TY - JOUR A1 - Herrmann, Johannes A1 - Lotz, Christopher A1 - Karagiannidis, Christian A1 - Weber-Carstens, Steffen A1 - Kluge, Stefan A1 - Putensen, Christian A1 - Wehrfritz, Andreas A1 - Schmidt, Karsten A1 - Ellerkmann, Richard K. A1 - Oswald, Daniel A1 - Lotz, Gösta A1 - Zotzmann, Viviane A1 - Moerer, Onnen A1 - Kühn, Christian A1 - Kochanek, Matthias A1 - Muellenbach, Ralf A1 - Gaertner, Matthias A1 - Fichtner, Falk A1 - Brettner, Florian A1 - Findeisen, Michael A1 - Heim, Markus A1 - Lahmer, Tobias A1 - Rosenow, Felix A1 - Haake, Nils A1 - Lepper, Philipp M. A1 - Rosenberger, Peter A1 - Braune, Stephan A1 - Kohls, Mirjam A1 - Heuschmann, Peter A1 - Meybohm, Patrick T1 - Key characteristics impacting survival of COVID-19 extracorporeal membrane oxygenation JF - Critical Care N2 - Background Severe COVID-19 induced acute respiratory distress syndrome (ARDS) often requires extracorporeal membrane oxygenation (ECMO). Recent German health insurance data revealed low ICU survival rates. Patient characteristics and experience of the ECMO center may determine intensive care unit (ICU) survival. The current study aimed to identify factors affecting ICU survival of COVID-19 ECMO patients. Methods 673 COVID-19 ARDS ECMO patients treated in 26 centers between January 1st 2020 and March 22nd 2021 were included. Data on clinical characteristics, adjunct therapies, complications, and outcome were documented. Block wise logistic regression analysis was applied to identify variables associated with ICU-survival. Results Most patients were between 50 and 70 years of age. PaO\(_{2}\)/FiO\(_{2}\) ratio prior to ECMO was 72 mmHg (IQR: 58–99). ICU survival was 31.4%. Survival was significantly lower during the 2nd wave of the COVID-19 pandemic. A subgroup of 284 (42%) patients fulfilling modified EOLIA criteria had a higher survival (38%) (p = 0.0014, OR 0.64 (CI 0.41–0.99)). Survival differed between low, intermediate, and high-volume centers with 20%, 30%, and 38%, respectively (p = 0.0024). Treatment in high volume centers resulted in an odds ratio of 0.55 (CI 0.28–1.02) compared to low volume centers. Additional factors associated with survival were younger age, shorter time between intubation and ECMO initiation, BMI > 35 (compared to < 25), absence of renal replacement therapy or major bleeding/thromboembolic events. Conclusions Structural and patient-related factors, including age, comorbidities and ECMO case volume, determined the survival of COVID-19 ECMO. These factors combined with a more liberal ECMO indication during the 2nd wave may explain the reasonably overall low survival rate. Careful selection of patients and treatment in high volume ECMO centers was associated with higher odds of ICU survival. KW - Covid-19 KW - extracorporeal membrane oxygenation (ECMO) KW - intensive care unit Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-299686 VL - 26 IS - 1 ER - TY - THES A1 - Weber, Matthias T1 - Kapillarisierung und No-Reflow-Phänomen am Skelettmuskel des Göttinger Miniaturschweins T1 - Capillarization an no-reflow-phenomenon in skeletal muscle of the minipig N2 - Am Göttinger Miniaturschwein sollten die Rolle der Kapillarisierung des Skelettmus-kels und die möglichen Pathomechanismen für das Zustandekommen des No-Reflow-Phänomens untersucht werden. Deshalb wurden zunächst über verschiedene Manipulationen die Ausgangsbedin-gungen des Kapillarbetts variiert: Durch Induzieren einer Rarefikation sollte die Situa-tion im hypertonen bzw. altersveränderten Gefäßbett dargestellt werden, eine an-schließende Behandlung mit Calciumkanalblockern die Umkehrbarkeit dieser Kapil-larbettveränderungen zeigen. Eine Hyperkapillarisierung sollte durch eine operativ angelegte chronische Ischämie erzeugt werden. Diese drei Kapillarbettsituationen wurden während einer akuten Ischämie und der anschließenden Reperfusion analy-siert und einem unbeeinträchtigten Kapillarsystem als Kontrolle gegenübergestellt. Folgende Erkenntnisse ergeben sich: Die Basiskapillarzahlen beeinflussen die Reperfusion nach einer experimentellen Ischämie. Sowohl das Auftreten als auch die Intensität eines NoRe hängt hierbei von der Kapillarisierung ab. Das kapillarrarefizierte Gefäßsystem erweist sich gegenüber der Entwicklung eines NoRe nach Muskelischämien gefährdeter als das normale Kapillarbett. Auch bei nicht vollständig restituierter Kapillarzahl wird das hypertonieinduziert rarefizierte Gefäß-bett nach Behandlung mit Calciumkanalblockern postischämisch besser perfundiert. Calciumkanalblocker können hier möglicherweise einen positiven Effekt zur Präven-tion eines NoRe ausüben. Der chronisch ischämische Muskel zeigt trotz unbeabsich-tigt erniedrigter Kapillarzahl eine verbesserte Kapillarreperfusion nach aktuer Ischä-misierung. Das Auftreten von Nekrosen und deren Ausmaß wird zusätzlich von anderen Fakto-ren bestimmt. Um diese genau zu differenzieren, bedarf es weiterer quantitativer Messungen. N2 - The objective of this study was to examine the role of capillarization of the skeletal muscle and to investigate the possible pathomechanisms for realizing the no-reflow-phenomenon in the “Göttinger” minipig. To achieve this different operative interventions were performed to vary the basic conditions of the capillary bed: By inducing a rarefication, the situation of a hyperten-sive respectivley an age-adapted vascular bed should be represented; the subse-quent therapy with ca-anatgonists should demonstrate the reversibility of these changes of the capillary bed. A hypercapillarization should be generated by opera-tively induced chronic ischemia. These three conditions of the capillary bed were analyzed during acute ischemia and the following reperfusion and then were com-pared to an unimpaired capillary system as a control. The following results were found: The basic number of capillaries influences the reperfusion after experimental ische-mia. The occurrence as well as the intensity of no-reflow depends on capillarization. The rareficated vascular system is more sensitive to no-reflow after ischemia of the muscle than the normal capillary bed. Even if capillary density is not completely re-stored the rareficated vascular bed induced by hypertension will show a better postischemic perfusion after treatment with ca-antagonists. Ca-anatgonists may pos-sibly have a positive influence on prevention of no-reflow. Despite of a not intended impairment of capillary density the muscle exposed to chronic ischemia shows an increased capillary reperfusion after acute ischemia. Occurance and extent of necrosis are furthermore determined by additional factors. To examine these factors, further quantitativ mesurements are necessary. KW - Kapillarisierung KW - No-Reflow KW - Hypertonie KW - Ca-antagonisten KW - Ischämie KW - Capillarization KW - no-reflow KW - hypertension KW - ca-antagonists KW - ischemia Y1 - 2002 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-4906 ER - TY - JOUR A1 - Vogel, Patrick A1 - Markert, Jonathan A1 - Rückert, Martin A. A1 - Herz, Stefan A1 - Keßler, Benedikt A1 - Dremel, Kilian A1 - Althoff, Daniel A1 - Weber, Matthias A1 - Buzug, Thorsten M. A1 - Bley, Thorsten A. A1 - Kullmann, Walter H. A1 - Hanke, Randolf A1 - Zabler, Simon A1 - Behr, Volker C. T1 - Magnetic Particle Imaging meets computed tomography: first simultaneous imaging JF - Scientific Reports N2 - Magnetic Particle Imaging (MPI) is a promising new tomographic modality for fast as well as three-dimensional visualization of magnetic material. For anatomical or structural information an additional imaging modality such as computed tomography (CT) is required. In this paper, the first hybrid MPI-CT scanner for multimodal imaging providing simultaneous data acquisition is presented. KW - Applied physics KW - Biomedical engineering KW - Imaging techniques Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202501 VL - 9 ER - TY - JOUR A1 - Wobser, Marion A1 - Weber, Alexandra A1 - Glunz, Amelie A1 - Tauch, Saskia A1 - Seitz, Kristina A1 - Butelmann, Tobias A1 - Hesbacher, Sonja A1 - Goebeler, Matthias A1 - Bartz, René A1 - Kohlhof, Hella A1 - Schrama, David A1 - Houben, Roland T1 - Elucidating the mechanism of action of domatinostat (4SC-202) in cutaneous T cell lymphoma cells JF - Journal of Hematology & Oncology N2 - Background Targeting epigenetic modifiers is effective in cutaneous T cell lymphoma (CTCL). However, there is a need for further improvement of this therapeutic approach. Here, we compared the mode of action of romidepsin (FK228), an established class I histone deacetylase inhibitor, and domatinostat (4SC-202), a novel inhibitor of class I HDACs, which has been reported to also target the lysine-specific histone demethylase 1A (LSD1). Methods We performed MTS assays and flow cytometric analyses of propidium iodide or annexin V-stained cells to assess drug impact on cellular proliferation, cell cycle distribution, and survival. Histone acetylation and methylation as well as caspase activation was analyzed by immunoblot. Gene expression analysis was performed using NanosString technology. Knockdown and knockout of LSD1 was achieved with shRNA and CRISPR/Cas9, respectively, while the CRISPR/Cas9 synergistic activation mediator system was used to induce expression of endogenous HDACs and LSD1. Furthermore, time-lapse fluorescence microscopy and an in vitro tubulin polymerization assay were applied. Results While FK228 as well as 4SC-202 potently induced cell death in six different CTCL cell lines, only in the case of 4SC-202 death was preceded by an accumulation of cells in the G2/M phase of the cell cycle. Surprisingly, apoptosis and accumulation of cells with double DNA content occurred already at 4SC-202 concentrations hardly affecting histone acetylation and methylation, and provoking significantly less changes in gene expression compared to biologically equivalent doses of FK228. Indeed, we provide evidence that the 4SC-202-induced G2/M arrest in CTCL cells is independent of de novo transcription. Furthermore, neither enforced expression of HDAC1 nor knockdown or knockout of LSD1 affected the 4SC-202-induced effects. Since time-lapse microscopy revealed that 4SC-202 could affect mitotic spindle formation, we performed an in vitro tubulin polymerization assay revealing that 4SC-202 can directly inhibit microtubule formation. Conclusions We demonstrate that 4SC-202, a drug currently tested in clinical trials, effectively inhibits growth of CTCL cells. The anti-cancer cell activity of 4SC-202 is however not limited to LSD1-inhibition, modulation of histone modifications, and consecutive alteration of gene expression. Indeed, the compound is also a potent microtubule-destabilizing agent. KW - Cutaneous lymphoma KW - Epigenetic regulation KW - Histone deacetylase KW - HDAC KW - Lysine-specific methylase KW - LSD1 KW - Tubulin Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200703 VL - 12 ER - TY - JOUR A1 - Wurmb, Thomas A1 - Franke, Axel A1 - Schorscher, Nora A1 - Kowalzik, Barbara A1 - Helm, Matthias A1 - Bohnen, Renate A1 - Helmerichs, Jutta A1 - Grueneisen, Ulrich A1 - Cwojdzinski, Detlef A1 - Jung, Georg A1 - Lücking, Gesa A1 - Weber, Martin T1 - Emergency response to terrorist attacks: results of the federal-conducted evaluation process in Germany JF - European Journal of Trauma and Emergency Surgery N2 - Purpose Rescue missions during terrorist attacks are extremely challenging for all rescue forces (police as well as non-police forces) involved. To improve the quality and safety of the rescue missions during an active killing event, it is obligatory to adapt common rescue mission goals and strategies. Methods After the recent attacks in Europe, the Federal Office of Civil Protection and Disaster Assistance started an evaluation process on behalf of the Federal Ministry of the Interior and the Federal Ministry of Health. This was done to identify weaknesses, lessons learned and to formulate new adapted guidelines. Results The presented bullet point recommendations summarise the basic and most important results of the ongoing evaluation process for the Federal Republic of Germany. The safety of all the rescue forces and survival of the greatest possible number of casualties are the priority goals. Furthermore, the preservation and re-establishment of the socio-political integrity are the overarching goals of the management of active killing events. Strategic incident priorities are to stop the killing and to save as much lives as possible. The early identification and prioritised transportation of casualties with life-threatening non-controllable bleeding are major tasks and the shortest possible on-scene time is an important requirement with respect to safety issues. Conclusion With respect to hazard prevention tactics within Germany, we attributed the highest priority impact to the bullet points. The focus of the process has now shifted to intense work about possible solutions for the identified deficits and implementation strategies of such solutions during mass killing incidents. KW - terror attack KW - mission strategies KW - lessons learned KW - first responders KW - safety Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231777 SN - 1863-9933 VL - 46 ER - TY - JOUR A1 - Glutsch, Valerie A1 - Grän, Franziska A1 - Weber, Judith A1 - Gesierich, Anja A1 - Goebeler, Matthias A1 - Schilling, Bastian T1 - Response to combined ipilimumab and nivolumab after development of a nephrotic syndrome related to PD-1 monotherapy JF - Journal for ImmunoTherapy of Cancer N2 - Background High response rates of metastatic melanoma have been reported upon immune checkpoint inhibition by PD-1 blockade alone or in combination with CTLA-4 inhibitors. However, the majority of patients with a primary resistance to anti-PD-1 monotherapy is also refractory to a subsequent combined checkpoint inhibition. In BRAF wildtype patients with a primary resistance to PD-1 inhibitors, therapeutic options are therefore limited and immune-related adverse events (irAE) have to be taken into consideration when discussing a subsequent immunotherapy. Case presentation We report the case of a 68-year-old male patient with metastatic melanoma who experienced an acute renal failure with nephrotic syndrome due to a minimal change disease developing after a single dose of the anti-PD-1 antibody pembrolizumab. A kidney biopsy revealed a podocytopathy without signs of interstitial nephritis. Renal function recovered to almost normal creatinine and total urine protein levels upon treatment with oral steroids and diuretics. Unfortunately, a disease progression (PD, RECIST 1.1) was observed in a CT scan after resolution of the irAE. In a grand round, re-exposure to a PD-1-containing regime was recommended. Consensually, a combined immunotherapy with ipilimumab and nivolumab was initiated. Nephrotoxicity was tolerable during combined immunotherapy and a CT scan of chest and abdomen showed a deep partial remission (RECIST 1.1) after three doses of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg). Conclusion This case illustrates that a fulminant response to combined checkpoint inhibition is possible after progression after anti-PD-1 monotherapy and a severe irAE. KW - PD-1 KW - Immune-related adverse event KW - Minimal change disease KW - Ipilimumab KW - Nivolumab Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201214 VL - 7 ER - TY - JOUR A1 - Tanoey, Justine A1 - Baechle, Christina A1 - Brenner, Hermann A1 - Deckert, Andreas A1 - Fricke, Julia A1 - Günther, Kathrin A1 - Karch, André A1 - Keil, Thomas A1 - Kluttig, Alexander A1 - Leitzmann, Michael A1 - Mikolajczyk, Rafael A1 - Obi, Nadia A1 - Pischon, Tobias A1 - Schikowski, Tamara A1 - Schipf, Sabine M. A1 - Schulze, Matthias B. A1 - Sedlmeier, Anja A1 - Moreno Velásquez, Ilais A1 - Weber, Katharina S. A1 - Völzke, Henry A1 - Ahrens, Wolfgang A1 - Gastell, Sylvia A1 - Holleczek, Bernd A1 - Jöckel, Karl-Heinz A1 - Katzke, Verena A1 - Lieb, Wolfgang A1 - Michels, Karin B. A1 - Schmidt, Börge A1 - Teismann, Henning A1 - Becher, Heiko T1 - Birth order, Caesarean section, or daycare attendance in relation to child- and adult-onset type 1 diabetes: results from the German National Cohort JF - International Journal of Environmental Research and Public Health N2 - (1) Background: Global incidence of type 1 diabetes (T1D) is rising and nearly half occurred in adults. However, it is unclear if certain early-life childhood T1D risk factors were also associated with adult-onset T1D. This study aimed to assess associations between birth order, delivery mode or daycare attendance and type 1 diabetes (T1D) risk in a population-based cohort and whether these were similar for childhood- and adult-onset T1D (cut-off age 15); (2) Methods: Data were obtained from the German National Cohort (NAKO Gesundheitsstudie) baseline assessment. Self-reported diabetes was classified as T1D if: diagnosis age ≤ 40 years and has been receiving insulin treatment since less than one year after diagnosis. Cox regression was applied for T1D risk analysis; (3) Results: Analyses included 101,411 participants (100 childhood- and 271 adult-onset T1D cases). Compared to “only-children”, HRs for second- or later-born individuals were 0.70 (95% CI = 0.50–0.96) and 0.65 (95% CI = 0.45–0.94), respectively, regardless of parental diabetes, migration background, birth year and perinatal factors. In further analyses, higher birth order reduced T1D risk in children and adults born in recent decades. Caesarean section and daycare attendance showed no clear associations with T1D risk; (4) Conclusions: Birth order should be considered in both children and adults’ T1D risk assessment for early detection. KW - perinatal KW - adult-onset KW - late-onset KW - autoimmune KW - delivery mode KW - sex KW - offspring KW - NAKO Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286216 SN - 1660-4601 VL - 19 IS - 17 ER - TY - JOUR A1 - Gröbner, Susanne N. A1 - Worst, Barbara C. A1 - Weischenfeldt, Joachim A1 - Buchhalter, Ivo A1 - Kleinheinz, Kortine A1 - Rudneva, Vasilisa A. A1 - Johann, Pascal D. A1 - Balasubramanian, Gnana Prakash A1 - Segura-Wang, Maia A1 - Brabetz, Sebastian A1 - Bender, Sebastian A1 - Hutter, Barbara A1 - Sturm, Dominik A1 - Pfaff, Elke A1 - Hübschmann, Daniel A1 - Zipprich, Gideon A1 - Heinold, Michael A1 - Eils, Jürgen A1 - Lawerenz, Christian A1 - Erkek, Serap A1 - Lambo, Sander A1 - Waszak, Sebastian A1 - Blattmann, Claudia A1 - Borkhardt, Arndt A1 - Kuhlen, Michaela A1 - Eggert, Angelika A1 - Fulda, Simone A1 - Gessler, Manfred A1 - Wegert, Jenny A1 - Kappler, Roland A1 - Baumhoer, Daniel A1 - Stefan, Burdach A1 - Kirschner-Schwabe, Renate A1 - Kontny, Udo A1 - Kulozik, Andreas E. A1 - Lohmann, Dietmar A1 - Hettmer, Simone A1 - Eckert, Cornelia A1 - Bielack, Stefan A1 - Nathrath, Michaela A1 - Niemeyer, Charlotte A1 - Richter, Günther H. A1 - Schulte, Johannes A1 - Siebert, Reiner A1 - Westermann, Frank A1 - Molenaar, Jan J. A1 - Vassal, Gilles A1 - Witt, Hendrik A1 - Burkhardt, Birgit A1 - Kratz, Christian P. A1 - Witt, Olaf A1 - van Tilburg, Cornelis M. A1 - Kramm, Christof M. A1 - Fleischhack, Gudrun A1 - Dirksen, Uta A1 - Rutkowski, Stefan A1 - Frühwald, Michael A1 - Hoff, Katja von A1 - Wolf, Stephan A1 - Klingebeil, Thomas A1 - Koscielniak, Ewa A1 - Landgraf, Pablo A1 - Koster, Jan A1 - Resnick, Adam C. A1 - Zhang, Jinghui A1 - Liu, Yanling A1 - Zhou, Xin A1 - Waanders, Angela J. A1 - Zwijnenburg, Danny A. A1 - Raman, Pichai A1 - Brors, Benedikt A1 - Weber, Ursula D. A1 - Northcott, Paul A. A1 - Pajtler, Kristian W. A1 - Kool, Marcel A1 - Piro, Rosario M. A1 - Korbel, Jan O. A1 - Schlesner, Matthias A1 - Eils, Roland A1 - Jones, David T. W. A1 - Lichter, Peter A1 - Chavez, Lukas A1 - Zapatka, Marc A1 - Pfister, Stefan M. T1 - The landscape of genomic alterations across childhood cancers JF - Nature N2 - Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7–8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials. KW - cancer genomics KW - oncogenesis KW - paediatric cancer KW - predictive markers KW - translational research Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229579 VL - 555 ER -