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Schulze, Johannes B. ; Drolshagen, Stefan ; Nürnberger, Frank ; Ochsendorf, Falk ; Schäfer, Volker ; Brandt, Claudia
Multiple choice (MC)-Klausuren sind im deutschen Medizinstudium trotz weitgehend fehlender Daten zur Validität dieser Prüfungsform zur Regelprüfung geworden. Darüber hinaus ist unklar, in welchem Ausmaß die Studierenden - auch solche mit guten Prüfungsergebnissen - den geprüften Lernstoff tatsächlich beherrschen. Am Fachbereich Medizin der Johann-Wolfgang-Goethe-Universität Frankfurt wurde am Ende des SS 2003 im Fach Mikrobiologie für die Studierenden des 2. klinischen Semesters eine MC-basierte Abschlussprüfung geschrieben. Die Studierenden des 1. klinischen Semesters hatten - bedingt durch Umstellungen des Curriculums - eine identische Ausbildung. Diese wurde durch eine inhaltlich weitgehend identische, im Format aber andere Klausur abgeschlossen, in der sowohl offene Fragen enthalten waren als auch Fragen, bei denen die Studierenden jede Aussage einzeln auf Korrektheit bewerten mussten. Der Vergleich der Ergebnisse für inhaltlich gleiche Fragen zeigt, dass die Studierenden im MC-Format eine hohe Quote richtiger Antworten erzielen, diese jedoch durch ein geändertes Fragenformat stark reduziert wird. So erreichten nur 20 - 30% der Studierenden ein vollständig richtiges Ergebnis, wenn jede Aussage einzeln bewertet werden musste, während die inhaltlich gleiche Frage im MC-Format 80 - 90% richtige Ergebnisse erzielte. In freien Fragen konnten nur 30 - 40% der Studierenden die richtige Antwort aktiv niederschreiben, während 90 -99% der Studierenden die richtige Lösung passiv erkannten. Wir interpretieren diese Ergebnisse dahin, dass der Entscheidungszwang in MC-basierten Fragen einen starken Einfluss auf die Quote richtiger Antworten hat, und die Prüfungsergebnisse damit wesentlich durch das Format beeinflusst werden, das Wissen dagegen nicht beherrscht wird. Die Ergebnisse dieser Studie legen nahe, Sorgfalt bei der Auswahl des Prüfungsverfahrens walten zu lassen und der Steuerung des studentischen Lernverhaltens durch das Prüfungsformat wesentlich mehr Aufmerksamkeit zu widmen als bisher.
Bacak, Michael ; Aïche, Mourad ; Bélier, Gilbert ; Berthoumieux, Eric ; Diakaki, Maria ; Dupont, Emmeric ; Gunsing, Frank ; Heyse, Jan ; Kopecky, Stefan ; Krtička, Milan ; Laurent, Benoit ; Leeb, Helmut ; Mathieu, Ludovic ; Schillebeeckx, Peter ; Serot, Olivier ; Taieb, Julien ; Valenta, Stanislav ; Vlachoudis, Vasilis ; Aberle, Oliver ; Andrzejewski, Józef ; Audouin, Laurent ; Balibrea Correa, Javier ; Barbagallo, Massimo ; Bečvář, František ; Billowes, Jonathan ; Bosnar, Damir ; Brown, Adam ; Caamaño, Manuel ; Calviño Tavares, Francisco ; Calviani, Marco ; Cano-Ott, Daniel ; Cardella, Roberto ; Casanovas Hoste, Adrià ; Cerutti, Francesco ; Chen, Yonghao ; Chiaveri, Enrico ; Colonna, Nicola ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Cosentino, Luigi ; Damone, Lucia Anna ; Domingo-Pardo, César ; Dressler, Rugard ; Durán, Ignacio ; Fernández Domínguez, Beatriz ; Ferrari, Alfredo ; Ferreira, Pedro G. ; Finocchiaro, Paolo ; Furman, Valter ; Göbel, Kathrin ; García Ríos, Aczel Regino ; Gawlik, Aleksandra ; Gilardoni, Simone ; Glodariu, Tudor ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Griesmayer, Erich ; Guerrero Sánchez, Carlos ; Harada, Hideo ; Heinitz, Stephan ; Jenkins, David ; Jericha, Erwin ; Käppeler, Franz ; Kadi, Yacine ; Kalamara, Antigoni ; Kavrigin, Pavel ; Kimura, Atsushi ; Kivel, Nikolay ; Knapová, Ingrid ; Kokkoris, Michael ; Kurtulgil, Cem Deniz ; Leal Cidoncha, Esther ; Lederer, Claudia ; Lerendegui-Marco, Jorge ; Lo Meo, Sergio ; Lonsdale, Sarah Jane ; Macina, Daniela ; Manna, Alice ; Marganiec, Justyna ; Martı́nez, Trinitario ; Masi, Alessandro ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Maugeri, Emilio Andrea ; Mazzone, Annamaria ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Milazzo, Paolo Maria ; Mingrone, Federica ; Musumarra, Agatino ; Negret, Alexandru ; Nolte, Ralf ; Oprea, Andreea ; Patronis, Nikolas ; Pavlik, Andreas ; Perkowski, Jarosław ; Porras Sánchez, José Ignacio ; Praena, Javier ; Quesada Molina, José Manuel ; Radeck, Désirée ; Rauscher, Thomas ; Reifarth, René ; Rubbia, Carlo ; Ryan, James A. ; Sabaté-Gilarte, Marta ; Saxena, Alok ; Schumann, Dorothea ; Sedyshev, Pavel V. ; Smith, Alastair Gavin ; Sosnin, Nikolay V. ; Stamatopoulos, Athanasios ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarifeño-Saldivia, Ariel ; Tassan-Got, Laurent ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Vlastou, Rosa ; Wallner, Anton ; Warren, Stephen J. ; Weiß, Christina ; Woods, Philip John ; Wright, Tobias ; Žugec, Petar
233U is the fissile nuclei in the Th-U fuel cycle with a particularily small neutron capture cross setion which is on average about one order of magnitude lower than its fission cross section. Hence, the measurement of the 233U(n, γ) cross section relies on a method to accurately distinguish between capture and fission γ-rays. A measurement of the 233U α-ratio has been performed at the n_TOF facility at CERN using a so-called fission tagging setup, coupling n_TOF 's Total Absorption Calorimeter with a novel fission chamber to tag the fission γ-rays. The experimental setup is described and essential parts of the analysis are discussed. Finally, a preliminary 233U α-ratio is presented.
Bacak, Michael ; Aïche, Mourad ; Bélier, Gilbert ; Berthoumieux, Eric ; Diakaki, Maria ; Dupont, Emmeric ; Gunsing, Frank ; Heyse, Jan ; Kopecky, Stefan ; Laurent, Benoit ; Leeb, Helmut ; Mathieu, Ludovic ; Schillebeeckx, Peter ; Serot, Olivier ; Taieb, Julien ; Vlachoudis, Vasilis ; Aberle, Oliver ; Andrzejewski, Józef ; Audouin, Laurent ; Balibrea Correa, Javier ; Barbagallo, Massimo ; Bečvář, František ; Billowes, Jonathan ; Bosnar, Damir ; Brown, Adam ; Caamaño, Manuel ; Calviño Tavares, Francisco ; Calviani, Marco ; Cano-Ott, Daniel ; Cardella, Roberto ; Casanovas Hoste, Adrià ; Cerutti, Francesco ; Chen, Yonghao ; Chiaveri, Enrico ; Colonna, Nicola ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Cosentino, Luigi ; Damone, Lucia Anna ; Domingo-Pardo, César ; Dressler, Rugard ; Durán, Ignacio ; Fernández Domínguez, Beatriz ; Ferrari, Alfredo ; Ferreira, Pedro G. ; Finocchiaro, Paolo ; Furman, Valter ; Göbel, Kathrin ; García Ríos, Aczel Regino ; Gawlik, Aleksandra ; Gilardoni, Simone ; Glodariu, Tudor ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Griesmayer, Erich ; Guerrero Sánchez, Carlos ; Harada, Hideo ; Heinitz, Stephan ; Jenkins, David ; Jericha, Erwin ; Käppeler, Franz ; Kadi, Yacine ; Kalamara, Antigoni ; Kavrigin, Pavel ; Kimura, Atsushi ; Kivel, Nikolay ; Knapová, Ingrid ; Kokkoris, Michael ; Krtička, Milan ; Kurtulgil, Cem Deniz ; Leal Cidoncha, Esther ; Lederer, Claudia ; Lerendegui-Marco, Jorge ; Lo Meo, Sergio ; Lonsdale, Sarah Jane ; Macina, Daniela ; Manna, Alice ; Marganiec, Justyna ; Martı́nez, Trinitario ; Masi, Alessandro ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Maugeri, Emilio Andrea ; Mazzone, Annamaria ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Milazzo, Paolo Maria ; Mingrone, Federica ; Musumarra, Agatino ; Negret, Alexandru ; Nolte, Ralf ; Oprea, Andreea ; Patronis, Nikolas ; Pavlik, Andreas ; Perkowski, Jarosław ; Porras Sánchez, José Ignacio ; Praena, Javier ; Quesada Molina, José Manuel ; Radeck, Désirée ; Rauscher, Thomas ; Reifarth, René ; Rubbia, Carlo ; Ryan, James A. ; Sabaté-Gilarte, Marta ; Saxena, Alok ; Schumann, Dorothea ; Sedyshev, Pavel V. ; Smith, Alastair Gavin ; Sosnin, Nikolay V. ; Stamatopoulos, Athanasios ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarifeño-Saldivia, Ariel ; Tassan-Got, Laurent ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Vlastou, Rosa ; Wallner, Anton ; Warren, Stephen J. ; Weiß, Christina ; Woods, Philip John ; Wright, Tobias ; Žugec, Petar
233U is of key importance among the fissile nuclei in the Th-U fuel cycle. A particularity of 233U is its small neutron capture cross-section, which is on average about one order of magnitude lower than the fission cross-section. The accuracy in the measurement of the 233U capture cross-section depends crucially on an efficient capture-fission discrimination, thus a combined set-up of fission and γ-detectors is needed. A measurement of the 233U capture cross-section and capture-to-fission ratio was performed at the CERN n_TOF facility. The Total Absorption Calorimeter (TAC) of n_TOF was employed as γ-detector coupled with a novel compact ionization chamber as fission detector. A brief description of the experimental set-up will be given, and essential parts of the analysis procedure as well as the preliminary response of the set-up to capture are presented and discussed.
Mendoza Cembranos, Emilio ; Cano-Ott, Daniel ; Altstadt, Sebastian ; Andriamonje, Samuel ; Andrzejewski, Józef ; Audouin, Laurent ; Balibrea Correa, Javier ; Bécares, Vicente ; Barbagallo, Massimo ; Bečvář, František ; Belloni, Fabio ; Berthier, B. ; Berthoumieux, Eric ; Billowes, Jonathan ; Boccone, Vittorio ; Bosnar, Damir ; Brugger, Markus ; Calviño Tavares, Francisco ; Calviani, Marco ; Carrapiço, Carlos ; Cerutti, Francesco ; Chiaveri, Enrico ; Chin, Michael ; Colonna, Nicola ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Diakaki, Maria ; Dillmann, Iris ; Domingo-Pardo, César ; Durán, Ignacio ; Dzysiuk, Nataliia ; Eleftheriadis, Christos ; Fernández-Ordóñez, M. ; Ferrari, Alfredo ; Fraval, Kevin ; Furman, Valter ; Gómez Hornillos, María Belén ; Ganesan, Srinivasan ; García Ríos, Aczel Regino ; Giubrone, Giuseppe ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Goverdovski, Andrey ; Gramegna, F. ; Griesmayer, Erich ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Gurusamy, Perumal ; Heftrich, Tanja ; Heinitz, Stephan ; Hernández Prieto, Álvaro ; Heyse, Jan ; Jenkins, David ; Jericha, Erwin ; Käppeler, Franz ; Kadi, Yacine ; Karadimos, Dimitri ; Katabuchi, Tatsuya ; Ketlerov, Vladimir ; Khryachkov, Vitaly ; Koehler, Paul ; Kokkoris, Michael ; Kroll, Jiří ; Krtička, Milan ; Lampoudis, Christos ; Langer, Christoph ; Leal Cidoncha, Esther ; Lederer, Claudia ; Leeb, Helmut ; Leong, Lou Sai ; Lerendegui-Marco, Jorge ; Licata, Mauro ; Losito, Roberto ; Manousos, Athanasios ; Marganiec, Justyna ; Martı́nez, Trinitario ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Mengoni, Alberto ; Milazzo, Paolo Maria ; Mingrone, Federica ; Mirea, Mihail ; Mondelaers, Willy ; Paradela Dobarro, Carlos ; Pavlik, Andreas ; Perkowski, Jarosław ; Plompen, Arjan J. M. ; Praena, Javier ; Quesada Molina, José Manuel ; Rauscher, Thomas ; Reifarth, René ; Riego Pérez, Albert ; Robles Manzano, Maria Soledad ; Roman, Faustin Laurenţiu ; Rubbia, Carlo ; Ryan, James A. ; Sabaté-Gilarte, Marta ; Sarmento, Raul ; Saxena, Alok ; Schillebeeckx, Peter ; Schmidt, Stefan ; Schumann, Dorothea ; Sedyshev, Pavel V. ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarifeño-Saldivia, Ariel ; Tarrío Vilas, Diego ; Tassan-Got, Laurent ; Tsinganis, Andrea ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Vermeulen, Mark J. ; Versaci, Roberto ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Ware, Timothy ; Weigand, Mario ; Weiss, Christian ; Wright, Tobias ; Žugec, Petar
New neutron cross section measurements of minor actinides have been performed recently in order to reduce the uncertainties in the evaluated data, which is important for the design of advanced nuclear reactors and, in particular, for determining their performance in the transmutation of nuclear waste. We have measured the 241Am(n,γ) cross section at the n_TOF facility between 0.2 eV and 10 keV with a BaF2 Total Absorption Calorimeter, and the analysis of the measurement has been recently concluded. Our results are in reasonable agreement below 20 eV with the ones published by C. Lampoudis et al. in 2013, who reported a 22% larger capture cross section up to 110 eV compared to experimental and evaluated data published before. Our results also indicate that the 241Am(n,γ) cross section is underestimated in the present evaluated libraries between 20 eV and 2 keV by 25%, on average, and up to 35% for certain evaluations and energy ranges.
Lerendegui-Marco, Jorge ; Guerrero Sánchez, Carlos ; Mendoza Cembranos, Emilio ; Quesada Molina, José Manuel ; Eberhardt, Klaus ; Junghans, Arnd Rudolf ; Krtička, Milan ; Belgya, T. ; Maróti, B. ; Aberle, Oliver ; Andrzejewski, Józef ; Audouin, Laurent ; Bécares, Vicente ; Bacak, Michael ; Balibrea Correa, Javier ; Barbagallo, Massimo ; Barros, Susana C.C. ; Bečvář, František ; Beinrucker, Clemens ; Berthoumieux, Eric ; Billowes, Jonathan ; Bosnar, Damir ; Brugger, Markus ; Caamaño, Manuel ; Calviño Tavares, Francisco ; Calviani, Marco ; Cano-Ott, Daniel ; Cardella, Roberto ; Casanovas Hoste, Adrià ; Castelluccio, Donato Maurizio ; Cerutti, Francesco ; Chen, Yonghao ; Chiaveri, Enrico ; Colonna, Nicola ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Cosentino, Luigi ; Damone, Lucia Anna ; Diakaki, Maria ; Domingo-Pardo, César ; Dressler, Rugard ; Dupont, Emmeric ; Durán, Ignacio ; Fernández Domínguez, Beatriz ; Ferrari, Alfredo ; Ferreira, Pedro G. ; Finocchiaro, Paolo ; Furman, Valter ; Göbel, Kathrin ; García Ríos, Aczel Regino ; Gawlik, Aleksandra ; Glodariu, Tudor ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Goverdovski, Andrey ; Griesmayer, Erich ; Gunsing, Frank ; Harada, Hideo ; Heftrich, Tanja ; Heinitz, Stephan ; Heyse, Jan ; Jenkins, David ; Jericha, Erwin ; Käppeler, Franz ; Kadi, Yacine ; Katabuchi, Tatsuya ; Kavrigin, Pavel ; Ketlerov, Vladimir ; Khryachkov, Vitaly ; Kimura, Atsushi ; Kivel, Nikolay ; Knapová, Ingrid ; Kokkoris, Michael ; Leal Cidoncha, Esther ; Lederer, Claudia ; Leeb, Helmut ; Lo Meo, Sergio ; Lonsdale, Sarah Jane ; Losito, Roberto ; Macina, Daniela ; Marganiec, Justyna ; Martı́nez, Trinitario ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Matteucci, Francesca ; Maugeri, Emilio Andrea ; Mengoni, Alberto ; Milazzo, Paolo Maria ; Mingrone, Federica ; Mirea, Mihail ; Montesano, Simone ; Musumarra, Agatino ; Nolte, Ralf ; Oprea, Andreea ; Patronis, Nikolas ; Pavlik, Andreas ; Perkowski, Jarosław ; Porras Sánchez, José Ignacio ; Praena, Javier ; Rajeev, K. ; Rauscher, Thomas ; Reifarth, René ; Riego Pérez, Albert ; Rout, Prakash Chandra ; Rubbia, Carlo ; Ryan, James A. ; Sabaté-Gilarte, Marta ; Saxena, Alok ; Schillebeeckx, Peter ; Schmidt, Stefan ; Schumann, Dorothea ; Sedyshev, Pavel V. ; Smith, Alastair Gavin ; Stamatopoulos, Athanasios ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarifeño-Saldivia, Ariel ; Tassan-Got, Laurent ; Tsinganis, Andrea ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Vescovi, Diego ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Warren, Stephen J. ; Weigand, Mario ; Weiß, Christina ; Wolf, Clemens ; Woods, Philip John ; Wright, Tobias ; Žugec, Petar
The design and operation of innovative nuclear systems requires a better knowledge of the capture and fission cross sections of the Pu isotopes. For the case of capture on 242Pu, a reduction of the uncertainty in the fast region down to 8-12% is required. Moreover, aiming at improving the evaluation of the fast energy range in terms of average parameters, the OECD NEA High Priority Request List (HPRL) requests high-resolution capture measurements with improved accuracy below 2 keV. The current uncertainties also affect the thermal point, where previous experiments deviate from each other by 20%. A fruitful collaboration betwen JGU Mainz and HZ Dresden-Rossendorf within the EC CHANDA project resulted in a 242Pu sample consisting of a stack of seven fission-like targets making a total of 95(4) mg of 242Pu electrodeposited on thin (11.5 μm) aluminum backings. This contribution presents the results of a set of measurements of the 242Pu(n, γ) cross section from thermal to 500 keV combining different neutron beams and techniques. The thermal point was determined at the Budapest Research Reactor by means of Neutron Activation Analysis and Prompt Gamma Analysis, and the resolved (1 eV - 4 keV) and unresolved (1 - 500 keV) resonance regions were measured using a set of four Total Energy detectors at the CERN n_TOF-EAR1.
Balibrea Correa, Javier ; Mendoza Cembranos, Emilio ; Cano-Ott, Daniel ; Krtička, Milan ; Altstadt, Sebastian ; Andrzejewski, Józef ; Audouin, Laurent ; Bécares, Vicente ; Barbagallo, Massimo ; Bečvář, František ; Belloni, Fabio ; Berthoumieux, Eric ; Billowes, Jonathan ; Boccone, Vittorio ; Bosnar, Damir ; Brugger, Markus ; Calviño Tavares, Francisco ; Calviani, Marco ; Carrapiço, Carlos ; Cerutti, Francesco ; Chiaveri, Enrico ; Chin, Michael ; Colonna, Nicola ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Diakaki, Maria ; Domingo-Pardo, César ; Dressler, Rugard ; Durán, Ignacio ; Eleftheriadis, Christos ; Ferrari, Alfredo ; Fraval, Kevin ; Furman, Valter ; Göbel, Kathrin ; Guerrero Sánchez, Carlos ; Gómez Hornillos, María Belén ; Ganesan, Srinivasan ; García Ríos, Aczel Regino ; Giubrone, Giuseppe ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Goverdovski, Andrey ; Griesmayer, Erich ; Gunsing, Frank ; Heftrich, Tanja ; Heinitz, Stephan ; Hernández Prieto, Álvaro ; Heyse, Jan ; Jenkins, David ; Jericha, Erwin ; Käppeler, Franz ; Kadi, Yacine ; Karadimos, Dimitri ; Katabuchi, Tatsuya ; Ketlerov, Vladimir ; Khryachkov, Vitaly ; Kivel, Nikolay ; Koehler, Paul ; Kokkoris, Michael ; Kroll, Jiří ; Lampoudis, Christos ; Langer, Christoph ; Leal Cidoncha, Esther ; Lederer, Claudia ; Leeb, Helmut ; Leong, Lou Sai ; Lerendegui-Marco, Jorge ; Licata, Mauro ; Losito, Roberto ; Mallick, Amod Kishore ; Manousos, Athanasios ; Marganiec, Justyna ; Martı́nez, Trinitario ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Mengoni, Alberto ; Milazzo, Paolo Maria ; Mingrone, Federica ; Mirea, Mihail ; Mondelaers, Willy ; Paradela Dobarro, Carlos ; Pavlik, Andreas ; Perkowski, Jarosław ; Plompen, Arjan J. M. ; Praena, Javier ; Quesada Molina, José Manuel ; Rauscher, Thomas ; Reifarth, René ; Riego Pérez, Albert ; Robles Manzano, Maria Soledad ; Rubbia, Carlo ; Ryan, James A. ; Sabaté-Gilarte, Marta ; Sarmento, Raul ; Saxena, Alok ; Schillebeeckx, Peter ; Schmidt, Stefan ; Schumann, Dorothea ; Sedyshev, Pavel V. ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarifeño-Saldivia, Ariel ; Tarrío Vilas, Diego ; Tassan-Got, Laurent ; Tsinganis, Andrea ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Vermeulen, Mark J. ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Ware, Timothy ; Weigand, Mario ; Weiss, Christian ; Wright, Tobias ; Žugec, Petar
The accuracy on neutron capture cross section of fissile isotopes must be improved for the design of future nuclear systems such as Gen-IV reactors and Accelerator Driven Systems. The High Priority Request List of the Nuclear Energy Agency, which lists the most important nuclear data requirements, includes also the neutron capture cross sections of fissile isotopes such as 233,235U and 239,241Pu. A specific experimental setup has been used at the CERN n_TOF facility for the measurement of the neutron capture cross section of 235U by a set of micromegas fission detectors placed inside a segmented BaF2 Total Absorption Calorimeter.
Chen, Yong Hao ; Tassan-Got, Laurent ; Audouin, Laurent ; Le Naour, Claire ; Durán, Ignacio ; Casarejos Ruiz, Enrique ; Aberle, Oliver ; Andrzejewski, Józef ; Bécares, Vicente ; Bacak, Michael ; Balibrea Correa, Javier ; Barbagallo, Massimo ; Barros, Susana C.C. ; Bečvář, František ; Beinrucker, Clemens ; Berthoumieux, Eric ; Billowes, Jonathan ; Bosnar, Damir ; Brugger, Markus ; Caamaño, Manuel ; Calviño Tavares, Francisco ; Calviani, Marco ; Cano-Ott, Daniel ; Cardella, Roberto ; Casanovas Hoste, Adrià ; Castelluccio, Donato Maurizio ; Cerutti, Francesco ; Chiaveri, Enrico ; Colonna, Nicola ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Cosentino, Luigi ; Damone, Lucia Anna ; Diakaki, Maria ; Domingo-Pardo, César ; Dressler, Rugard ; Dupont, Emmeric ; Fernández Domínguez, Beatriz ; Ferrari, Alfredo ; Ferreira, Pedro G. ; Finocchiaro, Paolo ; Furman, Valter ; Göbel, Kathrin ; Gómez Hornillos, María Belén ; García Ríos, Aczel Regino ; Gawlik, Aleksandra ; Glodariu, Tudor ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Goverdovski, Andrey ; Griesmayer, Erich ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Harada, Hideo ; Heftrich, Tanja ; Heinitz, Stephan ; Heyse, Jan ; Jenkins, David ; Jericha, Erwin ; Käppeler, Franz ; Kadi, Yacine ; Katabuchi, Tatsuya ; Kavrigin, Pavel ; Ketlerov, Vladimir ; Khryachkov, Vitaly ; Kimura, Atsushi ; Kivel, Nikolay ; Kokkoris, Michael ; Krtička, Milan ; Leal Cidoncha, Esther ; Lederer, Claudia ; Leeb, Helmut ; Lerendegui-Marco, Jorge ; Lo Meo, Sergio ; Lonsdale, Sarah Jane ; Losito, Roberto ; Macina, Daniela ; Marganiec, Justyna ; Martı́nez, Trinitario ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Matteucci, Francesca ; Maugeri, Emilio Andrea ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Milazzo, Paolo Maria ; Mingrone, Federica ; Mirea, Mihail ; Montesano, Simone ; Musumarra, Agatino ; Nolte, Ralf ; Oprea, Andreea ; Patronis, Nikolas ; Pavlik, Andreas ; Perkowski, Jarosław ; Porras Sánchez, José Ignacio ; Praena, Javier ; Quesada Molina, José Manuel ; Rajeev, K. ; Rauscher, Thomas ; Reifarth, René ; Riego Pérez, Albert ; Robles Manzano, Maria Soledad ; Rout, Prakash Chandra ; Rubbia, Carlo ; Ryan, James A. ; Sabaté-Gilarte, Marta ; Saxena, Alok ; Schillebeeckx, Peter ; Schmidt, Stefan ; Schumann, Dorothea ; Sedyshev, Pavel V. ; Smith, Alastair Gavin ; Stamatopoulos, Athanasios ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarifeño-Saldivia, Ariel ; Tsinganis, Andrea ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Warren, Stephen J. ; Weigand, Mario ; Weiß, Christina ; Wolf, Clemens ; Woods, Philip John ; Wright, Tobias ; Žugec, Petar
The experimental area 2 (EAR-2) at CERNs neutron time-of-flight facility (n_TOF), which is operational since 2014, is designed and built as a short-distance complement to the experimental area 1 (EAR-1). The Parallel Plate Avalanche Counter (PPAC) monitor experiment was performed to characterize the beam pro↓le and the shape of the neutron 'ux at EAR-2. The prompt γ-flash which is used for calibrating the time-of-flight at EAR-1 is not seen by PPAC at EAR-2, shedding light on the physical origin of this γ-flash.
Huckins, Laura M. ; Hatzikotoulas, Konstantinos ; Southam, Lorraine ; Thornton, Laura M. ; Steinberg, Julia ; Mckay Aguilera, Fernando Riveros ; Treasure, Janet ; Schmidt, Ulrike ; Gunasinghe, Cerisse ; Romero, Anibal ; Curtis, Charles ; Rhodes, Daniel ; Moens, Julie ; Kalsi, Gursharan ; Dempster, David ; Leung, Rufina ; Keohane, Aoife ; Burghardt, Roland ; Ehrlich, Stefan ; Hebebrand, Johannes ; Hinney, Anke ; Ludolph, Anja ; Walton, Esther ; Deloukas, Panos ; Hofman, Albert ; Palotie, Aarno ; Palta, Priit ; Rooij, Frank J. A. van ; Stirrups, Kathleen ; Adan, Roger ; Boni, Claudette ; Cone, Roger ; Dedoussis, George ; Furth, Eric van ; Gonidakis, Fragiskos ; Gorwood, Philip ; Hudson, James I. ; Kaprio, Jaakko ; Kas, Martien ; Keski-Rahkonen, Anna ; Kiezebrink, Kirsty ; Knudsen, Gun Peggy ; Slof-Op ‘t Landt, Margarita C. T. ; Maj, Mario ; Monteleone, Alessio Maria ; Monteleone, Palmiero ; Raevuori, Anu ; Reichborn-Kjennerud, Ted ; Tozzi, Federica ; Tsitsika, Artemis ; Elburg, Annemarie van ; Collier, David A. ; Sullivan, Patrick F. ; Breen, Gerome ; Bulik, Cynthia M. ; Zeggini, Eleftheria
Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10−6), and rs7700147, an intergenic variant (P=2.93 × 10−5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes.
Andlauer, Till ; Guzman-Parra, José ; Streit, Fabian ; Strohmaier, Jana ; González, Maria José ; Flores, Susana Gil ; Cabaleiro Fabeiro, Francisco J. ; Rı́o Noriega, Francisco del ; Perez, Fermin Perez ; González, Jesus Haro ; Orozco Diaz, Guillermo ; de Diego-Otero, Yolanda ; Moreno-Kuestner, Berta ; Auburger, Georg ; Degenhardt, Franziska ; Heilmann-Heimbach, Stefanie ; Herms, Stefan ; Hoffmann, Per ; Frank, Josef ; Foo, Jerome Clifford ; Treutlein, Jens ; Witt, Stephanie H. ; Cichon, Sven ; Kogevinas, Manolis ; Rivas, Fabio ; Mayoral, Fermı́n ; Müller-Myhsok, Bertram ; Forstner, Andreas Josef ; Nöthen, Markus Maria ; Rietschel, Marcella
Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families as well as 438 subjects from an independent, sporadic BD case-control cohort were analysed. Polygenic risk scores (PRS) for BD, schizophrenia, and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had significantly higher PRS for all three psychiatric disorders than the independent controls, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and sporadic BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses, therefore, demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. The PRS explained only part of the observed phenotypic variance and rare variants might have also contributed to disease development.
Andlauer, Till ; Guzman-Parra, José ; Streit, Fabian ; Strohmaier, Jana ; González, Maria José ; Flores, Susana Gil ; Cabaleiro Fabeiro, Francisco J. ; Rı́o Noriega, Francisco del ; Perez, Fermin Perez ; González, Jesus Haro ; Orozco Diaz, Guillermo ; de Diego-Otero, Yolanda ; Moreno-Kuestner, Berta ; Auburger, Georg ; Degenhardt, Franziska ; Heilmann-Heimbach, Stefanie ; Herms, Stefan ; Hoffmann, Per ; Frank, Josef ; Foo, Jerome Clifford ; Treutlein, Jens ; Witt, Stephanie H. ; Cichon, Sven ; Kogevinas, Manolis ; Rivas, Fabio ; Mayoral, Fermı́n ; Müller-Myhsok, Bertram ; Forstner, Andreas Josef ; Nöthen, Markus Maria ; Rietschel, Marcella
Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development.
Eckardt, Jan-Niklas ; Stasik, Sebastian ; Kramer, Michael ; Röllig, Christoph ; Krämer, Alwin ; Scholl, Sebastian ; Hochhaus, Andreas ; Crysandt, Martina ; Brümmendorf, Tim Henrik ; Naumann, Ralph ; Steffen, Björn ; Kunzmann, Volker ; Einsele, Hermann ; Schaich, Markus ; Burchert, Andreas ; Neubauer, Andreas ; Schäfer-Eckart, Kerstin ; Schliemann, Christoph ; Krause, Stefan W. ; Herbst, Regina ; Hänel, Mathias ; Frickhofen, Norbert ; Noppeney, Richard ; Kaiser, Ulrich ; Baldus, Claudia ; Kaufmann, Martin ; Rácil, Zdenek ; Platzbecker, Uwe ; Berdel, Wolfgang E. ; Mayer, Jiří ; Serve, Hubert ; Müller-Tidow, Carsten ; Ehninger, Gerhard ; Stölzel, Friedrich ; Kroschinsky, Frank ; Schetelig, Johannes ; Bornhäuser, Martin ; Thiede, Christian ; Middeke, Jan Moritz
Simple Summary: Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Clinical phenotypes of frequent mutations and their impact on patient outcome are well established. However, the role of rare mutations often remains elusive. We retrospectively analyzed 1529 newly diagnosed and intensively treated AML patients for mutations of BCOR and BCORL1. We report a distinct co-mutational pattern that suggests a role in disease progression rather than initiation, especially affecting mechanisms of DNA-methylation. Further, we found loss-of-function mutations of BCOR to be independent markers of poor outcomes in multivariable analysis. Therefore, loss-of-function mutations of BCOR need to be considered for AML management, as they may influence risk stratification and subsequent treatment allocation.
Abstract: Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005–2.134), p = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163–3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990–2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation.
Malkomes, Patrizia ; Lunger, Ilaria ; Oppermann, Elsie ; Abou-El-Ardat, Khalil ; Oellerich, Thomas ; Günther, Stefan ; Canbulat, Can ; Bothur, Sabrina ; Schnütgen, Frank ; Yu, Weijia ; Wingert, Susanne ; Hätscher, Nadine ; Catapano, Claudia ; Dietz, Marina ; Heilemann, Mike ; Kvasnicka, Hans Michael ; Holzer, Katharina ; Serve, Hubert ; Bechstein, Wolf Otto ; Rieger, Michael A.
Despite a high clinical need for the treatment of colorectal carcinoma (CRC) as the second leading cause of cancer-related deaths, targeted therapies are still limited. The multifunctional enzyme Transglutaminase 2 (TGM2), which harbors transamidation and GTPase activity, has been implicated in the development and progression of different types of human cancers. However, the mechanism and role of TGM2 in colorectal cancer are poorly understood. Here, we present TGM2 as a promising drug target.
In primary patient material of CRC patients, we detected an increased expression and enzymatic activity of TGM2 in colon cancer tissue in comparison to matched normal colon mucosa cells. The genetic ablation of TGM2 in CRC cell lines using shRNAs or CRISPR/Cas9 inhibited cell expansion and tumorsphere formation. In vivo, tumor initiation and growth were reduced upon genetic knockdown of TGM2 in xenotransplantations. TGM2 ablation led to the induction of Caspase-3-driven apoptosis in CRC cells. Functional rescue experiments with TGM2 variants revealed that the transamidation activity is critical for the pro-survival function of TGM2. Transcriptomic and protein–protein interaction analyses applying various methods including super-resolution and time-lapse microscopy showed that TGM2 directly binds to the tumor suppressor p53, leading to its inactivation and escape of apoptosis induction.
We demonstrate here that TGM2 is an essential survival factor in CRC, highlighting the therapeutic potential of TGM2 inhibitors in CRC patients with high TGM2 expression. The inactivation of p53 by TGM2 binding indicates a general anti-apoptotic function, which may be relevant in cancers beyond CRC.
Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide via the ENIGMA Consortium
(2017)
Kong, Xiang-Zhen ; Mathias, Samuel R. ; Guadalupe, Tulio ; Abé, Christoph ; Agartz, Ingrid ; Akudjedu, Theophilus N. ; Andre, Aleman ; Saud, Alhusaini ; Allen, Nicholas B. ; Ames, David ; Andreassen, Ole A. ; Arias Vásquez, Alejandro ; Armstrong, Nicola J. ; Bergo, Felipe ; Bastin, Mark E. ; Batalla, Albert ; Bauer, Jochen ; Baune, Bernhard T. ; Baur, Ramona ; Biederman, Joseph ; Blaine, Sara K. ; Boedhoe, Premika ; Bøen, Erlend ; Bose, Anushree ; Bralten, Janita ; Brandeis, Daniel ; Brem, Silvia ; Brodaty, Henry ; Bröhl, Henrieke ; Brooks, Samantha J. ; Buitelaar, Jan K. ; Bürger, Christian ; Bülow, Robin ; Calhoun, Vince D. ; Calvo, Anna ; Canales-Rodrı́guez, Erick Jorge ; Canive, Jose M. ; Cannon, Dara M. ; Caparelli, Elisabeth C. ; Castellanos, Francisco X. ; Cavalleri, Gianpiero L. ; Cendes, Fernando ; Chaim-Avancini, Tiffany Moukbel ; Chantiluke, Kaylita ; Chen, Qun-lin ; Chen, Xiayu ; Cheng, Yuqi ; Christakou, Anastasia ; Clark, Vincent P. ; Coghill, David ; Connolly, Colm G. ; Conzelmann, Annette ; Cόrdova-Palomera, Aldo ; Cousijn, Janna ; Crow, Tim ; Cubillo, Ana ; Dannlowski, Udo ; de Bruttopilo, Sara Ambrosino ; Zeeuw, Patrick de ; Deary, Ian J. ; Delanty, Norman ; Demeter, Damion V. ; Di Martino, Adriana ; Dickie, Erin W ; Dietsche, Bruno ; Doan, N. Trung ; Doherty, Colin P. ; Doyle, Alysa ; Durston, Sarah ; Earl, Eric ; Ehrlich, Stefan ; Ekman, Carl Johan ; Elvsåshagen, Torbjørn ; Epstein, Jeffery N. ; Fair, Damien A. ; Faraone, Stephen V. ; Fatouros-Bergman, Helena ; Fernndez, Guillen ; Busatto Filho, Geraldo ; Flyckt, Lena ; Forster, Katharina ; Jean-Paul, Fouche ; Foxe, John J. ; Fuentes-Claramonte, Paola ; Fullerton, Janice M. ; Garavan, Hugh ; Garcia, Danielle do Santos ; Gotlib, Ian H. ; Goudriaan, Anna E. ; Grabe, Hans Jörgen ; Groenewold, Nynke A. ; Grotegerd, Dominik ; Gruber, Oliver ; Gurholt, Tiril ; Haavik, Jan ; Hahn, Tim ; Hansell, Narelle K. ; Harris, Mathew A. ; Hartman, Catharina ; Hernandez, Maria del Carmen Valdes ; Heslenfeld, Dirk ; Hester, Robert ; Hibar, Derrek Paul ; Ho, Beng-Choon ; Ho, Tiffany C. ; Hoekstra, Pieter J. ; van Holst, Ruth J. ; Hoogman, Martine ; Hovik, Marie F. ; Howells, Fleur M. ; Hugdahl, Kenneth ; Huyser, Chaim ; Ingvar, Martind ; Irwin, Lourdes ; Ishikawa, Akari ; James, Anthony ; Jahanshad, Neda ; Jernigan, Terry L. ; Jönsson, Erik G. ; Kahler, Claas ; Kaleda, Vasily ; Kelly, Clare ; Kerich, Michael ; Keshavan, Matcheri S ; Khadka, Sabin ; Kircher, Tilo ; Kohls, Gregor ; Konrad, Kerstin ; Korucuoglu, Ozlem ; Krämer, Bernd ; Krug, Axel ; Kwon, Jun Soo ; Lambregts-Rommelse, Nanda ; Landén, Mikael ; Lázaro, Luisa ; Lebedeva, Irina ; Lenroot, Rhoshel ; Lesch, Klaus-Peter J. ; Li, Qinqin ; Lim, Kelvin O. ; Liu, Jia ; Lochner, Christine ; London, Edythe D. ; Lonning, Vera ; Lorenzetti, Valentina ; Luciano, Michelle ; Luijten, Maartje ; Lundervold, Astri J. ; Mackey, Scott ; MacMaster, Frank P. ; Maingault, Sophie ; Malpas, Charles B. ; Malt, Ulrik F. ; Mataix-Cols, David ; Martin-Santos, Rocio ; Mayer, Andrew R. ; McCarthy, Hazel ; Mitchell, Philip B. ; Mueller, Bryon A. ; Maniega, Susana Munoz ; Mazoyer, Bernard ; McDonald, Colm ; McLellan, Quinn ; McMahon, Katie L. ; McPhilemy, Genevieve ; Momenan, Reza ; Morales, Angelica M. ; Narayanaswamy, Janardhanan C. ; Moreira, José Carlos Vasques ; Nerland, Stener ; Nestor, Liam ; Nigg, Joel T. ; Nordvik, Jan-Egil ; Novotny, Stephanie ; Oberwelland, Eileen ; O’Gorman, Ruth L. ; Oosterlaan, Jaap ; Oranje, Bob ; Orr, Catherine ; Overs, Bronwyn ; Pauli, Paul ; Paulus, Martin ; Plessen, Kerstin ; Polier, Georg von ; Pomarol-Clotet, Edith ; Qiu, Jiang ; Radua, Joaquim ; Ramos-Quiroga, J. Antoni ; Reddy, Y.C. Janardhan ; Reif, Andreas ; Roberts, Gloria ; Rosa, Pedro ; Rubia, Katya ; Sacchet, Matthew D. ; Sachdev, Perminder S. ; Salvador, Raymond ; Schmaal, Lianne ; Schweren, Lisanne ; Seidman, Larry J. ; Seitz, Jochen ; Serpa, Mauricio Henriques ; Shaw, Philip ; Shumskaya, Elena ; Silk, Timothy J. ; Simmons, Alan N. ; Simulionyte, Egle ; Sinha, Rajita ; Sjoerds, Zsuzsika ; Smelror, Runar Elle ; Soliva, Joan Carlos ; Solowij, Nadia ; Sponheim, Scott R. ; Stein, Dan J. ; Stein, Elliot A. ; Stevens, Michael ; Strike, Lachlan T. ; Sudre, Gustavo ; Sui, Jing ; Tamm, Leanne ; Temmingh, Hendrik S. ; Thoma, Robert J. ; Tomyshev, Alexander S. ; Tronchin, Giulia ; Turner, Jessica A. ; Uhlmann, Anne ; van Erp, Theo G.M. ; van den Heuvel, Odile ; Meer, Dennis van der ; Eijk, Liza van ; Vance, Alasdair ; Veer, Ilya M. ; Veltman, Dick J. ; Venkatasubramanian, Ganesan ; Vilarroya, Oscar ; Vives-Gilabert, Yolanda ; Voineskos, Aristotle N. ; Völzke, Henry ; Vuletic, Daniella ; Walitza, Susanne ; Walter, Henrik ; Walton, Esther ; Wardlaw, Joanna M. ; Wen, Wei ; Westlye, Lars T. ; Whelan, Christopher D. ; White, Tonya ; Wiers, Reinout W. ; Wright, Margaret J. ; Wittfeld, Katharina ; Yang, Tony T. ; Yasuda, Clarissa L. ; Yoncheva, Yuliya ; Yucel, Murat ; Yun, Je-Yeon ; Zanetti, Marcus Vinicius ; Zhen, Zonglei ; Zhu, Xing-xing ; Ziegler, Georg Christoph ; Zierhut, Kathrin ; De Zubicaray, Greig ; Zwiers, Marcel P. ; Glahn, David C. ; Franke, Barbara ; Crivello, Fabrice ; Tzourio-Mazoyer, Nathalie ; Fisher, Simon E. ; Thompson, Paul M. ; Francks, Clyde ; Farde, Lars ; Engberg, Goran ; Erhardt, Sophie ; Cervenka, Simon ; Schwieler, Lilly ; Piehl, Fredrik ; Collste, Karin ; Victorsson, Pauliina ; Malmqvist, Anna ; Hedberg, Mikael ; Orhan, Funda
Karatas, Mehmet ; Chaikuad, Apirat ; Berger, Bianca ; Kubbutat, Michael H. G. ; Totzke, Frank ; Knapp, Stefan ; Kunick, Conrad
Although overexpression and hyperactivity of protein kinases are causative for a wide range of human cancers, protein kinase inhibitors currently approved as cancer drugs address only a limited number of these enzymes. To identify new chemotypes addressing alternative protein kinases, the basic structure of a known PLK1/VEGF-R2 inhibitor class was formally dissected and reassembled. The resulting 7-(2-anilinopyrimidin-4-yl)-1-benzazepin-2-ones were synthesized and proved to be dual inhibitors of Aurora A kinase and VEGF receptor kinases. Crystal structures of two representatives of the new chemotype in complex with Aurora A showed the ligand orientation in the ATP binding pocket and provided the basis for rational structural modifications. Congeners with attached sulfamide substituents retained Aurora A inhibitory activity. In vitro screening of two members of the new kinase inhibitor family against the cancer cell line panel of the National Cancer Institute (NCI) showed antiproliferative activity in the single-digit micromolar concentration range in the majority of the cell lines.
Camgoz, Aylin ; Paszkowski-Rogacz, Maciej ; Satpathy, Shankha ; Wermke, Martin ; Hamann, Martin V. ; Bonin, Malte von ; Choudhary, Chunaram ; Knapp, Stefan ; Buchholz, Frank
Acute myeloid leukemia (AML) is characterized by uncontrolled proliferation and accumulation of immature myeloblasts, which impair normal hematopoiesis. While this definition categorizes the disease into a distinctive group, the large number of different genetic and epigenetic alterations actually suggests that AML is not a single disease, but a plethora of malignancies. Still, most AML patients are not treated with targeted medication but rather by uniform approaches such as chemotherapy. The identification of novel treatment options likely requires the identification of cancer cell vulnerabilities that take into account the different genetic and epigenetic make-up of the individual tumors. Here we show that STK3 depletion by knock-down, knock-out or chemical inhibition results in apoptotic cells death in some but not all AML cell lines and primary cells tested. This effect is mediated by a premature activation of cyclin dependent kinase 1 (CDK1) in presence of elevated cyclin B1 levels. The anti-leukemic effects seen in both bulk and progenitor AML cells suggests that STK3 might be a promising target in a subset of AML patients.
Estes, Chris ; Anstee, Quentin M. ; Arias-Loste, María Teresa ; Bantel, Heike ; Bellentani, Stefano ; Caballeria, Joan ; Colombo, Massimo ; Craxi, Antonio ; Crespo, Javier ; Day, Christopher P. ; Eguchi, Yuichiro ; Geier, Andreas ; Kondili, Loreta A. ; Kroy, Daniela Christina ; Lazarus, Jeffrey V. ; Loomba, Rohit ; Manns, Michael P. ; Marchesini, Giulio ; Nakajima, Atsushi ; Negro, Francesco ; Petta, Salvatore ; Ratziu, Vlad ; Romero-Gomez, Manuel ; Sanyal, Arun ; Schattenberg, Jörn Markus ; Tacke, Frank ; Tanaka, Junko ; Trautwein, Christian ; Wei, Lai ; Zeuzem, Stefan ; Razavi, Homie
Background & Aims: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are increasingly a cause of cirrhosis and hepatocellular carcinoma globally. This burden is expected to increase as epidemics of obesity, diabetes and metabolic syndrome continue to grow. The goal of this analysis was to use a Markov model to forecast NAFLD disease burden using currently available data.
Methods: A model was used to estimate NAFLD and NASH disease progression in eight countries based on data for adult prevalence of obesity and type 2 diabetes mellitus (DM). Published estimates and expert consensus were used to build and validate the model projections.
Results: If obesity and DM level off in the future, we project a modest growth in total NAFLD cases (0–30%), between 2016–2030, with the highest growth in China as a result of urbanization and the lowest growth in Japan as a result of a shrinking population. However, at the same time, NASH prevalence will increase 15–56%, while liver mortality and advanced liver disease will more than double as a result of an aging/increasing population.
Conclusions: NAFLD and NASH represent a large and growing public health problem and efforts to understand this epidemic and to mitigate the disease burden are needed. If obesity and DM continue to increase at current and historical rates, both NAFLD and NASH prevalence are expected to increase. Since both are reversible, public health campaigns to increase awareness and diagnosis, and to promote diet and exercise can help manage the growth in future disease burden.
Lay summary: Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis can lead to advanced liver disease. Both conditions are becoming increasingly prevalent as the epidemics of obesity and diabetes continue to increase. A mathematical model was built to understand how the disease burden associated with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis will change over time. Results suggest increasing cases of advanced liver disease and liver-related mortality in the coming years.
Koch, Christine ; Göller, Markus ; Schott, Eckart ; Waidmann, Oliver ; Winkel, Mark op den ; Paprottka, Philipp Marius ; Zangos, Stephan ; Vogel, Thomas ; Bechstein, Wolf Otto ; Zeuzem, Stefan ; Kolligs, Frank Thomas ; Trojan, Jörg
Background and Aims. Systemic treatment with sorafenib has been the standard of care (SOC) in patients with advanced Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) for more than a decade. TACE has been reported to allow better local tumor control in selected patients with BCLC stage C HCC. Methods. A retrospective analysis of patients with BCLC stage C HCC that were treated with sorafenib and TACE was conducted; they were compared to BCLC stage C patients treated either with TACE or sorafenib in the same period of time outside a clinical trial. Results. A total of 201 patients with BCLC stage C were identified, who were treated with either sorafenib and TACE (group A; n = 54), sorafenib (group B; n = 82) or TACE (group C; n = 65). No significant difference in baseline characteristics was observed. Time to progression was 7.0 months (95% CI: 4.3–9.7), 4.1 months (95% CI: 3.6–4.7) and 5.0 months (95% CI: 2.9–7.1) in groups A, B and C, respectively, and overall survival was 16.5 months (95% CI: 15.0–18.1), 8.4 months (95% CI: 6.0–10.8) and 10.5 months (95% CI: 7.5–13.6), respectively (group A vs. group B: p < 0.001; group A vs. group C: p = 0.0023). Adverse events of grade 3/4 occurred in 34% of patients in group A. Conclusions. Although sorafenib is a SOC in patients with BCLC stage C HCC, TACE is frequently used as an additional locoregional treatment in selected patients. This combined approach resulted in a significant overall survival benefit in selected patients, although randomized trials have not yet proven this benefit.
Hofmann, Wolf-Peter ; Buggisch, Peter ; Schubert, Lisa ; Dikopoulos, Nektarios ; Schwenzer, Jeannette ; Muche, Marion ; Felten, Gisela ; Heyne, Renate ; Ingiliz, Patrick Philipp ; Schmidt, Anna ; Stein, Kerstin ; Wedemeyer, Heiner ; Berg, Thomas ; Wiegand, Johannes ; Lammert, Frank ; Zeuzem, Stefan ; Schattenberg, Jörn Markus
Background & Aims: NAFLD is a growing health concern. The aim of the Fatty Liver Assessment in Germany (FLAG) study was to assess disease burden and provide data on the standard of care from secondary care. Methods: The FLAG study is an observational real-world study in patients with NAFLD enrolled at 13 centres across Germany. Severity of disease was assessed by non-invasive surrogate scores and data recorded at baseline and 12 months. Results: In this study, 507 patients (mean age 53 years; 47% women) were enrolled. According to fibrosis-4 index, 64%, 26%, and 10% of the patients had no significant fibrosis, indeterminate stage, and advanced fibrosis, respectively. Patients with advanced fibrosis were older, had higher waist circumferences, and higher aspartate aminotransferase and gamma-glutamyltransferase as well as ferritin levels. The prevalence of obesity, arterial hypertension, and type 2 diabetes increased with fibrosis stages. Standard of care included physical exercise >2 times per week in 17% (no significant fibrosis), 19% (indeterminate), and 6% (advanced fibrosis) of patients. Medication with either vitamin E, silymarin, or ursodeoxycholic acid was reported in 5%. Approximately 25% of the patients received nutritional counselling. According to the FibroScan-AST score, 17% of patients presented with progressive non-alcoholic steatohepatitis (n = 107). On follow-up at year 1 (n = 117), weight loss occurred in 47% of patients, of whom 17% lost more than 5% of body weight. In the weight loss group, alanine aminotransferase activities were reduced by 20%. Conclusions: This is the first report on NAFLD from a secondary-care real-world cohort in Germany. Every 10th patient presented with advanced fibrosis at baseline. Management consisted of best supportive care and lifestyle recommendations. The data highlight the urgent need for systematic health agenda in NAFLD patients. Lay summary: FLAG is a real-world cohort study that examined the liver disease burden in secondary and tertiary care. Herein, 10% of patients referred to secondary care for NAFLD exhibited advanced liver disease, whilst 64% had no significant liver scarring. These findings underline the urgent need to define patient referral pathways for suspected liver disease.
Treatment of refractory ascites with an automated low-flow ascites pump in patients with cirrhosis
(2017)
Stirnimann, Guido ; Berg, Thomas ; Spahr, Laurent ; Zeuzem, Stefan ; McPherson, Stuart ; Lammert, Frank ; Storni, Federico ; Banz, Vanessa ; Babatz, Jana ; Vargas, Victor ; Geier, Andreas ; Stallmach, Andreas ; Engelmann, Cornelius ; Trepte, Claudia ; Capel, Jeroen ; De Gottardi, Andrea
Background: Refractory ascites (RA) is a frequent complication of cirrhosis, requiring large volume paracentesis or placement of a transjugular intrahepatic portosystemic shunt (TIPSS). The automated low-flow ascites pump (alfapump, Sequana Medical AG, Zurich, Switzerland) is an innovative treatment option for patients with RA.
Aim: To assess safety and efficacy of this treatment in patients with a contraindication to TIPSS.
Methods: Fifty-six patients (43 males; mean age 62 years) from centres in Germany, Switzerland, UK and Spain were included and followed for up to 24 months. Complications, device deficiencies, paracentesis frequency and patient survival were recorded.
Results: At the time of this analysis, 3 patients completed the 24-month observation period, monitoring of 3 was ongoing, 9 underwent liver transplantation, 17 patients were withdrawn due to serious adverse events and 23 patients died. Most frequently observed technical complication was blocking of the peritoneal catheter. Twenty-three pump-related reinterventions (17 patients) and 12 pump exchanges (11 patients) were required during follow-up. The pump system was explanted in 48% of patients (in 17 patients due to serious adverse events, in 9 at the time of liver transplantation and in 1 due to recovery from RA). Median frequency of paracentesis dropped from 2.17 to 0.17 per month.
Conclusions: The alfapump can expand therapeutic options for cirrhotic patients with RA. Continuous drainage of ascites in a closed loop automated system led to significant reduction in paracentesis frequency. Technical and procedural improvements are required to reduce the rate of adverse events and reinterventions.
Pathophysiological role of prostanoids in coagulation of the portal venous system in liver cirrhosis
(2019)
Queck, Alexander David Roger ; Thomas, Dominique Jeanette ; Jansen, Christian ; Schreiber, Yannick ; Rüschenbaum, Sabrina ; Praktiknjo, Michael ; Schwarzkopf, Katharina ; Mücke, Marcus Maximilian ; Schierwagen, Robert ; Uschner, Frank Erhard ; Meyer, Carsten ; Clària, Joan ; Zeuzem, Stefan ; Geisslinger, Gerd ; Trebicka, Jonel ; Lange, Christian
Background: Prostanoids are important regulators of platelet aggregation and thrombotic arterial diseases. Their involvement in the development of portal vein thrombosis, frequent in decompensated liver cirrhosis, is still not investigated.
Methods: Therefore, we used pro-thrombotic venous milieu generation by bare metal stent transjugular intrahepatic portosystemic shunt insertion, to study the role of prostanoids in decompensated liver cirrhosis. Here, 89 patients receiving transjugular intrahepatic portosystemic shunt insertion were included in the study, and baseline levels of thromboxane B2, prostaglandin D2 and prostaglandin E2 were measured in the portal and the hepatic vein.
Results: While the hepatic vein contained higher levels of thromboxane B2 than the portal vein, levels of prostaglandin E2 and D2 were higher in the portal vein (all P<0.0001). Baseline concentrations of thromboxane B2 in the portal vein were independently associated with an increase of portal hepatic venous pressure gradient during short term follow-up, as an indirect sign of thrombogenic potential (multivariable P = 0.004). Moreover, severity of liver disease was inversely correlated with portal as well as hepatic vein levels of prostaglandin D2 and E2 (all P<0.0001).
Conclusions: Elevated portal venous thromboxane B2 concentrations are possibly associated with the extent of thrombogenic potential in patients with decompensated liver cirrhosis.
Trial registration: ClinicalTrials.gov identifier: NCT03584204.
Sürün, Duran ; Schwäble, Joachim ; Tomasovic, Ana ; Ehling, Roy ; Stein, Stefan ; Kurrle, Nina Susanne ; Melchner, Harald von ; Schnütgen, Frank
The CRISPR/Cas9 prokaryotic adaptive immune system and its swift repurposing for genome editing enables modification of any prespecified genomic sequence with unprecedented accuracy and efficiency, including targeted gene repair. We used the CRISPR/Cas9 system for targeted repair of patient-specific point mutations in the Cytochrome b-245 heavy chain gene (CYBB), whose inactivation causes chronic granulomatous disease (XCGD)—a life-threatening immunodeficiency disorder characterized by the inability of neutrophils and macrophages to produce microbicidal reactive oxygen species (ROS). We show that frameshift mutations can be effectively repaired in hematopoietic cells by non-integrating lentiviral vectors carrying RNA-guided Cas9 endonucleases (RGNs). Because about 25% of most inherited blood disorders are caused by frameshift mutations, our results suggest that up to a quarter of all patients suffering from monogenic blood disorders could benefit from gene therapy employing personalized, donor template-free RGNs.
Altınçekiç, Nadide ; Korn, Sophie Marianne ; Qureshi, Nusrat Shahin ; Dujardin, Marie ; Ninot-Pedrosa, Martí ; Abele, Rupert ; Abi Saad, Marie Jose ; Alfano, Caterina ; Almeida, Fabio C. L. ; Alshamleh, Islam ; Amorim, Gisele Cardoso de ; Anderson, Thomas K. ; Anobom, Cristiane D. ; Anorma, Chelsea ; Bains, Jasleen Kaur ; Bax, Adriaan ; Blackledge, Martin ; Blechar, Julius ; Böckmann, Anja ; Brigandat, Louis ; Bula, Anna ; Bütikofer, Matthias ; Camacho-Zarco, Aldo R. ; Carlomagno, Teresa ; Caruso, Icaro Putinhon ; Ceylan, Betül ; Chaikuad, Apirat ; Chu, Feixia ; Cole, Laura ; Crosby, Marquise G. ; De Jesus, Vanessa ; Dhamotharan, Karthikeyan ; Felli, Isabella C. ; Ferner, Jan ; Fleischmann, Yanick ; Fogeron, Marie-Laure ; Fourkiotis, Nikolaos K. ; Fuks, Christin ; Fürtig, Boris ; Gallo, Angelo ; Gande, Santosh L. ; Gerez, Juan Atilio ; Ghosh, Dhiman ; Gomes-Neto, Francisco ; Gorbatyuk, Oksana ; Guseva, Serafima ; Hacker, Carolin ; Häfner, Sabine ; Hao, Bing ; Hargittay, Bruno ; Henzler-Wildman, Katherine ; Hoch, Jeffrey C. ; Hohmann, Katharina Felicitas ; Hutchison, Marie T. ; Jaudzems, Kristaps ; Jović, Katarina ; Kaderli, Janina ; Kalnins, Gints ; Kanepe, Iveta ; Kirchdoerfer, Robert N. ; Kirkpatrick, John ; Knapp, Stefan ; Krishnathas, Robin ; Kutz, Felicitas ; Zur Lage, Susanne ; Lambertz, Roderick ; Lang, Andras ; Laurents, Douglas ; Lecoq, Lauriane ; Linhard, Verena ; Löhr, Frank ; Malki, Anas ; Bessa, Luiza Mamigonian ; Martin, Rachel W. ; Matzel, Tobias ; Maurin, Damien ; McNutt, Seth W. ; Mebus-Antunes, Nathane Cunha ; Meier, Beat H. ; Meiser, Nathalie ; Mompeán, Miguel ; Monaca, Elisa ; Montserret, Roland ; Perez, Laura Mariño ; Moser, Celine ; Muhle-Goll, Claudia ; Neves-Martins, Thais Cristtina ; Ni, Xiamonin ; Norton-Baker, Brenna ; Pierattelli, Roberta ; Pontoriero, Letizia ; Pustovalova, Yulia ; Ohlenschläger, Oliver ; Orts, Julien ; Poian, Andrea T. da ; Pyper, Dennis Joshua ; Richter, Christian ; Riek, Roland ; Rienstra, Chad M. ; Robertson, Angus ; Pinheiro, Anderson S. ; Sabbatella, Raffaele ; Salvi, Nicola ; Saxena, Krishna ; Schulte, Linda ; Schiavina, Marco ; Schwalbe, Harald ; Silber, Mara ; Almeida, Marcius da Silva ; Sprague-Piercy, Marc A. ; Spyroulias, Georgios A. ; Sreeramulu, Sridhar ; Tants, Jan-Niklas ; Tars, Kaspars ; Torres, Felix ; Töws, Sabrina ; Trevino, Miguel A. ; Trucks, Sven ; Tsika, Aikaterini C. ; Varga, Krisztina ; Wang, Ying ; Weber, Marco E. ; Weigand, Julia E. ; Wiedemann, Christoph ; Wirmer-Bartoschek, Julia ; Wirtz Martin, Maria Alexandra ; Zehnder, Johannes ; Hengesbach, Martin ; Schlundt, Andreas
The highly infectious disease COVID-19 caused by the Betacoronavirus SARS-CoV-2 poses a severe threat to humanity and demands the redirection of scientific efforts and criteria to organized research projects. The international COVID19-NMR consortium seeks to provide such new approaches by gathering scientific expertise worldwide. In particular, making available viral proteins and RNAs will pave the way to understanding the SARS-CoV-2 molecular components in detail. The research in COVID19-NMR and the resources provided through the consortium are fully disclosed to accelerate access and exploitation. NMR investigations of the viral molecular components are designated to provide the essential basis for further work, including macromolecular interaction studies and high-throughput drug screening. Here, we present the extensive catalog of a holistic SARS-CoV-2 protein preparation approach based on the consortium’s collective efforts. We provide protocols for the large-scale production of more than 80% of all SARS-CoV-2 proteins or essential parts of them. Several of the proteins were produced in more than one laboratory, demonstrating the high interoperability between NMR groups worldwide. For the majority of proteins, we can produce isotope-labeled samples of HSQC-grade. Together with several NMR chemical shift assignments made publicly available on covid19-nmr.com, we here provide highly valuable resources for the production of SARS-CoV-2 proteins in isotope-labeled form.
Trebicka, Jonel ; Gu, Wenyi ; de Ledinghen, Victor ; Aubé, Christophe ; Krag, Aleksander ; Praktiknjo, Michael ; Castera, Laurent ; Dumortier, Jerome ; Bauer, David Josef Maria ; Friedrich-Rust, Mireen ; Pol, Stanislas ; Grgurevic, Ivica ; Zheng, Rongqin ; Francque, Sven ; Gottfriedovà, Halima ; Mustapic, Sanda ; Sporea, Ioan ; Berzigotti, Annalisa ; Uschner, Frank Erhard ; Simbrunner, Benedikt Michael ; Ronot, Maxime ; Cassinotto, Christophe ; Kjaergaard, Maria ; Andrade, Filipe ; Schulz, Martin ; Semmler, Georg ; Drinkovic, Ida Tjesic ; Chang, Johannes ; Brol, Maximilian ; Rautou, Pierre Emmanuel ; Vanwolleghem, Thomas ; Straßburg, Christian P. ; Boursier, Jerome ; Ferstl, Philip ; Rasmussen, Ditlev Nytoft ; Reiberger, Thomas ; Vilgrain, Valerie ; Guibal, Aymeric ; Guillaud, Olivier ; Zeuzem, Stefan ; Vassord, Camille ; Lu, Xue ; Vonghia, Luisa ; Senkerikova, Renata ; Popescu, Alina ; Margini, Cristina ; Wang, Wenping ; Thiele, Maja ; Jansen, Chrisitan
Objective
Liver stiffness measurement (LSM) is a tool used to screen for significant fibrosis and portal hypertension. The aim of this retrospective multicentre study was to develop an easy tool using LSM for clinical outcomes in advanced chronic liver disease (ACLD) patients.
Design
This international multicentre cohort study included a derivation ACLD patient cohort with valid two-dimensional shear wave elastography (2D-SWE) results. Clinical and laboratory parameters at baseline and during follow-up were recorded. LSM by transient elastography (TE) was also recorded if available. The primary outcome was overall mortality. The secondary outcome was the development of first/further decompensation.
Results
After screening 2148 patients (16 centres), 1827 patients (55 years, 62.4% men) were included in the 2D-SWE cohort, with median liver SWE (L-SWE) 11.8 kPa and a model for end stage liver disease (MELD) score of 8. Combination of MELD score and L-SWE predict independently of mortality (AUC 0.8). L-SWE cut-off at ≥20 kPa combined with MELD ≥10 could stratify the risk of mortality and first/further decompensation in ACLD patients. The 2-year mortality and decompensation rates were 36.9% and 61.8%, respectively, in the 305 (18.3%) high-risk patients (with L-SWE ≥20 kPa and MELD ≥10), while in the 944 (56.6%) low-risk patients, these were 1.1% and 3.5%, respectively. Importantly, this M10LS20 algorithm was validated by TE-based LSM and in an additional cohort of 119 patients with valid point shear SWE-LSM.
Conclusion
The M10LS20 algorithm allows risk stratification of patients with ACLD. Patients with L-SWE ≥20 kPa and MELD ≥10 should be followed closely and receive intensified care, while patients with low risk may be managed at longer intervals.