@article{ChopraBiehlSteinfattetal.2016, author = {Chopra, Martin and Biehl, Marlene and Steinfatt, Tim and Brandl, Andreas and Kums, Juliane and Amich, Jorge and Vaeth, Martin and Kuen, Janina and Holtappels, Rafaela and Podlech, J{\"u}rgen and Mottok, Anja and Kraus, Sabrina and Jord{\´a}n-Garotte, Ana-Laura and B{\"a}uerlein, Carina A. and Brede, Christian and Ribechini, Eliana and Fick, Andrea and Seher, Axel and Polz, Johannes and Ottmueller, Katja J. and Baker, Jeannette and Nishikii, Hidekazu and Ritz, Miriam and Mattenheimer, Katharina and Schwinn, Stefanie and Winter, Thorsten and Sch{\"a}fer, Viktoria and Krappmann, Sven and Einsele, Hermann and M{\"u}ller, Thomas D. and Reddehase, Matthias J. and Lutz, Manfred B. and M{\"a}nnel, Daniela N. and Berberich-Siebelt, Friederike and Wajant, Harald and Beilhack, Andreas}, title = {Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion}, series = {Journal of Experimental Medicine}, volume = {213}, journal = {Journal of Experimental Medicine}, number = {9}, doi = {10.1084/jem.20151563}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-187640}, pages = {1881-1900}, year = {2016}, abstract = {Donor CD4\(^+\)Foxp3\(^+\) regulatory T cells (T reg cells) suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HCT allo-HCT]). Current clinical study protocols rely on the ex vivo expansion of donor T reg cells and their infusion in high numbers. In this study, we present a novel strategy for inhibiting GvHD that is based on the in vivo expansion of recipient T reg cells before allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in T reg cell biology. Expanding radiation-resistant host T reg cells in recipient mice using a mouse TNFR2-selective agonist before allo-HCT significantly prolonged survival and reduced GvHD severity in a TNFR2-and T reg cell-dependent manner. The beneficial effects of transplanted T cells against leukemia cells and infectious pathogens remained unaffected. A corresponding human TNFR2-specific agonist expanded human T reg cells in vitro. These observations indicate the potential of our strategy to protect allo-HCT patients from acute GvHD by expanding T reg cells via selective TNFR2 activation in vivo.}, language = {en} } @article{DechHolzwarthAsametal.2021, author = {Dech, Stefan and Holzwarth, Stefanie and Asam, Sarah and Andresen, Thorsten and Bachmann, Martin and Boettcher, Martin and Dietz, Andreas and Eisfelder, Christina and Frey, Corinne and Gesell, Gerhard and Gessner, Ursula and Hirner, Andreas and Hofmann, Matthias and Kirches, Grit and Klein, Doris and Klein, Igor and Kraus, Tanja and Krause, Detmar and Plank, Simon and Popp, Thomas and Reinermann, Sophie and Reiners, Philipp and Roessler, Sebastian and Ruppert, Thomas and Scherbachenko, Alexander and Vignesh, Ranjitha and Wolfmueller, Meinhard and Zwenzner, Hendrik and Kuenzer, Claudia}, title = {Potential and challenges of harmonizing 40 years of AVHRR data: the TIMELINE experience}, series = {Remote Sensing}, volume = {13}, journal = {Remote Sensing}, number = {18}, issn = {2072-4292}, doi = {10.3390/rs13183618}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246134}, year = {2021}, abstract = {Earth Observation satellite data allows for the monitoring of the surface of our planet at predefined intervals covering large areas. However, there is only one medium resolution sensor family in orbit that enables an observation time span of 40 and more years at a daily repeat interval. This is the AVHRR sensor family. If we want to investigate the long-term impacts of climate change on our environment, we can only do so based on data that remains available for several decades. If we then want to investigate processes with respect to climate change, we need very high temporal resolution enabling the generation of long-term time series and the derivation of related statistical parameters such as mean, variability, anomalies, and trends. The challenges to generating a well calibrated and harmonized 40-year-long time series based on AVHRR sensor data flown on 14 different platforms are enormous. However, only extremely thorough pre-processing and harmonization ensures that trends found in the data are real trends and not sensor-related (or other) artefacts. The generation of European-wide time series as a basis for the derivation of a multitude of parameters is therefore an extremely challenging task, the details of which are presented in this paper.}, language = {en} } @article{SbieraDexneitReichardtetal.2011, author = {Sbiera, Silviu and Dexneit, Thomas and Reichardt, Sybille D. and Michel, Kai D. and van den Brandt, Jens and Schmull, Sebastian and Kraus, Luitgard and Beyer, Melanie and Mlynski, Robert and Wortmann, Sebastian and Allolio, Bruno and Reichardt, Holger M. and Fassnacht, Martin}, title = {Influence of Short-Term Glucocorticoid Therapy on Regulatory T Cells \(In\) \(Vivo\)}, series = {PLoS One}, volume = {6}, journal = {PLoS One}, number = {9}, doi = {10.1371/journal.pone.0024345}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140822}, pages = {e24345}, year = {2011}, abstract = {Background: Pre- and early clinical studies on patients with autoimmune diseases suggested that induction of regulatory T(T(reg)) cells may contribute to the immunosuppressive effects of glucocorticoids(GCs). Objective: We readdressed the influence of GC therapy on T(reg) cells in immunocompetent human subjects and naive mice. Methods: Mice were treated with increasing doses of intravenous dexamethasone followed by oral taper, and T(reg) cells in spleen and blood were analyzed by FACS. Sixteen patients with sudden hearing loss but without an inflammatory disease received high-dose intravenous prednisolone followed by stepwise dose reduction to low oral prednisolone. Peripheral blood T(reg) cells were analyzed prior and after a 14 day GC therapy based on different markers. Results: Repeated GC administration to mice for three days dose-dependently decreased the absolute numbers of T(reg) cells in blood (100 mg dexamethasone/kg body weight: 2.8 +/- 1.8 x 10(4) cells/ml vs. 33 +/- 11 x 10(4) in control mice) and spleen (dexamethasone: 2.8 +/- 1.9 x 10(5)/spleen vs. 95 +/- 22 x 10(5)/spleen in control mice), which slowly recovered after 14 days taper in spleen but not in blood. The relative frequency of FOXP3(+) T(reg) cells amongst the CD4(+) T cells also decreased in a dose dependent manner with the effect being more pronounced in blood than in spleen. The suppressive capacity of T(reg) cells was unaltered by GC treatment in vitro. In immunocompetent humans, GCs induced mild T cell lymphocytosis. However, it did not change the relative frequency of circulating T(reg) cells in a relevant manner, although there was some variation depending on the definition of the T(reg) cells (FOXP3(+): 4.0 +/- 1.5\% vs 3.4 +/- 1.5\%*; AITR(+): 0.660.4 vs 0.5 +/- 0.3\%, CD127(low): 4.0 +/- 1.3 vs 5.0 +/- 3.0\%* and CTLA4+: 13.8 +/- 11.5 vs 15.6 +/- 12.5\%; * p < 0.05). Conclusion: Short-term GC therapy does not induce the hitherto supposed increase in circulating T(reg) cell frequency, neither in immunocompetent humans nor in mice. Thus, it is questionable that the clinical efficacy of GCs is achieved by modulating T(reg) cell numbers.}, language = {en} } @article{FassnachtSbieraDexneitetal.2011, author = {Fassnacht, Martin and Sbiera, Silviu and Dexneit, Thomas and Reichardt, Sybille D. and Michel, Kai D. and van den Brandt, Jens and Schmull, Sebastian and Kraus, Luitgard and Beyer, Melanie and Mlynski, Robert and Wortmann, Sebastian and Allolio, Bruno and Reichardt, Holger M.}, title = {Influence of Short-Term Glucocorticoid Therapy on Regulatory T Cells In Vivo}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-74749}, year = {2011}, abstract = {Background: Pre- and early clinical studies on patients with autoimmune diseases suggested that induction of regulatory T(Treg) cells may contribute to the immunosuppressive effects of glucocorticoids(GCs). Objective: We readdressed the influence of GC therapy on Treg cells in immunocompetent human subjects and na{\i}¨ve mice. Methods: Mice were treated with increasing doses of intravenous dexamethasone followed by oral taper, and Treg cells in spleen and blood were analyzed by FACS. Sixteen patients with sudden hearing loss but without an inflammatory disease received high-dose intravenous prednisolone followed by stepwise dose reduction to low oral prednisolone. Peripheral blood Treg cells were analyzed prior and after a 14 day GC therapy based on different markers. Results: Repeated GC administration to mice for three days dose-dependently decreased the absolute numbers of Treg cells in blood (100 mg dexamethasone/kg body weight: 2.861.86104 cells/ml vs. 336116104 in control mice) and spleen (dexamethasone: 2.861.96105/spleen vs. 956226105/spleen in control mice), which slowly recovered after 14 days taper in spleen but not in blood. The relative frequency of FOXP3+ Treg cells amongst the CD4+ T cells also decreased in a dose dependent manner with the effect being more pronounced in blood than in spleen. The suppressive capacity of Treg cells was unaltered by GC treatment in vitro. In immunocompetent humans, GCs induced mild T cell lymphocytosis. However, it did not change the relative frequency of circulating Treg cells in a relevant manner, although there was some variation depending on the definition of the Treg cells (FOXP3+: 4.061.5\% vs 3.461.5\%*; AITR+: 0.660.4 vs 0.560.3\%, CD127low: 4.061.3 vs 5.063.0\%* and CTLA4+: 13.8611.5 vs 15.6612.5\%; * p,0.05). Conclusion: Short-term GC therapy does not induce the hitherto supposed increase in circulating Treg cell frequency, neither in immunocompetent humans nor in mice. Thus, it is questionable that the clinical efficacy of GCs is achieved by modulating Treg cell numbers.}, subject = {Medizin}, language = {en} } @article{WurmbVollmerSefrinetal.2015, author = {Wurmb, Thomas and Vollmer, Tina and Sefrin, Peter and Kraus, Martin and Happel, Oliver and Wunder, Christian and Steinisch, Andrias and Roewer, Norbert and Maier, Sebastian}, title = {Monitoring of in-hospital cardiac arrest events with the focus on Automated External Defibrillators - a retrospective observational study}, series = {Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine}, volume = {23}, journal = {Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine}, number = {87}, doi = {10.1186/s13049-015-0170-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125756}, year = {2015}, abstract = {Background Patients with cardiac arrest have lower survival rates, when resuscitation performance is low. In In-hospital settings the first responders on scene are usually nursing staff without rhythm analysing skills. In such cases Automated External Defibrillators (AED) might help guiding resuscitation performance. At the Wuerzburg University Hospital (Germany) an AED-program was initiated in 2007. Aim of the presented study was to monitor the impact of Automated External Defibrillators on the management of in-hospital cardiac arrest events. Methods The data acquisition was part of a continuous quality improvement process of the Wuerzburg University Hospital. For analysing the CPR performance, the chest compression rate (CCR), compression depth (CCD), the no flow fraction (NFF), time interval from AED-activation to the first compression (TtC), the time interval from AED-activation to the first shock (TtS) and the post schock pause (TtCS) were determined by AED captured data. A questionnaire was completed by the first responders. Results From 2010 to 2012 there were 359 emergency calls. From these 53 were cardiac arrests with an AED-application. Complete data were available in 46 cases. The TtC was 34 (32-52) seconds (median and IQR).The TtS was 30 (28-32) seconds (median and IQR) . The TtCS was 4 (3-6) seconds (median and IQR) . The CCD was 5.5 ± 1 cm while the CCR was 107 ± 11/min. The NFF was calculated as 41 \%. ROSC was achieved in 21 patients (45 \%), 8 patients (17 \%) died on scene and 17 patients (37 \%) were transferred under ongoing CPR to an Intensive Care Unit (ICU). Conclusion The TtS and TtC indicate that there is an AED-user dependent time loss. These time intervals can be markedly reduced, when the user is trained to interrupt the AED's "chain of advices" by placing the electrode-paddles immediately on the patient's thorax. At this time the AED switches directly to the analysing mode. Intensive training and adaption of the training contents is needed to optimize the handling of the AED in order to maximize its advantages and to minimize its disadvantages.}, language = {en} } @article{BeilhackChopraKrausetal.2013, author = {Beilhack, Andreas and Chopra, Martin and Kraus, Sabrina and Schwinn, Stefanie and Ritz, Miriam and Mattenheimer, Katharina and Mottok, Anja and Rosenwald, Andreas and Einsele, Hermann}, title = {Non-Invasive Bioluminescence Imaging to Monitor the Immunological Control of a Plasmablastic Lymphoma-Like B Cell Neoplasia after Hematopoietic Cell Transplantation}, doi = {10.1371/journal.pone.0081320}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111341}, year = {2013}, abstract = {To promote cancer research and to develop innovative therapies, refined pre-clinical mouse tumor models that mimic the actual disease in humans are of dire need. A number of neoplasms along the B cell lineage are commonly initiated by a translocation recombining c-myc with the immunoglobulin heavy-chain gene locus. The translocation is modeled in the C.129S1-Ighatm1(Myc)Janz/J mouse which has been previously engineered to express c-myc under the control of the endogenous IgH promoter. This transgenic mouse exhibits B cell hyperplasia and develops diverse B cell tumors. We have isolated tumor cells from the spleen of a C.129S1-Ighatm1(Myc)Janz/J mouse that spontaneously developed a plasmablastic lymphoma-like disease. These cells were cultured, transduced to express eGFP and firefly luciferase, and gave rise to a highly aggressive, transplantable B cell lymphoma cell line, termed IM380. This model bears several advantages over other models as it is genetically induced and mimics the translocation that is detectable in a number of human B cell lymphomas. The growth of the tumor cells, their dissemination, and response to treatment within immunocompetent hosts can be imaged non-invasively in vivo due to their expression of firefly luciferase. IM380 cells are radioresistant in vivo and mice with established tumors can be allogeneically transplanted to analyze graft-versus-tumor effects of transplanted T cells. Allogeneic hematopoietic stem cell transplantation of tumor-bearing mice results in prolonged survival. These traits make the IM380 model very valuable for the study of B cell lymphoma pathophysiology and for the development of innovative cancer therapies.}, language = {en} } @article{ChopraLangSalzmannetal.2013, author = {Chopra, Martin and Lang, Isabell and Salzmann, Steffen and Pachel, Christina and Kraus, Sabrina and B{\"a}uerlein, Carina A. and Brede, Christian and Jord{\´a}n Garrote, Ana-Laura and Mattenheimer, Katharina and Ritz, Miriam and Schwinn, Stefanie and Graf, Carolin and Sch{\"a}fer, Viktoria and Frantz, Stefan and Einsele, Hermann and Wajant, Harald and Beilhack, Andreas}, title = {Tumor Necrosis Factor Induces Tumor Promoting and Anti-Tumoral Effects on Pancreatic Cancer via TNFR1}, series = {PLoS ONE}, journal = {PLoS ONE}, doi = {10.1371/journal.pone.0075737}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97246}, year = {2013}, abstract = {Multiple activities are ascribed to the cytokine tumor necrosis factor (TNF) in health and disease. In particular, TNF was shown to affect carcinogenesis in multiple ways. This cytokine acts via the activation of two cell surface receptors, TNFR1, which is associated with inflammation, and TNFR2, which was shown to cause anti-inflammatory signaling. We assessed the effects of TNF and its two receptors on the progression of pancreatic cancer by in vivo bioluminescence imaging in a syngeneic orthotopic tumor mouse model with Panc02 cells. Mice deficient for TNFR1 were unable to spontaneously reject Panc02 tumors and furthermore displayed enhanced tumor progression. In contrast, a fraction of wild type (37.5\%), TNF deficient (12.5\%), and TNFR2 deficient mice (22.2\%) were able to fully reject the tumor within two weeks. Pancreatic tumors in TNFR1 deficient mice displayed increased vascular density, enhanced infiltration of CD4+ T cells and CD4+ forkhead box P3 (FoxP3)+ regulatory T cells (Treg) but reduced numbers of CD8+ T cells. These alterations were further accompanied by transcriptional upregulation of IL4. Thus, TNF and TNFR1 are required in pancreatic ductal carcinoma to ensure optimal CD8+ T cell-mediated immunosurveillance and tumor rejection. Exogenous systemic administration of human TNF, however, which only interacts with murine TNFR1, accelerated tumor progression. This suggests that TNFR1 has basically the capability in the Panc02 model to trigger pro-and anti-tumoral effects but the spatiotemporal availability of TNF seems to determine finally the overall outcome.}, language = {en} } @phdthesis{Kraus2010, author = {Kraus, Martin}, title = {Oszillationen der QT-Zeit nach ventrikul{\"a}ren Extrasystolen zur nichtinvasiven Risikostratifizierung von Patienten nach Myokardinfarkt}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45236}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2010}, abstract = {Imbalancen im Bereich der autonomen Innervation des Herzens auf Sinusknotenebene zeigen sich anhand des Fehlens der „heart rate variability" und der „heart rate turbulence" und werden bereits zur Risikoeinsch{\"a}tzung von KHK-Patienten herangezogen, w{\"a}hrend Untersuchungen zur autonomen Dysbalance auf Ventrikelebene bisher kaum durchgef{\"u}hrt wurden. Daher war das Ziel dieser Arbeit eine Risikostratifizierung von Patienten nach einem Myokardinfarkt anhand dynamischer Ver{\"a}nderungen der QT-Zeit, zu denen es nach einer ventrikul{\"a}ren Extrasystole kommt. In der Einleitung wird die Wichtigkeit der Beachtung allgemeiner kardiovaskul{\"a}rer Risikofaktoren erl{\"a}utert. Es wird auf die Komplexit{\"a}t der QT-Zeit, deren beeinflussende Faktoren sowie auf den Einfluss des autonomen Nervensystems auf die Repolarisation der Herzkammern eingegangen. Im Abschnitt „Material und Methode" und in „Auswertungen und Berechnungen" wird das Patientenkollektiv vorgestellt, außerdem werden die Programme beschrieben, die zum Erzeugen der Daten verwendet wurden. Als Ergebnis l{\"a}sst sich festhalten, dass Schlag-zu-Schlag-Analysen der QT-Zeit nach ventrikul{\"a}ren Extrasystolen signifikante Unterschiede aufzeigen zwischen den Patienten, die einen Follow-up von zwei Jahren nach einem Myokardinfarkt {\"u}berlebt haben und denen, die w{\"a}hrend dieses Beobachtungszeitraumes aufgrund kardiovaskul{\"a}rer Komplikationen verstarben. Der Aufwand, der hierf{\"u}r betrieben werden muss, ist jedoch so hoch, dass diese Analysen wohl nicht zur routinem{\"a}ßigen Anwendung kommen werden.}, subject = {QT-Zeit}, language = {de} } @article{HussHalbgebauerOeckletal.2016, author = {Huss, Andr{\´e} M. and Halbgebauer, Steffen and {\"O}ckl, Patrick and Trebst, Corinna and Spreer, Annette and Borisow, Nadja and Harrer, Andrea and Brecht, Isabel and Balint, Bettina and Stich, Oliver and Schlegel, Sabine and Retzlaff, Nele and Winkelmann, Alexander and Roesler, Romy and Lauda, Florian and Yildiz, {\"O}zlem and Voß, Elke and Muche, Rainer and Rauer, Sebastian and Bergh, Florian Then and Otto, Markus and Paul, Friedemann and Wildemann, Brigitte and Kraus, J{\"o}rg and Ruprecht, Klemens and Stangel, Martin and Buttmann, Mathias and Zettl, Uwe K. and Tumani, Hayrettin}, title = {Importance of cerebrospinal fluid analysis in the era of McDonald 2010 criteria: a German-Austrian retrospective multicenter study in patients with a clinically isolated syndrome}, series = {Journal of Neurology}, volume = {263}, journal = {Journal of Neurology}, number = {12}, doi = {10.1007/s00415-016-8302-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-186619}, pages = {2499-2504}, year = {2016}, abstract = {The majority of patients presenting with a first clinical symptom suggestive of multiple sclerosis (MS) do not fulfill the MRI criteria for dissemination in space and time according to the 2010 revision of the McDonald diagnostic criteria for MS and are thus classified as clinically isolated syndrome (CIS). To re-evaluate the utility of cerebrospinal fluid (CSF) analysis in the context of the revised McDonald criteria from 2010, we conducted a retrospective multicenter study aimed at determining the prevalence and predictive value of oligoclonal IgG bands (OCBs) in patients with CIS. Patients were recruited from ten specialized MS centers in Germany and Austria. We collected data from 406 patients; at disease onset, 44/406 (11 \%) fulfilled the McDonald 2010 criteria for MS. Intrathecal IgG OCBs were detected in 310/362 (86 \%) of CIS patients. Those patients were twice as likely to convert to MS according to McDonald 2010 criteria as OCB-negative individuals (hazard ratio = 2.1, p = 0.0014) and in a shorter time period of 25 months (95 \% CI 21-34) compared to 47 months in OCB-negative individuals (95 \% CI 36-85). In patients without brain lesions at first attack and presence of intrathecal OCBs (30/44), conversion rate to MS was 60 \% (18/30), whereas it was only 21 \% (3/14) in those without OCBs. Our data confirm that in patients with CIS the risk of conversion to MS substantially increases if OCBs are present at onset. CSF analysis definitely helps to evaluate the prognosis in patients who do not have MS according to the revised McDonald criteria.}, language = {en} } @article{GaritanoTrojaolaSanchoGoetzetal.2021, author = {Garitano-Trojaola, Andoni and Sancho, Ana and G{\"o}tz, Ralph and Eiring, Patrick and Walz, Susanne and Jetani, Hardikkumar and Gil-Pulido, Jesus and Da Via, Matteo Claudio and Teufel, Eva and Rhodes, Nadine and Haertle, Larissa and Arellano-Viera, Estibaliz and Tibes, Raoul and Rosenwald, Andreas and Rasche, Leo and Hudecek, Michael and Sauer, Markus and Groll, J{\"u}rgen and Einsele, Hermann and Kraus, Sabrina and Kort{\"u}m, Martin K.}, title = {Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia}, series = {Communications Biology}, volume = {4}, journal = {Communications Biology}, number = {1}, doi = {10.1038/s42003-021-02215-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260709}, year = {2021}, abstract = {The presence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with an unfavorable prognosis. FLT3 inhibitors, such as midostaurin, are used clinically but fail to entirely eradicate FLT3-ITD+AML. This study introduces a new perspective and highlights the impact of RAC1-dependent actin cytoskeleton remodeling on resistance to midostaurin in AML. RAC1 hyperactivation leads resistance via hyperphosphorylation of the positive regulator of actin polymerization N-WASP and antiapoptotic BCL-2. RAC1/N-WASP, through ARP2/3 complex activation, increases the number of actin filaments, cell stiffness and adhesion forces to mesenchymal stromal cells (MSCs) being identified as a biomarker of resistance. Midostaurin resistance can be overcome by a combination of midostaruin, the BCL-2 inhibitor venetoclax and the RAC1 inhibitor Eht1864 in midostaurin-resistant AML cell lines and primary samples, providing the first evidence of a potential new treatment approach to eradicate FLT3-ITD+AML. Garitano-Trojaola et al. used a combination of human acute myeloid leukemia (AML) cell lines and primary samples to show that RAC1-dependent actin cytoskeleton remodeling through BCL2 family plays a key role in resistance to the FLT3 inhibitor, Midostaurin in AML. They showed that by targeting RAC1 and BCL2, Midostaurin resistance was diminished, which potentially paves the way for an innovate treatment approach for FLT3 mutant AML.}, language = {en} } @article{HeidrichCordesKlinkeretal.2015, author = {Heidrich, Benjamin and Cordes, Hans-J{\"o}rg and Klinker, Hartwig and M{\"o}ller, Bernd and Naumann, Uwe and R{\"o}ssle, Martin and Kraus, Michael R. and B{\"o}ker, Klaus H. and Roggel, Christoph and Schuchmann, Marcus and Stoehr, Albrecht and Trein, Andreas and Hardtke, Svenja and Gonnermann, Andrea and Koch, Armin and Wedemeyer, Heiner and Manns, Michael P. and Cornberg, Markus}, title = {Treatment Extension of Pegylated Interferon Alpha and Ribavirin Does Not Improve SVR in Patients with Genotypes 2/3 without Rapid Virological Response (OPTEX Trial): A Prospective, Randomized, Two-Arm, Multicentre Phase IV Clinical Trial}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0128069}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151811}, pages = {e0128069}, year = {2015}, abstract = {Although sofosbuvir has been approved for patients with genotypes 2/3 (G2/3), many parts of the world still consider pegylated Interferon alpha (P) and ribavirin (R) as standard of care for G2/3. Patients with rapid virological response (RVR) show response rates >80\%. However, SVR (sustained virological response) in non-RVR patients is not satisfactory. Longer treatment duration may be required but evidence from prospective trials are lacking. A total of 1006 chronic HCV genotype 2/3 patients treated with P/R were recruited into a German HepNet multicenter screening registry. Of those, only 226 patients were still HCV RNA positive at week 4 (non-RVR). Non-RVR patients with ongoing response after 24 weeks P-2b/R qualified for OPTEX, a randomized trial investigating treatment extension of additional 24 weeks (total 48 weeks, Group A) or additional 12 weeks (total 36 weeks, group B) of 1.5 \(\mu\)g/kg P-2b and 800-1400 mg R. Due to the low number of patients without RVR, the number of 150 anticipated study patients was not met and only 99 non-RVR patients (n=50 Group A, n=49 Group B) could be enrolled into the OPTEX trial. Baseline factors did not differ between groups. Sixteen patients had G2 and 83 patients G3. Based on the ITT (intention-to-treat) analysis, 68\% [55\%; 81\%] in Group A and 57\% [43\%; 71\%] in Group B achieved SVR (p=0.31). The primary endpoint of better SVR rates in Group A compared to a historical control group (SVR 70\%) was not met. In conclusion, approximately 23\% of G2/3 patients did not achieve RVR in a real world setting. However, subsequent recruitment in a treatment-extension study was difficult. Prolonged therapy beyond 24 weeks did not result in higher SVR compared to a historical control group.}, language = {en} } @article{HauerPoppTaheretal.2019, author = {Hauer, Nadine N. and Popp, Bernt and Taher, Leila and Vogl, Carina and Dhandapany, Perundurai S. and B{\"u}ttner, Christian and Uebe, Steffen and Sticht, Heinrich and Ferrazzi, Fulvia and Ekici, Arif B. and De Luca, Alessandro and Klinger, Patrizia and Kraus, Cornelia and Zweier, Christiane and Wiesener, Antje and Abou Jamra, Rami and Kunstmann, Erdmute and Rauch, Anita and Wieczorek, Dagmar and Jung, Anna-Marie and Rohrer, Tilman R. and Zenker, Martin and Doerr, Helmuth-Guenther and Reis, Andr{\´e} and Thiel, Christian T.}, title = {Evolutionary conserved networks of human height identify multiple Mendelian causes of short stature}, series = {European Journal of Human Genetics}, volume = {27}, journal = {European Journal of Human Genetics}, doi = {10.1038/s41431-019-0362-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227899}, pages = {1061-1071}, year = {2019}, abstract = {Height is a heritable and highly heterogeneous trait. Short stature affects 3\% of the population and in most cases is genetic in origin. After excluding known causes, 67\% of affected individuals remain without diagnosis. To identify novel candidate genes for short stature, we performed exome sequencing in 254 unrelated families with short stature of unknown cause and identified variants in 63 candidate genes in 92 (36\%) independent families. Based on systematic characterization of variants and functional analysis including expression in chondrocytes, we classified 13 genes as strong candidates. Whereas variants in at least two families were detected for all 13 candidates, two genes had variants in 6 (UBR4) and 8 (LAMA5) families, respectively. To facilitate their characterization, we established a clustered network of 1025 known growth and short stature genes, which yielded 29 significantly enriched clusters, including skeletal system development, appendage development, metabolic processes, and ciliopathy. Eleven of the candidate genes mapped to 21 of these clusters, including CPZ, EDEM3, FBRS, IFT81, KCND1, PLXNA3, RASA3, SLC7A8, UBR4, USP45, and ZFHX3. Fifty additional growth-related candidates we identified await confirmation in other affected families. Our study identifies Mendelian forms of growth retardation as an important component of idiopathic short stature.}, language = {en} }