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Adamczewski-Musch, Jörn ; Arnold, Oliver Werner ; Behnke, Claudia ; Belounnas, Amel ; Belyaev, A. ; Berger-Chen, Jia-Chii ; Biernat, Jacek ; Blanco, Alberto ; Blume, Christoph ; Böhmer, Michael ; Bordalo, Paula ; Chernenko, Sergey P. ; Chlad, Lukáš ; Deveaux, Christina Anna ; Dreyer, J. ; Dybczak, Adrian ; Epple, Eliane ; Fabbietti, Laura ; Fateev, Oleg ; Filip, Peter ; Fonte, Paulo ; Franco, Celso ; Friese, Jürgen ; Fröhlich, Ingo ; Galatyuk, Tetyana ; Garzón, Juan A. ; Gernhäuser, Roman ; Golubeva, Marina ; Greifenhagen, Robert ; Guber, Fedor ; Gumberidze, Malgorzata ; Harabasz, Szymon ; Heinz, Tobias ; Hennino, Thierry ; Hlaváč, Stanislav ; Höhne, Claudia ; Holzmann, Romain ; Ierusalimov, Alexander P. ; Ivashkin, Alexander ; Kämpfer, Burkhard ; Karavicheva, Tatiana L. ; Kardan, Behruz ; Koenig, Ilse ; Koenig, W. ; Kolb, Burkhard W. ; Korcyl, Grzegorz ; Kornakov, Georgy ; Kotte, Roland ; Kühn, Wolfgang ; Kugler, Andrej ; Kunz, Tobias ; Kurepin, Alexander ; Kurilkin, Aleksey K. ; Kurilkin, Pavel ; Ladygin, Vladimir P. ; Lalik, Rafał Tomasz ; Lapidus, Kirill ; Lebedev, Alexei ; Lopes, Lourenco Vaz Gil ; Lorenz, Manuel ; Mahmoud, Tariq ; Maier, Ludwig W. ; Mangiarotti, Alessio ; Markert, Jochen ; Maurus, Steffen ; Metag, Volker ; Michel, Jan ; Mihaylov, Dimitar ; Morozov, Sergey ; Müntz, Christian ; Münzer, Robert Helmut ; Naumann, Lothar ; Nowakowski, K.N. ; Palka, Marek ; Parpottas, Yannis ; Pechenov, Vladimir ; Pechenova, Olga ; Petukhov, Oleg ; Pietraszko, Jerzy ; Przygoda, Witold ; Ramos, S. ; Ramstein, Béatrice ; Reshetin, Andrey ; Rodriguez Ramos, Pablo ; Rosier, Philippe ; Rost, Adrian ; Sadovsky, Alexander ; Salabura, Piotr ; Scheib, Timo ; Schuldes, Heidi ; Schwab, Erwin ; Scozzi, Federico ; Seck, Florian ; Sellheim, Patrick ; Siebenson, Johannes Stephan ; Silva, L. ; Sobolev, Yuri G. ; Spataro, Stefano ; Ströbele, Herbert ; Stroth, Joachim ; Strzempek, Paweł ; Sturm, Christian Thomas ; Svoboda, Ondřej ; Szala, Melanie ; Tlustý, Pavel ; Traxler, Michael ; Tsertos, Haralabos ; Usenko, Evgeny A. ; Wagner, Vladimir ; Wendisch, Christian ; Wiebusch, Michael ; Wirth, Joana ; Zanevsky, Yuri V. ; Zumbruch, Peter W.
We present data on charged kaons (K±) and ϕ mesons in Au(1.23A GeV)+Au collisions. It is the first simultaneous measurement of K− and ϕ mesons in central heavy-ion collisions below a kinetic beam energy of 10A GeV. The ϕ/K− multiplicity ratio is found to be surprisingly high with a value of 0.52±0.16 and shows no dependence on the centrality of the collision. Consequently, the different slopes of the K+ and K− transverse-mass spectra can be explained solely by feed-down, which substantially softens the spectra of K− mesons. Hence, in contrast to the commonly adapted argumentation in literature, the different slopes do not necessarily imply diverging freeze-out temperatures of K+ and K− mesons caused by different couplings to baryons.
Müller, Mareike ; Merz, Felicitas ; Durante, Marco ; Seifert, Volker ; Rieger, Johannes ; Mittelbronn, Michel Guy André ; Harter, Patrick Nikolaus ; Mishustin, Igor N. ; Pshenichnov, Igor A. ; Rödel, Franz ; Stöcker, Horst ; Schopow, Kosta ; Dehghani, Faramarz ; Taucher-Scholz, Gisela ; Bechmann, Ingo
Background: In this interdisciplinary project, the biological effects of heavy ions are compared to those of X-rays using tissue slice culture preparations from rodents and humans. Advantages of this biological model are the conservation of an organotypic environment and the independency from genetic immortalization strategies used to generate cell lines. Its open access allows easy treatment and observation via live-imaging microscopy. Materials and methods: Rat brains and human brain tumor tissue are cut into 300 micro m thick tissue slices. These slices are cultivated using a membrane-based culture system and kept in an incubator at 37°C until treatment. The slices are treated with X-rays at the radiation facility of the University Hospital in Frankfurt at doses of up to 40 Gy. The heavy ion irradiations were performed at the UNILAC facility at GSI with different ions of 11.4 A MeV and fluences ranging from 0.5–10 x 106 particles/cm². Using 3D-confocal microscopy, cell-death and immune cell activation of the irradiated slices are analyzed. Planning of the irradiation experiments is done with simulation programs developed at GSI and FIAS. Results: After receiving a single application of either X-rays or heavy ions, slices were kept in culture for up to 9d post irradiation. DNA damage was visualized using gamma H2AXstaining. Here, a dose-dependent increase and time-dependent decrease could clearly be observed for the X-ray irradiation. Slices irradiated with heavy ions showed less gamma H2AX-positive cells distributed evenly throughout the slice, even though particles were calculated to penetrate only 90–100 micro m into the slice. Conclusions: Single irradiations of brain tissue, even at high doses of 40 Gy, will result neither in tissue damage visible on a macroscopic level nor necrosis. This is in line with the view that the brain is highly radio-resistant. However, DNA damage can be detected very well in tissue slices using gamma H2AX-immuno staining. Thus, slice cultures are an excellent tool to study radiation-induced damage and repair mechanisms in living tissues.
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.
Sylvester, Francisco ; Weichert, Fabian G. ; Lozano, Verónica L. ; Groh, Ksenia J. ; Bálint, Miklós ; Baumann, Lisa ; Bässler, Claus ; Brack, Werner ; Brandl, Barbara ; Curtius, Joachim ; Dierkes, Paul ; Döll, Petra ; Ebersberger, Ingo ; Fragkostefanakis, Sotirios ; Helfrich, Eric J. N. ; Hickler, Thomas ; Johann, Sarah ; Jourdan, Jonas ; Klimpel, Sven ; Kminek, Helge ; Liquin, Florencia ; Möllendorf, Darrel ; Mueller, Thomas ; Oehlmann, Jörg ; Ottermanns, Richard ; Pauls, Steffen U. ; Piepenbring, Meike ; Pfefferle, Jakob ; Schenk, Gerrit Jasper ; Scheepens, Johannes Fredericus ; Scheringer, Martin ; Schiwy, Sabrina ; Schlottmann, Antje ; Schneider, Flurina ; Schulte, Lisa Maria ; Schulze-Sylvester, Maria ; Stelzer, Ernst H. K. ; Strobl, Frederic ; Sundermann, Andrea ; Tockner, Klement ; Tröger, Tobias ; Vilcinskas, Andreas ; Völker, Carolin ; Winkelmann, Ricarda ; Hollert, Henner