... By Fellows? § 650.34 What conditions must be met by fellows? In order to continue to receive...

  3. 34 CFR 650.34 - What conditions must be met by fellows?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 34 Education 3 2011-07-01 2011-07-01 false What conditions must be met by fellows? 650.34 Section 650.34 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF... By Fellows? § 650.34 What conditions must be met by fellows? In order to continue to receive...

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

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 34 Education 3 2012-07-01 2012-07-01 false What conditions must be met by fellows? 650.34 Section 650.34 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF... By Fellows? § 650.34 What conditions must be met by fellows? In order to continue to receive...

  5. 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…

  6. 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…

  7. "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…

  8. 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? All...

  9. Val66Met polymorphism association with serum BDNF and inflammatory biomarkers in major depression.

    PubMed

    Caldieraro, Marco Antonio; McKee, Madison; Leistner-Segal, Sandra; Vares, Edgar Arrua; Kubaski, Francyne; Spanemberg, Lucas; Brusius-Facchin, Ana Carolina; Fleck, Marcelo P; Mischoulon, David

    2017-07-12

    Current evidence supports participation of neurotrophic and inflammatory factors in the pathogenesis of major depressive disorder (MDD). Some studies reported an association between the Val66Met polymorphism (rs6265) of brain-derived neurotrophic factor (BDNF) gene with MDD and peripheral BDNF levels. However, no previous studies have examined the association of this polymorphism with inflammation. The present study assessed the association of the Val66Met polymorphism with serum levels of BDNF and inflammatory markers among depressed outpatients. All participants (n = 73) met DSM-IV criteria for a unipolar depressive episode. The serum levels of BDNF and inflammatory biomarkers (IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ) were compared between individuals presenting with at least one Met allele (Met-carriers) and those homozygous for the Val allele. In our sample (84.9% female, mean age 52.4 ± 10.3 years), 24.7% (n = 18) were Met-carriers. After Bonferroni correction, the Met allele was significantly associated with higher BDNF and lower TNF-α. These associations persisted after adjusting for potential confounders. The pattern of low BDNF and high inflammation in MDD may be influenced by the Val66Met polymorphism. The association of a polymorphism in the BDNF gene with inflammatory markers in addition to BDNF levels suggests an interaction between these systems.

  10. Protective autophagy is involved in resistance towards MET inhibitors in human gastric adenocarcinoma cells.

    PubMed

    Humbert, Magali; Medová, Michaela; Aebersold, Daniel M; Blaukat, Andree; Bladt, Friedhelm; Fey, Martin F; Zimmer, Yitzhak; Tschan, Mario P

    2013-02-08

    MET, also known as hepatocyte growth factor receptor (HGFR), is a receptor tyrosine kinase with an important role, both in normal cellular function as well as in oncogenesis. In many cancer types, abnormal activation of MET is related to poor prognosis and various strategies to inhibit its function, including small molecule inhibitors, are currently in preclinical and clinical evaluation. Autophagy, a self-digesting recycling mechanism with cytoprotective functions, is induced by cellular stress. This process is also induced upon cytotoxic drug treatment of cancer cells and partially allows these cells to escape cell death. Thus, since autophagy protects different tumor cells from chemotherapy-induced cell death, current clinical trials aim at combining autophagy inhibitors with different cancer treatments. We found that in a gastric adenocarcinoma cell line GTL-16, where MET activity is deregulated due to receptor overexpression, two different MET inhibitors PHA665752 and EMD1214063 lead to cell death paralleled by the induction of autophagy. A combined treatment of MET inhibitors together with the autophagy inhibitor 3-MA or genetically impairing autophagy by knocking down the key autophagy gene ATG7 further decreased cell viability of gastric cancer cells. In general, we observed the induction of cytoprotective autophagy in MET expressing cells upon MET inhibition and a combination of MET and autophagy inhibition resulted in significantly decreased cell viability in gastric cancer cells.

  11. Activating mutations for the Met tyrosine kinase receptor in human cancer

    PubMed Central

    Jeffers, Michael; Schmidt, Laura; Nakaigawa, Noboru; Webb, Craig P.; Weirich, Gregor; Kishida, Takeshi; Zbar, Berton; Vande Woude, George F.

    1997-01-01

    Recently, mutations in the Met tyrosine kinase receptor have been identified in both hereditary and sporadic forms of papillary renal carcinoma. We have introduced the corresponding mutations into the met cDNA and examined the effect of each mutation in biochemical and biological assays. We find that the Met mutants exhibit increased levels of tyrosine phosphorylation and enhanced kinase activity toward an exogenous substrate when compared with wild-type Met. Moreover, NIH 3T3 cells expressing mutant Met molecules form foci in vitro and are tumorigenic in nude mice. Enzymatic and biological differences were evident among the various mutants examined, and the somatic mutations were generally more active than those of germ-line origin. A strong correlation between the enzymatic and biological activity of the mutants was observed, indicating that tumorigenesis by Met is quantitatively related to its level of activation. These results demonstrate that the Met mutants originally identified in human papillary renal carcinoma are oncogenic and thus are likely to play a determinant role in this disease, and these results raise the possibility that activating Met mutations also may contribute to other human malignancies. PMID:9326629

  12. 77 FR 59036 - Public Hearing To Determine Whether Wildfire Has Met Remedy Requirements

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-25

    ... National Highway Traffic Safety Administration Public Hearing To Determine Whether Wildfire Has Met Remedy... Systems, Inc., also known as Wildfire Motors (Wildfire),\\1\\ of Steubenville, Ohio, have reasonably met... Wildfire imported from China. \\1\\ Wildfire Motors is a registered trade name of Snyder Computer...

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

    PubMed Central

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

    1997-01-01

    The Met/Hepatocyte Growth Factor (HGF) receptor tyrosine kinase is oncogenically activated through a rearrangement that creates a hybrid gene Tpr-Met. The resultant chimeric p65(Tpr-Met) protein is constitutively phosphorylated on tyrosine residues in vivo and associates with a number of SH2-containing signaling molecules including the p85 subunit of PI-3 kinase and the Grb2 adaptor protein, which couples receptor tyrosine kinases to the Ras signaling pathway. Mutation of the binding site for Grb2 impairs the ability of Tpr-Met oncoprotein to transform fibroblasts, suggesting that the activation of the Ras/MAP kinase signaling pathway through Grb2 may be essential for cellular transformation. To test this hypothesis dominant-negative mutants of Grb2 with deletions of the SH3 domains were introduced into Tpr-Met transformed fibroblasts. Cells overexpressing the mutants were found to be morphologically reverted and exhibited reduced growth in soft agar. Surprisingly, the Grb2 mutants blocked activation of the JNK/SAPK but not MAP kinase activity induced by the Tpr-Met oncoprotein. Additionally, cells expressing dominant-negative Grb2 mutants had reduced PI-3-kinase activity and dominant-negative mutants of Rac1 blocked both Tpr-Met-induced transformation and activation of JNK. These experiments reveal a novel link between Met and the JNK pathway, which is essential for transformation by this oncogene. PMID:9184210

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

    PubMed

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

    2010-08-06

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

  15. 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.

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

    PubMed

    2016-11-01

    Pediatric glioblastoma is one of the most common and most deadly brain tumors in childhood. Using an integrative genetic analysis of 53 pediatric glioblastomas and five in vitro model systems, we identified previously unidentified gene fusions involving the MET oncogene in ∼10% of cases. These MET fusions activated mitogen-activated protein kinase (MAPK) signaling and, in cooperation with lesions compromising cell cycle regulation, induced aggressive glial tumors in vivo. MET inhibitors suppressed MET tumor growth in xenograft models. Finally, we treated a pediatric patient bearing a MET-fusion-expressing glioblastoma with the targeted inhibitor crizotinib. This therapy led to substantial tumor shrinkage and associated relief of symptoms, but new treatment-resistant lesions appeared, indicating that combination therapies are likely necessary to achieve a durable clinical response.

  17. Indazoles as potential c-Met inhibitors: design, synthesis and molecular docking studies.

    PubMed

    Ye, Lianbao; Ou, Xiaomin; Tian, Yuanxin; Yu, Bangwei; Luo, Yan; Feng, Binghong; Lin, Hansen; Zhang, Jiajie; Wu, Shuguang

    2013-07-01

    Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is considered as an attractive target for small molecule drug discovery. In this study, a series of indazoles were designed, synthesized and evaluated as novel c-Met inhibitors. The results showed that the majority of the compounds exhibited significant inhibition on c-Met and compound 4d showed highest activity against c-Met with IC50 value of 0.17 μM in TR-FRET-based assay and IC50 value of 5.45 μM in cell-based assay as compared to other tested compounds. Molecular docking experiments verified the results and explained the molecular mechanism of pretty activities to c-Met.

  18. Understanding c-MET signalling in squamous cell carcinoma of the head & neck.

    PubMed

    Szturz, P; Raymond, E; Abitbol, C; Albert, S; de Gramont, A; Faivre, S

    2017-03-01

    c-MET is a membrane spanning receptor tyrosine kinase for hepatocyte growth factor (HGF) also termed scatter factor. Transmitting signals from mesenchymal to epithelial cells, the HGF/c-MET axis mediates a range of biological processes that stimulate proliferation, motility, invasiveness, morphogenesis, apoptosis, and angiogenesis. Aberrant c-MET signal transduction favours tumorigenesis with the acquisition of invasive and metastatic phenotypes. Biological functions of c-MET may strongly vary according to microenvironmental changes, which occur at different stages of tumorigenesis and include also HGF/c-MET activation in stromal cells. In this review, we focused on abnormalities in non-nasopharyngeal squamous cell carcinoma of the head & neck. While the prevalence of c-MET mutations and amplifications ranges 0-25%, c-MET upregulation can be found in the majority of squamous head & neck carcinomas. Despite marked heterogeneity in published scoring methods, immunohistochemical overexpression of c-MET has been typically linked to advanced stages and associated with impaired survival and/or resistance to radiotherapy, chemoradiotherapy, and cetuximab. Experimental studies in cell lines and patient-derived xenografts using various c-MET antagonists (both as single-agents and in combination with cytotoxic and epidermal growth factor receptor [EGFR]-directed agents) yielded promising results, albeit benefit in clinical trials remains to be demonstrated. Consequently, selecting more active agents and integrating them effectively in studies, which incorporate predictive biomarkers such as c-MET gene mutations, amplifications, and overexpression, remains challenging. Further investigations should increase emphasis on disentangling the role of tumour-stromal interactions and analyse their potential as modifiers of drug response.

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

    Several receptor tyrosine kinases (RTKs) including EGFR, ALK, and MET have been identified as therapeutic targets in non-small cell lung cancer (NSCLC). Among the downstream pathways of RTKs, the MAPK pathway is particularly important for cancer cell proliferation, differentiation, and survival. In this study, the effects of MEK inhibitors (trametinib and PD0325901) in several NSCLC cell lines with driver gene alterations, especially RTK genes, were tested in vitro using an MTT assay, and a wide range of sensitivities was found. In particular, all the EGFR-mutated cell lines were resistant to MEK inhibitors, whereas all the MET-amplified cell lines were sensitive. A bioinformatics technique and western blot analyses showed that the PI3K/AKT pathway is more activated in EGFR-mutated NSCLC than in MET-amplified NSCLC, and a PI3K inhibitor enhanced the sensitivity to trametinib in the EGFR-mutated cell lines, suggesting that this pathway is associated with resistance to MEK inhibitors. Although the HCC827 cell line (EGFR mutation) was resistant to MEK inhibitors, the HCC827CNXR cell line, whose driver gene shifts from EGFR to MET, exhibited enhanced sensitivity to MEK inhibitors, indicating the biological importance of the MAPK pathway for MET-amplified NCSLC. Furthermore, a synergistic effect of crizotinib (a MET inhibitor) and trametinib was observed in MET-amplified NCLC cell lines. Our findings indicate that the MAPK pathway is biologically important for MET-amplified NSCLC and strongly encourage the development of combination therapy with a MET inhibitor and a MEK inhibitor against MET-amplified NSCLC. PMID:27748834

  1. Central pain sensitization, COMT Val158Met polymorphism, and emotional factors in fibromyalgia.

    PubMed

    Desmeules, Jules; Chabert, Jocelyne; Rebsamen, Michela; Rapiti, Elisabetta; Piguet, Valerie; Besson, Marie; Dayer, Pierre; Cedraschi, Christine

    2014-02-01

    Neurobiological evidence points to altered central nervous system processing of nociceptive stimuli in fibromyalgia. Enzymes like catechol-O-methyl-transferase (COMT) are involved in the elimination of catecholamines playing a possible role in central sensitization and pain. We used quantitative sensory testing to evidence central sensitization in fibromyalgia patients and test whether COMTVal158Met polymorphism, associated with a reduction in enzyme activity, plays a role in sensitized patients. Pain evaluation and quantitative sensory testing were performed including the spinal nociceptive flexion reflex, a physiologic correlate for the evaluation of central nociceptive pathways. Quality of life and distress questionnaires were used. A total of 137 fibromyalgia patients were assessed and compared to 99 matched controls. Central sensitization (nociceptive flexion reflex <27 mA) was present in 95/134 (71%) patients. Among them, COMT p.Val158Met polymorphism displayed a significant linear "genotype effect" (P = .033), with the Met/Met (mean = 17.8 ± 4.8 mA) and Val/Val (mean = 21.4 ± 4.6 mA) subgroups at the opposite ends of the nociceptive flexion reflex threshold (Met/Met vs Val/Val P = .015) and the Val/Met subgroup (mean = 19 ± 4.9 mA) in between (Val/Met vs Val/Val P = .041). Spontaneous moderate to severe pain was more likely to be associated with COMT Met/Met genotype. Patients showed important emotional distress compared to controls. In sensitized patients, the COMT Met/Met subgroup showed systematically-though not significantly-worse scores for all psychological variables. The association between COMT p.Val158Met polymorphism and central sensitization in fibromyalgia is essential as it refers to the severity of central sensitization and may be a risk factor for treatment outcome. Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.

  2. 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

  3. 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

  4. 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.

  5. Agonist antibodies activating the Met receptor protect cardiomyoblasts from cobalt chloride-induced apoptosis and autophagy.

    PubMed

    Gallo, S; Gatti, S; Sala, V; Albano, R; Costelli, P; Casanova, E; Comoglio, P M; Crepaldi, T

    2014-04-17

    Met, the tyrosine kinase receptor for hepatocyte growth factor (HGF), mainly activates prosurvival pathways, including protection from apoptosis. In this work, we investigated the cardioprotective mechanisms of Met activation by agonist monoclonal antibodies (mAbs). Cobalt chloride (CoCl2), a chemical mimetic of hypoxia, was used to induce cardiac damage in H9c2 cardiomyoblasts, which resulted in reduction of cell viability by (i) caspase-dependent apoptosis and (ii) - surprisingly - autophagy. Blocking either apoptosis with the caspase inhibitor benzyloxycarbonyl-VAD-fluoromethylketone or autophagosome formation with 3-methyladenine prevented loss of cell viability, which suggests that both processes contribute to cardiomyoblast injury. Concomitant treatment with Met-activating antibodies or HGF prevented apoptosis and autophagy. Pro-autophagic Redd1, Bnip3 and phospho-AMPK proteins, which are known to promote autophagy through inactivation of the mTOR pathway, were induced by CoCl2. Mechanistically, Met agonist antibodies or HGF prevented the inhibition of mTOR and reduced the flux of autophagosome formation. Accordingly, their anti-autophagic function was completely blunted by Temsirolimus, a specific mTOR inhibitor. Targeted Met activation was successful also in the setting of low oxygen conditions, in which Met agonist antibodies or HGF demonstrated anti-apoptotic and anti-autophagic effects. Activation of the Met pathway is thus a promising novel therapeutic tool for ischaemic injury.

  6. 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. Crown Copyright © 2014. Published by Elsevier B.V. All rights reserved.

  7. Clinical Significance of MET Gene Copy Number in Patients with Curatively Resected Gastric Cancer

    PubMed Central

    Kang, Byung Woog; Park, Heyoung; Park, Bo Eun; Jeon, Seong Woo; Bae, Han Ik; Kwon, Oh-kyoung; Chung, Ho Young; Yu, Wansik

    2015-01-01

    The present study analyzed the prognostic impact of MET gene copy number in patients with curatively resected gastric cancer who received a combination regimen of cisplatin and S-1. The MET gene copy number was analyzed by use of quantitative real-time polymerase chain reaction. From January 2006 to July 2010, 70 tumor samples from 74 patients enrolled in a pilot study were analyzed. According to a cutoff MET gene copy number of ≥2 copies, a high MET gene copy number was observed in 38 patients (54.3%). The characteristics of the 2 groups divided according to MET gene copy number were similar. With a median follow-up duration of 26.4 months (range, 2.6-73.2 months), the estimated 3-year relapse-free survival and overall survival rates were 54.3% and 77.4%, respectively. No significant association was observed between the MET gene copy number and survival in a multivariate analysis. The MET gene copy number investigated in this study was not found to be associated with prognosis in patients with curatively resected gastric cancer. PMID:26306302

  8. 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

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

    PubMed

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

    2012-01-01

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

  10. Identification of a novel population of highly cytotoxic c-Met-expressing CD8(+) T lymphocytes.

    PubMed

    Benkhoucha, Mahdia; Molnarfi, Nicolas; Kaya, Gürkan; Belnoue, Elodie; Bjarnadóttir, Kristbjörg; Dietrich, Pierre-Yves; Walker, Paul R; Martinvalet, Denis; Derouazi, Madiha; Lalive, Patrice H

    2017-09-01

    CD8(+) cytotoxic T lymphocytes (CTLs) are critical mediators of anti-tumor immunity, and controlling the mechanisms that govern CTL functions could be crucial for enhancing patient outcome. Previously, we reported that hepatocyte growth factor (HGF) limits effective murine CTL responses via antigen-presenting cells. Here, we show that a fraction of murine effector CTLs expresses the HGF receptor c-Met (c-Met(+) CTLs). Phenotypic and functional analysis of c-Met(+) CTLs reveals that they display enhanced cytolytic capacities compared to their c-Met(-) CTL counterparts. Furthermore, HGF directly restrains the cytolytic function of c-Met(+) CTLs in cell-mediated cytotoxicity reactions in vitro and in vivo and abrogates T-cell responses against metastatic melanoma in vivo Finally, we establish in three murine tumor settings and in human melanoma tissues that c-Met(+) CTLs are a naturally occurring CD8(+) T-cell population. Together, our findings suggest that the HGF/c-Met pathway could be exploited to control CD8(+) T-cell-mediated anti-tumor immunity. © 2017 The Authors.

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

    PubMed

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

    2015-06-01

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

  12. Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas.

    PubMed

    Di Renzo, M F; Olivero, M; Martone, T; Maffe, A; Maggiora, P; Stefani, A D; Valente, G; Giordano, S; Cortesina, G; Comoglio, P M

    2000-03-16

    A metastatic cancer develops by accumulation of mutations in genes that control growth, survival and spreading. The latter genes have not yet been identified. In lymph node metastases of head and neck squamous cell carcinomas (HNSCC), we found mutations in the MET oncogene, which encodes the tyrosine kinase receptor for Scatter Factor, a cytokine that stimulates epithelial cell motility and invasiveness during embryogenesis and tissue remodeling. We identified two somatic mutations: the Y1230C, known as a MET germline mutation which predisposes to hereditary renal cell carcinoma, and the Y1235D that is novel and changes a critical tyrosine, known to regulate MET kinase activity. The mutated MET receptors are constitutively active and confer an invasive phenotype to transfected cells. Interestingly, cells carrying the MET mutations are selected during metastatic spread: transcripts of the mutant alleles are highly represented in metastases, but barely detectable in primary tumors. These data indicate that cells expressing mutant MET undergo clonal expansion during HNSCC progression and suggest that MET might be one of the long sought oncogenes controlling progression of primary cancers to metastasis.

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

    PubMed

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

    2015-01-01

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

  14. Changes in PlGF and MET-HGF expressions in paired initial and recurrent glioblastoma.

    PubMed

    Tabouret, Emeline; Denicolai, Emilie; Delfino, Christine; Graillon, Thomas; Boucard, Celine; Nanni, Isabelle; Padovani, Laetitia; Figarella-Branger, Dominique; Chinot, Olivier

    2016-12-01

    Angiogenesis is one of the key features of glioblastoma (GB). However, the use of anti-angiogenic therapies directed against vascular endothelial growth factor (VEGF) is limited by primary or acquired resistance. MET/HGF and PlGF signaling are involved in potential alternative escape mechanisms to VEGF pathway. Our objective was to explore the potential changes of MET/HGF and PlGF expression, comparing initial diagnosis and recurrence after radiotherapy-temozolomide (RT/TMZ). Paired frozen tumors from both initial and recurrent surgery after radio-chemotherapy were available for 28 patients. RNA expressions of PlGF, MET, and HGF genes were analyzed by RT-qPCR. PlGF expression significantly decreased at recurrence (p = 0.021), and expression of MET showed a significant increase (p = 0.011) at recurrence. RNA expressions of MET and HGF significantly correlated both at baseline and recurrence (baseline: p = 0.005; recurrence: p = 0.019). Evolutive profile (increasing versus decreasing expression at recurrence) of MET was associated with PFS (p = 0.002) and OS (p = 0.022) at recurrence, while the evolutive profile of HGF was associated with PFS at relapse (p = 0.049). Recurrence of GB after chemo-radiation could be associated with a variation in PlGF and MET expression. These results contribute to suggest a modification of the GB angiogenic process between initial diagnosis and recurrence.

  15. Characterization of an oncolytic adenovirus vector constructed to target the cMet receptor

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2017-12-01

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

  17. 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.

  18. Catechol-O-methyltransferase Val158Met polymorphism influences prefrontal executive function in early Parkinson's disease.

    PubMed

    Zhang, Youwen; Feng, Shujun; Nie, Kun; Zhao, Xin; Gan, Rong; Wang, Limin; Zhao, Jiehao; Tang, Hongmei; Gao, Liang; Zhu, Ruiming; Wang, Lijuan; Zhang, Yuhu

    2016-10-15

    The catechol-O-methyltransferase (COMT) Val158Met polymorphism has been proposed to be associated with increased risk of Parkinson's disease (PD) and have a specific impact on dopamine-mediated prefrontal executive function in an inverted-U curve manner. We explored the influence of this genetic polymorphism on prefrontal executive function in a well-established Chinese cohort of early PD patients with no current or past history of motor fluctuations or dyskinesias. Cognitive functions were assessed in 250 patients with early PD using Wechsler Adult Intelligence Scale-Chinese Revision (WAIS-RC) and Wechsler Memory Scale-Chinese Revision (WMS-RC). These patients and 300 healthy controls were subsequently genotyped for the COMT gene Val158Met polymorphism. We employed analysis of covariance (ANCOVA) and a stratified analysis to determine the associations between the COMT Val158Met genotype and cognitive functions. The COMT Val158Met allele frequency and genotype distributions showed no statistically significant differences between PD patients and controls. However, patients with met/met genotype performed significantly worse on WAIS-RC similarities, a measure of executive function, compared to individuals with val/val genotype. Subsequent ANCOVA analysis revealed that COMT genotype interacted with sex and daily levodopa equivalent dose (LED) to influence executive function. Further stratified analysis showed that the lower-activity COMT met/met genotype has a detrimental effect on executive function among women. Our results demonstrate that COMT Val158Met polymorphism is probably not associated with increased risk of PD, but has an effect on prefrontal executive function interacting with gender and dopaminergic medication. Copyright © 2016. Published by Elsevier B.V.

  19. C-met inhibition blocks bone metastasis development induced by renal cancer stem cells

    PubMed Central

    D'Amico, Lucia; Belisario, Dimas; Migliardi, Giorgia; Grange, Cristina; Bussolati, Benedetta; D'Amelio, Patrizia; Perera, Timothy; Dalmasso, Ettore; Carbonare, Luca Dalle; Godio, Laura; Comoglio, Paolo; Trusolino, Livio; Ferracini, Riccardo; Roato, Ilaria

    2016-01-01

    Cancer stem cells (CSCs) are key players in bone metastasis. In some renal tumors CSCs overexpress the HGF receptor c-MET, speculating that c-MET targeting could lead to bone metastasis inhibition. To address this hypothesis we isolated renal CD105+/CD24−CSCs, expressing c-MET receptor from a primary renal carcinoma. Then, to study their ability to metastasize to bone, we injected renal CSCs in NOD/SCID mice implanted with a human bone and we tested the effect of a c-MET inhibitor (JNJ-38877605) on bone metastasis development. JNJ-38877605 inhibited the formation of metastases at bone implant site. We showed that JNJ-38877605 inhibited the activation of osteoclasts induced by RCC stem cells and it stimulated osteoblast activity, finally resulting in a reduction of bone turnover consistent with the inhibition of bone metastases. We measured the circulating levels of osteotropic factors induced by RCC stem cells in the sera of mice treated with c-Met inhibitor, showing that IL-11 and CCL20 were reduced in mice treated with JNJ-38877605, strongly supporting the involvement of c-MET in the regulation of this process. To address the clinical relevance of c-MET upregulation during tumor progression, we analysed c-MET in renal cancer patients detecting an increased expression in the bone metastatic lesions by IHC. Then, we dosed CCL20 serum levels resulting significantly increased in patients with bone metastases compared to non-metastatic ones. Collectively, our data highlight the importance of the c-MET pathway in the pathogenesis of bone metastases induced by RCC stem cells in mice and humans. PMID:27322553

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2015-12-01

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

  3. The global met need for emergency obstetric care: a systematic review.

    PubMed

    Holmer, H; Oyerinde, K; Meara, J G; Gillies, R; Liljestrand, J; Hagander, L

    2015-01-01

    Of the 287,000 maternal deaths every year, 99% happen in low- and middle-income countries. The vast majority could be averted with timely access to appropriate emergency obstetric care (EmOC). The proportion of women with complications of pregnancy or childbirth who actually receive treatment is reported as 'Met need for EmOC'. To estimate the global met need for EmOC and to examine the correlation between met need, maternal mortality ratio and other indicators. A systematic review was performed according to the PRISMA guidelines. Searches were made in PubMed, EMBASE and Google Scholar. Studies containing data on met need in EmOC were selected. Analysis was performed with data extracted from 62 studies representing 51 countries. World Bank data were used for univariate and multiple linear regression. Global met need for EmOC was 45% (IQR: 28-57%), with significant disparity between low- (21% [12-31%]), middle- (32% [15-56%]), and high-income countries (99% [99-99%]), (P = 0.041). This corresponds to 11.4 million (8.8-14.8) untreated complications yearly and 951 million (645-1174 million) women without access to EmOC. We found an inverse correlation between met need and maternal mortality ratio (r = -0.42, P < 0.001). Met need was significantly correlated with the proportion of births attended by skilled birth attendants (β = 0.53 [95% CI 0.41-0.65], P < 0.001). The results suggest a considerable inadequacy in global met need for EmOC, with vast disparities between countries of different income levels. Met need is a powerful indicator of the response to maternal mortality and strategies to improve EmOC act in synergy with the expansion of skilled birth attendance. © 2014 Royal College of Obstetricians and Gynaecologists.

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

    PubMed

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

    2012-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  6. Estimating MET values using the ratio of HR for persons with paraplegia.

    PubMed

    Lee, Miyoung; Zhu, Weimo; Hedrick, Brad; Fernhall, Bo

    2010-05-01

    The current compendium of physical activity (CPA) cannot be applied to persons with disabilities due to the lack of physical activity (PA) they are regularly engaged in and inaccurate MET values when applied to persons with disabilities. The purposes of this study were (a) to determine whether HR ratio during PA and resting can be used to accurately predict MET values of PA in persons with paraplegia, (b) to compare individual calibration (IC) with group calibration (GC) in error reduction, and (c) to examine prediction generalizability through a cross-validation design. Twenty-seven participants (aged 18-45 yr) with complete and incomplete paraplegia at T6 to L4 participated in this study. Oxygen uptake (VO2) and HR were measured simultaneously at rest and during 10 PA using indirect calorimetry and a Polar HR monitor. Predicted METs were calculated using the HR ratio for six activities by applying regression analysis by group (GC) and individuals (IC), respectively. The derived equations were then cross-validated using the four other activities, and corresponding METs were calculated. Absolute error rates (AC), paired t-test, and correlation (r) were used to determine the absolute and relative difference between observed and predicted METs. The overall correlation coefficient (r) between HR ratio and observed METs was 0.77 using group regression and 0.93 +/- 0.05 using individual regression. GC (R2 = 0.59, AC = 0.07%-65.25%) was less accurate than IC (R2 = 0.90 +/- 0.10, AC = 1.64%-10.26%). Cross-validation results also showed higher correlations for IC (r = 0.90 in IC and 0.72 in GC) between observed and predicted METs. HR ratio was able to accurately predict METs of persons with paraplegia. IC estimated METs more accurately than GC.

  7. Comparison Between Histology, Funduscopy and Densitometry for Assessment of Photochemical Damage Thresholds

    DTIC Science & Technology

    1989-10-01

    korte expositie (500 of 1800 s) en ddn oog aan 4 niveaus in een lange expositie (12 hr). De tatale dosis was bij beide expositieduren ongeveer gelijk...Gegeven een vaste dosis bleek de schade bij lange expositie iets kiciner dan bij korte expositie, hetgeen wijst op een hersteiproces met een tijdscon

  8. Estradiol influences the LH response to met-enkephalin. An immunocytochemical and morphometric study.

    PubMed

    Rubio, M; Carretero, J; Sánchez, F; Riesco, J M; Vázquez, R; Vázquez, R

    1992-01-01

    In order to test the possible role of estradiol in the response of the LH-adenohypophyseal cells to the administration of met-enkephalin in the albino male rat, an immunocytochemical (peroxidase-antiperoxidase), morphometric (cellular and nuclear areas and numerical density) and radioimmunoassay (LH serum levels at the moment of sacrifice) study was carried out. The intraventricular administration of met-enkephalin (150 micrograms in 25 microliters of distilled water) does not produce any changes in the parameters considered. However, when the animals were pretreated with estradiol (chronically, 15 days), met-enkephalin produced a significant decrease in all the parameters considered.

  9. PET of c-Met in cancer with 64Cu-labeled Hepatocyte Growth Factor

    PubMed Central

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

    2015-01-01

    The hepatocyte growth factor (HGF) and its receptor, c-Met, are actively involved in tumor progression/metastasis and associated closely with poor prognostic outcome of cancer patients. Thus developing positron emission tomography (PET) agents for assessing c-Met expression would be extremely useful for diagnosis of cancer and subsequent monitoring of responses to c-Met-targeted therapies. Here we report the characterization of recombinant human hepatocyte growth factor (rh-HGF) as a PET tracer for detection of c-Met expression in vivo. Methods rh-HGF was expressed in human embryonic kidney (HEK) 293 cells and purified by nickel-nitrilogriacetic acid (Ni-NTA) affinity chromatography. The concentrated rh-HGF was conjugated to 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) and labeled with 64Cu. c-Met binding evaluation by flow cytometry was performed in both U87MG and MDA-MB-231 cell lines, which have high and low level of c-Met, respectively. PET imaging and biodistribution studies were performed in nude mice bearing U87MG and MDA-MB-231 xenografted tumors. Results The rh-HGF expression yield was 150–200 µg protein per 5 × 106 cells after 48 h transfection with purity of 85% ~ 90%. Flow cytometry examination confirmed strong and specific binding capacity of rh-HGF to c-Met. After labeled with 64Cu, PET imaging revealed specific and prominent uptake of 64Cu-NOTA-rh-HGF in c-Met positive U87MG tumors (6.7 ± 1.8 %ID/g at 9 h post-injection) and significantly lower uptake in c-Met negative MDA-MB-231 tumors (1.8 ± 0.6 %ID/g at 9 h post-injection). The fact that sonicated-denatured rh-HGF (termed as dnrh-HGF) had significantly lower uptake in U87MG tumors, along with histology analysis, confirmed the c-Met specificity of 64Cu-NOTA-rh-HGF. Conclusion The study provided the initial evidence to confirm that 64Cu-NOTA-rh-HGF is applicable for visualizing c-Met expression in vivo, which may also find potential applications in

  10. 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

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

    PubMed

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

    2015-05-01

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

  12. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product

    SciTech Connect

    Bottaro, D.P.; Rubin, J.S.; Chan, A.M.L.; Aaronson, S.A. ); Faletto, D.L.; Kmiecik, T.E.; Vande Woude, G.F. )

    1991-02-15

    Hepatocyte growth factor (HGF) is a plasminogen-like protein thought to be a humoral mediator of liver regeneration. A 145-kilodalton tyrosyl phosphoprotein observed in rapid response to HGF treatment of intact target cells was identified by immunoblot analysis as the {beta} subunit of the c-met proto-oncogene product, a membrane-spanning tyrosine kinase. Covalent cross-linking of {sup 125}I-labeled ligand to cellular proteins of appropriate size that were recognized by antibodies to c-met directly established the c-met product as the cell-surface receptor for HGF.

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2010-01-01

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

  15. 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.

  16. 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...

  17. MetLife Stadium (formerly New Meadowlands Stadium) Environmental Assessment: MOU Annual Report - March 20, 2014

    EPA Pesticide Factsheets

    MetLife Stadium, home of the New York Giants and New York Jets, signed a Memorandum of Understanding (MOU) pledging to become an environmental steward by implementing a number of green initiatives that would reduce its carbon footprint.

  18. 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...

  19. Autism-associated promoter variant in MET impacts functional and structural brain networks.

    PubMed

    Rudie, Jeffrey D; Hernandez, Leanna M; Brown, Jesse A; Beck-Pancer, Devora; Colich, Natalie L; Gorrindo, Philip; Thompson, Paul M; Geschwind, Daniel H; Bookheimer, Susan Y; Levitt, Pat; Dapretto, Mirella

    2012-09-06

    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. Copyright © 2012 Elsevier Inc. All rights reserved.

  20. [No association between catechol-O-methyltransferase val158met polymorphism and alexithymia].

    PubMed

    Hermes, Sandra; Hennig, Jürgen; Stingl, Markus; Leichsenring, Falk; Leweke, Frank

    2011-01-01

    Reduced concentrations of dopamine in prefrontal brain structures may play a role in alexithymia. Dopamine degradation in the orbitofrontal cortex is regulated by catechol-O-methyltransferase (COMT), and a functional single nucleotide polymorphism of the COMT gene, Val158Met, has been related to psychiatric illness. This study examines the association between the COMT Val158Met gene polymorphism, and alexithymia. 120 healthy students and 120 patients with mental disorders were genotyped for the COMT Val158Met polymorphism. Additionally, the Toronto Alexithymia Scale (TAS-20) was administered. COMT genotype did not show a significant correlation with the TAS-20 in either group. COMT Val158Met polymorphism alone does not seem to be a major factor in alexithymia in healthy students. This is true even if patients with mental disorders covering a broader range of alexithymia are included. Thus, other genes, possibly interacting with cultural, environmental, and developmental factors, may be implicated.

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

    PubMed Central

    Landry, Mélissa; Pomerleau, Véronique; Saucier, Caroline

    2016-01-01

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

  2. Hereditary and Sporadic Papillary Renal Carcinomas with c-met Mutations Share a Distinct Morphological Phenotype

    PubMed Central

    Lubensky, Irina A.; Schmidt, Laura; Zhuang, Zhengping; Weirich, Gregor; Pack, Svetlana; Zambrano, Norman; Walther, McClellan M.; Choyke, Peter; Linehan, W. Marston; Zbar, Berton

    1999-01-01

    Germline mutations of c-met oncogene at 7q31 have been detected in patients with hereditary papillary renal cell carcinoma. In addition, c-met mutations were shown to play a role in 13% of patients with papillary renal cell carcinoma and no family history of renal tumors. The histopathology of papillary renal cell carcinoma with c-met mutations has not been previously described. We analyzed the histopathology of 103 bilateral archival papillary renal cell carcinomas and 4 metastases in 29 patients from 6 hereditary papillary renal cell carcinoma families with germline c-met mutations and 6 papillary renal cell carcinomas with c-met mutations from 5 patients with no family history of renal tumors. Twenty-five sporadic renal tumors with prominent papillary architecture and without somatic c-met mutations were evaluated for comparison. All papillary renal cell carcinomas with c-met mutations were 75 to 100% papillary/tubulopapillary in architecture and showed chromophil basophilic, papillary renal cell carcinoma type 1 histology. Fuhrman nuclear grade 1–2 was seen in tumors from 23 patients, and nuclear grade 3 was observed focally in 8 patients. Seventeen patients had multiple papillary adenomas and microscopic papillary lesions in the surrounding renal parenchyma. Clear cells with intracytoplasmic lipid and glycogen were focally present in tumors of 94% papillary renal cell carcinoma patients. Clear cells of papillary renal cell carcinoma had small basophilic nuclei, and clear cell areas lacked a fine vascular network characteristic of conventional (clear) cell renal cell carcinoma. We conclude that papillary renal cell carcinoma patients with c-met mutations develop multiple, bilateral, papillary macroscopic and microscopic renal lesions. Renal tumors with c-met genotype show a distinctive papillary renal cell carcinoma type 1 phenotype and are genetically and histologically different from renal tumors seen in other hereditary renal syndromes and most sporadic

  3. Association between XRCC3 Thr241Met polymorphism and colorectal cancer risk.

    PubMed

    Wang, ZhiZhen; Zhang, Wencheng

    2013-06-01

    The x-ray repair cross-complementing group 3 (XRCC3), a member of DNA repair genes, plays a critical role in the maintenance of genome stability by homologous recombination repair for DNA double-strand breaks. The polymorphism of XRCC3 Thr241Met has been indicated to be involved in the development of some cancers, but previous individual studies on the association between XRCC3 Thr241Met polymorphism and colorectal cancer (CRC) risk have yielded conflicting and inconclusive results. To shed some light on the contradictory findings and improve our understanding of the pathogenesis of CRC, we carried out this updated meta-analysis by pooling all available publications. Databases including PubMed, Embase, Web of Science and China National Knowledge Infrastructure were searched for relevant publications. The odds ratios (ORs) with the corresponding 95 % confidence intervals (95 % CIs) were calculated to estimate the strength of the association between XRCC3 Thr241Met polymorphism and CRC risk. A total of 15 case-control studies involving 4,475 cases and 6,373 controls were included. Overall, the pooled ORs for the meta-analysis of total included studies showed no statistically significant association of XRCC3 Thr241Met polymorphism with CRC risk in any genetic model (ORMet allele vs. Thr allele=1.17, 95 % CI 0.97-1.42, P OR=0.102; ORMetMet vs. ThrThr =1.32, 95 % CI 0.93-1.87, P OR=0.121; ORThrMet vs. ThrThr =1.17, 95 % CI 0.94-1.45, P OR=0.150; ORMetMet + ThrMet vs. ThrThr =1.20, 95 % CI 0.96-1.51, P OR=0.114; ORMetMet vs. ThrThr + ThrMet =1.37, 95 % CI 0.98-1.93, P OR=0.065). However, in subgroup analyses stratified by source of controls and ethnicity, the XRCC3 Thr241Met polymorphism was associated with an elevated risk of CRC in the hospital-based case-control studies and the Asian population. Sensitivity analysis indicated that the findings were unlikely due to chance. This meta-analysis suggests that the XRCC3 Thr241Met polymorphism may modify the risk of

  4. 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

  5. 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/ .

  6. Factors Associated With Met Expectations in Patients With Hand and Upper Extremity Disorders: A Pilot Study.

    PubMed

    Briet, Jan Paul; Hageman, Michiel G J S; Overbeek, Celeste L; Mudgal, Chaitanya; Ring, David C; Vranceanu, Ana-Maria

    2016-01-01

    The degree to which patients' expectations are met during an office visit consistently correlates with patients' satisfaction, whereas the relationship between previsit expectations and satisfaction varies. The aim of this pilot study was to preliminarily assess the relationship of psychosocial factors, pain intensity, and magnitude of disability to previsit expectations, met expectations, and satisfaction with medical care in patients with hand and upper extremity conditions in a surgical outpatient clinic. A cohort of 85 outpatients with upper extremity illnesses indicated their previsit expectations (Patients Intention Questionnaire), degree to which these expectations were met (Expectations Met Questionnaire), level of depressive symptoms (Patient Health Questionnaire-2), confidence about the ability to achieve one's goals in spite of pain (Pain Self-Efficacy Questionnaire), pain intensity (Numerical Rating Scale for pain), disability (Disabilities of the Arm Shoulder and Hand, short version; QuickDASH), and satisfaction with the medical visit (Medical Interview Satisfaction Scale). Higher previsit expectations were associated with more depressive symptoms, lower pain self-efficacy, higher pain intensity, and fewer years of education. Patients in the low and moderate met expectations categories had significantly more symptoms of depression, fewer years of education, and more pain compared to those in the high-met expectations category. Fewer years of education and higher pain intensity predicted higher previsit expectations and explained 19% of variance. Psychosocial factors affect both previsit expectations and met expectations during an outpatient visit to a hand surgeon. Met expectations, but not previsit expectations, affect satisfaction. Prognostic, level II. Copyright © 2016 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

  7. Posttranscriptional regulation of the expression of MET2 gene of Saccharomyces cerevisiae.

    PubMed

    Forlani, N; Martegani, E; Alberghina, L

    1991-05-02

    The first step of the specific pathway for methionine biosynthesis in the yeast Saccharomyces cerevisiae is catalyzed by the enzyme L-homoserine-O-acetyltransferase (HSTase) (EC 2.3.1.31), encoded by the MET2 gene. In order to ascertain whether there is a posttranscriptional control on the MET2 gene expression, as suggested by previous results on the expression of the cloned gene, systems for high inducible expression of MET2 gene were constructed. In these constructs the MET2 gene was cloned in yeast expression vectors under the control of an inducible yeast GAL promoter element so that the MET2 was transcribed at very high levels under induced conditions. Measurements of the specific mRNA levels showed a strong stimulation of MET2 gene transcription in yeast transformants grown on galactose as carbon source, corresponding to 50-100-fold the repressed conditions, while only a 2-fold increase of the enzymatic activity was observed. In addition, no evidence of a strong induced polypeptide of appropriate size on two dimensional gel electrophoresis was obtained. To understand the functional role of the non-coding 5' region of MET2 mRNA, we performed either a partial and a complete deletion of the 5' leader sequence, but even with these constructs an elevated mRNA level was not associated to a marked increase of the HSTase activity. These data support the idea of a posttranscriptional regulation of MET2 gene expression and show that the untranslated region of the specific mRNA is not involved in this regulatory mechanism.

  8. DrugMetZ DB: an anthology of human drug metabolizing Chytochrome P450 enzymes.

    PubMed

    Antony, Tresa Remya Thomas; Nagarajan, Shanthi

    2006-11-14

    Understandings the basics of Cytochrome P450 (P450 or CYP) will help to discern drug metabolism. CYP, a super-family of heme-thiolate proteins, are found in almost all living organisms and is involved in the biotransformation of a diverse range of xenobiotics, therapeutic drugs and toxins. Here, we describe DrugMetZ DB, a database for CYP metabolizing drugs. The DB is implemented in MySQL, PHP and HTML. www.bicpu.edu.in/DrugMetZDB/

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2017-09-19

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

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

    PubMed

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

    2014-03-01

    Small cell lung cancer (SCLC) is a devastating disease, and current therapies have not greatly improved the 5-year survival rates. Topoisomerase (Top) inhibition is a treatment modality for SCLC; however, the response is short lived. Consequently, our research has focused on improving SCLC therapeutics through the identification of novel targets. Previously, we identified MNNG HOS transforming gene (MET) to be overexpressed and functional in SCLC. Herein, we investigated the therapeutic potential of combinatorial targeting of MET using SU11274 and Top1 using 7-ethyl-10-hydroxycamptothecin (SN-38). MET and TOP1 gene copy numbers and protein expression were determined in 29 patients with limited (n = 11) and extensive (n = 18) disease. MET gene copy number was significantly increased (>6 copies) in extensive disease compared with limited disease (P = 0.015). Similar TOP1 gene copy numbers were detected in limited and extensive disease. Immunohistochemical staining revealed a significantly higher Top1 nuclear expression in extensive (0.93) versus limited (0.15) disease (P = 0.04). Interestingly, a significant positive correlation was detected between MET gene copy number and Top1 nuclear expression (r = 0.5). In vitro stimulation of H82 cells revealed hepatocyte growth factor (HGF)-induced nuclear colocalization of p-MET and Top1. Furthermore, activation of the HGF/MET axis enhanced Top1 activity, which was abrogated by SU11274. Combination of SN-38 with SU11274 dramatically decreased SCLC growth as compared with either drug alone. Collectively, these findings suggest that the combinatorial inhibition of MET and Top1 is a potentially efficacious treatment strategy for SCLC. ©2013 AACR.

  12. The BDNF Val66Met Polymorphism Affects the Vulnerability of the Brain Structural Network.

    PubMed

    Park, Chang-Hyun; Kim, Jungyoon; Namgung, Eun; Lee, Do-Wan; Kim, Geon Ha; Kim, Myeongju; Kim, Nayeon; Kim, Tammy D; Kim, Seunghee; Lyoo, In Kyoon; Yoon, Sujung

    2017-01-01

    Val66Met, a naturally occurring polymorphism in the human brain-derived neurotrophic factor (BDNF) gene resulting in a valine (Val) to methionine (Met) substitution at codon 66, plays an important role in neuroplasticity. While the effect of the BDNF Val66Met polymorphism on local brain structures has previously been examined, its impact on the configuration of the graph-based white matter structural networks is yet to be investigated. In the current study, we assessed the effect of the BDNF polymorphism on the network properties and robustness of the graph-based white matter structural networks. Graph theory was employed to investigate the structural connectivity derived from white matter tractography in two groups, Val homozygotes (n = 18) and Met-allele carriers (n = 55). Although there were no differences in the global network measures including global efficiency, local efficiency, and modularity between the two genotype groups, we found the effect of the BDNF Val66Met polymorphism on the robustness properties of the white matter structural networks. Specifically, the white matter structural networks of the Met-allele carrier group showed higher vulnerability to targeted removal of central nodes as compared with those of the Val homozygote group. These findings suggest that the central role of the BDNF Val66Met polymorphism in regards to neuroplasticity may be associated with inherent differences in the robustness of the white matter structural network according to the genetic variants. Furthermore, greater susceptibility to brain disorders in Met-allele carriers may be understood as being due to their limited stability in white matter structural connectivity.

  13. Splicing of arabidopsis tRNA(Met) precursors in tobacco cell and wheat germ extracts.

    PubMed

    Akama, K; Junker, V; Yukawa, Y; Sugiura, M; Beier, H

    2000-09-01

    Intron-containing tRNA genes are exceptional within nuclear plant genomes. It appears that merely two tRNA gene families coding for tRNA(GpsiA(Tyr)) and elongator tRNA(CmAU(Met)) contain intervening sequences. We have previously investigated the features required by wheat germ splicing endonuclease for efficient and accurate intron excision from Arabidopsis pre-tRNA(Tyr). Here we have studied the expression of an Arabidopsis elongator tRNA(Met) gene in two plant extracts of different origin. This gene was first transcribed either in HeLa or in tobacco cell nuclear extract and splicing of intron-containing tRNA(Met) precursors was then examined in wheat germ S23 extract and in the tobacco system. The results show that conversion of pre-tRNA(Met) to mature tRNA proceeds very efficiently in both plant extracts. In order to elucidate the potential role of specific nucleotides at the 3' and 5' splice sites and of a structured intron for pre-tRNA(Met) splicing in either extract, we have performed a systematic survey by mutational analyses. The results show that cytidine residues at intron-exon boundaries impair pre-tRNA(Met) splicing and that a highly structured intron is indispensable for pre-tRNA(Met) splicing. tRNA precursors with an extended anticodon stem of three to four base pairs are readily accepted as substrates by wheat and tobacco splicing endonuclease, whereas pre-tRNA molecules that can form an extended anticodon stem of only two putative base pairs are not spliced at all. An amber suppressor, generated from the intron-containing elongator tRNA(Met) gene, is efficiently processed and spliced in both plant extracts.

  14. 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.

  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. Discovery and Biological Evaluation of Novel Dual EGFR/c-Met Inhibitors

    PubMed Central

    2014-01-01

    Activating mutations in the epidermal growth factor receptor (EGFR) have been identified in a subset of non-small cell lung cancer (NSCLC), which is one of the leading cancer types worldwide. Application of EGFR tyrosine kinase inhibitors leads to acquired resistance by secondary EGFR mutations or by amplification of the hepatocyte growth factor receptor (c-Met) gene. Although several EGFR and c-Met inhibitors have been reported, potent dual EGFR/c-Met inhibitors, which can overcome this latter resistance mechanism, have hitherto not been published and have not reached clinical trials. In the present study we have identified dual EGFR/c-Met inhibitors and designed novel N-[4-(quinolin-4-yloxy)-phenyl]-biarylsulfonamide derivatives, which inhibit the c-Met receptor and both the wild-type and the activating mutant EGFR kinases in nanomolar range. We have demonstrated by Western blot analysis that compound 10 inhibits EGFR and c-Met phosphorylation at cellular level and effectively inhibits viability of the NSCLC cell lines. PMID:24900830

  17. Discovery and Biological Evaluation of Novel Dual EGFR/c-Met Inhibitors.

    PubMed

    Szokol, Bálint; Gyulavári, Pál; Kurkó, Ibolya; Baska, Ferenc; Szántai-Kis, Csaba; Greff, Zoltán; Orfi, Zoltán; Peták, István; Pénzes, Kinga; Torka, Robert; Ullrich, Axel; Orfi, László; Vántus, Tibor; Kéri, György

    2014-04-10

    Activating mutations in the epidermal growth factor receptor (EGFR) have been identified in a subset of non-small cell lung cancer (NSCLC), which is one of the leading cancer types worldwide. Application of EGFR tyrosine kinase inhibitors leads to acquired resistance by secondary EGFR mutations or by amplification of the hepatocyte growth factor receptor (c-Met) gene. Although several EGFR and c-Met inhibitors have been reported, potent dual EGFR/c-Met inhibitors, which can overcome this latter resistance mechanism, have hitherto not been published and have not reached clinical trials. In the present study we have identified dual EGFR/c-Met inhibitors and designed novel N-[4-(quinolin-4-yloxy)-phenyl]-biarylsulfonamide derivatives, which inhibit the c-Met receptor and both the wild-type and the activating mutant EGFR kinases in nanomolar range. We have demonstrated by Western blot analysis that compound 10 inhibits EGFR and c-Met phosphorylation at cellular level and effectively inhibits viability of the NSCLC cell lines.

  18. BDNF Val66Met is associated with introversion and interacts with 5-HTTLPR to influence neuroticism.

    PubMed

    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

    2010-04-01

    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 x 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.

  19. Usefulness of FDG, MET and FLT-PET Studies for the Management of Human Gliomas

    PubMed Central

    Miyake, Keisuke; Shinomiya, Aya; Okada, Masaki; Hatakeyama, Tetsuhiro; Kawai, Nobuyuki; Tamiya, Takashi

    2012-01-01

    The use of positron imaging agents such as FDG, MET, and FLT is expected to lead the way for novel applications toward efficient malignancy grading and treatment of gliomas. In this study, the usefulness of FDG, MET and FLT-PET images was retrospectively reviewed by comparing their histopathological findings. FDG, MET, and FLT-PET were performed in 27 patients with WHO grade IV, 15 patients with WHO grade III, and 12 patients with WHO grade II during 5.5 years. The resulting PET images were compared by measuring SUVs and T/N ratios (tumor to normal tissue ratios). Although there were no significant differences in FDG-PET, there were significant differences in the T/N ratios in the MET-PET between WHO grades II and IV and in the FLT-PET between the WHO grades III and IV. In glioblastoma patients, the SUVs of the areas depicted by MRI in the MET-PET were different from those SUVs in the FLT-PET. Importantly, the areas with high SUVs in both MET-PET and FLT-PET were also high in Ki-67 index and were histologically highly malignant. PET imaging is a noninvasive modality that is useful in determining a tumor area for removal as well as improving preoperative diagnosis for gliomas. PMID:22577290

  20. 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. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  1. Stimulatory effect of intracerebroventricular met- and leu-enkephalin on corticosterone secretion in rats.

    PubMed

    Gadek-Michalska, A; Bugajski, J

    1996-01-01

    The significance of enkephalins for the function of the hypothalamic-pituitary-adrenal (HPA) axis, in spite of many efforts, is still elusive. We investigated the effect of leucine- and methionine-enkephalin on the HPA activity in conscious rats. These enkephalins, given intracerebroventricularly (i.c.v.) increased dose-dependently the activity of the HPA axis, measured indirectly through serum corticosterone levels. On a molar basis, leu-enkephalin exerted a stronger effect that met-enkephalin. Naloxone, an opioid receptor antagonist, given i.c.v. prior to enkephalins almost abolished the corticosterone response to met-enkephalin and significantly impaired the response to leu-enkephalin. Prazosin, an alpha 1-adrenergic antagonist, considerably reduced the increase in serum corticosterone levels induced by both enkephalins. Pretreatment of rats with yohimbine, an alpha 2-adrenergic antagonist, also considerably reduced the corticosterone response to met-enkephalin and significantly diminished the response induced by leu-enkephalin. Naloxone and yohimbine inhibited to the same extent the corticosterone response to met- and leu-enkephalin. This suggests an interaction between presynaptic opioid and alpha 2-receptors in regulation of the HPA function. Propranolol, a beta-adrenergic antagonist, given i.c.v. did not alter the corticosterone levels raised by met- and leu-enkephalin. These results indicate that both met- and leu-enkephalin increase the activity of the HPA axis in rats and both central opioid and adrenergic alpha-receptors are involved in this stimulation.

  2. Activation of the Met receptor by cell attachment induces and sustains hepatocellular carcinomas in transgenic mice.

    PubMed

    Wang, R; Ferrell, L D; Faouzi, S; Maher, J J; Bishop, J M

    2001-05-28

    Overexpression is the most common abnormality of receptor tyrosine kinases (RTKs) in human tumors. It is presumed that overexpression leads to constitutive activation of RTKs, but the mechanism of that activation has been uncertain. Here we show that overexpression of the Met RTK allows activation of the receptor by cell attachment and that this form of activation can be tumorigenic. Transgenic mice that overexpressed Met in hepatocytes developed hepatocellular carcinoma (HCC), one of the human tumors in which Met has been implicated previously. The tumorigenic Met was activated by cell attachment rather than by ligand. Inactivation of the transgene led to regression of even highly advanced tumors, apparently mediated by apoptosis and cessation of cellular proliferation. These results reveal a previously unappreciated mechanism by which the tumorigenic action of RTKs can be mediated, provide evidence that Met may play a role in both the genesis and maintenance of HCC, and suggest that Met may be a beneficial therapeutic target in tumors that overexpress the receptor.

  3. 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

  4. The MetJ regulon in gammaproteobacteria determined by comparative genomics methods

    PubMed Central

    2011-01-01

    Background Whole-genome sequencing of bacteria has proceeded at an exponential pace but annotation validation has lagged behind. For instance, the MetJ regulon, which controls methionine biosynthesis and transport, has been studied almost exclusively in E. coli and Salmonella, but homologs of MetJ exist in a variety of other species. These include some that are pathogenic (e.g. Yersinia) and some that are important for environmental remediation (e.g. Shewanella) but many of which have not been extensively characterized in the literature. Results We have determined the likely composition of the MetJ regulon in all species which have MetJ homologs using bioinformatics techniques. We show that the core genes known from E. coli are consistently regulated in other species, and we identify previously unknown members of the regulon. These include the cobalamin transporter, btuB; all the genes involved in the methionine salvage pathway; as well as several enzymes and transporters of unknown specificity. Conclusions The MetJ regulon is present and functional in five orders of gammaproteobacteria: Enterobacteriales, Pasteurellales, Vibrionales, Aeromonadales and Alteromonadales. New regulatory activity for MetJ was identified in the genomic data and verified experimentally. This strategy should be applicable for the elucidation of regulatory pathways in other systems by using the extensive sequencing data currently being generated. PMID:22082356

  5. 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

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

    PubMed

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

    2017-04-01

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

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

    PubMed

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

    2010-01-14

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

  9. 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

  10. 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.

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

    PubMed

    Amemiya, Hideki; Menolascino, Francisco; Peña, Alix

    2010-09-01

    The product of the proto-oncogene C-MET (the c-Met receptor) and its ligand, hepatocyte growth factor (HGF), have been implicated in the progression of gastric cancer. The aim of this study was to analyze the expression of c-Met receptor, HGF and proliferating cell nuclear antigen (PCNA) by the immunohistochemistry method of labeled streptavidin-biotin, as well as survival, and they were correlated with anatomopathological factors in stomach specimens of 40 patients, who underwent gastrectomy for gastric cancer in the Department of General Surgery, Hospital Central Universitario "Antonio María Pineda" in Barquisimeto, Venezuela, in 2001-2004. High expression of c-Met receptor and PCNA was observed in patients with advanced stages of gastric cancer (III and IV) compared with early stages (I and II) (p<0.01). There was also overexpression of the c-Met receptor in histologic variables with low degree of differentiation, deeper tumor invasion into the submucosa, liver metastases and it is reported a lower survival rate in patients with increased receptor expression (+++ and ++++) when compared with patients with the lowest expression (+ and ++) (p<0.01). The expression of HGF was constant in both, advanced and early groups. The c-Met receptor is associated with proliferation and cell migration in Venezuelan patients with gastric cancer and could be used as a prognostic factor in this pathology.

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

    PubMed

    Kwon, Youngjoo; Godwin, Andrew K

    2017-04-01

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

  13. BDNF Val66Met, stress, and positive mothering: Differential susceptibility model of adolescent trait anxiety.

    PubMed

    Chen, Jie; Yu, Jing; Liu, Yujie; Zhang, Leilei; Zhang, Jianxin

    2015-08-01

    Etiological research has indicated the gene-environment interaction (G × E) on adolescent anxiety. This study aimed to examine how the BDNF Val66Met polymorphism interacted with stressful life events and positive mothering to influence youth trait anxiety. The study sample included 780 community adolescents of Chinese Han ethnicity (M = 13.6, 51.3% females). Participants' trait anxiety, exposure to stressful life events, and mother's warmth-reasoning were assessed by self-reported questionnaires. We found that BDNF Val66Met polymorphism significantly moderated the influences of stressful life events and mother's warmth-reasoning on adolescent anxiety. The influences were significantly greater in adolescents carrying one or two Val allele than those with Met/Met genotype. Moreover, the G × E interactions were more consistent with the differential susceptibility than the diathesis-stress model. Adolescents carrying Val allele who were more susceptible to adversity were also more likely to benefit from supportive experiences. These findings provide novel evidence for the role of BDNF Val66Met as a genetic susceptibility modulating the influences of stressful life events and mother's warmth-reasoning on adolescent anxiety. We speculate that BDNF Val66Met may moderate anxious youths' responses to mindfulness-based stress reduction program and family-based treatment targeting the enhancement of positive parenting. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. MET/HGF pathway activation as a paradigm of resistance to targeted therapies

    PubMed Central

    Ko, Brian; He, Tianfang; Gadgeel, Shirish

    2017-01-01

    Resistance to targeted therapeutics is a key issue limiting the long-term utility of these medications in the management of molecularly selected subsets of cancer patients, including patients with non-small cell lung cancer harboring oncogenic alterations affecting EGFR, ALK and other genes. Bypass resistance mediated by activation of MET kinase has emerged as a frequent, validated and pivotal resistance mechanism in multiple types of cancers. Biochemical understanding is accumulating to explain the unique role of MET in such bypass pathways, providing alternate downstream activation opportunities and intricate interactions during epithelial-mesenchymal transitions. Multiple diagnostic testing platforms have become available for selecting appropriate patients for MET targeting in a variety of settings. Importantly, in light of the failures of several earlier clinical studies of MET targeting agents, a large array of recent and current MET-focused trials are incorporating stricter patient selection and more robust predictive biomarkers providing hope for validation of MET targeting as a clinically impactful strategy. PMID:28164089

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

    PubMed Central

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

    2015-01-01

    Brain-derived neurotrophic factor (BDNF), the most abundant neutrophin in the mammalian central nervous system, is critically involved in synaptic plasticity. In both rodents and humans, BDNF has been implicated in hippocampus- and amygdala-dependent learning and memory and has more recently been linked to fear extinction processes. Fifty-nine healthy participants, genotyped for the functional BDNFval66met polymorphism, underwent a fear conditioning and 24h-delayed extinction protocol while skin conductance and blood oxygenation level dependent (BOLD) responses (functional magnetic resonance imaging) were acquired. We present the first report of neural activation pattern during fear acquisition ‘and’ extinction for the BDNFval66met polymorphism using a differential conditioned stimulus (CS)+ > CS− comparison. During conditioning, we observed heightened allele dose-dependent responses in the amygdala and reduced responses in the subgenual anterior cingulate cortex in BDNFval66met met-carriers. During early extinction, 24h later, we again observed heightened responses in several regions ascribed to the fear network in met-carriers as opposed to val-carriers (insula, amygdala, hippocampus), which likely reflects fear memory recall. No differences were observed during late extinction, which likely reflects learned extinction. Our data thus support previous associations of the BDNFval66met polymorphism with neural activation in the fear and extinction network, but speak against a specific association with fear extinction processes. PMID:25103087

  16. Association between XRCC3 Thr241Met polymorphism and laryngeal cancer susceptibility in Turkish population.

    PubMed

    Mutlu, Pelin; Mutlu, Murad; Yalçın, Serap; Yaylacı, Atılay; Ünsoy, Gözde; Saylam, Güleser; Akın, İstemihan; Gündüz, Ufuk; Korkmaz, Hakan

    2015-12-01

    DNA repair systems are essential for normal cell function. Genetic alterations in the DNA repair genes such as X-ray repair cross-complementing group 3 (XRCC3), can cause a change in protein activity which results in cancer susceptibility. The aim of this study was to investigate the association of XRCC3 Thr241Met single nucleotide polymorphism (SNP), smoking and alcohol consumption with the risk of laryngeal cancer in Turkish population. The frequencies of Thr241Met SNP were studied in 58 laryngeal cancer cases (SSC) and 67 healthy individuals. Genomic DNA was isolated from peripheral blood samples of both controls and laryngeal cancer cases. Thr241Met SNP was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The genotype and allele frequencies of Thr241Met polymorphism were not statistically significant between the laryngeal cancer and control groups. Carrying mutant allele was not associated with the risk of laryngeal cancer. On the other hand, smoking and chronic alcohol consumption were associated with the risk of laryngeal cancer but there is no association between Thr241Met, smoking and alcohol consumption in laryngeal cancer cases. These results indicate that Thr241Met polymorphism was not associated with the development of laryngeal cancer in Turkish population. However, it should be kept in mind that the association of a polymorphism with cancer susceptibility can differ due to several factors such as cancer type, selection criteria, ethnic differences and size of the studied population.

  17. 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. Copyright © 2015 Elsevier Inc. All rights reserved.

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

    PubMed

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

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

  19. Translation initiation factor 2gamma mutant alters start codon selection independent of Met-tRNA binding.

    PubMed

    Alone, Pankaj V; Cao, Chune; Dever, Thomas E

    2008-11-01

    Selection of the AUG start codon for translation in eukaryotes is governed by codon-anticodon interactions between the initiator Met-tRNA(i)(Met) and the mRNA. Translation initiation factor 2 (eIF2) binds Met-tRNA(i)(Met) to the 40S ribosomal subunit, and previous studies identified Sui(-) mutations in eIF2 that enhanced initiation from a noncanonical UUG codon, presumably by impairing Met-tRNA(i)(Met) binding. Consistently, an eIF2gamma-N135D GTP-binding domain mutation impairs Met-tRNA(i)(Met) binding and causes a Sui(-) phenotype. Intragenic A208V and A382V suppressor mutations restore Met-tRNA(i)(Met) binding affinity and cell growth; however, only A208V suppresses the Sui(-) phenotype associated with the eIF2gamma-N135D mutation. An eIF2gamma-A219T mutation impairs Met-tRNA(i)(Met) binding but unexpectedly enhances the fidelity of initiation, suppressing the Sui(-) phenotype associated with the eIF2gamma-N135D,A382V mutant. Overexpression of eIF1, which is thought to monitor codon-anticodon interactions during translation initiation, likewise suppresses the Sui(-) phenotype of the eIF2gamma mutants. We propose that structural alterations in eIF2gamma subtly alter the conformation of Met-tRNA(i)(Met) on the 40S subunit and thereby affect the fidelity of start codon recognition independent of Met-tRNA(i)(Met) binding affinity.

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

    PubMed

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

    2016-12-01

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

  1. Association between XRCC3 Thr241Met polymorphism and risk of brain tumors: a meta-analysis.

    PubMed

    Liu, Jun; Zhou, Zheng; Lai, Ting; Yin, Jinbo

    2014-02-01

    X-ray repair cross-complementing group 3 (XRCC3) plays an important role in the process of homologous recombination repair for DNA double-strand breaks which further maintains the stability of the genome. XRCC3 Thr241Met polymorphism has been indicated in the development of cancers, but the association of the XRCC3 Thr241Met polymorphism with risk of brain tumors is still unclear owing to the conflicting findings from previous studies. We performed a meta-analysis to provide a better understanding on the association between the XRCC3 Thr241Met polymorphism and risk of brain tumors. The pooled odds ratio (OR) with corresponding 95 % confidence interval (95 % CI) was used to assess the association. Thirteen case-control studies involving a total of 4,984 cases and 7,472 controls were included. Overall, there was no statistically significant association between the XRCC3 Thr241Met polymorphism and risk of brain tumors under all contrast models. Subgroup analysis by race suggested that the XRCC3 Thr241Met polymorphism was associated with increased risk of brain tumors in Asians under all four contrast models (Met vs. Thr: OR = 1.22, 95 % CI 1.09-1.36, P < 0.01; MetMet vs. ThrThr: OR = 1.89, 95 % CI 1.38-2.57, P < 0.01; MetMet vs. ThrThr/ThrMet: OR = 1.78, 95 % CI 1.31-2.40, P < 0.01; and MetMet vs. ThrThr/ThrMet: OR = 1.19, 95 % CI 1.04-1.36, P = 0.01). However, there was no significant association between the XRCC3 Thr241Met polymorphism and risk of brain tumors in Caucasians. Therefore, the XRCC3 Thr241Met polymorphism is associated with increased risk of brain tumors, especially in Asians.

  2. Prognostic value and clinical pathology of MACC-1 and c-MET expression in gastric carcinoma.

    PubMed

    Ma, Jie; Ma, Jun; Meng, Qun; Zhao, Zhong-Sheng; Xu, Wen-juan

    2013-10-01

    This study was to assess the expression of MACC-1 and c-MET in gastric cancer, and to correlate this expression with clinicohistological parameters and patient prognosis. Total RNA was extracted from cancer tissue and adjacent normal mucosa from frozen biopsy specimens of 30 patients with gastric cancer, and MACC-1 expression was assessed by RT-PCR. MACC-1 and c-MET protein expression were also assessed in paraffin-embedded tissues obtained from 436 tumor mucosa and 92 normal mucosa specimens by immunohistochemistry. The correlation between MACC-1 and c-MET expression and clinicopathological factors (age, sex, histology, tumor depth, lymph node status and vessel invasion) were also evaluated. RT-PCR analysis revealed that MACC-1 expression was significantly higher in cancerous mucosa compared with normal tissue. Immunohistochemical analysis indicated that MACC-1 and c-MET were moderately or strongly expressed in gastric cancer tissue, whereas expression was weak or absent in non-cancer tissue. Expression of MACC-1 or c-MET was significantly associated with larger tumor size, deeper tumor invasion, presence of lymph node metastasis, lymphatic involvement, venous invasion, distant metastasis and advanced clinical stage. However, only MACC-1 exhibited significantly greater expression in carcinomas from the higher age group. The intensity of MACC-1 and c-MET expression was also positively correlated. Survival analysis of the 436 gastric cancer patients revealed that patients in clinical stages I, II and III exhibiting lower MACC-1 and c-MET expression had a higher 5-year survival rate compared with patients expressing high levels of these proteins. Multivariate analysis revealed that MACC-1 and c-MET may be independent prognostic indexes of gastric carcinoma (P < 0.01). Our findings confirm that MACC-1 and c-MET expression is strongly related to gastric cancer stage and degree of malignancy, and is inversely correlated to patient prognosis. Thus, MACC-1 and c-MET may

  3. 75 FR 29811 - 21st Meeting: RTCA Special Committee 206: EUROCAE WG 76 Plenary: AIS and MET Data Link Services

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-27

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

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

    PubMed Central

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

    2015-01-01

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

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

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 33 Navigation and Navigable Waters 2 2012-07-01 2012-07-01 false Safety Zones; TriMet Bridge... Coast Guard District § 165.T13-209 Safety Zones; TriMet Bridge Project, Willamette River; Portland, OR... directions, and within 140 feet, in all directions, of the TriMet bridge construction cranes. (b) Regulation...

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

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 33 Navigation and Navigable Waters 2 2014-07-01 2014-07-01 false Safety Zones; TriMet Bridge... Coast Guard District § 165.T13-209 Safety Zones; TriMet Bridge Project, Willamette River; Portland, OR... directions, and within 140 feet, in all directions, of the TriMet bridge construction cranes. (b) Regulation...

  7. 33 CFR 165.T13-209 - Safety Zones; TriMet Bridge Project, Willamette River; Portland, OR.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 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, OR... directions, and within 140 feet, in all directions, of the TriMet bridge construction cranes. (b) Regulation...

  8. Tea catechins inhibit hepatocyte growth factor receptor (MET kinase) activity in human colon cancer cells: kinetic and molecular docking studies

    PubMed Central

    Larsen, Christine A.; Bisson, William H.; Dashwood, Roderick H.

    2009-01-01

    Most cancer deaths result from spread of the primary tumor to distant sites (metastasis). MET is an important protein for metastasis in multiple tumor types. Here we report on the ability of tea catechins to suppress MET activation in human colon cancer cells, and propose a mechanism by which they might compete for the kinase domain of the MET protein. PMID:19839593

  9. 75 FR 55847 - 22nd Meeting: RTCA Special Committee 206: EUROCAE WG 76 Plenary: AIS and MET Data Link Services

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-14

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

  10. 43 CFR 404.19 - What requirements must be met before I can request assistance to conduct a feasibility study?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

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

  11. 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

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

    PubMed

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

    2015-10-13

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

  13. c-Met Overexpression in Cervical Cancer, A Prognostic Factor and A Potential Molecular Therapeutic Target

    PubMed Central

    Refaat, Tamer; Donnelly, Eric D.; Sachdev, Sean; Parimi, Vamsi; Achy, Samar El; Dalal, Prarthana; Farouk, Mohamed; Berg, Kim Natasha; Helenowksi, Irene; Gross, Jeffrey Paul; Lurain, John; Strauss, Jonathan; Woloschak, Gayle; Wei, Jian-Jun; Small, William

    2015-01-01

    Purpose This study aimed to assess the association between pretreatment c-Met overexpression in local-regional advanced cervical cancer patients treated definitively with concurrent chemoradiation (CRT) and treatment outcomes including overall survival (OS), progression free survival (PFS), distant metastases control (DM), and local-regional control (LC). Patients and Methods This IRB approved study included cervical cancer patients treated definitively and consecutively with CRT. Evaluation of cytoplasmic immunoreactivity for c-Met was performed and scored semi-quantitatively by three pathologists, blinded to the treatment outcomes, and incorporated both the intensity and percentage of immunoreactivity in invasive carcinoma (H-score). Treatment- outcomes were reviewed and reported. Outcomes were stratified by c-Met overexpression and tumor characteristics. OS, PFS, LC, and DC rates were obtained via the Kaplan-Meier method and differences between groups were evaluated by the log-rank test. Hazard ratios were obtained via Cox regression for both univariate and multivariate analyses. Results The 5-year OS, PFS, LC, and DC were 57.18%, 48.07%, 72.11%, and 62.85%, respectively. Ten (35.7%), and 18 patients (64.3%) had c-Met H-index > 30 and < 30, respectively. c-Met overexpression was significantly associated with worse 3-year and 5-year OS (p= 0.003), PFS (p = 0.002), LC (p = 0.01), and DC (p = 0.0003). Patients with c-Met overexpression had a hazard ratio of 6.297, 5.782, 6.28, and 18.173 for the risks of death, disease progression, local recurrence, and distant metastases, respectively. Conclusion c-Met overexpression could be a potential predictive marker and therapeutic target for local-regional advanced cervical cancer patients treated definitively with CRT. PMID:26083558

  14. Sustained endoplasmic reticulum stress inhibits hepatocyte proliferation via downregulation of c-Met expression.

    PubMed

    He, Yihuai; Long, Jun; Zhong, Weiwei; Fu, Yu; Li, Ying; Lin, Shide

    2014-04-01

    The molecular mechanisms of impaired liver regeneration in several liver diseases remain poorly understood. Endoplasmic reticulum (ER) stress has been observed in a variety of liver diseases. The aims of this study were to explore the impacts of ER stress on hepatocyte growth factor (HGF)-induced proliferation and c-Met expression in human hepatocyte L02 cells. Human hepatocyte L02 cells were incubated with thapsigargin (TG) to induce ER stress. 4-Phenylbutyric acid (PBA) was used to rescue ER stress. Activation of glucose-regulated protein 78, phosphorylation of PKR-like ER kinase and eukaryotic translation initiation factor-2α, and the expression of c-Met were determined by western blotting. The expression of c-Met mRNA was observed by reverse transcription polymerase chain reaction. L02 cell proliferation was determined by the MTS assay. L02 cell proliferation was significantly impaired in TG-treated L02 cells from 24 to 48 h, while PBA partly restored the proliferation of L02 cells. In addition, TG treatment significantly decreased the sensitivity of L02 cells to HGF-induced proliferation. PBA partly resumed the sensitivity of L02 cells to HGF-induced proliferation. The expression of c-Met protein in L02 cells was downregulated from 6 h after TG treatment, and PBA partly restored c-Met expression inhibited by TG. The expression of c-Met mRNA was also significantly downregulated from 24 to 48 h after TG treatment. Our results strongly suggest that sustained ER stress inhibits hepatocyte proliferation via downregulation of both c-Met mRNA and protein expression in human hepatocyte L02 cells.

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

    PubMed

    Neeshpapa, Alexander; Antonov, Alexander; Agafonov, Vadim

    2014-12-26

    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.

  16. 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

  17. COMT Val158Met polymorphism is associated with nonverbal cognition following mild traumatic brain injury

    PubMed Central

    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

    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 Val158Met 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 Met158/Met158 29 %, Met158/Val158 47 %, Val158/Val158 24 %) show that the COMT Met158 allele (mean 101.6±SE 2.1) associates with higher nonverbal processing speed on the WAIS-PSI when compared to Val158/Val158 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 Val158Met polymorphism did not associate with mental flexibility on the TMT or with verbal learning on the CVLT-II. Hence, COMT Val158Met may preferentially modulate nonverbal cognition following uncomplicated mTBI. PMID:26576546

  18. MetNetGE: interactive views of biological networks and ontologies

    PubMed Central

    2010-01-01

    Background Linking high-throughput experimental data with biological networks is a key step for understanding complex biological systems. Currently, visualization tools for large metabolic networks often result in a dense web of connections that is difficult to interpret biologically. The MetNetGE application organizes and visualizes biological networks in a meaningful way to improve performance and biological interpretability. Results MetNetGE is an interactive visualization tool based on the Google Earth platform. MetNetGE features novel visualization techniques for pathway and ontology information display. Instead of simply showing hundreds of pathways in a complex graph, MetNetGE gives an overview of the network using the hierarchical pathway ontology using a novel layout, called the Enhanced Radial Space-Filling (ERSF) approach that allows the network to be summarized compactly. The non-tree edges in the pathway or gene ontology, which represent pathways or genes that belong to multiple categories, are linked using orbital connections in a third dimension. Biologists can easily identify highly activated pathways or gene ontology categories by mapping of summary experiment statistics such as coefficient of variation and overrepresentation values onto the visualization. After identifying such pathways, biologists can focus on the corresponding region to explore detailed pathway structure and experimental data in an aligned 3D tiered layout. In this paper, the use of MetNetGE is illustrated with pathway diagrams and data from E. coli and Arabidopsis. Conclusions MetNetGE is a visualization tool that organizes biological networks according to a hierarchical ontology structure. The ERSF technique assigns attributes in 3D space, such as color, height, and transparency, to any ontological structure. For hierarchical data, the novel ERSF layout enables the user to identify pathways or categories that are differentially regulated in particular experiments. Met

  19. 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. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  20. Brain-Derived Neurotrophic Factor Gene Val66Met Polymorphism Modulates Reversible Cerebral Vasoconstriction Syndromes

    PubMed Central

    Chen, Shih-Pin; Fuh, Jong-Ling; Wang, Shuu-Jiun; Tsai, Shih-Jen; Hong, Chen-Jee; Yang, Albert C.

    2011-01-01

    Background Reversible cerebral vasoconstriction syndrome (RCVS) could be complicated by cerebral ischemic events. Hypothetical mechanisms of RCVS involve endothelial dysfunction and sympathetic overactivity, both of which were reported to be related to brain-derived neurotrophic factor (BDNF). The study investigated the association between functional BDNF Val66Met polymorphism and RCVS. Methods Patients with RCVS and controls were prospectively recruited and genotyped for the BDNF Val66Met polymorphism. Magnetic resonance angiography (MRA) and transcranial color-coded Doppler sonography were employed to evaluate cerebral vasoconstriction. Genotyping results, clinical parameters, vasoconstriction scores, mean flow velocities of the middle cerebral artery (VMCA), and Lindegaard indices were analyzed. Split-sample approach was employed to internally validate the data. Principal Findings Ninety Taiwanese patients with RCVS and 180 age- and gender-matched normal controls of the same ethnicity completed the study. The genotype frequencies did not differ between patients and controls. Compared to patients with Met/Met homozygosity, patients with Val allele had higher mean vasoconstriction scores of all arterial segments (1.60±0.72 vs. 0.87±0.39, p<0.001), VMCA values (116.7±36.2 vs. 82.7±17.9 cm/s, p<0.001), and LI (2.41±0.91 vs. 1.89±0.41, p = 0.001). None of the Met/Met homozygotes, but 38.9% of the Val carriers, had VMCA values of >120 cm/s (p<0.001). Split-sample validation by randomization, age, entry time or residence of patients demonstrated concordant findings. Conclusions Our findings link BDNF Val66Met polymorphism with the severity of RCVS for the first time and implicate possible pathogenic mechanisms for vasoconstriction in RCVS. PMID:21437208

  1. Brain-derived neurotrophic factor gene Val66Met polymorphism modulates reversible cerebral vasoconstriction syndromes.

    PubMed

    Chen, Shih-Pin; Fuh, Jong-Ling; Wang, Shuu-Jiun; Tsai, Shih-Jen; Hong, Chen-Jee; Yang, Albert C

    2011-03-18

    Reversible cerebral vasoconstriction syndrome (RCVS) could be complicated by cerebral ischemic events. Hypothetical mechanisms of RCVS involve endothelial dysfunction and sympathetic overactivity, both of which were reported to be related to brain-derived neurotrophic factor (BDNF). The study investigated the association between functional BDNF Val66Met polymorphism and RCVS. Patients with RCVS and controls were prospectively recruited and genotyped for the BDNF Val66Met polymorphism. Magnetic resonance angiography (MRA) and transcranial color-coded Doppler sonography were employed to evaluate cerebral vasoconstriction. Genotyping results, clinical parameters, vasoconstriction scores, mean flow velocities of the middle cerebral artery (V(MCA)), and Lindegaard indices were analyzed. Split-sample approach was employed to internally validate the data. Ninety Taiwanese patients with RCVS and 180 age- and gender-matched normal controls of the same ethnicity completed the study. The genotype frequencies did not differ between patients and controls. Compared to patients with Met/Met homozygosity, patients with Val allele had higher mean vasoconstriction scores of all arterial segments (1.60±0.72 vs. 0.87±0.39, p<0.001), V(MCA) values (116.7±36.2 vs. 82.7±17.9 cm/s, p<0.001), and LI (2.41±0.91 vs. 1.89±0.41, p = 0.001). None of the Met/Met homozygotes, but 38.9% of the Val carriers, had V(MCA) values of >120 cm/s (p<0.001). Split-sample validation by randomization, age, entry time or residence of patients demonstrated concordant findings. Our findings link BDNF Val66Met polymorphism with the severity of RCVS for the first time and implicate possible pathogenic mechanisms for vasoconstriction in RCVS.

  2. EGFR family and cMet expression profiles and prognostic significance in esophagogastric adenocarcinoma

    PubMed Central

    Chan, Ellie; Alkhasawneh, Ahmad; Duckworth, Lizette Vila; Aijaz, Tabish; Toro, Tania Zuluaga; Lu, Xiaomin; Hughes, Steven J.; Collinsworth, Amy

    2016-01-01

    Background Targeted therapy with anti-human epidermal growth factor receptor-2 (HER2) monoclonal antibody in patients with HER2 overexpressed esophagogastric adenocarcinoma (EGA) improves survival; however, the effect is transient due to the development of resistance. Some studies suggest that cMet overexpression provides cross talk for epidermal growth factor receptor (EGFR) and HER2 inhibition. We sought to characterize the expression profile of the EGFR family and cMet receptors in untreated, resected EGA. Methods This retrospective analysis included all sequential patients with esophageal or gastroesophageal junction (GEJ) adenocarcinoma who underwent primary resection, without neoadjuvant therapy or HER2 inhibition, with adequate tissue, at the University of Florida from 2001 to 2011. Central blinded immunohistochemistry (IHC) was performed on tumor specimens with EGFR, HER2, HER3, HER4 and cMet expression scored as low (0, 1+) or high (2+, 3+). Demographic and tumor characteristics were compared using Fisher exact test. Kaplan-Meier curves and univariate analysis compared survival among different receptors. Results Total 52 patients were included in the study with median age 66 years. High expression of EGFR (73%), HER2 (40%), HER3 (75%), HER4 (35%) and cMet (69%) was detected among the study group. HER3 and HER4 co-expression was found in 18 (35%) cases. Pan expression of all four EGFR family members with cMet was noted in only 17% of cases. On univariate analysis, tumor stage and depth correlated with survival, while cMet + HER3 +/– EGFR receptor co-expression trended towards a worse survival. Conclusions EGFR family and cMet are frequently co-expressed in treatment naïve resected EGA or GEJ tumors. Although our data do not significantly show receptor status as a prognostic factor, the co-expression profiles support for further investigation to improve targeting of this signal transduction axis. PMID:28078108

  3. Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia

    PubMed Central

    Kentsis, Alex; Reed, Casie; Rice, Kim L.; Sanda, Takaomi; Rodig, Scott J.; Tholouli, Eleni; Christie, Amanda; Valk, Peter J.M.; Delwel, Ruud; Ngo, Vu; Kutok, Jeffery L.; Dahlberg, Suzanne E.; Moreau, Lisa A.; Byers, Richard J.; Christensen, James G.; Woude, George Vande; Licht, Jonathan D.; Kung, Andrew L.; Staudt, Louis M.; Look, A. Thomas

    2012-01-01

    Although the treatment of acute myeloid leukemia (AML) has improved significantly, more than half of all patients develop disease that is refractory to intensive chemotherapy1,2. Functional genomics approaches offer a means to discover specific molecules mediating aberrant growth and survival of cancer cells3–8. Thus, using a loss-of-function RNA interference genomic screen, we identified aberrant expression of the hepatocyte growth factor (HGF) as a critical factor in AML pathogenesis. We found HGF expression leading to autocrine activation of its receptor tyrosine kinase, MET, in nearly half of the AML cell lines and clinical samples studied. Genetic depletion of HGF or MET potently inhibited the growth and survival of HGF-expressing AML cells. However, leukemic cells treated with the specific MET kinase inhibitor crizotinib developed resistance due to compensatory upregulation of HGF expression, leading to restoration of MET signaling. In cases of AML where MET is coactivated with other tyrosine kinases, such as fibroblast growth factor receptor 1 (FGFR1)9, concomitant inhibition of FGFR1 and MET blocked compensatory HGF upregulation, resulting in sustained logarithmic cell kill both in vitro and in xenograft models in vivo. Our results demonstrate widespread dependence of AML cells on autocrine activation of MET, as well as the importance of compensatory upregulation of HGF expression in maintaining leukemogenic signaling by this receptor. We anticipate that these findings will lead to the design of additional strategies to block adaptive cellular responses that drive compensatory ligand expression as an essential component of the targeted inhibition of oncogenic receptors in human cancers. PMID:22683780

  4. 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.

  5. 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

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

    PubMed

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

    2017-10-01

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

  7. The autism risk genes MET and PLAUR differentially impact cortical development

    PubMed Central

    Eagleson, Kathie L.; Campbell, Daniel B.; Thompson, Barbara L.; Bergman, Mica Y.; Levitt, Pat

    2013-01-01

    Over the past decade, candidate genes that increase risk for autism spectrum disorder (ASD) have been identified. However, little is known about how these findings of increased genetic risk translate into the disruptions in brain development that cause the behaviors that are characteristic of ASD. One idea has been that risk genes for ASD cause an imbalance in excitation and inhibition in circuits of the cerebral cortex, the structure that controls complex functions. Imbalances would lead to problems in information flow and, in extreme cases, cause seizure disorder, a common medical condition in children with ASD. Our laboratory has identified changes in the DNA sequence of two genes, MET and PLAUR, that are associated with increased risk for ASD. Our previous work suggested that both of these genes were involved in controlling inhibitory neuron development. Through the use of genetic mouse models and biochemical and molecular analysis, we show that Met can only be involved directly in the development and function of excitatory neurons. In contrast, PLAUR modulates the maturation of inhibitory neurons, which act as a brake on projection neuron function. We also find, however, that under certain environmental conditions, Met can be activated in inhibitory neurons and therefore could influence the development of this cell type under certain pathological conditions during pregnancy. Our data support a popular hypothesis that a disruption in the balance of function between excitatory projection neurons and inhibitory interneurons underlies, in part, altered cortical architecture in ASD. Candidate risk genes for autism spectrum disorder (ASD) have been identified, but the challenge of determining their contribution to pathogenesis remains. We previously identified two ASD risk genes encoding the receptor tyrosine kinase MET and the urokinase plasminogen activator receptor (PLAUR), which is thought to modulate availability of the MET ligand. We also reported a role for

  8. 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

    2016-07-18

    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

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

    PubMed Central

    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

  10. Compendium of physical activities: an update of activity codes and MET intensities.

    PubMed

    Ainsworth, B E; Haskell, W L; Whitt, M C; Irwin, M L; Swartz, A M; Strath, S J; O'Brien, W L; Bassett, D R; Schmitz, K H; Emplaincourt, P O; Jacobs, D R; Leon, A S

    2000-09-01

    We provide an updated version of the Compendium of Physical Activities, a coding scheme that classifies specific physical activity (PA) by rate of energy expenditure. It was developed to enhance the comparability of results across studies using self-reports of PA. The Compendium coding scheme links a five-digit code that describes physical activities by major headings (e.g., occupation, transportation, etc.) and specific activities within each major heading with its intensity, defined as the ratio of work metabolic rate to a standard resting metabolic rate (MET). Energy expenditure in MET-minutes, MET-hours, kcal, or kcal per kilogram body weight can be estimated for specific activities by type or MET intensity. Additions to the Compendium were obtained from studies describing daily PA patterns of adults and studies measuring the energy cost of specific physical activities in field settings. The updated version includes two new major headings of volunteer and religious activities, extends the number of specific activities from 477 to 605, and provides updated MET intensity levels for selected activities.

  11. 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.

  12. HEY1 Leu94Met gene polymorphism dramatically modifies its biological functions

    PubMed Central

    Villaronga, MA; Lavery, DN; Bevan, CL; Llanos, S; Belandia, B

    2012-01-01

    The hairy/enhancer-of-split related with YRPW motif 1 (HEY1) is a member of the basic-helix-loop-helix-Orange (bHLH-O) family of transcriptional repressors that mediate Notch signaling. Several cancer-related pathways also regulate HEY1 expression, and HEY1 itself acts as an indirect positive regulator of the p53 tumor suppressor protein and a negative regulator of androgen receptor activity. In this study we show how a naturally occurring non-synonymous polymorphism at codon 94 of HEY1, which results in a substitution of leucine by methionine (Leu94Met), converts HEY1 from an androgen receptor corepressor to an androgen receptor co-activator without affecting its intrinsic transcriptional repressive domains. The polymorphism Leu94Met also abolishes HEY1-mediated activation of p53 and suppresses the ability of HEY1 to induce p53-dependent cell-cycle arrest and aberrant cell differentiation in human osteosarcoma U2OS cells. Moreover, expression of HEY1, but not of the variant Leu94Met, confers sensitivity to p53-activating chemotherapeutic drugs on U2OS cells. In addition, we have identified motifs in HEY1 that are critical for the regulation of its subcellular localization and analysed how mutations in those motifs affect both HEY1 and HEY1-Leu94Met functions. These findings suggest that the polymorphism Leu94Met in HEY1 radically alters its biological activities and may affect oncogenic processes. PMID:19802006

  13. Purification and characterization of the Streptococcus salivarius methionine aminopeptidase (MetAP).

    PubMed

    Boufous, El Houssine; Vadeboncoeur, Christian

    2003-10-01

    Streptococcus salivarius methionine aminopeptidase (MetAP) was purified from a recombinant Escherichia coli strain containing the S. salivarius map gene, which codes for MetAP. S. salivarius map coded for a protein of 286 amino acids with a calculated molecular mass of 31,723 Da and a pI of 4.6. The native enzyme eluted from a Superdex column as a protein with a molecular mass of 30.6 kDa and cleaved N-terminal Met of peptide only when the penultimate amino acid was Gly, Ala, Ser, Val, Pro, or Thr. The enzyme was more active against tetrapeptides than tripeptides and did not recognize dipeptides. It required the presence of a metal cation for activity, with a preference for Co(2+) over Mn(2+). S. salivarius MetAP has a pH optimum of 8.0 and an optimal temperature at 50 degrees C. The S. salivarius protein had an extra sequence of 24 amino acids between two conserved aspartate residues involved in the coordination of the metal ion. A similar extra sequence is present in MetAP from other streptococci and from Lactococcus lactis, but not from other bacteria or eukaryotes.

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

    PubMed

    Yuspa, Stuart H; VanHook, Annalisa M

    2016-06-21

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

  15. Resveratrol suppresses human hepatocellular carcinoma via targeting HGF-c-Met signaling pathway.

    PubMed

    Gao, Feng; Deng, Gang; Liu, Wenbin; Zhou, Kechao; Li, Ming

    2017-02-01

    Resveratrol, one of the major polyphenols found in red wine, is suggested to have a role as a chemo-prevention or chemotherapy agent in various human cancer models. Herein, we report that resveratrol has a profound antitumor effect on human hepatocellular carcinoma (HCC) cells by down-regulation of the HGF-c-Met signaling pathway. Resveratrol inhibited anchorage-dependent and -independent growth of HCC cells in a dose-dependent manner. Short-term resveratrol exposure substantially decreased HGF-induced c-Met signaling pathway activation, and long-term exposure to resveratrol markedly inhibited c-Met expression on the cell membrane. Additionally, resveratrol suppressed HGF-induced cell invasion, and knockdown of c-Met decreased the sensitivity of HCC cells to resveratrol treatment. Finally, the antitumor activity of resveratrol was validated in xenograft model and resveratrol prominently restrained tumor growth in vivo. In summary, our results suggested that c-Met offers a candidate molecular target for hepatocellular carcinoma management.

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

    SciTech Connect

    Wei, S.; Guo, B.C.; Deng, H.T.; Kerns, K.; Purnell, J.; Buzza, S.A.; Castleman, A.W. Jr. )

    1994-05-18

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

  17. A meta-analysis of the Val158Met COMT polymorphism and violent behavior in schizophrenia.

    PubMed

    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.

  18. 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

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

    PubMed

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

    2011-10-15

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

  20. 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

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

    PubMed Central

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

    2013-01-01

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

  2. 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

  3. COMT Val158Met and cognitive and functional outcomes after traumatic brain injury.

    PubMed

    Willmott, Catherine; Withiel, Toni; Ponsford, Jennie; Burke, Richard

    2014-09-01

    There is significant variability in long-term outcomes after traumatic brain injury (TBI), making accurate prognosis difficult. In seeking to enhance understanding of outcomes, this study aimed to investigate whether COMT Val(158)Met allele status was associated with performance on neuropsychological measures of attention and working memory, executive functioning, learning and memory, and speed of information processing in the early rehabilitation phase. The study also aimed to examine whether the COMT polymorphism was associated with longer-term functional outcomes. A total of 223 participants (71.3% male) with moderate-to-severe TBI were recruited as rehabilitation inpatients to participate in a prospective, longitudinal head injury outcome study. The three COMT genotype groups (Val/Val, Val/Met, and Met/Met) were well matched for estimated full-scale IQ, years of education, age at injury, and injury severity. Results showed no significant difference between genotypes on neuropsychological measures (all p>0.05) or functional outcome, as measured by the Glasgow Outcome Scale-Extended (GOS-E), after controlling for age, education, and severity of injury. The presence of frontal lobe pathology was also not associated with cognitive performance. Those with greater injury severity (i.e., longer duration of post-traumatic amnesia) performed more poorly on measures of processing speed and verbal new learning and recall. It was concluded that there was little support for the influence of COMT Val(158)Met on cognitive function, or functional outcome measures, in the acute rehabilitation phase after TBI.

  4. Genetic Correlates of Maladaptive Beliefs: COMT VAL(158)MET and Irrational Cognitions Linked Depending on Distress.

    PubMed

    Podina, Ioana; Popp, Radu; Pop, Ioan; David, Daniel

    2015-11-01

    Maladaptive/irrational beliefs are significant cognitive vulnerability mechanisms in psychopathology. They are more likely to be associated with a genetic vulnerability marker under conditions of emotional distress when irrational beliefs are more salient. Therefore, in the current study we investigated the COMT Val(158)Met gene variation in relation to irrational beliefs, assuming this relationship depended on the level of emotional distress. Two hundred and sixty-seven genotyped volunteers were assessed for core/general maladaptive beliefs, as well as trait emotional distress. We focused on context-independent measures of irrational beliefs and emotional distress in the absence of a stressor. As expected, the relationship between COMT Val(158)Met and irrational beliefs depended on the level of emotional distress (f(2)=.314). The COMT Val(158)Met-irrationality association was significant only when individuals fell in the average to above average range of emotional distress. Furthermore, within this range the Met allele seemed to relate to higher irrational beliefs. These results were significant for overall irrational beliefs and its subtypes, but not for rational beliefs, the functional counterpart of irrationality. In light of the study's limitations, the results should be considered as preliminary. If replicable, these findings have potential implications for therapygenetics, changing the view that COMT Val(158)Met might be of greater relevance when treatment modality does not rely on cognitive variables.

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

    PubMed Central

    Lashkari, Kameran

    2012-01-01

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

  6. Association between XRCC3 Thr241Met polymorphism and risk of osteosarcoma in a Chinese population

    PubMed Central

    Yang, Libin; An, Yongbo; Wang, Guodong; Lu, Tan; Yang, Shujuan

    2015-01-01

    The aim of this study was to investigate whether XRCC3 Thr241Met polymorphism could affect the development of osteosarcoma in a Chinese population. A total of 152 osteosarcoma patients and 304 health control subjects were included in our study. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay was applied to assess the XRCC3 Thr241Met gene polymorphism. By conditional logistic regression analysis, we found that TT genotype of XRCC3 Thr241Met was associated with increased risk of osteosarcoma in codominant model (OR = 2.53, 95% CI = 1.28-5.39). Moreover, XRCC3 Thr241Met gene polymorphism was correlated with an elevated increased risk of osteosarcoma in dominant (OR = 1.55, 95% CI = 1.03-2.34) and recessive models (OR = 2.30, 95% CI = 1.16-4.56). In conclusion, we found that XRCC3 Thr241Met gene polymorphism was associated with increased risk of osteosarcoma in codominant, dominant and recessive models. PMID:26617908

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

    PubMed Central

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

    2013-01-01

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

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

    SciTech Connect

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

    1996-03-01

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

  9. Association between XRCC3 Thr241Met polymorphism and risk of osteosarcoma in a Chinese population.

    PubMed

    Yang, Libin; An, Yongbo; Wang, Guodong; Lu, Tan; Yang, Shujuan

    2015-01-01

    The aim of this study was to investigate whether XRCC3 Thr241Met polymorphism could affect the development of osteosarcoma in a Chinese population. A total of 152 osteosarcoma patients and 304 health control subjects were included in our study. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay was applied to assess the XRCC3 Thr241Met gene polymorphism. By conditional logistic regression analysis, we found that TT genotype of XRCC3 Thr241Met was associated with increased risk of osteosarcoma in codominant model (OR = 2.53, 95% CI = 1.28-5.39). Moreover, XRCC3 Thr241Met gene polymorphism was correlated with an elevated increased risk of osteosarcoma in dominant (OR = 1.55, 95% CI = 1.03-2.34) and recessive models (OR = 2.30, 95% CI = 1.16-4.56). In conclusion, we found that XRCC3 Thr241Met gene polymorphism was associated with increased risk of osteosarcoma in codominant, dominant and recessive models.

  10. Pseudo-active sites of protease domains: HGF/Met and Sonic hedgehog signaling in cancer.

    PubMed

    Maun, Henry R; Kirchhofer, Daniel; Lazarus, Robert A

    2010-08-01

    Proteases represent a large class of enzymes with crucial biological functions. Although targeting various relevant proteases for therapeutic intervention has been widely investigated, structurally related proteins lacking proteolytic activity (pseudo-proteases) have received relatively little attention. Two distinct clinically relevant cancer pathways that contain signaling proteins with pseudo-protease domains include the Met and Hedgehog (Hh) pathways. The receptor tyrosine kinase Met pathway is driven by hepatocyte growth factor (HGF), a plasminogen-related ligand that binds Met and activates intracellular pathways resulting in cell proliferation, angiogenesis, motility and survival. HGF is a disulfide-linked alpha/beta-heterodimer having a trypsin serine protease-like beta-chain. The Hh pathway is driven by Sonic hedgehog (Shh), which has a Zn(2+) metalloprotease fold and binds Patched1 (Ptc1), which de-represses Smoothened and ultimately activates Gli-dependent transcription. Although HGF and Shh differ in structure and function, the pseudo-catalytic sites of both HGF and Shh are crucial for signal transduction. For HGF, this region binds the Met beta-propeller domain, which leads to Met dimerization and signaling. For Hh, this region binds to the antagonist receptor Hedgehog-interacting protein (Hhip) and most probably to Ptc1 as well. Thus, for both HGF and Hh pathways, targeting ligand pseudo-active sites represents a new strategy for regulation.

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

    PubMed

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

    2016-09-01

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

  12. The MET13 methylenetetrahydrofolate reductase gene is essential for infection-related morphogenesis in the rice blast fungus Magnaporthe oryzae.

    PubMed

    Yan, Xia; Que, Yawei; Wang, Hong; Wang, Congcong; Li, Ya; Yue, Xiaofeng; Ma, Zhonghua; Talbot, Nicholas J; Wang, Zhengyi

    2013-01-01

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

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

    PubMed Central

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

    2015-01-01

    The human MET gene imparts a replicated risk for autism spectrum disorder (ASD), and is implicated in the structural and functional integrity of brain. MET encodes a receptor tyrosine kinase, MET, which plays a pleiotropic role in embryogenesis and modifies a large number of neurodevelopmental events. Very little is known, however, on how MET signaling engages distinct cellular events to collectively affect brain development in ASD-relevant disease domains. Here, we show that MET protein expression is dynamically regulated and compartmentalized in developing neurons. MET is heavily expressed in neuronal growth cones at early developmental stages and its activation engages small GTPase Cdc42 to promote neuronal growth, dendritic arborization, and spine formation. Genetic ablation of MET signaling in mouse dorsal pallium leads to altered neuronal morphology indicative of early functional maturation. In contrast, prolonged activation of MET represses the formation and functional maturation of glutamatergic synapses. Moreover, manipulating MET signaling levels in vivo in the developing prefrontal projection neurons disrupts the local circuit connectivity made onto these neurons. Therefore, normal time-delimited MET signaling is critical in regulating the timing of neuronal growth, glutamatergic synapse maturation and cortical circuit function. Dysregulated MET signaling may lead to pathological changes in forebrain maturation and connectivity, and thus contribute to the emergence of neurological symptoms associated with ASD. PMID:26728565

  14. MET expression and copy number status in clear-cell renal cell carcinoma: prognostic value and potential predictive marker

    PubMed Central

    Macher-Goeppinger, Stephan; Keith, Martina; Endris, Volker; Penzel, Roland; Tagscherer, Katrin E.; Pahernik, Sascha; Hohenfellner, Markus; Gardner, Humphrey; Grüllich, Carsten; Schirmacher, Peter; Roth, Wilfried

    2017-01-01

    Multiple targeted therapy for advanced clear-cell renal cell carcinoma (RCC) has substantially improved patient outcome, but complete remission is uncommon and many tumors eventually develop resistance. Mechanistic, preclinical, and early clinical data highlight c-Met / hepatocyte growth factor receptor as a promising target for RCC therapeutic agents. We have examined MET expression, frequency of MET gene copy gains and MET gene mutation in a large, hospital-based series of renal cell carcinomas with long-term follow-up information. Out of a total of 572 clear-cell RCC, only 17% were negative for MET expression whereas 32% showed high protein levels. High MET expression and MET copy number gains were associated with an aggressive phenotype and an unfavorable patient outcome. Elevated protein levels in absence of gene amplification were not attributed to mutations, based on results of targeted next-generation sequencing. Our data reveal that clear-cell RCC with MET upregulation show an aggressive behavior and MET copy number increase is evident in a substantial percentage of patients with high-grade carcinomas and metastatic disease. Diagnostic assessment of MET expression and amplification may be of predictive value to guide targeted therapy against MET signaling in patients with clear-cell RCC. PMID:27894094

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

    PubMed Central

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

    2013-01-01

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

  16. Met-enkephalin induces fast synaptic plasticity of magnocellular neurons in the rat supraoptic nucleus.

    PubMed

    Blanco, E; Carretero, J; Riesco, J M; Sanchez, F; Juanes, J A; Vazquez, R

    1992-01-01

    A morphometric-ultrastructural study was made of the supraoptic nucleus of rats of both sexes following central administration of met-enkephalin. Ten minutes after met-enkephalin treatment the number of axo-somatic synapses was significantly increased. This effect was more pronounced in female rats than in males and could be prevented by preceding administration of naloxone. Animals that received naloxone followed by met-enkephalin showed a dilation of the rough endoplasmic reticulum into a vesicular shape. Our results provide preliminary evidence for a fast remodeling of synaptic input to magnocellular hypothalamic neurons. It is likely that the known inhibitory action of opioids on the hypothalamo-neurohypophysial system is partly mediated by this plasticity.

  17. Catalase against met-Hb excess during oximetries of dilute Hb-A samples.

    PubMed

    Ricco, G; David, O; Lanza, C; Perfetto, F; Rabino-Massa, E

    1996-01-01

    Functional parameters of diluted Hb-A have been determined before and after addition of catalase and disodium-EDTA to the samples. There are no important differences between the results drawn from catalase added samples and catalase free ones, except for the fact the met-Hb level at pH 7.8 is significantly lower in the samples containing catalase. On the contrary, catalase is almost ineffective against met-Hb at pH 6.8, whereas its activity at pH 7.3 is rather modest. Another limitation is that catalase remains active against met-Hb for not more than 15-20 minutes after addition to the sample, which is just the time necessary for one complete (manual) oximetry.

  18. 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.

  19. Renewal of Metsähovi Fundamental Station and the GNSS reference network of Finland

    NASA Astrophysics Data System (ADS)

    Poutanen, M.; Arsov, K.; Kallio, U.; Koivula, H.; Mäkinen, J.; Näränen, J.; Raja-Halli, A.; Virtanen, H.; Zubko, N.

    2012-04-01

    We describe the plans for renewal of Metsähovi Fundamental Station and the GNSS reference network of Finland. During next five years a total of 8 M Euros are invested to the renewal by the Finnish Geodetic Institute. This include a new SLR and VLBI2010 compatible radio telescope, a super conducting gravimeter, and renewal of the reference GNSS network of Finland. Additionally, general infrastructure of Metsähovi will be improved as well as develop techniques for local ties between the instruments. At the same time, CNES is renewing the DORIS beacon at Metsähovi. One purpose of the renewal is to better meet the requirements of a GGOS core station.

  20. Molecular basis for specificity of the Met1-linked polyubiquitin signal.

    PubMed

    Elliott, Paul R

    2016-12-15

    The post-translational modification of proteins provides a rapid and versatile system for regulating all signalling pathways. Protein ubiquitination is one such type of post-translational modification involved in controlling numerous cellular processes. The unique ability of ubiquitin to form polyubiquitin chains creates a highly complex code responsible for different subsequent signalling outcomes. Specialised enzymes ('writers') generate the ubiquitin code, whereas other enzymes ('erasers') disassemble it. Importantly, the ubiquitin code is deciphered by different ubiquitin-binding proteins ('readers') functioning to elicit particular cellular responses. Ten years ago, the methionine1 (Met1)-linked (linear) polyubiquitin code was first identified and the intervening years have witnessed a seismic shift in our understanding of Met1-linked polyubiquitin in cellular processes, particularly inflammatory signalling. This review will discuss the molecular mechanisms of specificity determination within Met1-linked polyubiquitin signalling.

  1. Meanings of being received and met by others as experienced by women with fibromyalgia.

    PubMed

    Juuso, Päivi; Skär, Lisa; Olsson, Malin; Söderberg, Siv

    2014-10-01

    Fibromyalgia (FM) is a common chronic pain syndrome that mostly affects middle-aged women. Our aim with this study was to elucidate meanings of being received and met by others as experienced by women with FM. Interviews with a narrative approach were conducted with 9 women. We analyzed the transcribed interviews with a phenomenological hermeneutical interpretation. The findings revealed two themes: being seen as a malingerer and being acknowledged. Meanings of being received and met by others, as experienced by women with FM, can be understood as a movement between the two perspectives. When they were acknowledged, their feelings of security and trust increased, but the women could not rely on this because others received and met them in such an unpredictable manner. © The Author(s) 2014.

  2. Molecular basis for specificity of the Met1-linked polyubiquitin signal

    PubMed Central

    Elliott, Paul R.

    2016-01-01

    The post-translational modification of proteins provides a rapid and versatile system for regulating all signalling pathways. Protein ubiquitination is one such type of post-translational modification involved in controlling numerous cellular processes. The unique ability of ubiquitin to form polyubiquitin chains creates a highly complex code responsible for different subsequent signalling outcomes. Specialised enzymes (‘writers’) generate the ubiquitin code, whereas other enzymes (‘erasers’) disassemble it. Importantly, the ubiquitin code is deciphered by different ubiquitin-binding proteins (‘readers’) functioning to elicit particular cellular responses. Ten years ago, the methionine1 (Met1)-linked (linear) polyubiquitin code was first identified and the intervening years have witnessed a seismic shift in our understanding of Met1-linked polyubiquitin in cellular processes, particularly inflammatory signalling. This review will discuss the molecular mechanisms of specificity determination within Met1-linked polyubiquitin signalling. PMID:27913667

  3. The research of BL Lacertae objects in Metsähovi Radio Observatory

    NASA Astrophysics Data System (ADS)

    Nieppola, E.; Tornikoski, M.; Lähteenmäki, A.; Valtaoja, E.

    2006-10-01

    We present the Metsähovi Radio Observatory research related to BL Lacertae objects during the ENIGMA era. The Metsähovi BLO sample consists of 398 objects. For most of them, we have determined the spectral energy distribution (SED) using archival multi-frequency data. We fitted a parabolic function to the synchrotron component of the SEDs and calculated the synchrotron peak frequencies, ν_{peak}, of the sample sources. When we studied the correlations of ν_{peak} and the source luminosities on several wavelengths, we found that the peak luminosity does not depend on ν_{peak}, contrary to the blazar sequence scenario. We also give a summary of the BLO observing project at Metsähovi and the impending BLO data publication, and close with some plans for the future.

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

    PubMed

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

    2017-08-15

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

  5. Analysis of progress and challenges for various patterns of c-MET-targeted molecular imaging: a systematic review.

    PubMed

    Han, Zhaoguo; Wu, Yongyi; Wang, Kai; Xiao, Yadi; Cheng, Zhen; Sun, Xilin; Shen, Baozhong

    2017-12-01

    Mesenchymal-epithelial transition factor also named c-MET is a receptor tyrosine kinase for the hepatocyte growth factor that plays a pivotal role in tumorigenesis. c-MET-targeted therapies have been tested in preclinical models and patients, with significant benefits for cancer treatment. In recent years, many studies have shown that the expression level and activation status of c-MET are closely correlated to c-MET-targeted therapy response and clinical prognosis, thus highlighting the importance of evaluating the c-MET status during and prior to targeted therapy. Molecular imaging allows the monitoring of abnormal alterations of c-MET in real time and in vivo. In this review, we initially summarize the recent advances in c-MET-targeted molecular imaging, with a special focus on the development of imaging agents ranging in size from monoclonal antibody to small molecule. The aim of this review is to report the preclinical results and clinical application of all molecular imaging studies completed until now for in vivo detection of c-MET in cancer, in order to be beneficial to development of molecular probe and the combination of molecular imaging technologies for in vivo evaluation of c-MET. Various molecular probe targeted to c-MET possesses distinctive advantages and disadvantages. For example, antibody-based probes have high binding affinity but with long metabolic cycle as well as remarkable immunogenicity. Although studies for c-MET-targeted molecular imaging have made many important advances, most of imaging agents specifically target to extracellular area of c-MET receptor; however, it is difficult to reflect entirely activation of c-MET. Therefore, small molecule probes based on tyrosine kinase inhibitors, which could target to intracellular area of c-MET without any immunogenicity, should be paid more attention.

  6. 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

  7. MicroRNA-613 suppresses proliferation, migration and invasion of osteosarcoma by targeting c-MET

    PubMed Central

    Li, Xinyu; Sun, Xufang; Wu, Jing; Li, Zhihong

    2016-01-01

    MicroRNA-613 (miR-613) has been reported to play an important role in the pathogenesis of multiple cancers by negatively regulating gene expression at posttranscriptional level. However, the biological role of miR-613 in osteosarcoma (OS) remained unclear. In this study, we aimed to determine the expression and biological roles of miR-613 in OS. We found that miR-613 was significantly downregulated in OS tissues and cell lines, and that decreased miR-613 expression was correlated negatively with advanced TNM stage and lymph node metastasis. Overexpression of miR-613 in OS cells significantly suppressed the proliferation and colony formation by regulating cell arrest at G0/G1 phase, and impaired the migration and invasive abilities of OS cells, followed by suppression of the epithelial mesenchymal transition (EMT). Bioinformatic and luciferase reporter analysis identified cellular-mesenchymal to epithelial transition factor (c-MET, also named as MET) as a direct target of miR-613. Overexpression of miR-613 significantly inhibited the c-MET expression and its downstream PI3k/Akt/mTOR signaling pathway in OS cells. In OS clinical samples, there was a significant inverse correlation between miR-613 and c-MET mRNA expression. Rescue experiments showed that overexpression of c-MET partially prevented miR-613-induced suppression of OS cell proliferation, colony formation, migration and invasion. In conclusion, we provide first evidence for the suppressive activity of miR-613 by repressing c-MET, suggesting that miR-613 might be a potential therapeutic strategy for OS. PMID:28042506

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

    DOE PAGES

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

    2003-01-01

    MetNet (http://www.botany.iastate.edu/∼mash/metnetex/metabolicnetex.html) is publicly available software in development for analysis of genome-wide RNA, protein and metabolite profiling data. The software is designed to enable the biologist to visualize, statistically analyse and model a metabolic and regulatory network map of Arabidopsis , combined with gene expression profiling data. It contains a JAVA interface to an interactions database (MetNetDB) containing information on regulatory and metabolic interactions derived from a combination of web databases (TAIR, KEGG, BRENDA) and input from biologists in their area of expertise. FCModeler captures input from MetNetDB in a graphical form. Sub-networks can be identified and interpreted 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

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

    PubMed

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

    2016-12-01

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

  10. Methoprene-Tolerant (Met) Knockdown in the Adult Female Cockroach, Diploptera punctata Completely Inhibits Ovarian Development

    PubMed Central

    Marchal, Elisabeth; Hult, Ekaterina F.; Huang, Juan; Pang, Zhenguo; Stay, Barbara; Tobe, Stephen S.

    2014-01-01

    Independent of the design of the life cycle of any insect, their growth and reproduction are highly choreographed through the action of two versatile hormones: ecdysteroids and juvenile hormones (JH). However, the means by which JH can target tissues and exert its pleiotropic physiological effects is currently still not completely elucidated. Although the identity of the one JH receptor is currently still elusive, recent evidence seems to point to the product of the Methoprene-tolerant gene (Met) as the most likely contender in transducing the action of JH. Studies on the role of this transcription factor have mostly been focused on immature insect stages. In this study we used the viviparous cockroach Diploptera punctata, a favorite model in studying JH endocrinology, to examine the role of Met during reproduction. A tissue distribution and developmental profile of transcript levels was determined for Met and its downstream partners during the first gonadotropic cycle of this cockroach. Using RNA interference, our study shows that silencing Met results in an arrest of basal oocyte development; vitellogenin is no longer transcribed in the fat body and no longer taken up by the ovary. Patency is not induced in these animals which fail to produce the characteristic profile of JH biosynthesis typical of the first gonadotropic cycle. Moreover, the ultrastructure of the follicle cells showed conspicuous whorls of rough endoplasmic reticulum and a failure to form chorion. Our study describes the role of Met on a cellular and physiological level during insect reproduction, and confirms the role of Met as a key factor in the JH signaling pathway. PMID:25197795

  11. 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

  12. Characterization of PacMetUT1, a recently isolated human prostate cancer cell line.

    PubMed

    Troyer, D A; Tang, Y; Bedolla, R; Adhvaryu, S G; Thompson, I M; Abboud-Werner, S; Sun, L-Z; Friedrichs, W E; deGraffenried, L A

    2008-06-01

    Existing prostate cancer cell lines have limitations. Cells were characterized using Western blotting, immunohistochemistry, invasion into Matrigel, and by studying xenograft tumors. We describe a cell line (PacMetUT1) isolated from a lymph node of a 57-year-old male with prostate cancer. Compared to existing prostate cancer cell lines, the growth rate of PacMetUT1 xenograft tumors is slower with tumors occurring at injection sites and with metastases to lung and liver. Androgen receptor (AR) was detected in vivo by Western blotting and the cells responded to methyltrienolone (R1881). PacMetUT1 cells are more invasive in Matrigel than DU-145, PC-3, and LNCaP cells, and showed greater anchorage-independent growth in soft agar. The cells do not express prostate specific antigen (PSA) in vitro or in xenografts. However, the green fluorescent protein (GFP) gene was introduced and stably expressed in PacMetUT1 cells, allowing tumor imaging in vivo. Xenograft tumors show epithelial features and are positive for keratin, epithelial membrane antigen, EGF receptor, and E cadherin. In contrast, fibroblast markers vimentin, desmin, and Factor VIII, were negative. Karyotyping showed losses of 6p, 7q, 8p, 18q, and 22q, and gains of 8q and 9q; additional genetic material was observed at 2q and 12p. The PacMetUT1 cell line allows metastases to be assessed using a single animal model. Because of its slower growth, PacMetUT1 more closely mimics the human disease. Studies of tumor progression or metastasis can be conducted over a longer period of time. (c) 2008 Wiley-Liss, Inc.

  13. MetR-Regulated Vibrio cholerae Metabolism Is Required for Virulence

    PubMed Central

    Bogard, Ryan W.; Davies, Bryan W.; Mekalanos, John J.

    2012-01-01

    ABSTRACT LysR-type transcriptional regulators (LTTRs) are the largest, most diverse family of prokaryotic transcription factors, with regulatory roles spanning metabolism, cell growth and division, and pathogenesis. Using a sequence-defined transposon mutant library, we screened a panel of V. cholerae El Tor mutants to identify LTTRs required for host intestinal colonization. Surprisingly, out of 38 LTTRs, only one severely affected intestinal colonization in the suckling mouse model of cholera: the methionine metabolism regulator, MetR. Genetic analysis of genes influenced by MetR revealed that glyA1 and metJ were also required for intestinal colonization. Chromatin immunoprecipitation of MetR and quantitative reverse transcription-PCR (qRT-PCR) confirmed interaction with and regulation of glyA1, indicating that misregulation of glyA1 is likely responsible for the colonization defect observed in the metR mutant. The glyA1 mutant was auxotrophic for glycine but exhibited wild-type trimethoprim sensitivity, making folate deficiency an unlikely cause of its colonization defect. MetJ regulatory mutants are not auxotrophic but are likely altered in the regulation of amino acid-biosynthetic pathways, including those for methionine, glycine, and serine, and this misregulation likely explains its colonization defect. However, mutants defective in methionine, serine, and cysteine biosynthesis exhibited wild-type virulence, suggesting that these amino acids can be scavenged in vivo. Taken together, our results suggest that glycine biosynthesis may be required to alleviate an in vivo nutritional restriction in the mouse intestine; however, additional roles for glycine may exist. Irrespective of the precise nature of this requirement, this study illustrates the importance of pathogen metabolism, and the regulation thereof, as a virulence factor. PMID:23015737

  14. Transmission of epi-alleles with MET1-dependent dense methylation in Arabidopsis thaliana.

    PubMed

    Watson, Michael; Hawkes, Emily; Meyer, Peter

    2014-01-01

    DNA methylation in plants targets cytosines in three sequence contexts, CG, CHG and CHH (H representing A, C or T). Each of these patterns has traditionally been associated with distinct DNA methylation pathways with CHH methylation being controlled by the RNA dependent DNA methylation (RdDM) pathway employing small RNAs as a guide for the de novo DOMAINS REARRANGED METHYLTRANSFERASE (DRM2), and maintenance DNA METHYLTRANSFERASE1 (MET1) being responsible for faithful propagation of CG methylation. Here we report an unusual 'dense methylation' pattern under the control of MET1, with methylation in all three sequence contexts. We identified epi-alleles of dense methylation at a non coding RNA locus (At4g15242) in Arabidopsis ecotypes, with distinct dense methylation and expression characteristics, which are stably maintained and transmitted in genetic crosses and which can be heritably altered by depletion of MET1. This suggests that, in addition to its classical CG maintenance function, at certain loci MET1 plays a role in creating transcriptional diversity based on the generation of independent epi-alleles. Database inspection identified several other loci with MET1-dependent dense methylation patterns. Arabidopsis ecotypes contain distinct epi-alleles of these loci with expression patterns that inversely correlate with methylation density, predominantly within the transcribed region. In Arabidopsis, dense methylation appears to be an exception as it is only found at a small number of loci. Its presence does, however, highlight the potential for MET1 as a contributor to epigenetic diversity, and it will be interesting to investigate the representation of dense methylation in other plant species.

  15. Modulating effect of COMT Val(158)Met polymorphism on interference resolution during a working memory task.

    PubMed

    Jaspar, Mathieu; Dideberg, Vinciane; Bours, Vincent; Maquet, Pierre; Collette, Fabienne

    2015-04-01

    Genetic variability related to the catechol-O-methyltransferase (COMT) gene has received increasing attention in the last 15years, in particular as a potential modulator of the neural substrates underlying inhibitory processes and updating in working memory (WM). In an event-related functional magnetic resonance imaging (fMRI) study, we administered a modified version of the Sternberg probe recency task (Sternberg, 1966) to 43 young healthy volunteers, varying the level of interference across successive items. The task was divided into two parts (high vs. low interference) to induce either proactive or reactive control processes. The participants were separated into three groups according to their COMT Val(158)Met genotype [Val/Val (VV); Val/Met (VM); Met/Met (MM)]. The general aim of the study was to determine whether COMT polymorphism has a modulating effect on the neural substrates of interference resolution during WM processing. Results indicate that interfering trials were associated with greater involvement of frontal cortices (bilateral medial frontal gyrus, left precentral and superior frontal gyri, right inferior frontal gyrus) in VV homozygous subjects (by comparison to Met allele carriers) only in the proactive condition of the task. In addition, analysis of peristimulus haemodynamic responses (PSTH) revealed that the genotype-related difference observed in the left SFG was specifically driven by a larger increase in activity from the storage to the recognition phase of the interfering trials in VV homozygous subjects. These results confirm the impact of COMT genotype on inhibitory processes during a WM task, with an advantage for Met allele carriers. Interestingly, this impact on frontal areas is present only when the level of interference is high, and especially during the transition from storage to recognition in the left superior frontal gyrus.

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

    PubMed Central

    Li, Jie; Diao, Lixia; Zhang, Hailong; Foster, Carol M.; Fatland, Beth; Dickerson, Julie; Brown, Andrew; Cox, Zach; Cook, Dianne; Lee, Eun-Kyung; Hofmann, Heike

    2003-01-01

    MetNet (http://www.botany.iastate.edu/∼mash/metnetex/metabolicnetex.html) is publicly available software in development for analysis of genome-wide RNA, protein and metabolite profiling data. The software is designed to enable the biologist to visualize, statistically analyse and model a metabolic and regulatory network map of Arabidopsis, combined with gene expression profiling data. It contains a JAVA interface to an interactions database (MetNetDB) containing information on regulatory and metabolic interactions derived from a combination of web databases (TAIR, KEGG, BRENDA) and input from biologists in their area of expertise. FCModeler captures input from MetNetDB in a graphical form. Sub-networks can be identified and interpreted using 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. PMID:18629120