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Oppold, Ann-Marie ; Schmidt, Hanno ; Rose, Marcel ; Hellmann, Sören Lukas ; Dolze, Florian ; Ripp, Fabian ; Weich, Bettina ; Schmidt-Ott, Urs ; Schmidt, Erwin ; Kofler, Robert ; Hankeln, Thomas ; Pfenninger, Markus
Active transposable elements (TEs) may result in divergent genomic insertion and abundance patterns among conspecific populations. Upon secondary contact, such divergent genetic backgrounds can theoretically give rise to classical Dobzhansky-Muller incompatibilities (DMI), a way how TEs can contribute to the evolution of endogenous genetic barriers and eventually population divergence. We investigated whether differential TE activity created endogenous selection pressures among conspecific populations of the non-biting midge Chironomus riparius, focussing on a Chironomus-specific TE, the minisatellite-like Cla-element, whose activity is associated with speciation in the genus. Using an improved and annotated draft genome for a genomic study with five natural C. riparius populations, we found highly population-specific TE insertion patterns with many private insertions. A highly significant correlation of pairwise population FST from genome-wide SNPs with the FST estimated from TEs suggests drift as the major force driving TE population differentiation. However, the significantly higher Cla-element FST level due to a high proportion of differentially fixed Cla-element insertions indicates that segregating, i.e. heterozygous insertions are selected against. With reciprocal crossing experiments and fluorescent in-situ hybridisation of Cla-elements to polytene chromosomes, we documented phenotypic effects on female fertility and chromosomal mispairings that might be linked to DMI in hybrids. We propose that the inferred negative selection on heterozygous Cla-element insertions causes endogenous genetic barriers and therefore acts as DMI among C. riparius populations. The intrinsic genomic turnover exerted by TEs, thus, may have a direct impact on population divergence that is operationally different from drift and local adaptation.
Reifarth, René ; Altstadt, Sebastian ; Göbel, Kathrin ; Heftrich, Tanja ; Heil, Michael ; Koloczek, Alexander ; Langer, Christoph ; Plag, Ralf ; Pohl, M. ; Sonnabend, Kerstin ; Weigand, Mario ; Adachi, T. ; Aksouh, Farouk ; Al-Khalili, J. ; AlGarawi, M. ; AlGhamdi, S. ; Alkhazov, G. ; Alkhomashi, N. ; Alvarez-Pol, Héctor ; Alvarez-Rodriguez, R. ; Andreev, V. ; Andrei, B. ; Atar, Leyla ; Aumann, Thomas ; Avdeichikov, Vladimir ; Bacri, C. ; Bagchi, S. ; Barbieri, Carlo ; Beceiro, Saul ; Beck, C. ; Beinrucker, Clemens ; Belier, Gilbert ; Bemmerer, Daniel ; Bendel, M. ; Benlliure Anaya, Jose Fernando ; Benzoni, G. ; Berjillos, R. ; Bertini, D. ; Bertulani, Carlos A. ; Bishop, S. ; Blasi, N. ; Bloch, T. ; Blumenfeld, Y. ; Bonaccorso, A. ; Boretzky, Konstanze ; Botvina, Alexander ; Boudard, A. ; Boutachkov, P. ; Boztosun, I. ; Bracco, A. ; Brambilla, S. ; Monago, J.Briz ; Caamano, Manuel ; Caesar, Christoph ; Camera, F. ; Casarejos Ruiz, Enrique ; Catford, Wilton N. ; Cederkäll, Joakim ; Cederwall, B. ; Chartier, Marielle ; Chatillon, Audrey ; Cherciu, M. ; Chulkov, Leonid V. ; Coleman-Smith, P. ; Cortina Gil, Dolores ; Crespi, F. ; Crespo, Raquel ; Cresswell, J. ; Csatlós, Margit ; Déchery, F. ; Davids, B. ; Davinson, Thomas ; Derya, Vera ; Detistov, P. ; Díaz Fernández, Paloma ; DiJulio, D. ; Dmitry, S. ; Doré, D. ; Dueñas, J. ; Dupont, Emmeric ; Egelhof, Peter ; Egorova, I. ; Elekes, Zoltán ; Enders, Joachim ; Endres, Janis ; Ershov, S. ; Ershova, Olga ; Fernández Domínguez, Beatriz ; Fetisov, A. ; Fiori, Enrico ; Fomichev, A. ; Fonseca, M. ; Fraile, L. ; Freer, Martin ; Friese, Jürgen ; Garcia Borge, Maria José ; Galaviz Redondo, Daniel ; Gannon, S. ; Garg, U. ; Gašparić, Igor ; Gasques, L. ; Gastineau, B. ; Geissel, Hans ; Gernhäuser, Roman ; Ghosh, T. ; Gilbert, M. ; Glorius, Jan ; Golubev, Pavel ; Gorshkov, Alexander ; Gourishetty, A. ; Grigorenko, Leonid V. ; Gulyas, J. ; Haiduc, Maria ; Hammache, F. ; Harakeh, Muhsin N. ; Hass, M. ; Heine, Marcel ; Hennig, Andreas ; Henriques, Ana ; Herzberg, Rolf-Dietmar ; Holl, Matthias ; Ignatov, Alexander ; Ignatyuk, A. ; Ilieva, Stoyanka ; Ivanov, Marian ; Iwasa, N. ; Jakobsson, B. ; Johansson, Håkan T. ; Jonson, Björn ; Joshi, P. ; Junghans, Arnd Rudolf ; Jurado Apruzzese, Beatriz ; Körner, G. ; Kalantar, N. ; Kanungo, Rituparna ; Kelic-Heil, Aleksandra ; Kezzar, K. ; Khan, E. ; Khanzadeev, Alexei ; Kiselev, Oleg A. ; Kogimtzis, M. ; Körper, D. ; Kräckmann, S. ; Kröll, Thorsten ; Krücken, Reiner ; Krasznahorkay, Attila ; Kratz, Jens-Volker ; Kresan, Dmytro ; Krings, Thomas ; Krumbholz, A. ; Krupko, S. ; Kulessa, Reinhard ; Kumar, Shyam ; Kurz, Nikolaus ; Kuzmin, E. ; Labiche, Marc ; Langanke, Karlheinz ; Lazarus, I. ; Bleis, T.Le ; Lederer, Claudia ; Lemasson, A. ; Lemmon, Roy Crawford ; Liberati, V. ; Litvinov, Yuri A. ; Löher, Bastian ; Herraiz, J.Lopez ; Münzenberg, G. ; Machado, Jorge ; Maev, E. ; Mahata, Kripamay ; Mancusi, D. ; Marganiec, Justyna ; Perez, M.Martinez ; Marusov, V. ; Mengoni, D. ; Million, B. ; Morcelle, V. ; Moreno, O. ; Movsesyan, Alina ; Nácher González, Enrique ; Najafi, Mohammad Ali ; Nakamura, T. ; Naqvi, F. ; Nikolski, E. ; Nilsson, Thomas ; Nociforo, Chiara ; Nolan, P. ; Novatsky, B. ; Nyman, Göran Hugo ; Ornelas, A. ; Palit, R. ; Pandit, S. ; Panin, Valerii ; Paradela Dobarro, Carlos ; Parkar, V. ; Paschalis, Stefanos ; Pawłowski, P. ; Perea Martinez, Angel ; Pereira, J. ; Petrache, C. ; Petri, Marina ; Pickstone, Simon Glynn ; Pietralla, Norbert ; Pietri, Stephane ; Pivovarov, Y. ; Potlog, P. ; Prokofiev, Andrey ; Rastrepina, G. ; Rauscher, Thomas ; Ribeiro Jimenez, Guillermo ; Ricciardi, Maria Valentina ; Richter, Achim ; Rigollet, Catherine ; Riisager, Karsten ; Rios, A. ; Ritter, C. ; Rodríguez Frutos, Tomás Raúl ; Rodríguez Vignote, Javier ; Röder, Marko ; Romig, Christopher ; Rossi, Dominic M. ; Roussel-Chomaz, P. ; Rout, Prakash Chandra ; Roy, S. ; Söderström, P. ; Saha Sarkar, Maitreyee ; Sakuta, S. ; Salsac, M. ; Sampson, J. ; Sanchez, J. ; Saez, del Rio ; Rosado, J.Sanchez ; Sanjari, Mohammad Shahab ; Sarriguren, P. ; Sauerwein, Anne ; Savran, Deniz ; Scheidenberger, Christoph ; Scheit, Heiko ; Schmidt, Stefan ; Schmitt, C. ; Schnorrenberger, Linda ; Schrock, P. ; Schwengner, R. ; Seddon, D. ; Sherrill, B. ; Shrivastava, A. ; Sidorchuk, S. ; Silva, Joel ; Simon, Haik ; Simpson, E. ; Singh, P. ; Slobodan, D. ; Sohler, D. ; Spieker, Mark-Christoph ; Stach, D. ; Stan, E. ; Stanoiu, M. ; Stepantsov, S. ; Stevenson, P. ; Strieder, F. ; Stuhl, László ; Suda, T. ; Sümmerer, Klaus ; Streicher, Branislav ; Taieb, Julien ; Takechi, M. ; Tanihata, I. ; Taylor, J. ; Tengblad, Olof ; Ter-Akopian, G. ; Terashima, S. ; Teubig, P. ; Thies, Ronja ; Thoennessen, M. ; Thomas, T. ; Thornhill, J. ; Thungstrom, G. ; Timar, J. ; Togano, Yasuhiro ; Tomohiro, U. ; Tornyi, T. ; Tostevin, J. ; Townsley, C. ; Trautmann, Wolfgang ; Trivedi, T. ; Typel, Stefan ; Uberseder, E. ; Udias, J. ; Uesaka, T. ; Uvarov, L. ; Vajta, Z. ; Velho, Paulo ; Vikhrov, V. ; Volknandt, Meiko ; Volkov, Vasily ; Neumann-Cosel, Peter von ; Schmid, Mirko von ; Wagner, A. ; Wamers, Felix ; Weick, Helmut ; Wells, D. ; Westerberg, L. ; Wieland, Oliver ; Wiescher, Michael ; Wimmer, Christine ; Wimmer, K. ; Winfield, John S. ; Winkel, M. ; Woods, Philip John ; Wyss, R. ; Yakorev, Dmitry ; Yavor, M. ; Zamora Cardona, Juan Carlos ; Zartova, I. ; Zerguerras, T. ; Zgura, M. ; Zhdanov, A. ; Zhukov, Mikhail V. ; Zieblinski, M. ; Zilges, Andreas ; Zuber, Kai
The nucleosynthesis of elements beyond iron is dominated by neutron captures in the s and r processes. However, 32 stable, proton-rich isotopes cannot be formed during those processes, because they are shielded from the s-process flow and r-process β-decay chains. These nuclei are attributed to the p and rp process.
For all those processes, current research in nuclear astrophysics addresses the need for more precise reaction data involving radioactive isotopes. Depending on the particular reaction, direct or inverse kinematics, forward or time-reversed direction are investigated to determine or at least to constrain the desired reaction cross sections.
The Facility for Antiproton and Ion Research (FAIR) will offer unique, unprecedented opportunities to investigate many of the important reactions. The high yield of radioactive isotopes, even far away from the valley of stability, allows the investigation of isotopes involved in processes as exotic as the r or rp processes.
Göbel, Kathrin ; Heil, Michael ; Bott, Lukas ; Brandenburg, Leonard ; Caesar, Christoph ; Deuter, Isabell ; Grein, Alexander ; Keliç-Heil, Aleksandra ; Körper, Daniel ; Löher, Bastian ; Reifarth, René ; Savran, Deniz ; Schulte, Hendrik ; Simon, Haik ; Törnqvist, Hans Toshihide ; Almusidi, Tahani ; Álvarez-Pol, Héctor ; Atkins, Liam ; Aumann, Thomas ; Bemmerer, Daniel ; Benlliure Anaya, Jose Fernando ; Boretzky, Konstanze ; Brückner, Benjamin ; Cabanelas Eiras, Pablo ; Casarejos Ruiz, Enrique ; Cederkäll, Joakim ; Chulkov, Leonid V. ; Cortina Gil, Dolores ; Danilov, Andrey ; Erbacher, Philipp ; Escribano Rodriguez, Sonia ; Fülöp, Zsolt ; Falduto, Ashton ; Fiebiger, Stefan ; Gašparić, Igor ; Garcia Borge, Maria José ; Gernhäuser, Roman ; Glorius, Jan ; Gonzales Caamaño, David ; Hartig, Anna-Lena ; Heftrich, Tanja ; Heggen, Henning ; Heine, Marcel ; Heinz, Andreas ; Hensel, Thomas ; Holl, Matthias ; Johansson, Håkan T. ; Jonson, Björn ; Kalantar-Nayestanaki, Nasser ; Kamenyero, Armel ; Khasawneh, Kafa al- ; Kiselev, Oleg A. ; Klenze, Philipp ; Kohls, Marvin ; Kröll, Thorsten ; Kresan, Dmytro ; Kurtulgil, Cem Deniz ; Kurz, Nikolaus ; Langer, Christoph ; Lehr, Christopher ; Litvinov, Yuri A. ; Lorenz, Enis ; Murillo Morales, Silvia ; Nácher González, Enrique ; Nilsson, Thomas ; Park, Joochun ; Paschalis, Stefanos ; Perea Martinez, Angel ; Petri, Marina ; Plag, Ralf ; Ponnath, Lukas ; Popočovski, Romana ; Reich, Markus ; Rhee, Han-Bum ; Rodriguez Sanchez, Jose Luis ; Rossi, Dominic M. ; Scheit, Heiko ; Schmidt, Konrad ; Slavkovská, Zuzana ; Starostin, Viktor ; Storck, Sonja ; Sürder, Christian ; Tanaka, Junki ; Tengblad, Olof ; Thomas, Benedikt ; Typel, Stefan ; Varga, László ; Volk, Klaus ; Volknandt, Meiko ; Wagner, Vadim ; Wamers, Felix ; Weigand, Mario ; Zanetti, Lorenzo
We measured the Coulomb dissociation of 16O into 4He and 12C at the R3B setup in a first campaign within FAIR Phase 0 at GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt. The goal was to improve the accuracy of the experimental data for the 12C(α,γ)16O fusion reaction and to reach lower center-ofmass energies than measured so far.
The experiment required beam intensities of 109 16O ions per second at an energy of 500 MeV/nucleon. The rare case of Coulomb breakup into 12C and 4He posed another challenge: The magnetic rigidities of the particles are so close because of the same mass-to-charge-number ratio A/Z = 2 for 16O, 12C and 4He. Hence, radical changes of the R3B setup were necessary. All detectors had slits to allow the passage of the unreacted 16O ions, while 4He and 12C would hit the detectors' active areas depending on the scattering angle and their relative energies. We developed and built detectors based on organic scintillators to track and identify the reaction products with sufficient precision.
Driller, Christine ; Koch, Markus ; Schmidt, Marco ; Weiland, Claus ; Hörnschemeyer, Thomas ; Hickler, Thomas ; Abrami, Giuseppe ; Ahmed, Sajawel ; Gleim, Rüdiger ; Hemati, Wahed ; Uslu, Tolga ; Mehler, Alexander ; Pachzelt, Adrian ; Rexhepi, Jashar ; Risse, Thomas ; Schuster, Janina ; Kasperek, Gerwin ; Hausinger, Angela
BIOfid is a specialized information service currently being developed to mobilize biodiversity data dormant in printed historical and modern literature and to offer a platform for open access journals on the science of biodiversity. Our team of librarians, computer scientists and biologists produce high-quality text digitizations, develop new text-mining tools and generate detailed ontologies enabling semantic text analysis and semantic search by means of user-specific queries. In a pilot project we focus on German publications on the distribution and ecology of vascular plants, birds, moths and butterflies extending back to the Linnaeus period about 250 years ago. The three organism groups have been selected according to current demands of the relevant research community in Germany. The text corpus defined for this purpose comprises over 400 volumes with more than 100,000 pages to be digitized and will be complemented by journals from other digitization projects, copyright-free and project-related literature. With TextImager (Natural Language Processing & Text Visualization) and TextAnnotator (Discourse Semantic Annotation) we have already extended and launched tools that focus on the text-analytical section of our project. Furthermore, taxonomic and anatomical ontologies elaborated by us for the taxa prioritized by the project’s target group - German institutions and scientists active in biodiversity research - are constantly improved and expanded to maximize scientific data output. Our poster describes the general workflow of our project ranging from literature acquisition via software development, to data availability on the BIOfid web portal (http://biofid.de/), and the implementation into existing platforms which serve to promote global accessibility of biodiversity data.
Engel, Andreas ; Bönisch, Harald ; Brunner, Dominik ; Fischer, Herbert ; Franke, Harald ; Günther, Gebhard ; Gurk, Christian Thomas ; Hegglin, Michaela I. ; Hoor, Peter ; Königstedt, Rainer ; Krebsbach, Michael ; Maser, Rolf ; Parchatka, Uwe ; Peter, Thomas ; Schell, Dieter ; Schiller, Cornelius ; Schmidt, Ulrich ; Spelten, Nicole ; Szabo, T. ; Weers, Uwe ; Wernli, Heini ; Wetter, Thomas ; Wirth, Volkmar
During SPURT (Spurenstofftransport in der Tropopausenregion, trace gas transport in the tropopause region) we performed measurements of a wide range of trace gases with different lifetimes and sink/source characteristics in the northern hemispheric upper troposphere (UT) and lowermost stratosphere (LMS). A large number of in-situ instruments were deployed on board a Learjet 35A, flying at altitudes up to 13.7 km, at times reaching to nearly 380 K potential temperature. Eight measurement campaigns (consisting of a total of 36 flights), distributed over all seasons and typically covering latitudes between 35° N and 75° N in the European longitude sector (10° W–20° E), were performed. Here we present an overview of the project, describing the instrumentation, the encountered meteorological situations during the campaigns and the data set available from SPURT. Measurements were obtained for N2O, CH4, CO, CO2, CFC12, H2, SF6, NO, NOy, O3 and H2O. We illustrate the strength of this new data set by showing mean distributions of the mixing ratios of selected trace gases, using a potential temperature – equivalent latitude coordinate system. The observations reveal that the LMS is most stratospheric in character during spring, with the highest mixing ratios of O3 and NOy and the lowest mixing ratios of N2O and SF6. The lowest mixing ratios of NOy and O3 are observed during autumn, together with the highest mixing ratios of N2O and SF6 indicating a strong tropospheric influence. For H2O, however, the maximum concentrations in the LMS are found during summer, suggesting unique (temperature- and convection-controlled) conditions for this molecule during transport across the tropopause. The SPURT data set is presently the most accurate and complete data set for many trace species in the LMS, and its main value is the simultaneous measurement of a suite of trace gases having different lifetimes and physical-chemical histories. It is thus very well suited for studies of atmospheric transport, for model validation, and for investigations of seasonal changes in the UT/LMS, as demonstrated in accompanying and elsewhere published studies.
Engel, Andreas ; Bönisch, Harald ; Brunner, Dominik ; Fischer, Herbert ; Franke, Harald ; Günther, Gebhard ; Gurk, Christian Thomas ; Hegglin, Michaela I. ; Hoor, Peter ; Königstedt, Rainer ; Krebsbach, Michael ; Maser, Rolf ; Parchatka, Uwe ; Peter, Thomas ; Schell, Dieter ; Schiller, Cornelius ; Schmidt, Ulrich ; Spelten, Nicole ; Szabo, T. ; Weers, Uwe ; Wernli, Heini ; Wetter, Thomas ; Wirth, Volkmar
During SPURT (Spurenstofftransport in der Tropopausenregion, trace gas transport in the tropopause region) we performed measurements of a wide range of trace gases with different lifetimes and sink/source characteristics in the northern hemispheric upper troposphere (UT) and lowermost stratosphere (LMS). A large number of in-situ instruments were deployed on board a Learjet 35A, flying at altitudes up to 13.7 km, at times reaching to nearly 380 K potential temperature. Eight measurement campaigns (consisting of a total of 36 flights), distributed over all seasons and typically covering latitudes between 35° N and 75° N in the European longitude sector (10° W–20° E), were performed. Here we present an overview of the project, describing the instrumentation, the encountered meteorological situations during the campaigns and the data set available from SPURT. Measurements were obtained for N2O, CH4, CO, CO2, CFC12, H2, SF6, NO, NOy, O3 and H2O. We illustrate the strength of this new data set by showing mean distributions of the mixing ratios of selected trace gases, using a potential temperature – equivalent latitude coordinate system. The observations reveal that the LMS is most stratospheric in character during spring, with the highest mixing ratios of O3 and NOy and the lowest mixing ratios of N2O and SF6. The lowest mixing ratios of NOy and O3 are observed during autumn, together with the highest mixing ratios of N2O and SF6 indicating a strong tropospheric influence. For H2O, however, the maximum concentrations in the LMS are found during summer, suggesting unique (temperature- and convection-controlled) conditions for this molecule during transport across the tropopause. The SPURT data set is presently the most accurate and complete data set for many trace species in the LMS, and its main value is the simultaneous measurement of a suite of trace gases having different lifetimes and physical-chemical histories. It is thus very well suited for studies of atmospheric transport, for model validation, and for investigations of seasonal changes in the UT/LMS, as demonstrated in accompanying and elsewhere published studies.
Vogel, Jens-Uwe ; Schmidt, Sophie Marion ; Schmidt, Daniel ; Rothweiler, Florian ; Koch, Benjamin Florian ; Baer, Patrick C. ; Rabenau, Holger ; Michel, Detlef ; Stamminger, Thomas ; Michaelis, Martin ; Cinatl, Jindrich
The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to the effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interfered with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and the addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after hematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses, and synergistically increase the effects of ganciclovir, eltrombopag is also a drug-repurposing candidate for the treatment of therapy-refractory HCMV diseas.
Bärtsch, Marc-Andrea ; Schlenzka, Jana ; Mai, Elias K. ; Merz, Maximilian ; Hillengaß, Jens ; Raab, Marc-Steffen ; Hose, Dirk ; Wuchter, Patrick ; Ho, Anthony Dick ; Jauch, Anna ; Hielscher, Thomas ; Kunz, Christina ; Luntz, Steffen ; Klein, Stefan ; Schmidt-Wolf, Ingo Gustav Hermann ; Görner, Martin ; Schmidt-Hieber, Martin ; Reimer, Peter ; Graeven, Ullrich ; Fenk, Roland ; Salwender, Hans ; Scheid, Christof ; Nogai, Axel ; Hänel, Mathias ; Lindemann, Hans-Walter ; Martin, Hans ; Noppeney, Richard ; Weisel, Katja ; Goldschmidt, Hartmut
Background: Despite novel therapeutic agents, most multiple myeloma (MM) patients eventually relapse. Two large phase III trials have shown significantly improved response rates (RR) of lenalidomide/dexamethasone compared with placebo/dexamethasone in relapsed MM (RMM) patients. These results have led to the approval of lenalidomide for RMM patients and lenalidomide/dexamethasone has since become a widely accepted second-line treatment. Furthermore, in RMM patients consolidation with high-dose chemotherapy plus autologous stem cell transplantation has been shown to significantly increase progression free survival (PFS) as compared to cyclophosphamide in a phase III trial. The randomized prospective ReLApsE trial is designed to evaluate PFS after lenalidomide/dexamethasone induction, high-dose chemotherapy consolidation plus autologous stem cell transplantation and lenalidomide maintenance compared with the well-established lenalidomide/dexamethasone regimen in RMM patients.
Methods/Design: ReLApsE is a randomized, open, multicenter phase III trial in a planned study population of 282 RMM patients. All patients receive three lenalidomide/dexamethasone cycles and - in absence of available stem cells from earlier harvesting - undergo peripheral blood stem cell mobilization and harvesting. Subsequently, patients in arm A continue on consecutive lenalidomide/dexamethasone cycles, patients in arm B undergo high dose chemotherapy plus autologous stem cell transplantation followed by lenalidomide maintenance until discontinuation criteria are met. Therapeutic response is evaluated after the 3rd (arm A + B) and the 5th lenalidomide/dexamethasone cycle (arm A) or 2 months after autologous stem cell transplantation (arm B) and every 3 months thereafter (arm A + B). After finishing the study treatment, patients are followed up for survival and subsequent myeloma therapies. The expected trial duration is 6.25 years from first patient in to last patient out. The primary endpoint is PFS, secondary endpoints include overall survival (OS), RR, time to best response and the influence of early versus late salvage high dose chemotherapy plus autologous stem cell transplantation on OS.
Discussion: This phase III trial is designed to evaluate whether high dose chemotherapy plus autologous stem cell transplantation and lenalidomide maintenance after lenalidomide/dexamethasone induction improves PFS compared with the well-established continued lenalidomide/dexamethasone regimen in RMM patients. Trial registration: ISRCTN16345835 (date of registration 2010-08-24).
Tony, Hans-Peter ; Burmester, Gerd-Rüdiger ; Schulze-Koops, Hendrik ; Grunke, Mathias ; Henes, Jörg Christoph ; Kötter, Ina ; Haas, Judith ; Unger, Leonore ; Lovric, Svjetlana ; Haubitz, Marion ; Fischer-Betz, Rebecca ; Chehab, Gamal ; Rubbert-Roth, Andrea ; Specker, Christof ; Weinerth, Jutta ; Holle, Julia Ulrike ; Müller-Ladner, Ulf ; König, Ramona ; Fiehn, Christoph ; Burgwinkel, Philip ; Budde, Klemens ; Sörensen, Helmut ; Meurer, Michael ; Aringer, Martin ; Kieseier, Bernd ; Erfurt-Berge, Cornelia ; Sticherling, Michael ; Veelken, Roland ; Ziemann, Ulf ; Strutz, Frank ; Wussow, Praxis von ; Meier, Florian Matthias Peter ; Hunzelmann, Nico ; Schmidt, Nico ; Bergner, Raoul ; Schwarting, Andreas ; Eming, Rüdiger ; Hertl, Michael ; Stadler, Rudolf ; Schwarz-Eywill, Michael ; Wassenberg, Siegfried ; Fleck, Martin ; Metzler, Claudia ; Zettl, Uwe Klaus ; Westphal, Jens ; Heitmann, Stefan ; Herzog, Anna Laura ; Wiendl, Heinz ; Jakob, Waltraud ; Schmidt, Enno ; Freivogel, Klaus ; Dörner, Thomas
Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting.
Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators.
Results: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm).
Conclusions: Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.
Kastirke, Gregor ; Schöffler, Markus S. ; Weller, Miriam ; Rist, Jonas ; Boll, Rebecca ; Anders, Nils ; Baumann, Thomas M. ; Eckart, Sebastian ; Erk, Benjamin ; De Fanis, Alberto ; Fehre, Kilian ; Gatton, Averell ; Grundmann, Sven Eric ; Grychtol, Patrik ; Hartung, Alexander ; Hofmann, Max ; Ilchen, Markus ; Janke, Christian Sören ; Kircher, Max ; Kunitski, Maksim ; Li, Xiang ; Mazza, Tommaso ; Melzer, Niklas ; Montano, Jacobo ; Music, Valerija ; Nalin, Giammarco ; Ovcharenko, Yevheniy ; Pier, Andreas ; Rennhack, Nils ; Rivas, Daniel E. ; Dörner, Reinhard ; Rolles, Daniel ; Rudenko, Artem ; Schmidt, Philipp ; Siebert, Juliane ; Strenger, Nico ; Trabert, Daniel ; Vela-Perez, Isabel ; Wagner, Rene ; Weber, Thorsten ; Williams, Joshua B. ; Ziolkowski, Pawel ; Schmidt, Lothar ; Czasch, Achim ; Trinter, Florian ; Meyer, Michael ; Ueda, Kiyoshi ; Demekhin, Philipp V. ; Jahnke, Till
A central motivation for the development of x-ray free-electron lasers has been the prospect of time-resolved single-molecule imaging with atomic resolution. Here, we show that x-ray photoelectron diffraction—where a photoelectron emitted after x-ray absorption illuminates the molecular structure from within—can be used to image the increase of the internuclear distance during the x-ray-induced fragmentation of an O2 molecule. By measuring the molecular-frame photoelectron emission patterns for a two-photon sequential K-shell ionization in coincidence with the fragment ions, and by sorting the data as a function of the measured kinetic energy release, we can resolve the elongation of the molecular bond by approximately 1.2 a.u. within the duration of the x-ray pulse. The experiment paves the road toward time-resolved pump-probe photoelectron diffraction imaging at high-repetition-rate x-ray free-electron lasers.