@article{MitchellLiWeinholdetal.2016, author = {Mitchell, Jonathan S. and Li, Ni and Weinhold, Niels and F{\"o}rsti, Asta and Ali, Mina and van Duin, Mark and Thorleifsson, Gudmar and Johnson, David C. and Chen, Bowang and Halvarsson, Britt-Marie and Gudbjartsson, Daniel F. and Kuiper, Rowan and Stephens, Owen W. and Bertsch, Uta and Broderick, Peter and Campo, Chiara and Einsele, Hermann and Gregory, Walter A. and Gullberg, Urban and Henrion, Marc and Hillengass, Jens and Hoffmann, Per and Jackson, Graham H. and Johnsson, Ellinor and J{\"o}ud, Magnus and Kristinsson, Sigurdur Y. and Lenhoff, Stig and Lenive, Oleg and Mellqvist, Ulf-Henrik and Migliorini, Gabriele and Nahi, Hareth and Nelander, Sven and Nickel, Jolanta and N{\"o}then, Markus M. and Rafnar, Thorunn and Ross, Fiona M. and da Silva Filho, Miguel Inacio and Swaminathan, Bhairavi and Thomsen, Hauke and Turesson, Ingemar and Vangsted, Annette and Vogel, Ulla and Waage, Anders and Walker, Brian A. and Wihlborg, Anna-Karin and Broyl, Annemiek and Davies, Faith E. and Thorsteinsdottir, Unnur and Langer, Christian and Hansson, Markus and Kaiser, Martin and Sonneveld, Pieter and Stefansson, Kari and Morgan, Gareth J. and Goldschmidt, Hartmut and Hemminki, Kari and Nilsson, Bj{\"o}rn and Houlston, Richard S.}, title = {Genome-wide association study identifies multiple susceptibility loci for multiple myeloma}, series = {Nature Communications}, volume = {7}, journal = {Nature Communications}, doi = {10.1038/ncomms12050}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165983}, pages = {12050}, year = {2016}, abstract = {Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10-8), 6q21 (rs9372120, P=9.09 × 10-15), 7q36.1 (rs7781265, P=9.71 × 10-9), 8q24.21 (rs1948915, P=4.20 × 10-11), 9p21.3 (rs2811710, P=1.72 × 10-13), 10p12.1 (rs2790457, P=1.77 × 10-8), 16q23.1 (rs7193541, P=5.00 × 10-12) and 20q13.13 (rs6066835, P=1.36 × 10-13), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.}, language = {en} } @article{FreyPoppPostetal.2014, author = {Frey, Anna and Popp, Sandy and Post, Antonia and Langer, Simon and Lehmann, Marc and Hofmann, Ulrich and Siren, Anna-Leena and Hommers, Leif and Schmitt, Angelika and Strekalova, Tatyana and Ertl, Georg and Lesch, Klaus-Peter and Frantz, Stefan}, title = {Experimental heart failure causes depression-like behavior together with differential regulation of inflammatory and structural genes in the brain}, series = {Frontiers in Behavioral Neuroscience}, volume = {8}, journal = {Frontiers in Behavioral Neuroscience}, issn = {1662-5153}, doi = {10.3389/fnbeh.2014.00376}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118234}, pages = {376}, year = {2014}, abstract = {Background: Depression and anxiety are common and independent outcome predictors in patients with chronic heart failure (CHF). However, it is unclear whether CHF causes depression. Thus, we investigated whether mice develop anxiety- and depression-like behavior after induction of ischemic CHF by myocardial infarction (MI). Methods and Results: In order to assess depression-like behavior, anhedonia was investigated by repeatedly testing sucrose preference for 8 weeks after coronary artery ligation or sham operation. Mice with large MI and increased left ventricular dimensions on echocardiography (termed CHF mice) showed reduced preference for sucrose, indicating depression-like behavior. 6 weeks after MI, mice were tested for exploratory activity, anxiety-like behavior and cognitive function using the elevated plus maze (EPM), light-dark box (LDB), open field (OF), and object recognition (OR) tests. In the EPM and OF, CHF mice exhibited diminished exploratory behavior and motivation despite similar movement capability. In the OR, CHF mice had reduced preference for novelty and impaired short-term memory. On histology, CHF mice had unaltered overall cerebral morphology. However, analysis of gene expression by RNA-sequencing in prefrontal cortical, hippocampal, and left ventricular tissue revealed changes in genes related to inflammation and cofactors of neuronal signal transduction in CHF mice, with Nr4a1 being dysregulated both in prefrontal cortex and myocardium after MI. Conclusions: After induction of ischemic CHF, mice exhibited anhedonic behavior, decreased exploratory activity and interest in novelty, and cognitive impairment. Thus, ischemic CHF leads to distinct behavioral changes in mice analogous to symptoms observed in humans with CHF and comorbid depression.}, language = {en} } @article{BachmannSchrederEngelhardtetal.2021, author = {Bachmann, Friederike and Schreder, Martin and Engelhardt, Monika and Langer, Christian and Wolleschak, Denise and M{\"u}gge, Lars Olof and D{\"u}rk, Heinz and Sch{\"a}fer-Eckart, Kerstin and Blau, Igor Wolfgang and Gramatzki, Martin and Liebisch, Peter and Grube, Matthias and Metzler, Ivana v. and Bassermann, Florian and Metzner, Bernd and R{\"o}llig, Christoph and Hertenstein, Bernd and Khandanpour, Cyrus and Dechow, Tobias and Hebart, Holger and Jung, Wolfram and Theurich, Sebastian and Maschmeyer, Georg and Salwender, Hans and Hess, Georg and Bittrich, Max and Rasche, Leo and Brioli, Annamaria and Eckardt, Kai-Uwe and Straka, Christian and Held, Swantje and Einsele, Hermann and Knop, Stefan}, title = {Kinetics of renal function during induction in newly diagnosed multiple myeloma: results of two prospective studies by the German Myeloma Study Group DSMM}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {6}, issn = {2072-6694}, doi = {10.3390/cancers13061322}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234139}, year = {2021}, abstract = {Background: Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) helps to prevent excess toxicity. Patients (pts) from two prospective trials were analyzed, provided postinduction (PInd) restaging was performed. Pts received three cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex; VCD) or btz, lenalidomide (len), and dex (VRd) or len, adriamycin, and dex (RAD). The minimum required estimated glomerular filtration rate (eGFR) was >30 mL/min. We analyzed the percent change of the renal function using the International Myeloma Working Group (IMWG) criteria and Kidney Disease: Improving Global Outcomes (KDIGO)-defined categories. Results: Seven hundred and seventy-two patients were eligible. Three hundred and fifty-six received VCD, 214 VRd, and 202 RAD. VCD patients had the best baseline eGFR. The proportion of pts with eGFR <45 mL/min decreased from 7.3\% at baseline to 1.9\% PInd (p < 0.0001). Thirty-seven point one percent of VCD versus 49\% of VRd patients had a decrease of GFR (p = 0.0872). IMWG-defined "renal complete response (CRrenal)" was achieved in 17/25 (68\%) pts after VCD, 12/19 (63\%) after RAD, and 14/27 (52\%) after VRd (p = 0.4747). Conclusions: Analyzing a large and representative newly diagnosed myeloma (NDMM) group, we found no difference in CRrenal that occurred independently from the myeloma response across the three regimens. A trend towards deterioration of the renal function with VRd versus VCD may be explained by a better pretreatment "renal fitness" in the latter group.}, language = {en} } @article{JohanssenHahnerSaegeretal.2010, author = {Johanssen, Sarah and Hahner, Stefanie and Saeger, Wolfgang and Quinkler, Marcus and Beuschlein, Felix and Dralle, Henning and Haaf, Michaela and Kroiss, Matthias and Jurowich, Christian and Langer, Peter and Oelkers, Wolfgang and Spahn, Martin and Willenberg, Holger S. and Maeder, Uwe and Allolio, Bruno and Fassnacht, Martin}, title = {Deficits in the Management of Patients With Adrenocortical Carcinoma in Germany}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-85897}, year = {2010}, abstract = {Background: Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. Often, the physicians who first treat patients with ACC have no prior experience with the disease. The aim of our study was to evaluate the quality of medical care for patients with ACC in Germany. Methods: Data from the German ACC registry were analyzed with regard to the patients' preoperative diagnostic evaluation, histopathological reporting, and clinical followup. The findings were compared with the recommendations of the European Network for the Study of Adrenal Tumors (ENSAT). Results: Data were analyzed from 387 patients who had been given an initial diagnosis of ACC in the years 1998 to 2009. 21\% of them underwent no hormonal evaluation before surgery, and 59\% underwent an inadequate hormonal evaluation. This exposed the patients to unnecessary perioperative risks and impaired their follow-up. 48\% did not undergo CT scanning of the chest, even though the lungs are the most frequent site of metastases of ACC. For 13\% of the patients, the diagnosis of ACC was later revised by a reference pathologist. For 11\% of the patients, the histopathology report contained no information about resection status, even though this is an important determinant of further treatment and prognosis. Optimal management requires re-staging at three-month intervals, yet some patients underwent re-staging only after a longer delay, or not at all. Conclusion: We have identified significant deficits in the care of patients with ACC in Germany. We suspect that the situation is similar for other rare diseases. The prerequisite to better care is close and early cooperation of the treating physicians with specialized centers.}, language = {en} } @article{TrudzinskiMinkoRappetal.2016, author = {Trudzinski, Franziska C. and Minko, Peter and Rapp, Daniel and F{\"a}hndrich, Sebastian and Haake, Hendrik and Haab, Myriam and Bohle, Rainer M. and Flaig, Monika and Kaestner, Franziska and Bals, Robert and Wilkens, Heinrike and Muellenbach, Ralf M. and Link, Andreas and Groesdonk, Heinrich V. and Lensch, Christian and Langer, Frank and Lepper, Philipp M.}, title = {Runtime and aPTT predict venous thrombosis and thromboembolism in patients on extracorporeal membrane oxygenation: a retrospective analysis}, series = {Annals of Intensive Care}, volume = {6}, journal = {Annals of Intensive Care}, doi = {10.1186/s13613-016-0172-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164455}, pages = {66}, year = {2016}, abstract = {Background Even though bleeding and thromboembolic events are major complications of extracorporeal membrane oxygenation (ECMO), data on the incidence of venous thrombosis (VT) and thromboembolism (VTE) under ECMO are scarce. This study analyzes the incidence and predictors of VTE in patients treated with ECMO due to respiratory failure. Methods Retrospective analysis of patients treated on ECMO in our center from 04/2010 to 11/2015. Patients with thromboembolic events prior to admission were excluded. Diagnosis was made by imaging in survivors and postmortem examination in deceased patients. Results Out of 102 screened cases, 42 survivors and 21 autopsy cases [mean age 46.0 ± 14.4 years; 37 (58.7 \%) males] fulfilling the above-mentioned criteria were included. Thirty-four patients (54.0 \%) underwent ECMO therapy due to ARDS, and 29 patients (46.0 \%) with chronic organ failure were bridged to lung transplantation. Despite systemic anticoagulation at a mean PTT of 50.6 ± 12.8 s, [VT/VTE 47.0 ± 12.3 s and no VT/VTE 53.63 ± 12.51 s (p = 0.037)], VT and/or VTE was observed in 29 cases (46.1 \%). The rate of V. cava thrombosis was 15/29 (51.7 \%). Diagnosis of pulmonary embolism prevailed in deceased patients [5/21 (23.8 \%) vs. 2/42 (4.8 \%) (p = 0.036)]. In a multivariable analysis, only aPTT and time on ECMO predicted VT/VTE. There was no difference in the incidence of clinically diagnosed VT in ECMO survivors and autopsy findings. Conclusions Venous thrombosis and thromboembolism following ECMO therapy are frequent. Quality of anticoagulation and ECMO runtime predicted thromboembolic events. "}, language = {en} } @article{GoebelPankratzAsaridouetal.2016, author = {G{\"o}bel, Kerstin and Pankratz, Susann and Asaridou, Chloi-Magdalini and Herrmann, Alexander M. and Bittner, Stefan and Merker, Monika and Ruck, Tobias and Glumm, Sarah and Langhauser, Friederike and Kraft, Peter and Krug, Thorsten F. and Breuer, Johanna and Herold, Martin and Gross, Catharina C. and Beckmann, Denise and Korb-Pap, Adelheid and Schuhmann, Michael K. and Kuerten, Stefanie and Mitroulis, Ioannis and Ruppert, Clemens and Nolte, Marc W. and Panousis, Con and Klotz, Luisa and Kehrel, Beate and Korn, Thomas and Langer, Harald F. and Pap, Thomas and Nieswandt, Bernhard and Wiendl, Heinz and Chavakis, Triantafyllos and Kleinschnitz, Christoph and Meuth, Sven G.}, title = {Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells}, series = {Nature Communications}, volume = {7}, journal = {Nature Communications}, number = {11626}, doi = {10.1038/ncomms11626}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165503}, year = {2016}, abstract = {Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein-kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders.}, language = {en} } @article{PoppSchmittBoehrerLangeretal.2021, author = {Popp, Sandy and Schmitt-B{\"o}hrer, Angelika and Langer, Simon and Hofmann, Ulrich and Hommers, Leif and Schuh, Kai and Frantz, Stefan and Lesch, Klaus-Peter and Frey, Anna}, title = {5-HTT Deficiency in Male Mice Affects Healing and Behavior after Myocardial Infarction}, series = {Journal of Clinical Medicine}, volume = {10}, journal = {Journal of Clinical Medicine}, number = {14}, issn = {2077-0383}, doi = {10.3390/jcm10143104}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242739}, year = {2021}, abstract = {Anxiety disorders and depression are common comorbidities in cardiac patients. Mice lacking the serotonin transporter (5-HTT) exhibit increased anxiety-like behavior. However, the role of 5-HTT deficiency on cardiac aging, and on healing and remodeling processes after myocardial infarction (MI), remains unclear. Cardiological evaluation of experimentally na{\"i}ve male mice revealed a mild cardiac dysfunction in ≥4-month-old 5-HTT knockout (-/-) animals. Following induction of chronic cardiac dysfunction (CCD) by MI vs. sham operation 5-HTT-/- mice with infarct sizes >30\% experienced 100\% mortality, while 50\% of 5-HTT+/- and 37\% of 5-HTT+/+ animals with large MI survived the 8-week observation period. Surviving (sham and MI < 30\%) 5-HTT-/- mutants displayed reduced exploratory activity and increased anxiety-like behavior in different approach-avoidance tasks. However, CCD failed to provoke a depressive-like behavioral response in either 5-Htt genotype. Mechanistic analyses were performed on mice 3 days post-MI. Electrocardiography, histology and FACS of inflammatory cells revealed no abnormalities. However, gene expression of inflammation-related cytokines (TGF-β, TNF-α, IL-6) and MMP-2, a protein involved in the breakdown of extracellular matrix, was significantly increased in 5-HTT-/- mice after MI. This study shows that 5-HTT deficiency leads to age-dependent cardiac dysfunction and disrupted early healing after MI probably due to alterations of inflammatory processes in mice.}, language = {en} }