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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.
Abou Yassine, Rayane ; Adamczewski-Musch, Jörn ; Becker, Marten ; Bergmann, Philip ; Blanco, Alberto ; Blume, Christoph ; Chlad, Lukas ; Chudoba, Petr ; Ciepał, Izabela ; Cordts, Malte ; Dreyer, Jörn ; Esmail, Waleed Ahmed ; Firlej, Miroslaw ; Fiutowski, Tomasz ; Floersheimer, Henrik ; Fonte, Paulo ; Friese, Jürgen ; Fröhlich, Ingo ; Förtsch, Jörg ; Galatyuk, Tetyana ; Gniazdowski, Tomasz ; Greifenhagen, Robert ; Grunwald, Mateusz ; Grzonka, Dieter ; Gumberidze, Malgorzata ; Harabasz, Szymon ; Heinz, Thorsten ; Höhne, Claudia ; Hojeij, Fatima ; Holzmann, Romain ; Huck, Holger ; Idzik, Marek ; Kämpfer, Burkhard ; Kampert, Karl-Heinz ; Kardan, Behruz ; Kedych, Vadym ; Koenig, Ilse ; Koenig, Wolfgang ; Kohls, Marvin ; Kołaś, Jędrzej ; Korcyl, Grzegorz ; Kornakov, Georgy ; Kornas, Frédéric Julian ; Kotte, Roland ; Krueger, Wilhelm ; Kugler, Andrej ; Kulessa, Pawel ; Lalik, Rafał Tomasz ; Lebedev, Semen ; Linev, Sergey ; Lopes, Luis Alberto Vieira ; Lorenz, Manuel ; Malige, Akshay ; Markert, Jochen ; Matulewicz, Tomasz ; Messchendorp, Johannes Gerhardus ; Metag, Volker ; Michel, Jan ; Molenda, Aleksandra ; Moron, Jakub ; Müntz, Christian ; Nabroth, Marvin ; Naumann, Lothar ; Orliński, Jan ; Otto, Jan-Hendrik ; Parpottas, Yannis ; Parschau, Mirco ; Pauly, Christian ; Pechenov, Vladimir ; Pechenova, Olga ; Perez Andrade, Gabriela ; Pfeifer, Dennis ; Piasecki, Krzysztof ; Pietraszko, Jerzy ; Povar, Tetiana ; Prozorov, Alexandr ; Przygoda, Witold ; Pysz, Krzysztof ; Ramstein, Béatrice ; Rathod, Narendra ; Ritman, James Lambrecht ; Rost, Adrian ; Rustamov, Anar ; Salabura, Piotr ; Saraiva, Joao ; Schadmand, Susan ; Schild, Niklas ; Schwab, Erwin ; Seck, Florian ; Selyuzhenkov, Ilya ; Singh, Udai ; Skorpil, Leon ; Smyrski, Jerzy ; Sobiella, Manfred ; Spataro, Stefano ; Spies, Simon ; Stefaniak, Maria ; Ströbele, Herbert ; Stroth, Joachim ; Sumara, Konrad ; Svoboda, Ondřej ; Swientek, Krzysztof ; Szala, Melanie ; Tlusty, Pavel ; Traxler, Michael ; Tsertos, Haralabos ; Wagner, Vladimir ; Wasiluk, Mateusz ; Weber, Adrian Amatus ; Wendisch, Christian ; Wintz, Peter ; Zbroszczyk, Hanna Paulina ; Zherebtsova, Elizaveta S. ; Zielinski, Marcin ; Zumbruch, Peter W.
In March 2019 the HADES experiment recorded 14 billion Ag+Ag collisions at √sNN = 2.55 GeV as a part of the FAIR phase-0 physics program. In this contribution, we present and investigate our capabilities to reconstruct and analyze weakly decaying strange hadrons and hypernuclei emerging from these collisions. The focus is put on measuring the mean lifetimes of these particles.
An integrative correlation of myopathology, phenotype and genotype in late onset Pompe disease
(2019)
Kulessa, Martin ; Weyer‐Menkhoff, Iris ; Viergutz, Lara ; Kornblum, Cornelia ; Claeys, Kristl G. ; Schneider, Ilka ; Plöckinger, Ursula ; Young, Peter ; Boentert, Matthias ; Vielhaber, Stefan ; Mawrin, Christian ; Bergmann, Markus ; Weis, Joachim ; Ziagaki, Athanasia ; Stenzel, Werner ; Deschauer, Marcus ; Nolte, Dagmar ; Hahn, Andreas ; Schoser, Benedikt ; Schänzer, Anne
Aims: Pompe disease is caused by pathogenic mutations in the alpha 1,4‐glucosidase (GAA) gene and in patients with late onset Pome disease (LOPD), genotype–phenotype correlations are unpredictable. Skeletal muscle pathology includes glycogen accumulation and altered autophagy of various degrees. A correlation of the muscle morphology with clinical features and the genetic background in GAA may contribute to the understanding of the phenotypic variability.
Methods: Muscle biopsies taken before enzyme replacement therapy were analysed from 53 patients with LOPD. On resin sections, glycogen accumulation, fibrosis, autophagic vacuoles and the degree of muscle damage (morphology‐score) were analysed and the results were compared with clinical findings. Additional autophagy markers microtubule‐associated protein 1A/1B‐light chain 3, p62 and Bcl2‐associated athanogene 3 were analysed on cryosections from 22 LOPD biopsies.
Results: The myopathology showed a high variability with, in most patients, a moderate glycogen accumulation and a low morphology‐score. High morphology‐scores were associated with increased fibrosis and autophagy highlighting the role of autophagy in severe stages of skeletal muscle damage. The morphology‐score did not correlate with the patient's age at biopsy, disease duration, nor with the residual GAA enzyme activity or creatine‐kinase levels. In 37 patients with LOPD, genetic analysis identified the most frequent mutation, c.‐32‐13T>G, in 95%, most commonly in combination with c.525delT (19%). No significant correlation was found between the different GAA genotypes and muscle morphology type.
Conclusions: Muscle morphology in LOPD patients shows a high variability with, in most cases, moderate pathology. Increased pathology is associated with more fibrosis and autophagy.
Voskens, Caroline J. ; Goldinger, Simone M. ; Loquai, Carmen ; Robert, Caroline ; Kähler, Katharina C. ; Berking, Carola ; Bergmann, Tanja Regina ; Bockmeyer, Clemens Luitpold ; Eigentler, Thomas Kurt ; Fluck, Michael ; Garbe, Claus ; Gutzmer, Ralf ; Grabbe, Stephan ; Hauschild, Axel ; Hein, Rüdiger ; Hundorfean, Gheorghe ; Justich, Armin ; Keller, Ullrich ; Klein, Christina ; Mateus, Christine ; Mohr, Peter ; Pätzold, Sylvie ; Satzger, Imke ; Schadendorf, Dirk ; Schlaeppi, Marc ; Schuler, Gerold ; Schuler-Thurner, Beatrice ; Trefzer, Uwe ; Ulrich, Jens ; Vaubel, Julia ; Moos, Roger von ; Weder, Patrik ; Wilhelm, Tabea ; Göppner, Daniela ; Dummer, Reinhard ; Heinzerling, Lucie
Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers.
Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment.
Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.
Seidler, Andreas ; Bergmann, Annekatrin ; Jäger, Matthias ; Ellegast, Rolf Peter ; Ditchen, Dirk Marcel ; Elsner, Gine ; Grifka, Joachim ; Haerting, Johannes ; Hofmann, Friedrich ; Linhardt, Oliver ; Luttmann, Alwin ; Michaelis, Martina ; Petereit-Haack, Gabriela ; Schumann, Barbara ; Bolm-Audorff, Ulrich
Background The to date evidence for a dose-response relationship between physical workload and the development of lumbar disc diseases is limited. We therefore investigated the possible etiologic relevance of cumulative occupational lumbar load to lumbar disc diseases in a multi-center case-control study. Methods In four study regions in Germany (Frankfurt/Main, Freiburg, Halle/Saale, Regensburg), patients seeking medical care for pain associated with clinically and radiologically verified lumbar disc herniation (286 males, 278 females) or symptomatic lumbar disc narrowing (145 males, 206 females) were prospectively recruited. Population control subjects (453 males and 448 females) were drawn from the regional population registers. Cases and control subjects were between 25 and 70 years of age. In a structured personal interview, a complete occupational history was elicited to identify subjects with certain minimum workloads. On the basis of job task-specific supplementary surveys performed by technical experts, the situational lumbar load represented by the compressive force at the lumbosacral disc was determined via biomechanical model calculations for any working situation with object handling and load-intensive postures during the total working life. For this analysis, all manual handling of objects of about 5 kilograms or more and postures with trunk inclination of 20 degrees or more are included in the calculation of cumulative lumbar load. Confounder selection was based on biologic plausibility and on the change-in-estimate criterion. Odds ratios (OR) and 95% confidence intervals (CI) were calculated separately for men and women using unconditional logistic regression analysis, adjusted for age, region, and unemployment as major life event (in males) or psychosocial strain at work (in females), respectively. To further elucidate the contribution of past physical workload to the development of lumbar disc diseases, we performed lag-time analyses. Results We found a positive dose-response relationship between cumulative occupational lumbar load and lumbar disc herniation as well as lumbar disc narrowing among men and women. Even past lumbar load seems to contribute to the risk of lumbar disc disease. Conclusions According to our study, cumulative physical workload is related to lumbar disc diseases among men and women.
Schumann, Barbara ; Bolm-Audorff, Ulrich ; Bergmann, Annekatrin ; Ellegast, Rolf Peter ; Elsner, Gine ; Grifka, Joachim ; Haerting, Johannes ; Jäger, Matthias ; Michaelis, Martina ; Seidler, Andreas
Introduction: In the large-scale case-control study EPILIFT, we investigated the dose-response relationship between lifestyle factors (weight, smoking amount, cumulative duration of different sports activities) and lumbar disc disease. Methods: In four German study regions (Frankfurt am Main, Freiburg, Halle/Saale, Regensburg), 564 male and female patients with lumbar disc herniation and 351 patients with lumbar disc narrowing (chondrosis) aged 25 to 70 years were prospectively recruited. From the regional population registers, 901 population control subjects were randomly selected. In a structured personal interview, we enquired as to body weight at different ages, body height, cumulative smoking amount and cumulative duration of different sports activities. Confounders were selected according to biological plausibility and to the change-in-estimate criterion. Adjusted, gender-stratified odds ratios with 95% confidence intervals were calculated using unconditional logistic regression analysis. Results: The results of this case-control study reveal a positive association between weight and lumbar disc herniation as well as lumbar disc narrowing among men and women. A medium amount of pack-years was associated with lumbar disc herniation and narrowing in men and women. A non-significantly lowered risk of lumbar disc disease was found in men with high levels of cumulative body building and strength training. Conclusions: According to our multi-center case-control study, body weight might be related to lumbar disc herniation as well as to lumbar disc narrowing. Further research should clarify the potential protective role of body building or strength training on lumbar disc disease.
The extension of the nuclear two-centre-oscillator to three and four centres is investigated. Some special symmetry-properties are required. In two cases an analytical solution of the Schrödinger equation is possible. A numerical procedure is developed which enables the diagonalization of the Hamiltonian in a non-orthogonal basis without applying Schmidt's method of orthonormalization. This is important for calculations of arbitrary two-dimensional arrangements of the centres.