TY - JOUR A1 - Bodden, Carina A1 - Richter, S. Helene A1 - Schreiber, Rebecca S. A1 - Kloke, Vanessa A1 - Gerß, Joachim A1 - Palme, Rupert A1 - Lesch, Klaus-Peter A1 - Lewejohann, Lars A1 - Kaiser, Sylvia A1 - Sachser, Norbert T1 - Benefits of adversity?! How life history affects the behavioral profile of mice varying in serotonin transporter genotype JF - Frontiers in Behavioral Neuroscience N2 - Behavioral profiles are influenced by both positive and negative experiences as well as the genetic disposition. Traditionally, accumulating adversity over lifetime is considered to predict increased anxiety like behavior ("allostatic load"). The alternative "mismatch hypothesis" suggests increased levels of anxiety if the early environment differs from the later-life environment. Thus, there is a need for a whole-life history approach to gain a deeper understanding of how behavioral profiles are shaped. The aim of this study was to elucidate the effects of life history on the behavioral profile of mice varying in serotonin transporter (5-HIT) genotype, an established mouse model of increased anxiety-like behavior. For this purpose, mice grew up under either adverse or beneficial conditions during early phases of life. In adulthood, they were further subdivided so as to face a situation that either matched or mismatched the condition experienced so far, resulting in four different life histories. Subsequently, mice were tested for their anxiety-like and exploratory behavior. The main results were: (1) Life history profoundly modulated the behavioral profile. Surprisingly, mice that experienced early beneficial and later escapable adverse conditions showed less anxiety-like and more exploratory behavior compared to mice of other life histories. (2) Genotype significantly influenced the behavioral profile, with homozygous 5-HTT knockout mice displaying highest levels of anxiety-like and lowest levels of exploratory behavior. Our findings concerning life history indicate that the absence of adversity does not necessarily cause lower levels of anxiety than accumulating adversity. Rather, some adversity may be beneficial, particularly when following positive events. Altogether, we conclude that for an understanding of behavioral profiles, it is not sufficient to look at experiences during single phases of life, but the whole life history has to be considered. KW - anxiety-like behavior KW - maternal care KW - dangerous world KW - animal behavior KW - match-mismatch KW - chronic social stress KW - elevated plus-maze KW - 5-HTT KW - life history KW - predictive adaptive response hypothesis KW - developmental plasticity KW - knockout mice KW - environmental enrichment KW - allostatic load Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143723 VL - 9 IS - 47 ER - TY - JOUR A1 - Bartelheim, Kerstin A1 - Nemes, Karolina A1 - Seeringer, Angela A1 - Kerl, Kornelius A1 - Buechner, Jochen A1 - Boos, Joachim A1 - Graf, Norbert A1 - Dürken, Matthias A1 - Gerss, Joachim A1 - Hasselblatt, Martin A1 - Kortmann, Rolf-Dieter A1 - Teichert von Luettichau, Irene A1 - Nagel, Inga A1 - Nygaard, Randi A1 - Oyen, Florian A1 - Quiroga, Eduardo A1 - Schlegel, Paul-Gerhardt A1 - Schmid, Irene A1 - Schneppenheim, Reinhard A1 - Siebert, Reiner A1 - Solano-Paez, Palma A1 - Timmermann, Beate A1 - Warmuth-Metz, Monika A1 - Frühwald, Michael Christoph T1 - Improved 6-year overall survival in AT/RT - results of the registry study Rhabdoid 2007 JF - Cancer Medicine N2 - Atypical teratoid rhabdoid tumors (AT/RT) are characterized by mutations and subsequent inactivation of SMARCB1 (INI1, hSNF5), a predilection for very young children and an unfavorable outcome. The European Registry for rhabdoid tumors (EU‐RHAB) was established to generate a common European database and to establish a standardized treatment regimen as the basis for phase I/II trials. Thus, genetic analyses, neuropathologic and radiologic diagnoses, and a consensus treatment regimen were prospectively evaluated. From 2005 to 2009, 31 patients with AT/RT from four countries were recruited into the registry study Rhabdoid 2007 and treated with systemic and intraventricular chemotherapy. Eight patients received high‐dose chemotherapy, 23 radiotherapy, and 17 maintenance therapy. Reference evaluations were performed in 64% (genetic analyses, FISH, MLPA, sequencing) up to 97% (neuropathology, INI1 stain). Germ‐line mutations (GLM) were detected in 6/21 patients. Prolonged overall survival was associated with age above 3 years, radiotherapy and achievement of a complete remission. 6‐year overall and event‐free survival rates were 46% (±0.10) and 45% (±0.09), respectively. Serious adverse events and one treatment‐related death due to insufficiency of a ventriculo peritoneal shunt (VP‐shunt) and consecutive herniation were noted. Acquisition of standardized data including reference diagnosis and a standard treatment schedule improved data quality along with a survival benefit. Treatment was feasible with significant but manageable toxicity. Although our analysis is biased due to heterogeneous adherence to therapy, EU‐RHAB provides the best available basis for phase I/II clinical trials. KW - AT/RT KW - EU‐RHAB Registry KW - pediatric brain tumor KW - Rhabdoid 2007 Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164799 VL - 5 IS - 8 ER - TY - JOUR A1 - Reinecke, Holger A1 - Jürgensmeyer, Sabine A1 - Engelbertz, Christiane A1 - Gerss, Joachim A1 - Kirchhof, Paulus A1 - Breithardt, Günter A1 - Bauersachs, Rupert A1 - Wanner, Christoph T1 - Design and rationale of a randomised controlled trial comparing apixaban to phenprocoumon in patients with atrial fibrillation on chronic haemodialysis: the AXADIA-AFNET 8 study JF - BMJ open N2 - Introduction Patients with end-stage kidney disease requiring maintenance haemodialysis treatment experience a dramatic cardiovascular morbidity and mortality. Due to the high atherosclerotic and arteriosclerotic burden and profound alterations in haemostasis, they frequently suffer and die from both thromboembolic and bleeding events. This is a particular concern in patients on haemodialysis with atrial fibrillation (AF). Controlled trials on the optimal anticoagulation in patients with AF on haemodialysis are not available. The randomised controlled phase IIIb AXADIA-AFNET 8 trial will evaluate the safety and efficacy of the factor Xa inhibitor apixaban in patients with AF requiring haemodialysis. Methods and analysis A total of 222 patients will be randomised in an open-labelled, 1:1 design to receive either apixaban 2.5mg twice daily or dose-adjusted vitamin K antagonist therapy (target international normalised ratio 2.0-3.0). All patients will be treated and followed up for a minimum of 6 months up to a maximum of 24 months. The primary outcome is major or clinically relevant, non-major bleedings or death of any cause. Secondary outcomes include stroke, cardiovascular death and other thromboembolic events, thus exploring the efficacy of apixaban. The first patient was randomised in June 2017. Ethics and dissemination The study protocol was approved by the Ethical Committee of the Landesaertzekammer, Westfalen-Lippe and the Medical Faculty of the University of Muenster, Muenster, Germany (reference number: 2016-598f-A). Written informed consent will be obtained from all patients prior to study participation, including their consent for long-term follow-up. AXADIA-AFNET 8 is an investigator-initiated trial. Sponsor is AFNET, Muenster, Germany. Study findings will be disseminated to Bristol-Myers Squibb, Munich, Germany, and Pfizer, Berlin, Germany, to the participating centres, at research conferences and in peer-reviewed journals. Trial registration numbers NCT02933697, Pre-results. KW - arial fibrillation KW - hemodialysis KW - cardiovascular morbidity KW - cardiovascular mortality KW - anticoagulation Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225156 VL - 8 IS - 9 ER - TY - JOUR A1 - Nemes, Karolina A1 - Johann, Pascal D. A1 - Steinbügl, Mona A1 - Gruhle, Miriam A1 - Bens, Susanne A1 - Kachanov, Denis A1 - Teleshova, Margarita A1 - Hauser, Peter A1 - Simon, Thorsten A1 - Tippelt, Stephan A1 - Eberl, Wolfgang A1 - Chada, Martin A1 - Lopez, Vicente Santa-Maria A1 - Grigull, Lorenz A1 - Hernáiz-Driever, Pablo A1 - Eyrich, Matthias A1 - Pears, Jane A1 - Milde, Till A1 - Reinhard, Harald A1 - Leipold, Alfred A1 - van de Wetering, Marianne A1 - Gil-da-Costa, Maria João A1 - Ebetsberger-Dachs, Georg A1 - Kerl, Kornelius A1 - Lemmer, Andreas A1 - Boztug, Heidrun A1 - Furtwängler, Rhoikos A1 - Kordes, Uwe A1 - Vokuhl, Christian A1 - Hasselblatt, Martin A1 - Bison, Brigitte A1 - Kröncke, Thomas A1 - Melchior, Patrick A1 - Timmermann, Beate A1 - Gerss, Joachim A1 - Siebert, Reiner A1 - Frühwald, Michael C. T1 - Infants and newborns with atypical teratoid rhabdoid tumors (ATRT) and extracranial malignant rhabdoid tumors (eMRT) in the EU-RHAB registry: a unique and challenging population JF - Cancers N2 - Introduction: Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005–2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option. KW - atypical teratoid rhabdoid tumors KW - extracranial malignant rhabdoid tumor KW - RTPS1 KW - RTPS2 KW - germline mutation KW - EU-RHAB registry Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270730 SN - 2072-6694 VL - 14 IS - 9 ER -