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Institute
Hou, Liping ; Bergen, Sarah E. ; Akula, Nirmala ; Song, Jie ; Hultman, Christina M. ; Landén, Mikael ; Adli, Mazda ; Alda, Martin ; Ardau, Raffaella ; Arias, Bárbara ; Aubry, Jean-Michel ; Backlund, Lena ; Badner, Judith A. ; Barrett, Thomas B. ; Bauer, Michael ; Baune, Bernhard T. ; Bellivier, Frank ; Benabarre Hernandez, Antonio ; Bengesser, Susanne ; Berrettini, Wade H. ; Bhattacharjee, Abesh Kumar ; Biernacka, Joanna ; Birner, Armin ; Bloss, Cinnamon S. ; Brichant-Petitjean, Clara ; Bui, Elise T. ; Byerley, William ; Cervantes, Pablo ; Chillotti, Caterina ; Cichon, Sven ; Colom, Francesc ; Coryell, William ; Craig, David W. ; Cruceanu, Cristiana ; Czerski, Piotr M. ; Davis, Tony ; Dayer, Alexandre ; Degenhardt, Franziska ; Del Zompo, Maria ; DePaulo, J. Raymond ; Edenberg, Howard J. ; Étain, Bruno ; Falkai, Peter ; Foroud, Tatiana ; Forstner, Andreas Josef ; Frisén, Louise ; Frye, Mark A. ; Fullerton, Janice M. ; Gard, Sébastien ; Garnham, Julie S. ; Gershon, Elliot S. ; Goes, Fernando S. ; Greenwood, Tiffany A. ; Grigoroiu-Serbanescu, Maria ; Hauser, Joanna ; Heilbronner, Urs ; Heilmann-Heimbach, Stefanie ; Herms, Stefan ; Hipolito, Maria ; Hitturlingappa, Shashi ; Hoffmann, Per ; Hofmann, Andrea ; Jamain, Stephane ; Jiménez, Esther ; Kahn, Jean-Pierre ; Kassem, Layla ; Kelsoe, John R. ; Kittel-Schneider, Sarah ; Kliwicki, Sebastian ; Koller, Daniel L. ; König, Barbara ; Lackner, Nina ; Laje, Gonzalo ; Lang, Maren ; Lavebratt, Catharina ; Lawson, William B. ; Leboyer, Marion ; Leckband, Susan G. ; Liu, Chunyu ; Maaser, Anna ; Mahon, Pamela B. ; Maier, Wolfgang ; Maj, Mario ; Manchia, Mirko ; Martinsson, Lina ; McCarthy, Michael J. ; McElroy, Susan L. ; McInnis, Melvin G. ; McKinney, Rebecca ; Mitchell, Philip B. ; Mitjans, Marina ; Mondimore, Francis Mark ; Monteleone, Palmiero ; Mühleisen, Thomas W. ; Nievergelt, Caroline M. ; Nöthen, Markus Maria ; Novák, Tomas ; Nurnberger, John I. ; Nwulia, Evaristus A. ; Ösby, Urban ; Pfennig, Andrea ; Potash, James B. ; Propping, Peter ; Reif, Andreas ; Reininghaus, Eva ; Rice, John ; Rietschel, Marcella ; Rouleau, Guy A. ; Rybakowski, Janusz K. ; Schalling, Martin ; Scheftner, William A. ; Schofield, Peter R. ; Schork, Nicholas J. ; Schulze, Thomas Gerd ; Schumacher, Johannes ; Schweizer, Barbara W. ; Severino, Giovanni ; Shekhtman, Tatyana ; Shilling, Paul D. ; Simhandl, Christian ; Slaney, Claire M. ; Smith, Erin N. ; Squassina, Alessio ; Stamm, Thomas ; Stopkova, Pavla ; Streit, Fabian ; Strohmaier, Jana ; Szelinger, Szabolcs ; Tighe, Sarah K. ; Tortorella, Alfonso ; Turecki, Gustavo ; Vieta, Eduard ; Volkert, Julia ; Witt, Stephanie H. ; Wright, Adam ; Zandi, Peter P. ; Zhang, Peng ; Zollner, Sebastian ; McMahon, Francis J.
Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the Xchromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p = 5.87×10-9; odds ratio = 1.12) and markers within ERBB2 (rs2517959, p = 4.53×10-9; odds ratio = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
Dongen, Jenny van ; Hagenbeek, Fiona A. ; Suderman, Matthew ; Roetman, Peter J. ; Sugden, Karen ; Geburtig-Chiocchetti, Andreas ; Ismail, Khadeeja ; Mulder, Rosa H. ; Hafferty, Jonathan D. ; Adams, Mark J. ; Walker, Rosie M. ; Morris, Stewart W. ; Lahti, Jari ; Küpers, Leanne K. ; Escaramis, Georgia ; Alemany, Silvia ; Bonder, Marc Jan ; Meijer, Mandy ; Ip, Hill F. ; Jansen, Rick ; Baselmans, Bart M. L. ; Parmar, Priyanka ; Lowry, Estelle ; Streit, Fabian ; Sirignano, Lea ; Send, Tabea S. ; Frank, Josef ; Jylhävä, Juulia ; Wang, Yunzhang ; Mishra, Pashupati Prasad ; Colins, Olivier F. ; Corcoran, David L. ; Poulton, Richie ; Mill, Jonathan ; Hannon, Eilis ; Arseneault, Louise ; Korhonen, Tellervo ; Vuoksimaa, Eero ; Felix, Janine F. ; Bakermans-Kranenburg, Marian J. ; Campbell, Archie ; Czamara, Darina ; Binder, Elisabeth ; Corpeleijn, Eva ; González Ruiz, Juan Ramon ; Grazuleviciene, Regina ; Gutzkow, Kristine B. ; Evandt, Jorunn ; Vafeiadi, Marina ; Klein, Marieke ; Meer, Dennis van der ; Ligthart, Lannie ; Heijmans, Bastiaan Theodoor ; Hoen, Peter A. C. 't ; Meurs, Joyce Berdina Josepha van ; Franke, Lude ; Boomsma, Dorret I. ; Pool, René ; Hottenga, Jouke J. ; Greevenbroek, Marleen M. J. van ; Stehouwer, Coen D. A. ; Kallen, Carla J. H. van der ; Schalkwijk, Casper G. ; Wijmenga, Cisca ; Zhernakova, Sasha ; Tigchelaar, Ettje F. ; Slagboom, P. Eline ; Beekman, Marian ; Deelen, Joris ; Heemst, Diana van ; Veldink, Jan H. ; Berg, Leonard H. van den ; Duijn, Cornelia M. van ; Hofman, Bert A. ; Isaacs, Aaron ; Uitterlinden, André G. ; Jhamai, P. Mila ; Verbiest, Michael ; Suchiman, H. Eka D. ; Verkerk, Marijn ; Breggen, Ruud van der ; Rooij, Jeroen van ; Lakenberg, Nico ; Mei, Hailiang ; Iterson, Maarten van ; Galen, Michiel van ; Bot, Jan ; Zhernakova, Dasha V. ; Hof, Peter van ’t ; Deelen, Patrick ; Nooren, Irene ; Moed, Matthijs ; Vermaat, Martijn ; Luijk, René ; Dijk, Freerk van ; Arindrarto, Wibowo ; Kielbasa, Szymon M. ; Swertz, Morris A. ; Zwet, Erik. W. van ; Hoen, Peter-Bram ’t ; Kluft, Cornelis ; Davies, Gareth E. ; Hakulinen, Christian ; Keltikangas-Järvinen, Liisa ; Franke, Barbara ; Freitag, Christine M. ; Konrad, Kerstin ; Hervás, Amaia ; Fernández-Rivas, Aranzazu ; Vetro, Agnes ; Raitakari, Olli ; Lehtimäki, Terho ; Vermeiren, Robert ; Strandberg, Timo ; Räikkönen, Katri ; Snieder, Harold ; Witt, Stephanie H. ; Deuschle, Michael ; Pedersen, Nancy L. ; Hägg, Sara ; Sunyer, Jordi ; Kaprio, Jaakko ; Ollikainen, Miina ; Moffitt, Terrie E. ; Tiemeier, Henning ; IJzendoorn, Marinus H. van ; Relton, Caroline ; Vrijheid, Martine ; Sebert, Sylvain ; Jarvelin, Marjo-Riitta ; Caspi, Avshalom ; Evans, Kathryn L. ; McIntosh, Andrew M. ; Bartels, Meike
DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10−7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3–82%) of the aggression–methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.
Wöckel, Achim ; Festl, Jasmin ; Stüber, Tanja ; Brust, Katharina ; Stangl, Stephanie ; Heuschmann, Peter Ulrich ; Albert, Ute Susann ; Budach, Wilfried ; Follmann, Markus ; Janni, Wolfgang ; Kopp, Ina ; Kreienberg, Rolf ; Kühn, Thorsten ; Langer, Thomas ; Nothacker, Monika ; Scharl, Anton ; Schreer, Ingrid ; Link, Hartmut ; Engel, Jutta ; Fehm, Tanja ; Weis, Joachim ; Welt, Anja ; Steckelberg, Anke ; Feyer, Petra ; König, Klaus ; Hahne, Andrea ; Kreipe, Hans H. ; Knoefel, Wolfram Trudo ; Denkinger, Michael ; Brucker, Sara ; Lüftner, Diana ; Kubisch, Christian ; Gerlach, Christina ; Lebeau, Annette ; Siedentopf, Friederike ; Petersen, Cordula ; Bartsch, Hans Helge ; Schulz-Wendtland, Rüdiger ; Hahn, Markus ; Hanf, Volker ; Müller-Schimpfle, Markus ; Henscher, Ulla ; Roncarati, Renza ; Katalinic, Alexander ; Heitmann, Christoph ; Honegger, Christoph ; Paradies, Kerstin ; Bjelic-Radisic, Vesna ; Degenhardt, Friedrich ; Wenz, Frederik ; Rick, Oliver ; Hölzel, Dieter ; Zaiss, Matthias ; Kemper, Gudrun ; Budach, Volker ; Denkert, Carsten Michael ; Gerber, Bernd ; Tesch, Hans ; Hirsmüller, Susanne ; Sinn, Hans-Peter ; Dunst, Jürgen ; Münstedt, Karsten ; Bick, Ulrich ; Fallenberg, Eva ; Tholen, Reina ; Hung, Roswita ; Baumann, Freerk T. ; Beckmann, Matthias Wilhelm ; Blohmer, Jens-Uwe ; Fasching, Peter Andreas ; Lux, Michael Patrick ; Harbeck, Nadia ; Hadji, Peyman ; Hauner, Hans ; Heywang-Köbrunner, Sylvia H. ; Huober, Jens ; Hübner, Jutta ; Jackisch, Christian ; Loibl, Sibylle ; Lück, Hans-Jürgen ; Minckwitz, Gunter von ; Möbus, Volker ; Müller, Volkmar ; Nöthlings, Ute ; Schmidt, Marcus ; Schmutzler, Rita Katharina ; Schneeweiss, Andreas ; Schütz, Florian ; Stickeler, Elmar ; Thomssen, Christoph ; Untch, Michael ; Wesselmann, Simone ; Bücker, Arno ; Krockenberger, Mathias Heinric
Ziele: Das Ziel dieser offiziellen Leitlinie, die von der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe (DGGG) und der Deutschen Krebsgesellschaft (DKG) publiziert und koordiniert wurde, ist es, die Früherkennung, Diagnostik, Therapie und Nachsorge des Mammakarzinoms zu optimieren.
Methoden: Der Aktualisierungsprozess der S3-Leitlinie aus 2012 basierte zum einen auf der Adaptation identifizierter Quellleitlinien und zum anderen auf Evidenzübersichten, die nach Entwicklung von PICO-(Patients/Interventions/Control/Outcome-)Fragen, systematischer Recherche in Literaturdatenbanken sowie Selektion und Bewertung der gefundenen Literatur angefertigt wurden. In den interdisziplinären Arbeitsgruppen wurden auf dieser Grundlage Vorschläge für Empfehlungen und Statements erarbeitet, die im Rahmen von strukturierten Konsensusverfahren modifiziert und graduiert wurden.
Empfehlungen: Der Teil 1 dieser Kurzversion der Leitlinie zeigt Empfehlungen zur Früherkennung, Diagnostik und Nachsorge des Mammakarzinoms: Der Stellenwert des Mammografie-Screenings wird in der aktualisierten Leitlinienversion bestätigt und bildet damit die Grundlage der Früherkennung. Neben den konventionellen Methoden der Karzinomdiagnostik wird die Computertomografie (CT) zum Staging bei höherem Rückfallrisiko empfohlen. Die Nachsorgekonzepte beinhalten Untersuchungsintervalle für die körperliche Untersuchung, Ultraschall und Mammografie, während weiterführende Gerätediagnostik und Tumormarkerbestimmungen bei der metastasierten Erkrankung Anwendung finden.
Wöckel, Achim ; Festl, Jasmin ; Stüber, Tanja ; Brust, Katharina ; Stangl, Stephanie ; Heuschmann, Peter Ulrich ; Albert, Ute Susann ; Budach, Wilfried ; Follmann, Markus ; Janni, Wolfgang ; Kopp, Ina ; Kreienberg, Rolf ; Kühn, Thorsten ; Langer, Thomas ; Nothacker, Monika ; Scharl, Anton ; Schreer, Ingrid ; Link, Hartmut ; Engel, Jutta ; Fehm, Tanja ; Weis, Joachim ; Welt, Anja ; Steckelberg, Anke ; Feyer, Petra ; König, Klaus ; Hahne, Andrea ; Kreipe, Hans H. ; Knoefel, Wolfram Trudo ; Denkinger, Michael ; Brucker, Sara ; Lüftner, Diana ; Kubisch, Christian ; Gerlach, Christina ; Lebeau, Annette ; Siedentopf, Friederike ; Petersen, Cordula ; Bartsch, Hans Helge ; Schulz-Wendtland, Rüdiger ; Hahn, Markus ; Hanf, Volker ; Müller-Schimpfle, Markus ; Henscher, Ulla ; Roncarati, Renza ; Katalinic, Alexander ; Heitmann, Christoph ; Honegger, Christoph ; Paradies, Kerstin ; Bjelic-Radisic, Vesna ; Degenhardt, Friedrich ; Wenz, Frederik ; Rick, Oliver ; Hölzel, Dieter ; Zaiss, Matthias ; Kemper, Gudrun ; Budach, Volker ; Denkert, Carsten Michael ; Gerber, Bernd ; Tesch, Hans ; Hirsmüller, Susanne ; Sinn, Hans-Peter ; Dunst, Jürgen ; Münstedt, Karsten ; Bick, Ulrich ; Fallenberg, Eva ; Tholen, Reina ; Hung, Roswita ; Baumann, Freerk T. ; Beckmann, Matthias Wilhelm ; Blohmer, Jens-Uwe ; Fasching, Peter Andreas ; Lux, Michael Patrick ; Harbeck, Nadia ; Hadji, Peyman ; Hauner, Hans ; Heywang-Köbrunner, Sylvia H. ; Huober, Jens ; Hübner, Jutta ; Jackisch, Christian ; Loibl, Sibylle ; Lück, Hans-Jürgen ; Minckwitz, Gunter von ; Möbus, Volker ; Müller, Volkmar ; Nöthlings, Ute ; Schmidt, Marcus ; Schmutzler, Rita Katharina ; Schneeweiss, Andreas ; Schütz, Florian ; Stickeler, Elmar ; Thomssen, Christoph ; Untch, Michael ; Wesselmann, Simone ; Bücker, Arno ; Krockenberger, Mathias Heinric
Purpose: The aim of this official guideline coordinated and published by the German Society for Gynecology and Obstetrics (DGGG) and the German Cancer Society (DKG) was to optimize the screening, diagnosis, therapy and follow-up care of breast cancer.
Methods: The process of updating the S3 guideline dating from 2012 was based on the adaptation of identified source guidelines which were combined with reviews of evidence compiled using PICO (Patients/Interventions/Control/Outcome) questions and the results of a systematic search of literature databases and the selection and evaluation of the identified literature. The interdisciplinary working groups took the identified materials as their starting point to develop recommendations and statements which were modified and graded in a structured consensus procedure.
Recommendations: Part 1 of this short version of the guideline presents recommendations for the screening, diagnosis and follow-up care of breast cancer. The importance of mammography for screening is confirmed in this updated version of the guideline and forms the basis for all screening. In addition to the conventional methods used to diagnose breast cancer, computed tomography (CT) is recommended for staging in women with a higher risk of recurrence. The follow-up concept includes suggested intervals between physical, ultrasound and mammography examinations, additional high-tech diagnostic procedures, and the determination of tumor markers for the evaluation of metastatic disease.
HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
(2021)
Le Clerc, Sigrid ; Lombardi, Laura ; Amare, Azmeraw T. ; Schubert, Klaus Oliver ; Hou, Liping ; Clark, Scott R. ; Papiol, Sergi ; Cearns, Micah ; Heilbronner, Urs ; Degenhardt, Franziska ; Tekola-Ayele, Fasil ; Hsu, Yi-Hsiang ; Shekhtman, Tatyana ; Adli, Mazda ; Akula, Nirmala ; Akiyama, Kazufumi ; Ardau, Raffaella ; Arias, Bárbara ; Aubry, Jean-Michel ; Backlund, Lena ; Bhattacharjee, Abesh Kumar ; Bellivier, Frank ; Benabarre, Antonio ; Bengesser, Susanne ; Biernacka, Joanna ; Birner, Armin ; Brichant-Petitjean, Clara ; Cervantes, Pablo ; Chen, Hsi-Chung ; Chillotti, Caterina ; Cichon, Sven ; Cruceanu, Cristiana ; Czerski, Piotr M. ; Dalkner, Nina ; Dayer, Alexandre ; Baune, Bernhard T. ; Del Zompo, Maria ; DePaulo, J. Raymond ; Étain, Bruno ; Jamain, Stephane ; Falkai, Peter ; Forstner, Andreas Josef ; Frisen, Louise ; Frye, Mark A. ; Fullerton, Janice M. ; Gard, Sébastien ; Garnham, Julie S. ; Goes, Fernando S. ; Grigoroiu-Serbanescu, Maria ; Grof, Paul ; Hashimoto, Ryota ; Hauser, Joanna ; Herms, Stefan ; Hoffmann, Per ; Jiménez, Esther ; Kahn, Jean-Pierre ; Kassem, Layla ; Kuo, Po-Hsiu ; Kato, Tadafumi ; Kelsoe, John R. ; Kittel-Schneider, Sarah ; Ferensztajn-Rochowiak, Ewa ; König, Barbara ; Kusumi, Ichiro ; Laje, Gonzalo ; Landén, Mikael ; Lavebratt, Catharina ; Leckband, Susan G. ; Tortorella, Alfonso ; Manchia, Mirko ; Martinsson, Lina ; McCarthy, Michael J. ; McElroy, Susan ; Colom, Francesc ; Millischer, Vincent ; Mitjans, Marina ; Mondimore, Francis Mark ; Monteleone, Palmiero ; Nievergelt, Caroline M. ; Nöthen, Markus Maria ; Novák, Tomas ; O'Donovan, Claire ; Ozaki, Norio ; Ösby, Urban ; Pfennig, Andrea ; Potash, James B. ; Reif, Andreas ; Reininghaus, Eva ; Rouleau, Guy A. ; Rybakowski, Janusz K. ; Schalling, Martin ; Schofield, Peter R. ; Schweizer, Barbara W. ; Severino, Giovanni ; Shilling, Paul D. ; Shimoda, Katzutaka ; Simhandl, Christian ; Slaney, Claire M. ; Pisanu, Claudia ; Squassina, Alessio ; Stamm, Thomas ; Stopkova, Pavla ; Maj, Mario ; Turecki, Gustavo ; Vieta, Eduard ; Veeh, Julia ; Witt, Stephanie H. ; Wright, Adam ; Zandi, Peter P. ; Mitchell, Philip B. ; Bauer, Michael ; Alda, Martin ; Rietschel, Marcella ; McMahon, Francis J. ; Schulze, Thomas Gerd ; Spadoni, Jean-Louis ; Boukouaci, Wahid ; Richard, Jean-Romain ; Le Corvoisier, Philippe ; Barrau, Caroline ; Zagury, Jean-François ; Leboyer, Marion ; Tamouza, Ryad
Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10−3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
Théry, Clotilde ; Witwer, Kenneth W. ; Aikawa, Elena ; Alcaraz, Maria Jose ; Anderson, Johnathon D. ; Andriantsitohaina, Ramaroson ; Antoniou, Anna ; Arab, Tanina ; Archer, Fabienne ; Atkin-Smith, Georgia K. ; Ayre, D. Craig ; Bach, Jean-Marie ; Bachurski, Daniel ; Baharvand, Hossein ; Balaj, Leonora ; Baldacchino, Shawn ; Bauer, Natalie N. ; Baxter, Amy A. ; Bebawy, Mary ; Beckham, Carla ; Zavec, Apolonija Bedina ; Benmoussa, Abderrahim ; Berardi, Anna C. ; Bergese, Paolo ; Bielska, Ewa ; Blenkiron, Cherie ; Bobis-Wozowicz, Sylwia ; Boilard, Eric ; Boireau, Wilfrid ; Bongiovanni, Antonella ; Borràs, Francesc E. ; Bosch, Steffi ; Boulanger, Chantal M. ; Breakefield, Xandra ; Breglio, Andrew M. ; Brennan, Meadhbh Aín ; Brigstock, David R. ; Brisson, Alain ; Broekman, Marike L. D. ; Bromberg, Jacqueline F. ; Bryl-Gorecka, Paulina ; Buch, Shilpa ; Buck, Amy H. ; Burger, Dylan ; Busatto, Sara ; Buschmann, Dominik ; Bussolati, Benedetta ; Buzás, Edit I. ; Byrd, James Bryan ; Camussi, Giovanni ; Carter, David R. F. ; Caruso, Sarah ; Chamley, Lawrence W. ; Chang, Yu-Ting ; Chen, Chihchen ; Chen, Shuai ; Cheng, Lesley ; Chin, Andrew R. ; Clayton, Aled ; Clerici, Stefano P. ; Cocks, Alex ; Cocucci, Emanuele ; Coffey, Robert J. ; Cordeiro-da-Silva, Anabela ; Couch, Yvonne ; Coumans, Frank A. W. ; Coyle, Beth ; Crescitelli, Rossella ; Criado, Miria Ferreira ; D’Souza-Schorey, Crislyn ; Das, Saumya ; Chaudhuri, Amrita Datta ; de-Candia, Paola ; De Santana, Eliezer F. ; De Wever, Olivier ; del Portillo, Hernando A. ; Demaret, Tanguy ; Deville, Sarah ; Devitt, Andrew ; Dhondt, Bert ; Di Vizio, Dolores ; Dieterich, Lothar C. ; Dolo, Vincenza ; Dominguez Rubio, Ana Paula ; Dominici, Massimo ; Dourado, Mauricio R. ; Driedonks, Tom A. P. ; Duarte, Filipe V. ; Duncan, Heather M. ; Eichenberger, Ramon Marc ; Ekström, Karin ; El Andaloussi, Samir ; Elie-Caille, Celine ; Erdbrügger, Uta ; Falcón-Pérez, Juan M. ; Fatima, Farah ; Fish, Jason E. ; Flores-Bellver, Miguel ; Försönits, András ; Frelet-Barrand, Annie ; Fricke, Fabia ; Fuhrmann, Gregor ; Gabrielsson, Susanne ; Gámez-Valero, Ana ; Gardiner, Chris ; Gärtner, Kathrin ; Gaudin, Raphael ; Gho, Yong Song ; Giebel, Bernd ; Gilbert, Caroline ; Gimona, Mario ; Giusti, Ilaria ; Goberdhan, Deborah C. I. ; Görgens, André ; Gorski, Sharon M. ; Greening, David W. ; Groß, Julia Christina ; Gualerzi, Alice ; Gupta, Gopal N. ; Gustafson, Dakota ; Handberg, Aase ; Haraszti, Réka Ágnes ; Harrison, Paul ; Hegyesi, Hargita ; Hendrix, An ; Hill, Andrew F. ; Hochberg, Fred H. ; Hoffmann, Karl F. ; Holder, Beth ; Holthofer, Harry ; Hosseinkhani, Baharak ; Hu, Guoku ; Huang, Yiyao ; Huber, Veronica ; Hunt, Stuart ; Ibrahim, Ahmed Gamal-Eldin ; Ikezu, Tsuneya ; Inal, Jameel M. ; Isin, Mustafa ; Ivanova, Alena ; Jackson, Hannah K. ; Jacobsen, Soren ; Jay, Steven M. ; Jayachandran, Muthuvel ; Jenster, Guido ; Jiang, Lanzhou ; Johnson, Suzanne M. ; Jones, Jennifer C. ; Jong, Ambrose ; Jovanovic-Talisman, Tijana ; Jung, Stephanie ; Kalluri, Raghu ; Kano, Shin-ichi ; Kaur, Sukhbir ; Kawamura, Yumi ; Keller, Evan T. ; Khamari, Delaram ; Khomyakova, Elena ; Khvorova, Anastasia ; Kierulf, Peter ; Kim, Kwang Pyo ; Kislinger, Thomas ; Klingeborn, Mikael ; Klinke, David J. ; Kornek, Miroslaw ; Kosanović, Maja M. ; Kovács, Árpád Ferenc ; Krämer-Albers, Eva-Maria ; Krasemann, Susanne ; Krause, Mirja ; Kurochkin, Igor V. ; Kusuma, Gina D. ; Kuypers, Sören ; Laitinen, Saara ; Langevin, Scott M. ; Languino, Lucia R. ; Lannigan, Joanne ; Lässer, Cecilia ; Laurent, Louise C. ; Lavieu, Gregory ; Lázaro-Ibáñez, Elisa ; Le Lay, Soazig ; Lee, Myung-Shin ; Lee, Yi Xin Fiona ; Lemos, Debora S. ; Lenassi, Metka ; Leszczynska, Aleksandra ; Li, Isaac T. S. ; Liao, Ke ; Libregts, Sten F. ; Ligeti, Erzsebet ; Lim, Rebecca ; Lim, Sai Kiang ; Linē, Aija ; Linnemannstöns, Karen ; Llorente, Alicia ; Lombard, Catherine Ann ; Lorenowicz, Magdalena J. ; Lörincz, Ákos M. ; Lötvall, Jan ; Lovett, Jason ; Lowry, Michelle C. ; Loyer, Xavier ; Lu, Quan ; Lukomska, Barbara ; Lunavat, Taral Rameshchand ; Maas, Sybren L. N. ; Malhi, Harmeet ; Marcilla, Antonio ; Mariani, Jacopo ; Mariscal, Javier ; Martens-Uzunova, Elena S. ; Martin-Jaular, Lorena ; Martinez, M. Carmen ; Martins, Vilma Regina ; Mathieu, Mathilde ; Mathivanan, Suresh ; Maugeri, Marco ; McGinnis, Lynda K. ; McVey, Mark J. ; Meckes, David G. ; Meehan, Katie ; Mertens, Inge ; Minciacchi, Valentina R. ; Möller, Andreas ; Møller Jørgensen, Malene ; Morales-Kastresana, Aizea ; Morhayim, Jess ; Mullier, François ; Muraca, Maurizio ; Musante, Luca ; Mussack, Veronika ; Muth, Dillon C. ; Myburgh, Kathryn H. ; Najrana, Tanbir ; Nawaz, Muhammad ; Nazarenko, Irina ; Nejsum, Peter ; Neri, Christian ; Neri, Tommaso ; Nieuwland, Rienk ; Nimrichter, Leonardo ; Nolan, John P. ; Nolte-’t Hoen, Esther N. M. ; Hooten, Nicole Noren ; O’Driscoll, Lorraine ; O’Grady, Tina ; O’Loghlen, Ana ; Ochiya, Takahiro ; Olivier, Martin ; Ortiz, Alberto ; Ortiz, Luis A. ; Osteikoetxea, Xabier ; Østergaard, Ole ; Ostrowski, Matias ; Park, Jaesung ; Pegtel, Dirk Michiel ; Peinado, Hector ; Perut, Francesca ; Pfaffl, Michael ; Phinney, Donald G. ; Pieters, Bartijn C. H. ; Pink, Ryan Charles ; Pisetsky, David S. ; Pogge von Strandmann, Elke ; Polakovicova, Iva ; Poon, Ivan K. H. ; Powell, Bonita H. ; Prada, Ilaria ; Pulliam, Lynn ; Quesenberry, Peter ; Radeghieri, Annalisa ; Raffai, Robert L. ; Raimondo, Stefania ; Rak, Janusz ; Ramirez, Marcel I. ; Raposo, Graça ; Rayyan, Morsi S. ; Regev-Rudzki, Neta ; Ricklefs, Franz Lennard ; Robbins, Paul D. ; Roberts, David D. ; Rodrigues, Silvia C. ; Rohde, Eva ; Rome, Sophie ; Rouschop, Kasper M. ; Rughetti, Aurelia ; Russell, Ashley E. ; Saá, Paula ; Sahoo, Susmita ; Salas-Huenuleo, Edison ; Sánchez, Catherine ; Saugstad, Julie A. ; Saul, Meike J. ; Schiffelers, Raymond M. ; Schneider, Raphael ; Schøyen, Tine Hiorth ; Scott, Aaron ; Shahaj, Eriomina ; Sharma, Shivani ; Shatnyeva, Olga ; Shekari, Faezeh ; Shelke, Ganesh Vilas ; Shetty, Ashok K. ; Shiba, Kiyotaka ; Siljander, Pia R.-M. ; Silva, Andreia M. ; Skowronek, Agata ; Snyder, Orman L. ; Soares, Rodrigo Pedro ; Sódar, Barbara W. ; Soekmadji, Carolina ; Sotillo, Javier ; Stahl, Philip D. ; Stoorvogel, Willem ; Stott, Shannon L. ; Strasser, Erwin F. ; Swift, Simon ; Tahara, Hidetoshi ; Tewari, Muneesh ; Timms, Kate ; Tiwari, Swasti ; Tixeira, Rochelle ; Tkach, Mercedes ; Toh, Wei Seong ; Tomasini, Richard ; Torrecilhas, Ana Claudia ; Tosar, Juan Pablo ; Toxavidis, Vasilis ; Urbanelli, Lorena ; Vader, Pieter ; Balkom, Bastiaan Wilhelmus Maria van ; Grein, Susanne G. van der ; Van Deun, Jan ; Herwijnen, Martijn J. C. van ; Van Keuren-Jensen, Kendall R. ; Niel, Guillaume van ; Royen, Martin E. van ; Wijnen, Andre J. van ; Vasconcelos, M. Helena ; Vechetti, Ivan J. ; Veit, Tiago D. ; Vella, Laura J. ; Velot, Émilie ; Verweij, Frederik ; Vestad, Beate ; Viñas, Jose Luis ; Visnovitz, Tamás ; Vukman, Krisztina V. ; Wahlgren, Jessica ; Watson, Dionysios C. ; Wauben, Marca H. M. ; Weaver, Alissa ; Webber, Jason P. ; Weber, Viktoria ; Wehman, Ann M. ; Weiss, Daniel J. ; Welsh, Joshua A. ; Wendt, Sebastian ; Wheelock, Åsa M. ; Wiener, Zoltán ; Witte, Leonie ; Wolfram, Joy ; Xagorari, Angeliki ; Xander, Patricia ; Xu, Jing ; Yan, Xiaomei ; Yáñez-Mó, María ; Yin, Hang ; Yuana, Yuana ; Zappulli, Valentina ; Zarubova, Jana ; Žėkas, Vytautas ; Zhang, Jian-ye ; Zhao, Zezhou ; Zheng, Lei ; Zheutlin, Alexander R. ; Zickler, Antje Maria ; Zimmermann, Pascale ; Zivkovic, Angela M. ; Zocco, Davide ; Zuba-Surma, Ewa K.
The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
López, Cristina ; Kleinheinz, Kortine ; Aukema, Sietse M. ; Rohde, Marius ; Bernhart, Stephan H. ; Hübschmann, Daniel ; Wagener, Rabea ; Toprak, Umut H. ; Raimondi, Francesco ; Kreuz, Markus ; Waszak, Sebastian Martin ; Huang, Zhiqin ; Sieverling, Lina ; Paramasivam, Nagarajan ; Seufert, Julian ; Sungalee, Stephanie ; Russell, Robert B. ; Bausinger, Julia ; Kretzmer, Helene ; Ammerpohl, Ole ; Bergmann, Anke K. ; Binder, Hans ; Borkhardt, Arndt ; Brors, Benedikt ; Claviez, Alexander ; Doose, Gero ; Feuerbach, Lars ; Haake, Andrea ; Hansmann, Martin-Leo ; Höll, Jessica ; Hummel, Michael ; Korbel, Jan Oliver ; Lawerenz, Chris ; Lenze, Dido ; Radlwimmer, Bernhard ; Richter, Julia ; Rosenstiel, Philip ; Rosenwald, Andreas ; Schilhabel, Markus B. ; Stein, Harald ; Stilgenbauer, Stephan ; Stadler, Peter F. ; Szczepanowski, Monika ; Weniger, Marc Andrèe ; Zapatka, Marc ; Eils, Roland ; Lichter, Peter ; Löffler, Markus ; Möller, Peter ; Trümper, Lorenz ; Klapper, Wolfram ; Hoffmann, Steve ; Küppers, Ralf ; Burkhardt, Birgit ; Schlesner, Matthias ; Siebert, Reiner
Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.
Magunia, Harry ; Lederer, Simone ; Verbuecheln, Raphael ; Gilot, Bryant ; Köppen, Michael ; Häberle, Helene ; Mirakaj, Valbona ; Hofmann, Pascal ; Marx, Gernot ; Bickenbach, Johannes ; Nohe, Boris ; Lay, Michael ; Spies, Claudia D. ; Edel, Andreas ; Schiefenhövel, Fridtjof ; Rahmel, Tim ; Putensen, Christian ; Sellmann, Timur ; Koch, Thea ; Brandenburger, Timo ; Kindgen-Milles, Detlef ; Brenner, Thorsten ; Berger, Marc ; Zacharowski, Kai ; Adam, Elisabeth ; Posch, Matthias ; Mörer, Onnen ; Scheer, Christian S. ; Sedding, Daniel ; Weigand, Markus A. ; Fichtner, Falk ; Nau, Carla ; Prätsch, Florian ; Wiesmann, Thomas ; Koch, Christian ; Schneider, Gerhard ; Lahmer, Tobias ; Straub, Andreas ; Meiser, Andreas ; Weiß, Manfred ; Jungwirth, Bettina ; Wappler, Frank ; Meybohm, Patrick ; Herrmann, Johannes ; Malek, Nisar Peter ; Kohlbacher, Oliver ; Biergans, Stephanie ; Rosenberger, Peter
Background: Intensive Care Resources are heavily utilized during the COVID-19 pandemic. However, risk stratification and prediction of SARS-CoV-2 patient clinical outcomes upon ICU admission remain inadequate. This study aimed to develop a machine learning model, based on retrospective & prospective clinical data, to stratify patient risk and predict ICU survival and outcomes. Methods: A Germany-wide electronic registry was established to pseudonymously collect admission, therapeutic and discharge information of SARS-CoV-2 ICU patients retrospectively and prospectively. Machine learning approaches were evaluated for the accuracy and interpretability of predictions. The Explainable Boosting Machine approach was selected as the most suitable method. Individual, non-linear shape functions for predictive parameters and parameter interactions are reported. Results: 1039 patients were included in the Explainable Boosting Machine model, 596 patients retrospectively collected, and 443 patients prospectively collected. The model for prediction of general ICU outcome was shown to be more reliable to predict “survival”. Age, inflammatory and thrombotic activity, and severity of ARDS at ICU admission were shown to be predictive of ICU survival. Patients’ age, pulmonary dysfunction and transfer from an external institution were predictors for ECMO therapy. The interaction of patient age with D-dimer levels on admission and creatinine levels with SOFA score without GCS were predictors for renal replacement therapy. Conclusions: Using Explainable Boosting Machine analysis, we confirmed and weighed previously reported and identified novel predictors for outcome in critically ill COVID-19 patients. Using this strategy, predictive modeling of COVID-19 ICU patient outcomes can be performed overcoming the limitations of linear regression models. Trial registration “ClinicalTrials” (clinicaltrials.gov) under NCT04455451.
Frahm, Jan-Peter ; Janßen, Anne-Maike ; Schumacher, Judith ; Thönnes, Daniela ; Hensel, Stephanie ; Heidelbach, Birgit ; Erler, David
Der starke Anstieg von nitrophytischen Flechten während der letzten 15 Jahren in landwirtschaftlich genutzten und städtischen Bereichen hat die Frage aufgeworfen, welche Stickstoffverbindung dafür verantwortlich sind, welche physiologischen Probleme diese machen, wo diese herkommen, welche Auswirkungen sie auf die Flechten haben, was mit dem Stickstoff in den Flechten passiert, wie sich Feinstaub und trockene Deposition auswirken und wieso Nitrophyten auch in unbelasteten Gebieten dominieren. Nach den Ergebnissen zahlreicher Einzelstudien, die hier mit neuen Daten ergänzt werden, ist Ammoniak die relevante Stickstoffquelle. Dieser wird als Ammoniumnitrat speziell in Form von trockener Deposition von den Flechten aufgenommen. Da Ammoniumnitrat ein Salz ist, haben Nitrophyten höhere osmotische Werte, weswegen sie in belasteten Gebieten konkurrenzkräftiger sind. Dies erlaubt Nitrophyten gleichzeitig die Existenz in Trockengebieten auch ohne Stickstoffemissionen, weswegen sie nicht unbedingt Stickstoffzeiger sondern auch Trockenzeiger sind. Der anfallende Stickstoff wird in Form von Aminosäuren in der Flechte passiv gespeichert, weswegen Nitrophyten nicht nitrophil sondern nitrotolerant, halotolerant und xerophytisch sind. Die momentane Temperaturerhöhung und die damit verbundene erhöhte Verdunstung sowie die Zunahme trockener Deposition (Feinstaubbelastung) führen zur Zeit trotz sinkender Gesamtstickstoffbelastung zu einem weiteren Anstieg der nitrophytischen Flechten.
Ist der Anstieg nitrophiler Flechten an Bäumen auf eine Erhöhung des Borken-pHs zurückzuführen?
(2009)
Der Anstieg nitrophiler Flechten an Bäumen in den letzten zehn Jahren wirft die Frage nach den dafür verantwortlichen Ursachen auf. Einer Hypothese zur Folge soll dieser Anstieg auf eine Erhöhung des Borken-pH beruhen, hervorgerufen durch die gesunkenen SO2-Emissionen, gestiegene Ammoniakemissionen oder auch Verkehrsstäube. Um diese Hypothese zu testen, wurden im Rheinland pH-Messungen unterschiedlicher Trägerbaumarten durchgeführt und mit Faktoren wie der Frequenz bzw. Diversität nitrophyischer Flechten oder der Verkehrsdichte korreliert. Dabei zeigte sich, dass der stärkere Verkehr den pH von Eichen mit pufferarmer Borke anhebt. Bei Linden lässt sich ein geringer, bei Ahornen kein Zusammenhang zum Verkehr finden. Ein Zusammenhang zwischen Frequenz oder Diversität von nitrophytischen Flechtenarten mit dem Borken-pH konnte nicht gefunden werden. Deswegen kann ein Anstieg der nitrophytischen Flechten generell nicht auf die Änderung des Borken-pHs zurückgeführt werden. Im Vergleich mit pH-Werten von Borken aus den Fünfziger Jahren ist ein deutlicher Anstieg der Werte zu verzeichnen, der dann aber auf den Rückgang der Säurewirkung von SO2 und nicht auf die basische Wirkung von eutrophierenden Emissionen zurückzuführen ist. Als mögliche Ursache für den Anstieg nitrophytischer Flechten wird die Salzwirkung von trockenen Stickstoffdepositionen erwogen.