@article{StoelzelMohrKrameretal.2016, author = {St{\"o}lzel, F. and Mohr, B. and Kramer, M. and Oelschl{\"a}gel, U. and Bochtler, T. and Berdel, W. E. and Kaufmann, M. and Baldus, C. D. and Sch{\"a}fer-Eckart, K. and Stuhlmann, R. and Einsele, H. and Krause, S. W. and Serve, H. and H{\"a}nel, M. and Herbst, R. and Neubauer, A. and Sohlbach, K. and Mayer, J. and Middeke, J. M. and Platzbecker, U. and Schaich, M. and Kr{\"a}mer, A. and R{\"o}llig, C. and Schetelig, J. and Bornh{\"a}user, M. and Ehninger, G.}, title = {Karyotype complexity and prognosis in acute myeloid leukemia}, series = {Blood Cancer Journal}, volume = {6}, journal = {Blood Cancer Journal}, doi = {10.1038/bcj.2015.114}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164530}, pages = {e386}, year = {2016}, abstract = {A complex aberrant karyotype consisting of multiple unrelated cytogenetic abnormalities is associated with poor prognosis in patients with acute myeloid leukemia (AML). The European Leukemia Net classification and the UK Medical Research Council recommendation provide prognostic categories that differ in the definition of unbalanced aberrations as well as the number of single aberrations. The aim of this study on 3526 AML patients was to redefine and validate a cutoff for karyotype complexity in AML with regard to adverse prognosis. Our study demonstrated that (1) patients with a pure hyperdiploid karyotype have an adverse risk irrespective of the number of chromosomal gains, (2) patients with translocation t(9;11)(p21∼22;q23) have an intermediate risk independent of the number of additional aberrations, (3) patients with 4 abnormalities have an adverse risk per se and (4) patients with three aberrations in the absence of abnormalities of strong influence (hyperdiploid karyotype, t(9;11)(p21∼22;q23), CBF-AML, unique adverse-risk aberrations) have borderline intermediate/adverse risk with a reduced overall survival compared with patients with a normal karyotype.}, language = {en} } @article{RoelligKramerGabrechtetal.2018, author = {R{\"o}llig, C. and Kramer, M. and Gabrecht, M. and H{\"a}nel, M. and Herbst, R. and Kaiser, U. and Schmitz, N. and Kullmer, J. and Fetscher, S. and Link, H. and Mantovani-L{\"o}ffler, L. and Kr{\"u}mpelmann, U. and Neuhaus, T. and Heits, F. and Einsele, H. and Ritter, B. and Bornh{\"a}user, M. and Schetelig, J. and Thiede, C. and Mohr, B. and Schaich, M. and Platzbecker, U. and Sch{\"a}fer-Eckart, K. and Kr{\"a}mer, A. and Berdel, W. E. and Serve, H. and Ehninger, G. and Schuler, U. S.}, title = {Intermediate-dose cytarabine plus mitoxantrone versus standard-dose cytarabine plus daunorubicin for acute myeloid leukemia in elderly patients}, series = {Annals of Oncology}, volume = {29}, journal = {Annals of Oncology}, number = {4}, doi = {doi:10.1093/annonc/mdy030}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226473}, pages = {973-978}, year = {2018}, abstract = {Background: The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) can induce high complete remission rates with acceptable toxicity in elderly patients with acute myeloid leukemia (AML). We present the final results of a randomized-controlled trial comparing IMA with the standard 7+3 induction regimen consisting of continuous infusion cytarabine plus daunorubicin (DA). Patients and methods: Patients with newly diagnosed AML>60 years were randomized to receive either intermediate-dose cytarabine (1000 mg/m(2) twice daily on days 1, 3, 5, 7) plus mitoxantrone (10 mg/m(2) days 1-3) (IMA) or standard induction therapy with cytarabine (100 mg/m(2) continuously days 1-7) plus daunorubicin (45 mg/m(2) days 3-5) (DA). Patients in complete remission after DA received intermediate-dose cytarabine plus amsacrine as consolidation treatment, whereas patients after IMA were consolidated with standard-dose cytarabine plus mitoxantrone. Results: Between February 2005 and October 2009, 485 patients were randomized; 241 for treatment arm DA and 244 for IMA; 76\% of patients were >65 years. The complete response rate after DA was 39\% [95\% confidence interval (95\% CI): 33-45] versus 55\% (95\% CI: 49-61) after IMA (odds ratio 1.89, P = 0.001). The 6-week early-death rate was 14\% in both arms. Relapse-free survival curves were superimposable in the first year, but separated afterwards, resulting in 3-year relapse-free survival rates of 29\% versus 14\% in the DA versus IMA arms, respectively (P = 0.042). The median overall survival was 10 months in both arms (P = 0.513). Conclusion: The dose escalation of cytarabine in induction therapy lead to improved remission rates in the elderly AML patients. This did not translate into a survival advantage, most likely due to differences in consolidation treatment. Thus, effective consolidation strategies need to be further explored. In combination with an effective consolidation strategy, the use of intermediate-dose cytarabine in induction may improve curative treatment for elderly AML patients.}, language = {en} } @article{vanKoolwijkRamdasIkrametal.2012, author = {van Koolwijk, Leonieke M. E. and Ramdas, Wishal D. and Ikram, M. Kamran and Jansonius, Nomdo M. and Pasutto, Francesca and Hys, Pirro G. and Macgregor, Stuart and Janssen, Sarah F. and Hewitt, Alex W. and Viswanathan, Ananth C. and ten Brink, Jacoline B. and Hosseini, S. Mohsen and Amin, Najaf and Despriet, Dominiek D. G. and Willemse-Assink, Jacqueline J. M. and Kramer, Rogier and Rivadeneira, Fernando and Struchalin, Maksim and Aulchenko, Yurii S. and Weisschuh, Nicole and Zenkel, Matthias and Mardin, Christian Y. and Gramer, Eugen and Welge-L{\"u}ssen, Ulrich and Montgomery, Grant W. and Carbonaro, Francis and Young, Terri L. and Bellenguez, C{\´e}line and McGuffin, Peter and Foster, Paul J. and Topouzis, Fotis and Mitchell, Paul and Wang, Jie Jin and Wong, Tien Y. and Czudowska, Monika A. and Hofman, Albert and Uitterlinden, Andre G. and Wolfs, Roger C. W. and de Jong, Paulus T. V. M. and Oostra, Ben A. and Paterson, Andrew D. and Mackey, David A. and Bergen, Arthur A. B. and Reis, Andre and Hammond, Christopher J. and Vingerling, Johannes R. and Lemij, Hans G. and Klaver, Caroline C. W. and van Duijn, Cornelia M.}, title = {Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma}, series = {PLoS Genetics}, volume = {8}, journal = {PLoS Genetics}, number = {5}, doi = {10.1371/journal.pgen.1002611}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131378}, pages = {e1002611}, year = {2012}, abstract = {Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p = 1.4 x 10\(^{-8}\)), and with rs7555523, located in TMCO1 at 1q24.1 (p = 1.6 x 10\(^{-8}\)). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p = 2.4 x 10\(^{-2}\) for rs11656696 and p = 9.1 x 10\(^{-4}\) for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.}, language = {en} } @article{WidowskiReynaertOpheldersetal.2021, author = {Widowski, Helene and Reynaert, Niki L. and Ophelders, Daan R. M. G. and H{\"u}tten, Matthias C. and Nikkels, Peter G. J. and Severens-Rijvers, Carmen A. H. and Cleutjens, Jack P. M. and Kemp, Matthew W. and Newnham, John P. and Saito, Masatoshi and Usuda, Haruo and Payne, Matthew S. and Jobe, Alan H. and Kramer, Boris W. and Delhaas, Tammo and Wolfs, Tim G. A. M.}, title = {Sequential Exposure to Antenatal Microbial Triggers Attenuates Alveolar Growth and Pulmonary Vascular Development and Impacts Pulmonary Epithelial Stem/Progenitor Cells}, series = {Frontiers in Medicine}, volume = {8}, journal = {Frontiers in Medicine}, issn = {2296-858X}, doi = {10.3389/fmed.2021.614239}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229695}, year = {2021}, abstract = {Perinatal inflammatory stress is strongly associated with adverse pulmonary outcomes after preterm birth. Antenatal infections are an essential perinatal stress factor and contribute to preterm delivery, induction of lung inflammation and injury, pre-disposing preterm infants to bronchopulmonary dysplasia. Considering the polymicrobial nature of antenatal infection, which was reported to result in diverse effects and outcomes in preterm lungs, the aim was to examine the consequences of sequential inflammatory stimuli on endogenous epithelial stem/progenitor cells and vascular maturation, which are crucial drivers of lung development. Therefore, a translational ovine model of antenatal infection/inflammation with consecutive exposures to chronic and acute stimuli was used. Ovine fetuses were exposed intra-amniotically to Ureaplasma parvum 42 days (chronic stimulus) and/or to lipopolysaccharide 2 or 7 days (acute stimulus) prior to preterm delivery at 125 days of gestation. Pulmonary inflammation, endogenous epithelial stem cell populations, vascular modulators and morphology were investigated in preterm lungs. Pre-exposure to UP attenuated neutrophil infiltration in 7d LPS-exposed lungs and prevented reduction of SOX-9 expression and increased SP-B expression, which could indicate protective responses induced by re-exposure. Sequential exposures did not markedly impact stem/progenitors of the proximal airways (P63+ basal cells) compared to single exposure to LPS. In contrast, the alveolar size was increased solely in the UP+7d LPS group. In line, the most pronounced reduction of AEC2 and proliferating cells (Ki67+) was detected in these sequentially UP + 7d LPS-exposed lambs. A similar sensitization effect of UP pre-exposure was reflected by the vessel density and expression of vascular markers VEGFR-2 and Ang-1 that were significantly reduced after UP exposure prior to 2d LPS, when compared to UP and LPS exposure alone. Strikingly, while morphological changes of alveoli and vessels were seen after sequential microbial exposure, improved lung function was observed in UP, 7d LPS, and UP+7d LPS-exposed lambs. In conclusion, although sequential exposures did not markedly further impact epithelial stem/progenitor cell populations, re-exposure to an inflammatory stimulus resulted in disturbed alveolarization and abnormal pulmonary vascular development. Whether these negative effects on lung development can be rescued by the potentially protective responses observed, should be examined at later time points.}, language = {en} } @article{JoosSaadatmandSchnabeletal.2018, author = {Joos, J. P. and Saadatmand, A. R. and Schnabel, C. and Viktorinov{\´a}, I. and Brand, T. and Kramer, M. and Nattel, S. and Dobrev, D. and Tomancak, P. and Backs, J. and Kleinbongard, P. and Heusch, G. and Lorenz, K. and Koch, E. and Weber, S. and El-Armouche, A.}, title = {Ectopic expression of S28A-mutated Histone H3 modulates longevity, stress resistance and cardiac function in Drosophila}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, doi = {10.1038/s41598-018-21372-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323637}, year = {2018}, abstract = {Histone H3 serine 28 (H3S28) phosphorylation and de-repression of polycomb repressive complex (PRC)-mediated gene regulation is linked to stress conditions in mitotic and post-mitotic cells. To better understand the role of H3S28 phosphorylation in vivo, we studied a Drosophila strain with ectopic expression of constitutively-activated H3S28A, which prevents PRC2 binding at H3S28, thus mimicking H3S28 phosphorylation. H3S28A mutants showed prolonged life span and improved resistance against starvation and paraquat-induced oxidative stress. Morphological and functional analysis of heart tubes revealed smaller luminal areas and thicker walls accompanied by moderately improved cardiac function after acute stress induction. Whole-exome deep gene-sequencing from isolated heart tubes revealed phenotype-corresponding changes in longevity-promoting and myotropic genes. We also found changes in genes controlling mitochondrial biogenesis and respiration. Analysis of mitochondrial respiration from whole flies revealed improved efficacy of ATP production with reduced electron transport-chain activity. Finally, we analyzed posttranslational modification of H3S28 in an experimental heart failure model and observed increased H3S28 phosphorylation levels in HF hearts. Our data establish a critical role of H3S28 phosphorylation in vivo for life span, stress resistance, cardiac and mitochondrial function in Drosophila. These findings may pave the way for H3S28 phosphorylation as a putative target to treat stress-related disorders such as heart failure.}, language = {en} } @article{DrubeWeberLoschinskietal.2015, author = {Drube, Sebastian and Weber, Franziska and Loschinski, Romy and Beyer, Mandy and Rothe, Mandy and Rabenhorst, Anja and G{\"o}pfert, Christiane and Meininger, Isabel and Diamanti, Michaela A. and Stegner, David and H{\"a}fner, Norman and B{\"o}ttcher, Martin and Reinecke, Kirstin and Herdegen, Thomas and Greten, Florian R. and Nieswandt, Bernhard and Hartmann, Karin and Kr{\"a}mer, Oliver H. and Kamradt, Thomas}, title = {Subthreshold IKK activation modulates the effector functions of primary mast cells and allows specific targeting of transformed mast cells}, series = {Oncotarget}, volume = {6}, journal = {Oncotarget}, number = {7}, doi = {10.18632/oncotarget.3022}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143681}, pages = {5354-5368}, year = {2015}, abstract = {Mast cell differentiation and proliferation depends on IL-3. IL-3 induces the activation of MAP-kinases and STATs and consequently induces proliferation and survival. Dysregulation of IL-3 signaling pathways also contribute to inflammation and tumorigenesis. We show here that IL-3 induces a SFK- and Ca2\(^{+}\)-dependent activation of the inhibitor of κB kinases 2 (IKK2) which results in mast cell proliferation and survival but does not induce IκBα-degradation and NFκB activation. Therefore we propose the term "subthreshold IKK activation". This subthreshold IKK activation also primes mast cells for enhanced responsiveness to IL-33R signaling. Consequently, co-stimulation with IL-3 and IL-33 increases IKK activation and massively enhances cytokine production induced by IL-33. We further reveal that in neoplastic mast cells expressing constitutively active Ras, subthreshold IKK activation is associated with uncontrolled proliferation. Consequently, pharmacological IKK inhibition reduces tumor growth selectively by inducing apoptosis in vivo. Together, subthreshold IKK activation is crucial to mediate the full IL-33-induced effector functions in primary mast cells and to mediate uncontrolled proliferation of neoplastic mast cells. Thus, IKK2 is a new molecularly defined target structure.}, language = {en} } @article{KochDegerKlotzetal.1986, author = {Koch, R. and Deger, A. and Klotz, Karl-Norbert and Schenzle, D. and Kr{\"a}mer, H. and Kelm, S. and M{\"u}ller, G. and Rapp, R. and Weber, U.}, title = {Characterization of solubilized insulin receptors from rat liver microsomes. Existence of two receptor species with different binding properties}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60215}, year = {1986}, abstract = {Insulin receptors were solubilized from rat liver microsomes by the nonionic detergent Triton X-100. After gel filtration of the extract on Sepharose CL-6B, two insulin-binding species (peak I and peak li) were obtained. The structure and binding properties of both peaks were characterized. Gel filtration yielded Stokes radii of 9.2 nm (peak I) and 8.0 nm (peak Il). Both peaks were glycoproteins. At 4°C peak 1 showed optimal insulin binding at pH 8.0 and high ionic strength. In contrast, peak li bad its binding optimum at pH 7.0 and low ionic strength, where peak I bindingwas minimal. For peak I the change in insulin binding under different conditions of pH and ionic strength was due to a change in receptor affinity only. For peak 11 an additional change in receptor number was found. Both peaks yielded non-linear Scatchard plots under most of the buffer conditions examined. At their binding optima at 4 oc the high affinity dissociation constants were 0.50 nM (peak I) and 0.55 nM (peak II). Sodium dodecyl sulfatejpolyacrylamide gel electrophoresis of peak I revealed five receptor bands with Mr 400000, 365000, 320000, 290000, and 245000 under non-reducing conditions. For peak II two major receptor bands with M\(_r\) 210000 and 115000 were found. The peak II receptor bands were also obtained aftermild reduction of peak I. After complete reduction both peaks showed one major receptor band with M\(_r\) 130000. The reductive generation of the peak II receptor together with molecular mass estimations suggest that the peak I receptor is the disulfide-linked dimer of the peak II receptor. Thus, Triton extracts from rat liver microsomes contain two receptor species, which are related, but differ considerably in their size and insulin-binding properties.}, subject = {Toxikologie}, language = {en} } @article{DoerhoeferLammertKraneetal.2013, author = {D{\"o}rh{\"o}fer, Lena and Lammert, Alexander and Krane, Vera and Gorski, Mathias and Banas, Bernhard and Wanner, Christoph and Kr{\"a}mer, Bernhard K. and Heid, Iris M. and B{\"o}ger, Carsten A.}, title = {Study design of DIACORE (DIAbetes COhoRtE) - a cohort study of patients with diabetes mellitus type 2}, series = {BMC Medical Genetics}, volume = {14}, journal = {BMC Medical Genetics}, number = {25}, issn = {1471-2350}, doi = {10.1186/1471-2350-14-25}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-122040}, year = {2013}, abstract = {Background: Diabetes mellitus type 2 (DM2) is highly associated with increased risk for chronic kidney disease (CKD), end stage renal disease (ESRD) and cardiovascular morbidity. Epidemiological and genetic studies generate hypotheses for innovative strategies in DM2 management by unravelling novel mechanisms of diabetes complications, which is essential for future intervention trials. We have thus initiated the DIAbetes COhoRtE study (DIACORE). Methods: DIACORE is a prospective cohort study aiming to recruit 6000 patients of self-reported Caucasian ethnicity with prevalent DM2 for at least 10 years of follow-up. Study visits are performed in University-based recruiting clinics in Germany using standard operating procedures. All prevalent DM2 patients in outpatient clinics surrounding the recruiting centers are invited to participate. At baseline and at each 2-year follow-up examination, patients are subjected to a core phenotyping protocol. This includes a standardized online questionnaire and physical examination to determine incident micro-and macrovascular DM2 complications, malignancy and hospitalization, with a primary focus on renal events. Confirmatory outcome information is requested from patient records. Blood samples are obtained for a centrally analyzed standard laboratory panel and for biobanking of aliquots of serum, plasma, urine, mRNA and DNA for future scientific use. A subset of the cohort is subjected to extended phenotyping, e. g. sleep apnea screening, skin autofluorescence measurement, non-mydriatic retinal photography and non-invasive determination of arterial stiffness. Discussion: DIACORE will enable the prospective evaluation of factors involved in DM2 complication pathogenesis using high-throughput technologies in biosamples and genetic epidemiological studies.}, language = {en} } @article{UeceylerHomolaGonzalezetal.2014, author = {{\"U}{\c{c}}eyler, Nurcan and Homola, Gy{\"o}rgy A. and Gonz{\´a}lez, Hans Guerrero and Kramer, Daniela and Wanner, Christoph and Weidemann, Frank and Solymosi, L{\´a}szl{\´o} and Sommer, Claudia}, title = {Increased Arterial Diameters in the Posterior Cerebral Circulation in Men with Fabry Disease}, doi = {10.1371/journal.pone.0087054}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112614}, year = {2014}, abstract = {A high load of white matter lesions and enlarged basilar arteries have been shown in selected patients with Fabry disease, a disorder associated with an increased stroke risk. We studied a large cohort of patients with Fabry disease to differentially investigate white matter lesion load and cerebral artery diameters. We retrospectively analyzed cranial magnetic resonance imaging scans of 87 consecutive Fabry patients, 20 patients with ischemic stroke, and 36 controls. We determined the white matter lesion load applying the Fazekas score on fluid-attenuated inversion recovery sequences and measured the diameters of cerebral arteries on 3D-reconstructions of the time-of-flight-MR-angiography scans. Data of different Fabry patient subgroups (males - females; normal - impaired renal function) were compared with data of patients with stroke and controls. A history of stroke or transient ischemic attacks was present in 4/30 males (13\%) and 5/57 (9\%) females with Fabry disease, all in the anterior circulation. Only one man with Fabry disease showed confluent cerebral white matter lesions in the Fazekas score assessment (1\%). Male Fabry patients had a larger basilar artery (p<0.01) and posterior cerebral artery diameter (p<0.05) compared to male controls. This was independent of disease severity as measured by renal function and did not lead to changes in arterial blood flow properties. A basilar artery diameter of >3.2 mm distinguished between men with Fabry disease and controls (sensitivity: 87\%, specificity: 86\%, p<0.001), but not from stroke patients. Enlarged arterial diameters of the posterior circulation are present only in men with Fabry disease independent of disease severity.}, language = {en} } @article{BrixnerAeschlimannFischeretal.2013, author = {Brixner, T. and Aeschlimann, M. and Fischer, A. and Geisler, P. and Goetz, S. and Hecht, B. and Huang, J. S. and Keitzl, T. and Kramer, C. and Melchior, P. and Pfeiffer, W. and Razinskas, G. and Rewitz, C. and Schneider, C. and Str{\"u}ber, C. and Tuchscherer, P. and Voronine, D. V.}, title = {Coherent spectroscopies on ultrashort time and length scales}, series = {EPJ Web of Conferences}, volume = {41}, journal = {EPJ Web of Conferences}, doi = {10.1051/epjconf/20134109017}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129073}, pages = {09017}, year = {2013}, abstract = {Three spectroscopic techniques are presented that provide simultaneous spatial and temporal resolution: modified confocal microscopy with heterodyne detection, space-time-resolved spectroscopy using coherent control concepts, and coherent two-dimensional nano-spectroscopy. Latest experimental results are discussed.}, language = {en} } @article{SilvestriBarrowdaleMulliganetal.2016, author = {Silvestri, Valentina and Barrowdale, Daniel and Mulligan, Anna Marie and Neuhausen, Susan L. and Fox, Stephen and Karlan, Beth Y. and Mitchell, Gillian and James, Paul and Thull, Darcy L. and Zorn, Kristin K. and Carter, Natalie J. and Nathanson, Katherine L. and Domchek, Susan M. and Rebbeck, Timothy R. and Ramus, Susan J. and Nussbaum, Robert L. and Olopade, Olufunmilayo I. and Rantala, Johanna and Yoon, Sook-Yee and Caligo, Maria A. and Spugnesi, Laura and Bojesen, Anders and Pedersen, Inge Sokilde and Thomassen, Mads and Jensen, Uffe Birk and Toland, Amanda Ewart and Senter, Leigha and Andrulis, Irene L. and Glendon, Gord and Hulick, Peter J. and Imyanitov, Evgeny N. and Greene, Mark H. and Mai, Phuong L. and Singer, Christian F. and Rappaport-Fuerhauser, Christine and Kramer, Gero and Vijai, Joseph and Offit, Kenneth and Robson, Mark and Lincoln, Anne and Jacobs, Lauren and Machackova, Eva and Foretova, Lenka and Navratilova, Marie and Vasickova, Petra and Couch, Fergus J. and Hallberg, Emily and Ruddy, Kathryn J. and Sharma, Priyanka and Kim, Sung-Won and Teixeira, Manuel R. and Pinto, Pedro and Montagna, Marco and Matricardi, Laura and Arason, Adalgeir and Johannsson, Oskar Th and Barkardottir, Rosa B. and Jakubowska, Anna and Lubinski, Jan and Izquierdo, Angel and Pujana, Miguel Angel and Balma{\~n}a, Judith and Diez, Orland and Ivady, Gabriella and Papp, Janos and Olah, Edith and Kwong, Ava and Nevanlinna, Heli and Aittom{\"a}ki, Kristiina and Segura, Pedro Perez and Caldes, Trinidad and Van Maerken, Tom and Poppe, Bruce and Claes, Kathleen B. M. and Isaacs, Claudine and Elan, Camille and Lasset, Christine and Stoppa-Lyonnet, Dominique and Barjhoux, Laure and Belotti, Muriel and Meindl, Alfons and Gehrig, Andrea and Sutter, Christian and Engel, Christoph and Niederacher, Dieter and Steinemann, Doris and Hahnen, Eric and Kast, Karin and Arnold, Norbert and Varon-Mateeva, Raymonda and Wand, Dorothea and Godwin, Andrew K. and Evans, D. Gareth and Frost, Debra and Perkins, Jo and Adlard, Julian and Izatt, Louise and Platte, Radka and Eeles, Ros and Ellis, Steve and Hamann, Ute and Garber, Judy and Fostira, Florentia and Fountzilas, George and Pasini, Barbara and Giannini, Giuseppe and Rizzolo, Piera and Russo, Antonio and Cortesi, Laura and Papi, Laura and Varesco, Liliana and Palli, Domenico and Zanna, Ines and Savarese, Antonella and Radice, Paolo and Manoukian, Siranoush and Peissel, Bernard and Barile, Monica and Bonanni, Bernardo and Viel, Alessandra and Pensotti, Valeria and Tommasi, Stefania and Peterlongo, Paolo and Weitzel, Jeffrey N. and Osorio, Ana and Benitez, Javier and McGuffog, Lesley and Healey, Sue and Gerdes, Anne-Marie and Ejlertsen, Bent and Hansen, Thomas V. O. and Steele, Linda and Ding, Yuan Chun and Tung, Nadine and Janavicius, Ramunas and Goldgar, David E. and Buys, Saundra S. and Daly, Mary B. and Bane, Anita and Terry, Mary Beth and John, Esther M. and Southey, Melissa and Easton, Douglas F. and Chenevix-Trench, Georgia and Antoniou, Antonis C. and Ottini, Laura}, title = {Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2}, series = {Breast Cancer Research}, volume = {18}, journal = {Breast Cancer Research}, number = {15}, doi = {10.1186/s13058-016-0671-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164769}, year = {2016}, abstract = {Background BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs). Methods We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database. Results Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10-5) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 \% confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 \% CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10-12). Conclusions On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.}, language = {en} } @article{GabrielJirůHillmannKraftetal.2020, author = {Gabriel, Katharina M. A. and J{\´i}rů-Hillmann, Steffi and Kraft, Peter and Selig, Udo and R{\"u}cker, Victoria and M{\"u}hler, Johannes and D{\"o}tter, Klaus and Keidel, Matthias and Soda, Hassan and Rascher, Alexandra and Schneider, Rolf and Pfau, Mathias and Hoffmann, Roy and Stenzel, Joachim and Benghebrid, Mohamed and Goebel, Tobias and Doerck, Sebastian and Kramer, Daniela and Haeusler, Karl Georg and Volkmann, Jens and Heuschmann, Peter U. and Fluri, Felix}, title = {Two years' experience of implementing a comprehensive telemedical stroke network comprising in mainly rural region: the Transregional Network for Stroke Intervention with Telemedicine (TRANSIT-Stroke)}, series = {BMC Neurology}, volume = {20}, journal = {BMC Neurology}, doi = {10.1186/s12883-020-01676-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229214}, year = {2020}, abstract = {Background Telemedicine improves the quality of acute stroke care in rural regions with limited access to specialized stroke care. We report the first 2 years' experience of implementing a comprehensive telemedical stroke network comprising all levels of stroke care in a defined region. Methods The TRANSIT-Stroke network covers a mainly rural region in north-western Bavaria (Germany). All hospitals providing acute stroke care in this region participate in TRANSIT-Stroke, including four hospitals with a supra-regional certified stroke unit (SU) care (level III), three of those providing teleconsultation to two hospitals with a regional certified SU (level II) and five hospitals without specialized SU care (level I). For a two-year-period (01/2015 to 12/2016), data of eight of these hospitals were available; 13 evidence-based quality indicators (QIs) related to processes during hospitalisation were evaluated quarterly and compared according to predefined target values between level-I- and level-II/III-hospitals. Results Overall, 7881 patients were included (mean age 74.6 years +/- 12.8; 48.4\% female). In level-II/III-hospitals adherence of all QIs to predefined targets was high ab initio. In level-I-hospitals, three patterns of QI-development were observed: a) high adherence ab initio (31\%), mainly in secondary stroke prevention; b) improvement over time (44\%), predominantly related to stroke specific diagnosis and in-hospital organization; c) no clear time trends (25\%). Overall, 10 out of 13 QIs reached predefined target values of quality of care at the end of the observation period. Conclusion The implementation of the comprehensive TRANSIT-Stroke network resulted in an improvement of quality of care in level-I-hospitals.}, language = {en} } @article{CarstenAGorskiLietal.2011, author = {Carsten A., B{\"o}ger and Gorski, Mathias and Li, Man and Hoffmann, Michael M. and Huang, Chunmei and Yang, Qiong and Teumer, Alexander and Krane, Vera and O'Seaghdha, Conall M. and Kutalik, Zolt{\´a}n and Wichmann, H.-Erich and Haak, Thomas and Boes, Eva and Coassin, Stefan and Coresh, Josef and Kollerits, Barbara and Haun, Margot and Paulweber, Bernhard and K{\"o}ttgen, Anna and Li, Guo and Shlipak, Michael G. and Powe, Neil and Hwang, Shih-Jen and Dehghan, Abbas and Rivadeneira, Fernando and Uitterlinden, Andr{\´e} and Hofman, Albert and Beckmann, Jacques S. and Kr{\"a}mer, Bernhard K. and Witteman, Jacqueline and Bochud, Murielle and Siscovick, David and Rettig, Rainer and Kronenberg, Florian and Wanner, Christoph and Thadhani, Ravi I. and Heid, Iris M. and Fox, Caroline S. and Kao, W.H.}, title = {Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD}, series = {PLoS Genetics}, volume = {7}, journal = {PLoS Genetics}, number = {9}, doi = {10.1371/journal.pgen.1002292}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133758}, pages = {e1002292}, year = {2011}, abstract = {Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR < 60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.}, language = {en} }