TY - JOUR A1 - Dumont, Martine A1 - Weber-Lassalle, Nana A1 - Joly-Beauparlant, Charles A1 - Ernst, Corinna A1 - Droit, Arnaud A1 - Feng, Bing-Jian A1 - Dubois, Stéphane A1 - Collin-Deschesnes, Annie-Claude A1 - Soucy, Penny A1 - Vallée, Maxime A1 - Fournier, Frédéric A1 - Lemaçon, Audrey A1 - Adank, Muriel A. A1 - Allen, Jamie A1 - Altmüller, Janine A1 - Arnold, Norbert A1 - Ausems, Margreet G. E. M. A1 - Berutti, Riccardo A1 - Bolla, Manjeet K. A1 - Bull, Shelley A1 - Carvalho, Sara A1 - Cornelissen, Sten A1 - Dufault, Michael R. A1 - Dunning, Alison M. A1 - Engel, Christoph A1 - Gehrig, Andrea A1 - Geurts-Giele, Willemina R. R. A1 - Gieger, Christian A1 - Green, Jessica A1 - Hackmann, Karl A1 - Helmy, Mohamed A1 - Hentschel, Julia A1 - Hogervorst, Frans B. L. A1 - Hollestelle, Antoinette A1 - Hooning, Maartje J. A1 - Horváth, Judit A1 - Ikram, M. Arfan A1 - Kaulfuß, Silke A1 - Keeman, Renske A1 - Kuang, Da A1 - Luccarini, Craig A1 - Maier, Wolfgang A1 - Martens, John W. M. A1 - Niederacher, Dieter A1 - Nürnberg, Peter A1 - Ott, Claus-Eric A1 - Peters, Annette A1 - Pharoah, Paul D. P. A1 - Ramirez, Alfredo A1 - Ramser, Juliane A1 - Riedel-Heller, Steffi A1 - Schmidt, Gunnar A1 - Shah, Mitul A1 - Scherer, Martin A1 - Stäbler, Antje A1 - Strom, Tim M. A1 - Sutter, Christian A1 - Thiele, Holger A1 - van Asperen, Christi J. A1 - van der Kolk, Lizet A1 - van der Luijt, Rob B. A1 - Volk, Alexander E. A1 - Wagner, Michael A1 - Waisfisz, Quinten A1 - Wang, Qin A1 - Wang-Gohrke, Shan A1 - Weber, Bernhard H. F. A1 - Devilee, Peter A1 - Tavtigian, Sean A1 - Bader, Gary D. A1 - Meindl, Alfons A1 - Goldgar, David E. A1 - Andrulis, Irene L. A1 - Schmutzler, Rita K. A1 - Easton, Douglas F. A1 - Schmidt, Marjanka K. A1 - Hahnen, Eric A1 - Simard, Jacques T1 - Uncovering the contribution of moderate-penetrance susceptibility genes to breast cancer by whole-exome sequencing and targeted enrichment sequencing of candidate genes in women of European ancestry JF - Cancers N2 - Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes. KW - breast cancer KW - genetic susceptibility KW - whole-exome sequencing KW - moderate-penetrance genes Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-281768 SN - 2072-6694 VL - 14 IS - 14 ER - TY - JOUR A1 - Weber-Lassalle, Nana A1 - Hauke, Jan A1 - Ramser, Juliane A1 - Richters, Lisa A1 - Groß, Eva A1 - Blümcke, Britta A1 - Gehrig, Andrea A1 - Kahlert, Anne-Karin A1 - Müller, Clemens R. A1 - Hackmann, Karl A1 - Honisch, Ellen A1 - Weber-Lassalle, Konstantin A1 - Niederacher, Dieter A1 - Borde, Julika A1 - Thiele, Holger A1 - Ernst, Corinna A1 - Altmüller, Janine A1 - Neidhardt, Guido A1 - Nürnberg, Peter A1 - Klaschik, Kristina A1 - Schroeder, Christopher A1 - Platzer, Konrad A1 - Volk, Alexander E. A1 - Wang-Gohrke, Shan A1 - Just, Walter A1 - Auber, Bernd A1 - Kubisch, Christian A1 - Schmidt, Gunnar A1 - Horvath, Judit A1 - Wappenschmidt, Barbara A1 - Engel, Christoph A1 - Arnold, Norbert A1 - Dworniczak, Bernd A1 - Rhiem, Kerstin A1 - Meindl, Alfons A1 - Schmutzler, Rita K. A1 - Hahnen, Eric T1 - BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer JF - Breast Cancer Research N2 - Background Germline mutations in the BRIP1 gene have been described as conferring a moderate risk for ovarian cancer (OC), while the role of BRIP1 in breast cancer (BC) pathogenesis remains controversial. Methods To assess the role of deleterious BRIP1 germline mutations in BC/OC predisposition, 6341 well-characterized index patients with BC, 706 index patients with OC, and 2189 geographically matched female controls were screened for loss-of-function (LoF) mutations and potentially damaging missense variants. All index patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germline testing and tested negative for pathogenic BRCA1/2 variants. Results BRIP1 LoF mutations confer a high OC risk in familial index patients (odds ratio (OR) = 20.97, 95% confidence interval (CI) = 12.02–36.57, P < 0.0001) and in the subgroup of index patients with late-onset OC (OR = 29.91, 95% CI = 14.99–59.66, P < 0.0001). No significant association of BRIP1 LoF mutations with familial BC was observed (OR = 1.81 95% CI = 1.00–3.30, P = 0.0623). In the subgroup of familial BC index patients without a family history of OC there was also no apparent association (OR = 1.42, 95% CI = 0.70–2.90, P = 0.3030). In 1027 familial BC index patients with a family history of OC, the BRIP1 mutation prevalence was significantly higher than that observed in controls (OR = 3.59, 95% CI = 1.43–9.01; P = 0.0168). Based on the negative association between BRIP1 LoF mutations and familial BC in the absence of an OC family history, we conclude that the elevated mutation prevalence in the latter cohort was driven by the occurrence of OC in these families. Compared with controls, predicted damaging rare missense variants were significantly more prevalent in OC (P = 0.0014) but not in BC (P = 0.0693) patients. Conclusions To avoid ambiguous results, studies aimed at assessing the impact of candidate predisposition gene mutations on BC risk might differentiate between BC index patients with an OC family history and those without. In familial cases, we suggest that BRIP1 is a high-risk gene for late-onset OC but not a BC predisposition gene, though minor effects cannot be excluded. KW - breast cancer KW - ovarian cancer KW - BRIP1 gene KW - germline mutations Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233433 VL - 20 ER - 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 - JOUR A1 - Couch, Fergus J. A1 - Wang, Xianshu A1 - McGuffog, Lesley A1 - Lee, Andrew A1 - Olswold, Curtis A1 - Kuchenbaecker, Karoline B. A1 - Soucy, Penny A1 - Fredericksen, Zachary A1 - Barrowdale, Daniel A1 - Dennis, Joe A1 - Gaudet, Mia M. A1 - Dicks, Ed A1 - Kosel, Matthew A1 - Healey, Sue A1 - Sinilnikova, Olga M. A1 - Lee, Adam A1 - Bacot, Françios A1 - Vincent, Daniel A1 - Hogervorst, Frans B. L. A1 - Peock, Susan A1 - Stoppa-Lyonnet, Dominique A1 - Jakubowska, Anna A1 - Radice, Paolo A1 - Schmutzler, Rita Katharina A1 - Domchek, Susan M. A1 - Piedmonte, Marion A1 - Singer, Christian F. A1 - Friedman, Eitan A1 - Thomassen, Mads A1 - Hansen, Thomas V. O. A1 - Neuhausen, Susan L. A1 - Szabo, Csilla I. A1 - Blanco, Ingnacio A1 - Greene, Mark H. A1 - Karlan, Beth Y. A1 - Garber, Judy A1 - Phelan, Catherine M. A1 - Weitzel, Jeffrey N. A1 - Montagna, Marco A1 - Olah, Edith A1 - Andrulis, Irene L. A1 - Godwin, Andrew K. A1 - Yannoukakos, Drakoulis A1 - Goldgar, David E. A1 - Caldes, Trinidad A1 - Nevanlinna, Heli A1 - Osorio, Ana A1 - Terry, Mary Beth A1 - Daly, Mary B. A1 - van Rensburg, Elisabeth J. A1 - Hamann, Ute A1 - Ramus, Susan J. A1 - Toland, Amanda Ewart A1 - Caligo, Maria A. A1 - Olopade, Olufunmilayo I. A1 - Tung, Nadine A1 - Claes, Kathleen A1 - Beattie, Mary S. A1 - Southey, Melissa C. A1 - Imyanitov, Evgeny N. A1 - Tischkowitz, Marc A1 - Janavicius, Ramunas A1 - John, Esther M. A1 - Kwong, Ava A1 - Diez, Orland A1 - Kwong, Ava A1 - Balmaña, Judith A1 - Barkardottir, Rosa B. A1 - Arun, Banu K. A1 - Rennert, Gad A1 - Teo, Soo-Hwang A1 - Ganz, Patricia A. A1 - Campbell, Ian A1 - van der Hout, Annemarie H. A1 - van Deurzen, Carolien H. M. A1 - Seynaeve, Caroline A1 - Garcia, Encarna B. Gómez A1 - van Leeuwen, Flora E. A1 - Meijers-Heijboer, Hanne E. J. A1 - Gille, Johannes J. P. A1 - Ausems, Magreet G. E. M. A1 - Blok, Marinus J. A1 - Ligtenberg, Marjolinjin J. L. A1 - Rookus, Matti A. A1 - Devilee, Peter A1 - Verhoef, Senno A1 - van Os, Theo A. M. A1 - Wijnen, Juul T. A1 - Frost, Debra A1 - Ellis, Steve A1 - Fineberg, Elena A1 - Platte, Radke A1 - Evans, D. Gareth A1 - Izatt, Luise A1 - Eeles, Rosalind A. A1 - Adlard, Julian A1 - Eccles, Diana M. A1 - Cook, Jackie A1 - Brewer, Carole A1 - Douglas, Fiona A1 - Hodgson, Shirley A1 - Morrison, Patrick J. A1 - Side, Lucy E. A1 - Donaldson, Alan A1 - Houghton, Catherine A1 - Rogers, Mark T. A1 - Dorkins, Huw A1 - Eason, Jacqueline A1 - Gregory, Helen A1 - McCann, Emma A1 - Murray, Alex A1 - Calender, Alain A1 - Hardouin, Agnès A1 - Berthet, Pascaline A1 - Delnatte, Capucine A1 - Nogues, Catherine A1 - Lasset, Christine A1 - Houdayer, Claude A1 - Leroux,, Dominique A1 - Rouleau, Etienne A1 - Prieur, Fabienne A1 - Damiola, Francesca A1 - Sobol, Hagay A1 - Coupier, Isabelle A1 - Venat-Bouvet, Laurence A1 - Castera, Laurent A1 - Gauthier-Villars, Marion A1 - Léoné, Mélanie A1 - Pujol, Pascal A1 - Mazoyer, Sylvie A1 - Bignon, Yves-Jean A1 - Zlowocka-Perlowska, Elzbieta A1 - Gronwald, Jacek A1 - Lubinski,, Jan A1 - Durda, Katarzyna A1 - Jaworska, Katarzyna A1 - Huzarski, Tomasz A1 - Spurdle, Amanda B. A1 - Viel, Alessandra A1 - Peissel, Bernhard A1 - Bonanni, Bernardo A1 - Melloni, Guilia A1 - Ottini, Laura A1 - Papi, Laura A1 - Varesco, Liliana A1 - Tibiletti, Maria Grazia A1 - Peterlongo, Paolo A1 - Volorio, Sara A1 - Manoukian, Siranoush A1 - Pensotti, Valeria A1 - Arnold, Norbert A1 - Engel, Christoph A1 - Deissler, Helmut A1 - Gadzicki, Dorothea A1 - Gehrig, Andrea A1 - Kast, Karin A1 - Rhiem, Kerstin A1 - Meindl, Alfons A1 - Niederacher, Dieter A1 - Ditsch, Nina A1 - Plendl, Hansjoerg A1 - Preisler-Adams, Sabine A1 - Engert, Stefanie A1 - Sutter, Christian A1 - Varon-Mateeva, Raymenda A1 - Wappenschmidt, Barbara A1 - Weber, Bernhard H. F. A1 - Arver, Brita A1 - Stenmark-Askmalm, Marie A1 - Loman, Niklas A1 - Rosenquist, Richard A1 - Einbeigi, Zakaria A1 - Nathanson, Katherine L. A1 - Rebbeck, Timothy R. A1 - Blank, Stephanie V. A1 - Cohn, David E. A1 - Rodriguez, Gustavo C. A1 - Small, Laurie A1 - Friedlander, Michael A1 - Bae-Jump, Victoria L. A1 - Fink-Retter, Anneliese A1 - Rappaport, Christine A1 - Gschwantler-Kaulich, Daphne A1 - Pfeiler, Georg A1 - Tea, Muy-Kheng A1 - Lindor, Noralane M. A1 - Kaufman, Bella A1 - Paluch, Shani Shimon A1 - Laitman, Yael A1 - Skytte, Anne-Bine A1 - Gerdes, Anne-Marie A1 - Pedersen, Inge Sokilde A1 - Moeller, Sanne Traasdahl A1 - Kruse, Torben A. A1 - Jensen, Uffe Birk A1 - Vijai, Joseph A1 - Sarrel, Kara A1 - Robson, Mark A1 - Kauff, Noah A1 - Mulligan, Anna Marie A1 - Glendon, Gord A1 - Ozcelik, Hilmi A1 - Ejlertsen, Bent A1 - Nielsen, Finn C. A1 - Jønson, Lars A1 - Andersen, Mette K. A1 - Ding, Yuan Chun A1 - Steele, Linda A1 - Foretova, Lenka A1 - Teulé, Alex A1 - Lazaro, Conxi A1 - Brunet, Joan A1 - Pujana, Miquel Angel A1 - Mai, Phuong L. A1 - Loud, Jennifer T. A1 - Walsh, Christine A1 - Lester, Jenny A1 - Orsulic, Sandra A1 - Narod, Steven A. A1 - Herzog, Josef A1 - Sand, Sharon R. A1 - Tognazzo, Silvia A1 - Agata, Simona A1 - Vaszko, Tibor A1 - Weaver, Joellen A1 - Stravropoulou, Alexandra V. A1 - Buys, Saundra S. A1 - Romero, Atocha A1 - de la Hoya, Miguel A1 - Aittomäki, Kristiina A1 - Muranen, Taru A. A1 - Duran, Mercedes A1 - Chung, Wendy K. A1 - Lasa, Adriana A1 - Dorfling, Cecilia M. A1 - Miron, Alexander A1 - Benitez, Javier A1 - Senter, Leigha A1 - Huo, Dezheng A1 - Chan, Salina B. A1 - Sokolenko, Anna P. A1 - Chiquette, Jocelyne A1 - Tihomirova, Laima A1 - Friebel, Tara M. A1 - Agnarsson, Bjarne A. A1 - Lu, Karen H. A1 - Lejbkowicz, Flavio A1 - James, Paul A. A1 - Hall, Per A1 - Dunning, Alison M. A1 - Tessier, Daniel A1 - Cunningham, Julie A1 - Slager, Susan L. A1 - Chen, Wang A1 - Hart, Steven A1 - Stevens, Kristen A1 - Simard, Jacques A1 - Pastinen, Tomi A1 - Pankratz, Vernon S. A1 - Offit, Kenneth A1 - Easton, Douglas F. A1 - Chenevix-Trench, Georgia A1 - Antoniou, Antonis C. T1 - Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk JF - PLOS Genetics N2 - BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers. KW - common variants KW - susceptibility alleles KW - genetic variants KW - modifiers KW - ZNF365 KW - investigators KW - population KW - consortium KW - selection KW - subtypes Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127947 SN - 1553-7404 VL - 9 IS - 3 ER - TY - JOUR A1 - Weber, Heike A1 - Scholz, Claus Jürgen A1 - Domschke, Katharina A1 - Baumann, Christian A1 - Klauke, Benedikt A1 - Jacob, Christian P. A1 - Maier, Wolfgang A1 - Fritze, Jürgen A1 - Bandelow, Borwin A1 - Zwanzger, Peter Michael A1 - Lang, Thomas A1 - Fehm, Lydia A1 - Ströhle, Andreas A1 - Hamm, Alfons A1 - Gerlach, Alexander L. A1 - Alpers, Georg W. A1 - Kircher, Tilo A1 - Wittchen, Hans-Ulrich A1 - Arolt, Volker A1 - Pauli, Paul A1 - Deckert, Jürgen A1 - Reif, Andreas T1 - Gender Differences in Associations of Glutamate Decarboxylase 1 Gene (GAD1) Variants with Panic Disorder N2 - Background: Panic disorder is common (5% prevalence) and females are twice as likely to be affected as males. The heritable component of panic disorder is estimated at 48%. Glutamic acid dehydrogenase GAD1, the key enzyme for the synthesis of the inhibitory and anxiolytic neurotransmitter GABA, is supposed to influence various mental disorders, including mood and anxiety disorders. In a recent association study in depression, which is highly comorbid with panic disorder, GAD1 risk allele associations were restricted to females. Methodology/Principal Findings: Nineteen single nucleotide polymorphisms (SNPs) tagging the common variation in GAD1 were genotyped in two independent gender and age matched case-control samples (discovery sample n = 478; replication sample n = 584). Thirteen SNPs passed quality control and were examined for gender-specific enrichment of risk alleles associated with panic disorder by using logistic regression including a genotype6gender interaction term. The latter was found to be nominally significant for four SNPs (rs1978340, rs3762555, rs3749034, rs2241165) in the discovery sample; of note, the respective minor/risk alleles were associated with panic disorder only in females. These findings were not confirmed in the replication sample; however, the genotype6gender interaction of rs3749034 remained significant in the combined sample. Furthermore, this polymorphism showed a nominally significant association with the Agoraphobic Cognitions Questionnaire sum score. Conclusions/Significance: The present study represents the first systematic evaluation of gender-specific enrichment of risk alleles of the common SNP variation in the panic disorder candidate gene GAD1. Our tentative results provide a possible explanation for the higher susceptibility of females to panic disorder. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75830 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 - TY - JOUR A1 - Chubanov, Vladimir A1 - Ferioli, Silvia A1 - Wisnowsky, Annika A1 - Simmons, David G. A1 - Leitzinger, Christin A1 - Einer, Claudia A1 - Jonas, Wenke A1 - Shymkiv, Yuriy A1 - Gudermann, Thomas A1 - Bartsch, Harald A1 - Braun, Attila A1 - Akdogan, Banu A1 - Mittermeier, Lorenz A1 - Sytik, Ludmila A1 - Torben, Friedrich A1 - Jurinovic, Vindi A1 - van der Vorst, Emiel P. C. A1 - Weber, Christian A1 - Yildirim, Önder A. A1 - Sotlar, Karl A1 - Schürmann, Annette A1 - Zierler, Susanna A1 - Zischka, Hans A1 - Ryazanov, Alexey G. T1 - Epithelial magnesium transport by TRPM6 is essential for prenatal development and adult survival JF - eLife N2 - Mg2+ regulates many physiological processes and signalling pathways. However, little is known about the mechanisms underlying the organismal balance of Mg2+. Capitalizing on a set of newly generated mouse models, we provide an integrated mechanistic model of the regulation of organismal Mg2+ balance during prenatal development and in adult mice by the ion channel TRPM6. We show that TRPM6 activity in the placenta and yolk sac is essential for embryonic development. In adult mice, TRPM6 is required in the intestine to maintain organismal Mg2+ balance, but is dispensable in the kidney. Trpm6 inactivation in adult mice leads to a shortened lifespan, growth deficit and metabolic alterations indicative of impaired energy balance. Dietary Mg2+ supplementation not only rescues all phenotypes displayed by Trpm6-deficient adult mice, but also may extend the lifespan of wildtype mice. Hence, maintenance of organismal Mg2+ balance by TRPM6 is crucial for prenatal development and survival to adulthood. KW - signalling pathways Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164987 VL - 5 ER - TY - JOUR A1 - Leonhardt, Ines A1 - Spielberg, Steffi A1 - Weber, Michael A1 - Albrecht-Eckardt, Daniela A1 - Bläss, Markus A1 - Claus, Ralf A1 - Barz, Dagmar A1 - Scherlach, Kirstin A1 - Hertweck, Christian A1 - Löffler, Jürgen A1 - Hünniger, Kerstin A1 - Kurzai, Oliver T1 - The fungal quorum-sensing molecule farnesol activates innate immune cells but suppresses cellular adaptive immunity JF - mBio N2 - Farnesol, produced by the polymorphic fungus Candida albicans, is the first quorum-sensing molecule discovered in eukaryotes. Its main function is control of C. albicans filamentation, a process closely linked to pathogenesis. In this study, we analyzed the effects of farnesol on innate immune cells known to be important for fungal clearance and protective immunity. Farnesol enhanced the expression of activation markers on monocytes (CD86 and HLA-DR) and neutrophils (CD66b and CD11b) and promoted oxidative burst and the release of proinflammatory cytokines (tumor necrosis factor alpha [TNF-\(\alpha\)] and macrophage inflammatory protein 1 alpha [MIP-1 \(\alpha\)]). However, this activation did not result in enhanced fungal uptake or killing. Furthermore, the differentiation of monocytes to immature dendritic cells (iDC) was significantly affected by farnesol. Several markers important for maturation and antigen presentation like CD1a, CD83, CD86, and CD80 were significantly reduced in the presence of farnesol. Furthermore, farnesol modulated migrational behavior and cytokine release and impaired the ability of DC to induce T cell proliferation. Of major importance was the absence of interleukin 12 (IL-12) induction in iDC generated in the presence of farnesol. Transcriptome analyses revealed a farnesol-induced shift in effector molecule expression and a down-regulation of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor during monocytes to iDC differentiation. Taken together, our data unveil the ability of farnesol to act as a virulence factor of C. albicans by influencing innate immune cells to promote inflammation and mitigating the Th1 response, which is essential for fungal clearance. KW - human dendritic cells KW - Pseudomonas aeruginosa KW - induced apoptosis KW - cytokine production KW - biofilm formation KW - Candida albicans KW - mouse model KW - systemic candidiasis KW - oxidative stress KW - carcinoma cells Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143756 VL - 6 IS - 2 ER - TY - THES A1 - Weber, Christian T1 - Evaluation eines Trainingsmodells für die perkutane Koronarintervention T1 - Evaluation of a training model for percutaneous coronary intervention N2 - Eine fundierte Ausbildung ist in der interventionellen Kardiologie essentiell, um die teilweise komplexen Prozeduren erfolgreich und sicher durchführen zu können. Bei der perkutanen Koronarintervention (PCI) können u.a. Fehler beim Handling des Führungsdrahtes auftreten. So kann es einerseits zum Drahtverlust, andererseits zur distalen Koronargefäßperforation kommen. Daher ist es sinnvoll, die Technik des Katheterwechsels ohne inadäquate Drahtbewegung vor der ersten Intervention im Herzkatheterlabor am Modell zu trainieren. Für diesen Zweck wurde der DACH-BOSS-Simulator entwickelt, an dem der Katheterwechsel trainiert werden kann. Die Validität des Modells wurde im Rahmen einer Studie bei 10 Medizinstudenten (S) sowie 10 angehenden interventionellen Kardiologen (F) untersucht. Jeder Teilnehmer führte eine Trainingsreihe bestehend aus 25 Prozeduren durch. Um den Trainingseffekt zu ermitteln, wurden die mittleren Punktzahlen der ersten 3 und der letzten 3 Prozeduren jedes Probanden in der Studenten- und Fortgeschrittenengruppe verglichen. Zur Bestimmung der Konstruktvalidität führte eine dritte Gruppe von 5 Experten (E, > 1000 PCIs) jeweils 3 Prozeduren durch. Ausmaß der Drahtbewegung und benötigte Zeit wurden mit Punkten bewertet und als Skills score dargestellt. Bei den ersten 3 Prozeduren erzielten die Experten signifikant höhere Werte als die Studenten oder die Fortgeschrittenengruppe (E: 12,9±1,0; S: 7,1±2,6, p = 0,001; F: 8,3±2,0; p = 0,001; Mann-Whitney-U). Anfänger und Fortgeschrittene durchliefen während der 25 Trainingsprozeduren eine Lernkurve; im Mittel verbesserte sich die Studentengruppe von 7,1±2,6 auf 12,2±2 (p=0,007, Wilcoxon) und die Fortgeschrittenengruppe von 8,3±2,0 auf 13,2±1,0 (p = 0,005, Wilcoxon). Der DACH-BOSS-Simulator stellt somit ein valides Modell zum Training des Katheterwechsels ohne inadäquate Drahtbewegung dar. Angehende interventionelle Kardiologen können diesen wichtigen Schritt der Prozedur am Modell trainieren und erlernen. Ob die am Simulator erworbenen Fähigkeiten auf die klinische Prozedur übertragbar sind, muss in weiteren Studien untersucht werden. N2 - Extensive training is required to successfully and safely perform a percutaneus coronary intervention (PCI). For example, uncontrolled movement of the guide wire during catheter exchange may cause “wire-loss” or distal coronary perforation and has to be avoided. The motor skills to hold the wire in a stable position during catheter exchange thus should systematically be trained, and a low cost benchtop model was developed to train catheter exchange without unintended guide wire movements. The effectiveness of the model was evaluated in 10 medical students (S) and 10 cardiology fellows (F) with previous experience in diagnostic catheterization. Both groups underwent a training series consisting of 25 single procedures. Effectiveness of training was assessed by comparing the first 3 and the last 3 procedures in the student and fellows group. To determine the construct validity a third group of 5 experts (E; performed >1000 PCIs) performed a series of 3 procedures. Wire movement and required time were combined into a skills score. These results were compared with the first 3 procedures of the other groups. For the first 3 procedures, experts scored significantly higher than students or fellows (E: 12.9±1.0; S: 7.1±2.6, p=0.001; F: 8.3±2.0, p=0.001; Mann-Whitney-U). Students and fellows improved significantly throughout the series training on the simulator (S: 12.2±2.0, p=0.007; F: 13.2±1.0, p=0.005, Wilcoxon). This low-cost simulator is a valid model to train adequate guide wire handling in interventional cardiology. It needs to be shown wether the acquired skills can be transfered to the clinical situation. KW - Simulation KW - Training KW - Herzkatheter KW - Koronarintervention KW - Simulationstraining Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200124 ER - TY - JOUR A1 - Szabó, Áron A1 - Papin, Christian A1 - Zorn, Daniela A1 - Ponien, Prishila A1 - Weber, Frank A1 - Raabe, Thomas A1 - Rouyer, François T1 - The CK2 Kinase Stabilizes CLOCK and Represses Its Activity in the Drosophila Circadian Oscillator JF - PLoS Biology N2 - Phosphorylation is a pivotal regulatory mechanism for protein stability and activity in circadian clocks regardless of their evolutionary origin. It determines the speed and strength of molecular oscillations by acting on transcriptional activators and their repressors, which form negative feedback loops. In Drosophila, the CK2 kinase phosphorylates and destabilizes the PERIOD (PER) and TIMELESS (TIM) proteins, which inhibit CLOCK (CLK) transcriptional activity. Here we show that CK2 also targets the CLK activator directly. Downregulating the activity of the catalytic alpha subunit of CK2 induces CLK degradation, even in the absence of PER and TIM. Unexpectedly, the regulatory beta subunit of the CK2 holoenzyme is not required for the regulation of CLK stability. In addition, downregulation of \(CK2\alpha\) activity decreases CLK phosphorylation and increases per and tim transcription. These results indicate that CK2 inhibits CLK degradation while reducing its activity. Since the CK1 kinase promotes CLK degradation, we suggest that CLK stability and transcriptional activity result from counteracting effects of CK1 and CK2. KW - negative feedback loop KW - PER-TIM complex KW - posttranslational regulation KW - transcription factor KW - in-vivo KW - behavioral rhythms KW - proteins period KW - beta-subunit KW - phosphorylation KW - gene KW - CT, circadian time KW - LD, light:dark KW - DD, constant darkness Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127234 SN - 1545-7885 VL - 11 IS - 8 ER - TY - JOUR A1 - Soehnlein, Oliver A1 - Drechsler, Maik A1 - Döring, Yvonne A1 - Lievens, Dirk A1 - Hartwig, Helene A1 - Kemmerich, Klaus A1 - Ortega-Gómez, Almudena A1 - Mandl, Manuela A1 - Vijayan, Santosh A1 - Projahn, Delia A1 - Garlichs, Christoph D. A1 - Koenen, Rory R. A1 - Hristov, Mihail A1 - Lutgens, Esther A1 - Zernecke, Alma A1 - Weber, Christian T1 - Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes JF - EMBO Molecular Medicine N2 - We used a novel approach of cytostatically induced leucocyte depletion and subsequent reconstitution with leucocytes deprived of classical \((inflammatory/Gr1^{hi})\) or non-classical \((resident/Gr1^{lo})\) monocytes to dissect their differential role in atheroprogression under high-fat diet (HFD). Apolipoprotein E-deficient \((Apoe^{-/-})\) mice lacking classical but not non-classical monocytes displayed reduced lesion size and macrophage and apoptotic cell content. Conversely, HFD induced a selective expansion of classical monocytes in blood and bone marrow. Increased CXCL1 levels accompanied by higher expression of its receptor CXCR2 on classical monocytes and inhibition of monocytosis by CXCL1-neutralization indicated a preferential role for the CXCL1/CXCR2 axis in mobilizing classical monocytes during hypercholesterolemia. Studies correlating circulating and lesional classical monocytes in gene-deficient \(Apoe^{-/-}\) mice, adoptive transfer of gene-deficient cells and pharmacological modulation during intravital microscopy of the carotid artery revealed a crucial function of CCR1 and CCR5 but not CCR2 or \(CX_3CR1\) in classical monocyte recruitment to atherosclerotic vessels. Collectively, these data establish the impact of classical monocytes on atheroprogression, identify a sequential role of CXCL1 in their mobilization and CCR1/CCR5 in their recruitment. KW - hypercholeterolemia KW - CCR2 KW - atherosclerosis KW - chemokine KW - accumulation KW - subsets KW - inflammatory sites KW - fractalkine KW - marcophages KW - mobilization KW - monocyte KW - recruitment KW - bone-marrow KW - atheriosclerotic lesions KW - hyperlipedemic mice Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122204 SN - 1757-4676 VL - 5 ER - TY - JOUR A1 - Frank, Benjamin A1 - Marcu, Ana A1 - de Oliveira Almeida Petersen, Antonio Luis A1 - Weber, Heike A1 - Stigloher, Christian A1 - Mottram, Jeremy C. A1 - Scholz, Claus Jürgen A1 - Schurigt, Uta T1 - Autophagic digestion of Leishmania major by host macrophages is associated with differential expression of BNIP3, CTSE, and the miRNAs miR-101c, miR-129, and miR-210 JF - Parasites & Vectors N2 - Background Autophagy participates in innate immunity by eliminating intracellular pathogens. Consequently, numerous microorganisms have developed strategies to impair the autophagic machinery in phagocytes. In the current study, interactions between Leishmania major (L. m.) and the autophagic machinery of bone marrow-derived macrophages (BMDM) were analyzed. Methods BMDM were generated from BALB/c mice, and the cells were infected with L. m. promastigotes. Transmission electron microscopy (TEM) and electron tomography were used to investigate the ultrastructure of BMDM and the intracellular parasites. Affymetrix® chip analyses were conducted to identify autophagy-related messenger RNAs (mRNAs) and microRNAs (miRNAs). The protein expression levels of autophagy related 5 (ATG5), BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), cathepsin E (CTSE), mechanistic target of rapamycin (MTOR), microtubule-associated proteins 1A/1B light chain 3B (LC3B), and ubiquitin (UB) were investigated through western blot analyses. BMDM were transfected with specific small interfering RNAs (siRNAs) against autophagy-related genes and with mimics or inhibitors of autophagy-associated miRNAs. The infection rates of BMDM were determined by light microscopy after a parasite-specific staining. Results The experiments demonstrated autophagy induction in BMDM after in vitro infection with L. m.. The results suggested a putative MTOR phosphorylation-dependent counteracting mechanism in the early infection phase and indicated that intracellular amastigotes were cleared by autophagy in BMDM in the late infection phase. Transcriptomic analyses and specific downregulation of protein expression with siRNAs suggested there is an association between the infection-specific over expression of BNIP3, as well as CTSE, and the autophagic activity of BMDM. Transfection with mimics of mmu-miR-101c and mmu-miR-129-5p, as well as with an inhibitor of mmu-miR-210-5p, demonstrated direct effects of the respective miRNAs on parasite clearance in L. m.-infected BMDM. Furthermore, Affymetrix® chip analyses revealed a complex autophagy-related RNA network consisting of differentially expressed mRNAs and miRNAs in BMDM, which indicates high glycolytic and inflammatory activity in the host macrophages. Conclusions Autophagy in L. m.-infected host macrophages is a highly regulated cellular process at both the RNA level and the protein level. Autophagy has the potential to clear parasites from the host. The results obtained from experiments with murine host macrophages could be translated in the future to develop innovative and therapeutic antileishmanial strategies for human patients. KW - autophagy KW - BNIP3 KW - CTSE KW - electron tomography KW - leishmania major KW - macrophages KW - miRNAs KW - MTOR KW - siRNAs KW - transmission electron microscopy Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124997 VL - 8 IS - 404 ER - TY - THES A1 - Weber, Christian T1 - Electrochemical Energy Storage: Carbon Xerogel-Manganese Oxide Composites as Supercapacitor Electrode Materials T1 - Elektrochemische Energiespeicher: Kohlenstoff Xerogel-Manganoxid Komposite als Elektrodenmaterial für Superkondensatoren N2 - Electrochemical double layer capacitors (EDLC), most commonly referred to as “supercapacitors”, have gained increasing scientific and commercial interest in recent years. Purely electrostatic charge storage processes allow charge- and discharge cycles in the second-time scale, exhibiting a theoretical capacitance in the order of 100 F per gram of electrode material, thereby providing efficient recuperation devices for electromechanical processes, for example. Introducing electrochemically active materials such as manganese oxides into the supercapacitor electrode, allows to combine the double-layer storage with a battery-like storage process, leading to capacitance that can be up to two orders of magnitude larger than those in EDLC. In the present work, an electroless deposition approach of manganese oxide on a carbon scaffold is adapted and further investigated. The carbon material is derived from an organic xerogel, which in turn is prepared via a sol-gel process, allowing tailoring of the structural properties of the carbon, making it an ideal model system to study the relation between morphology and electrochemical performance in the carbon-manganese oxide hybrid electrode. In the first part of this thesis, a variation of manganese oxide deposition time at a low concentration of precursor solution is analyzed. Mass uptakes reach up to 58 wt.%, leading to an increase of volumetric capacitance by a factor 5, however reducing the dynamic performance of the electrode. The structural characterization gives hints on the deposition location of the active material either in the intra-particular pores of the carbon backbone or on the enveloping surface area of the particles forming the backbone. In order to comprehensively answer the question of the location of the active material within the hybrid electrode, the particle size of the carbon backbone and therefore the enveloping surface area of the carbon particles was varied. For samples with high mass uptakes, scanning electron microscopy (SEM) images show a layer thickness of 27 nm of active material around the carbon particles. In order to quantitatively investigate this layer morphology, even for low mass uptakes where no layer is visible in SEM images, a model interpreting data from anomalous small angle X-ray scattering (ASAXS) measurements was developed. The results confirm the presence of a layer around the carbon particles, exhibiting a layer thickness ranging from 3 to 26 nm. From an electrochemical point of view, carbon backbones with a large enveloping surface area will lead to high mass uptakes in the electroless deposition process and therefore lead to high capacitance of the electrode. However, for future application, electrodeposition approaches should be investigated in detail, since no deposits will form on the interface between carbon backbone and current collector, leading to a better dynamic performance of the hybrid electrode. Furthermore, the ASAXS-method should be promoted and applied on other material systems, since this technique allows to draw important conclusions and allows to deduce integral and quantitative information towards a rational design of high performance electrodes. N2 - In den letzten Jahren haben elektrochemische Doppelschichtkondensatoren, meist als “Supercaps” bezeichnet, wachsendes wissenschaftliches und kommerzielles Interesse erfahren. Rein elektrostatische Ladungsspeicherungsprozesse erlauben Lade- und Entladezyklen im Sekundenregime, bei einer theoretischen Kapazität in der Größenordnung von 100 Farad pro Gramm Elektrodenmaterial. Damit steht beispielsweise ein ideales Bauteil zur Energierekuperation in elektromechanischen Prozessen zur Verfügung. Die Verbindung der Doppelschichtelektrode mit elektrochemisch aktiven Materialien, wie zum Beispiel Manganoxiden, erlaubt eine Kombination der elektrostatischen Ladungsspeicherung mit batterieähnlichen Ladungsspeicherungsprozessen. Dies führt zu Kapazitätswerten, die bis zu zwei Größenordnungen über den Kapazitätswerten im Doppelschichtkondensator liegen können. In der vorliegenden Arbeit wurde ein nasschemischer Abscheidungsprozess für die Deposition von Manganoxid auf einem Kohlenstoffgerüst angewendet und weitergehend untersucht. Das Kohlenstoffmaterial wurde aus einem organischem Xerogel hergestellt, welches wiederum durch einen Sol-Gel Prozess dargestellt wurde. Diese Vorgehensweise erlaubt eine gezielte Beeinflussung der strukturellen Eigenschaften des Kohlenstoffes. Dadurch wird das Material zum idealen Modellsystem, um den Einfluss der Morphologie auf die elektrochemischen Eigenschaften der Kohlenstoff-Manganoxid Hybridelektrode zu untersuchen. Im ersten Teil der Arbeit wurde die Abscheidungsdauer des Manganoxids bei einer niedrigen Ausgangskonzentration in der Vorstufe systematisch variiert und die resultierenden Elektroden analysiert. Die MnO2 Massenaufnahme erreichte bis zu 58 wt.%, was zu einer Steigerung der volumetrischen Kapazität um einen Faktor 5 führte. Der Preis für diese Steigerung liegt jedoch in einer Reduktion der Lade- bzw. Entladegeschwindigkeit. Die strukturelle Charakterisierung der Hybridelektroden deutet auf eine Abscheidung des MnO2 in den intrapartikulären Poren der Kohlenstoffpartikel oder auf deren einhüllenden Oberfläche hin. Um den Abscheidungsort des aktiven Materials innerhalb der Hybridelektrode eindeutig zu bestimmen, wurde die Größe der Kohlenstoffpartikel und damit die externe Oberfläche des Kohlenstoffgerüstes systematisch variiert. Aufnahmen mittels Rasterelektronenmikroskopie (REM) zeigen eine Schicht von MnO2 um die Kohlenstoffpartikel mit einer Dicke von bis zu 27 nm für Proben mit Massenzuwächsen von bis zu 130 %. Um die Schichtdicke auch für geringe Massenaufnahmen, bei denen im REM keine Schicht erkennbar ist, quantitativ untersuchen zu können, wurde ein Modell zur Analyse von anomaler Röntgenkleinwinkelstreuung (ASAXS) entwickelt. Die Ergebnisse bestätigen die Existenz einer Schicht um die Kohlenstoffpartikel, deren Dicke zwischen 3 und 26 nm liegt. Aus elektrochemischer Sicht wird ein Kohlenstoffgerüst mit großer einhüllender Oberfläche zu einer großen Massenaufnahme im nasschemischen Abscheidungsprozess und damit zu hohen Kapazitätswerten führen. Für eine zukünftige Anwendung sollten jedoch auch elektrochemische Abscheidungsprozesse genau untersucht werden, da bei dieser Methode kein Material auf der Kontaktfläche zwischen Stromabnehmer und Elektrode abgeschieden wird. Dadurch ist eine Verbesserung der elektrochemischen Performance der Hybridelektrode zu erwarten. Weiterhin sollte die ASAXS-Methode weiterentwickelt und auf andere Materialsysteme angewendet werden, da diese Technik wichtige Schlüsse erlaubt, sowie die Bestimmung integraler und quantitativer Information, die zu gezieltem Design von hocheffizienten Elektroden führen wird. KW - Superkondensator KW - Electrochemical energy storage KW - ASAXS KW - Supercapacitor KW - Energiespeicher KW - Experimental physics Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130748 ER - TY - JOUR A1 - Projahn, Delia A1 - Simsekyilmaz, Sakine A1 - Singh, Smriti A1 - Kanzler, Isabella A1 - Kramp, Birgit K. A1 - Langer, Marcella A1 - Burlacu, Alexandrina A1 - Bernhagen, Jürgen A1 - Klee, Doris A1 - Zernecke, Alma A1 - Hackeng, Tilman M. A1 - Groll, Jürgen A1 - Weber, Christian A1 - Liehn, Elisa A. A1 - Koenen, Roy R. T1 - Controlled intramyocardial release of engineered chemokines by biodegradable hydrogels as a treatment approach of myocardial infarction JF - Journal of Cellular and Molecular Medicine N2 - Myocardial infarction (MI) induces a complex inflammatory immune response, followed by the remodelling of the heart muscle and scar formation. The rapid regeneration of the blood vessel network system by the attraction of hematopoietic stem cells is beneficial for heart function. Despite the important role of chemokines in these processes, their use in clinical practice has so far been limited by their limited availability over a long time-span in vivo. Here, a method is presented to increase physiological availability of chemokines at the site of injury over a defined time-span and simultaneously control their release using biodegradable hydrogels. Two different biodegradable hydrogels were implemented, a fast degradable hydrogel (FDH) for delivering Met-CCL5 over 24hrs and a slow degradable hydrogel (SDH) for a gradual release of protease-resistant CXCL12 (S4V) over 4weeks. We demonstrate that the time-controlled release using Met-CCL5-FDH and CXCL12 (S4V)-SDH suppressed initial neutrophil infiltration, promoted neovascularization and reduced apoptosis in the infarcted myocardium. Thus, we were able to significantly preserve the cardiac function after MI. This study demonstrates that time-controlled, biopolymer-mediated delivery of chemokines represents a novel and feasible strategy to support the endogenous reparatory mechanisms after MI and may compliment cell-based therapies. KW - chemokines KW - therapy KW - cardiovascular pharmacology KW - remodelling KW - endothelial progenitor cells KW - left-ventricular function KW - heart-failure KW - rat model KW - recruitment KW - factor-I Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116597 SN - 1582-4934 VL - 18 IS - 5 ER - TY - JOUR A1 - Tilstam, Pathricia V. A1 - Gijbels, Marion J. A1 - Habbeddine, Mohamed A1 - Cudejko, Celine A1 - Asare, Yaw A1 - Theelen, Wendy A1 - Zhou, Baixue A1 - Döring, Yvonne A1 - Drechsler, Maik A1 - Pawig, Lukas A1 - Simsekyilmaz, Sakine A1 - Koenen, Rory R. A1 - de Winther, Menno P. J. A1 - Lawrence, Toby A1 - Bernhagen, Jürgen A1 - Zernecke, Alma A1 - Weber, Christian A1 - Noels, Heidi T1 - Bone Marrow-Specific Knock-In of a Non-Activatable Ikkα Kinase Mutant Influences Haematopoiesis but Not Atherosclerosis in Apoe-Deficient Mice JF - PLOS ONE N2 - Background: The Ikkα kinase, a subunit of the NF-kappa B-activating IKK complex, has emerged as an important regulator of inflammatory gene expression. However, the role of Ikkα-mediated phosphorylation in haematopoiesis and atherogenesis remains unexplored. In this study, we investigated the effect of a bone marrow (BM)-specific activation-resistant Ikk alpha mutant knock-in on haematopoiesis and atherosclerosis in mice. Methods and Results: Apolipoprotein E (Apoe)-deficient mice were transplanted with BM carrying an activation-resistant Ikkα gene (Ikkα(AA/AA) Apoe(-/-)) or with Ikkα(+/+) Apoe(-/-) BM as control and were fed a high-cholesterol diet for 8 or 13 weeks. Interestingly, haematopoietic profiling by flow cytometry revealed a significant decrease in B-cells, regulatory T-cells and effector memory T-cells in Ikkα(AA/AA) Apoe(-/-) BM-chimeras, whereas the naive T-cell population was increased. Surprisingly, no differences were observed in the size, stage or cellular composition of atherosclerotic lesions in the aorta and aortic root of Ikkα(AA/AA) Apoe(-/-) vs Ikkα(+/+) Apoe(-/-) BM-transplanted mice, as shown by histological and immunofluorescent stainings. Necrotic core sizes, apoptosis, and intracellular lipid deposits in aortic root lesions were unaltered. In vitro, BM-derived macrophages from Ikkα(AA/AA) Apoe(-/-) vs Ikkα(+/+) Apoe(-/-) mice did not show significant differences in the uptake of oxidized low-density lipoproteins (oxLDL), and, with the exception of Il-12, the secretion of inflammatory proteins in conditions of Tnf-α or oxLDL stimulation was not significantly altered. Furthermore, serum levels of inflammatory proteins as measured with a cytokine bead array were comparable. Conclusion: Our data reveal an important and previously unrecognized role of haematopoietic Ikkα kinase activation in the homeostasis of B-cells and regulatory T-cells. However, transplantation of Ikkα AA mutant BM did not affect atherosclerosis in Apoe(-/-) mice. This suggests that the diverse functions of Ikkα in haematopoietic cells may counterbalance each other or may not be strong enough to influence atherogenesis, and reveals that targeting haematopoietic Ikkα kinase activity alone does not represent a therapeutic approach. KW - NF-KAPPA-B KW - regulatory T cells KW - indoleamine 2,3-dioxygenase KW - dendritic cells KW - gene expression KW - increases atherosclersosis KW - receptor KW - inhibition KW - pathway KW - beta Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117450 VL - 9 IS - 2 ER - TY - THES A1 - Weber, Christian T1 - Bedeutung des Her-2/neu beim Ovarialkarzinom - Korrelation und Vergleich mit klinischen Prognosefaktoren T1 - Meaning of Her-2/neu in ovarian carcinoma - Korrelation and comparison with clinical prognostic factors N2 - In der vorgelegten Arbeit werden klinische Prognosefaktoren des Ovarialkarzinoms an einem Kollektiv von 105 Patientinnen untersucht, die in den Jahren 1996 bis 1998 in der Universitäts-Frauenklinik Würzburg behandelt wurden. Zudem wird eine immunhistochemische Bestimmung des Her-2/neu - Status vorgenommen, der beim Mamma-Karzinom als unabhängiger Prognosefaktor bekannt ist und mit einer schlechteren Prognose einhergeht. Zusammenfassend ließ sich in dieser Arbeit keine Überexpression des Her-2/neu am Ovar feststellen, eine unabhängige prognostische Relevanz muß aus unserer Sicht verneint werden. N2 - In this work we investigated in clinical prognsotic factors of ovarian cancer on patients that were treated because of such a cancer in the Universitäts-Frauenklinik Würzburg from 1996 till 1998. Furthermore we did an immunohistochemical analysis of her-2/neu on ovarian carcinoma, which is known as a significant independent prognostic factor in breast cancer. In conclusion we didn't find an overexpression of her-2/neu in ovarian carcinoma. An independent prognsotic relevance must be denied from our point of view. KW - her-2/neu KW - Ovarialkarzinom KW - prognosefaktor KW - her-2/neu KW - ovarian carcinoma KW - prognsotic significance Y1 - 2005 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-15611 ER - TY - JOUR A1 - Grimm, Oliver A1 - Weber, Heike A1 - Kittel-Schneider, Sarah A1 - Kranz, Thorsten M. A1 - Jacob, Christian P. A1 - Lesch, Klaus-Peter A1 - Reif, Andreas T1 - Impulsivity and Venturesomeness in an Adult ADHD Sample: Relation to Personality, Comorbidity, and Polygenic Risk JF - Frontiers in Psychiatry N2 - While impulsivity is a basic feature of attention-deficit/hyperactivity disorder (ADHD), no study explored the effect of different components of the Impulsiveness (Imp) and Venturesomeness (Vent) scale (IV7) on psychiatric comorbidities and an ADHD polygenic risk score (PRS). We used the IV7 self-report scale in an adult ADHD sample of 903 patients, 70% suffering from additional comorbid disorders, and in a subsample of 435 genotyped patients. Venturesomeness, unlike immediate Impulsivity, is not specific to ADHD. We consequently analyzed the influence of Imp and Vent also in the context of a PRS on psychiatric comorbidities of ADHD. Vent shows a distinctly different distribution of comorbidities, e.g., less anxiety and depression. PRS showed no effect on different ADHD comorbidities, but correlated with childhood hyperactivity. In a complementary analysis using principal component analysis with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ADHD criteria, revised NEO Personality Inventory, Imp, Vent, and PRS, we identified three ADHD subtypes. These are an impulsive–neurotic type, an adventurous–hyperactive type with a stronger genetic component, and an anxious–inattentive type. Our study thus suggests the importance of adventurousness and the differential consideration of impulsivity in ADHD. The genetic risk is distributed differently between these subtypes, which underlines the importance of clinically motivated subtyping. Impulsivity subtyping might give insights into the organization of comorbid disorders in ADHD and different genetic background. KW - impulsivity KW - ADHD KW - polygenic risk score KW - venturesomeness KW - substance abuse disorder KW - attention KW - hyperactivity Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219751 SN - 1664-0640 VL - 11 ER - TY - JOUR A1 - Jaite, Charlotte A1 - Bühren, Katharina A1 - Dahmen, Brigitte A1 - Dempfle, Astrid A1 - Becker, Katja A1 - Correll, Christoph U. A1 - Egberts, Karin M. A1 - Ehrlich, Stefan A1 - Fleischhaker, Christian A1 - von Gontard, Alexander A1 - Hahn, Freia A1 - Kolar, David A1 - Kaess, Michael A1 - Legenbauer, Tanja A1 - Renner, Tobias J. A1 - Schulze, Ulrike A1 - Sinzig, Judith A1 - Thomae, Ellen A1 - Weber, Linda A1 - Wessing, Ida A1 - Antony, Gisela A1 - Hebebrand, Johannes A1 - Föcker, Manuel A1 - Herpertz-Dahlmann, Beate T1 - Clinical Characteristics of Inpatients with Childhood vs. Adolescent Anorexia Nervosa JF - Nutrients N2 - We aimed to compare the clinical data at first presentation to inpatient treatment of children (<14 years) vs. adolescents (≥14 years) with anorexia nervosa (AN), focusing on duration of illness before hospital admission and body mass index (BMI) at admission and discharge, proven predictors of the outcomes of adolescent AN. Clinical data at first admission and at discharge in 289 inpatients with AN (children: n = 72; adolescents: n = 217) from a German multicenter, web-based registry for consecutively enrolled patients with childhood and adolescent AN were analyzed. Inclusion criteria were a maximum age of 18 years, first inpatient treatment due to AN, and a BMI <10th BMI percentile at admission. Compared to adolescents, children with AN had a shorter duration of illness before admission (median: 6.0 months vs. 8.0 months, p = 0.004) and higher BMI percentiles at admission (median: 0.7 vs. 0.2, p = 0.004) as well as at discharge (median: 19.3 vs. 15.1, p = 0.011). Thus, in our study, children with AN exhibited clinical characteristics that have been associated with better outcomes, including higher admission and discharge BMI percentile. Future studies should examine whether these factors are actually associated with positive long-term outcomes in children. KW - anorexia nervosa KW - children KW - adolescents KW - clinical characteristics KW - BMI KW - outcome Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193160 SN - 2072-6643 VL - 11 IS - 11 ER - TY - JOUR A1 - Rayner, Christopher A1 - Coleman, Jonathan R. I. A1 - Purves, Kirstin L. A1 - Hodsoll, John A1 - Goldsmith, Kimberley A1 - Alpers, Georg W. A1 - Andersson, Evelyn A1 - Arolt, Volker A1 - Boberg, Julia A1 - Bögels, Susan A1 - Creswell, Cathy A1 - Cooper, Peter A1 - Curtis, Charles A1 - Deckert, Jürgen A1 - Domschke, Katharina A1 - El Alaoui, Samir A1 - Fehm, Lydia A1 - Fydrich, Thomas A1 - Gerlach, Alexander L. A1 - Grocholewski, Anja A1 - Hahlweg, Kurt A1 - Hamm, Alfons A1 - Hedman, Erik A1 - Heiervang, Einar R. A1 - Hudson, Jennifer L. A1 - Jöhren, Peter A1 - Keers, Robert A1 - Kircher, Tilo A1 - Lang, Thomas A1 - Lavebratt, Catharina A1 - Lee, Sang-hyuck A1 - Lester, Kathryn J. A1 - Lindefors, Nils A1 - Margraf, Jürgen A1 - Nauta, Maaike A1 - Pané-Farré, Christiane A. A1 - Pauli, Paul A1 - Rapee, Ronald M. A1 - Reif, Andreas A1 - Rief, Winfried A1 - Roberts, Susanna A1 - Schalling, Martin A1 - Schneider, Silvia A1 - Silverman, Wendy K. A1 - Ströhle, Andreas A1 - Teismann, Tobias A1 - Thastum, Mikael A1 - Wannemüller, Andre A1 - Weber, Heike A1 - Wittchen, Hans-Ulrich A1 - Wolf, Christiane A1 - Rück, Christian A1 - Breen, Gerome A1 - Eley, Thalia C. T1 - A genome-wide association meta-analysis of prognostic outcomes following cognitive behavioural therapy in individuals with anxiety and depressive disorders JF - Translational Psychiatry N2 - Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (r(g) approximate to 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We (h(SNP)(2)) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and estimated the variance in therapy outcomes that could be explained by common genetic variants learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h(SNP)(2) could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits. KW - Human behaviour KW - Personalized medicine KW - Prognostic markers KW - Psychiatric disorders Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225048 VL - 9 IS - 150 ER - TY - JOUR A1 - Sepahi, Ilnaz A1 - Faust, Ulrike A1 - Sturm, Marc A1 - Bosse, Kristin A1 - Kehrer, Martin A1 - Heinrich, Tilman A1 - Grundman-Hauser, Kathrin A1 - Bauer, Peter A1 - Ossowski, Stephan A1 - Susak, Hana A1 - Varon, Raymonda A1 - Schröck, Evelin A1 - Niederacher, Dieter A1 - Auber, Bernd A1 - Sutter, Christian A1 - Arnold, Norbert A1 - Hahnen, Eric A1 - Dworniczak, Bernd A1 - Wang-Gorke, Shan A1 - Gehrig, Andrea A1 - Weber, Bernhard H. F. A1 - Engel, Christoph A1 - Lemke, Johannes R. A1 - Hartkopf, Andreas A1 - Huu Phuc, Nguyen A1 - Riess, Olaf A1 - Schroeder, Christopher T1 - Investigating the effects of additional truncating variants in DNA-repair genes on breast cancer risk in BRCA1-positive women JF - BMC Cancer N2 - Background Inherited pathogenic variants in BRCA1 and BRCA2 are the most common causes of hereditary breast and ovarian cancer (HBOC). The risk of developing breast cancer by age 80 in women carrying a BRCA1 pathogenic variant is 72%. The lifetime risk varies between families and even within affected individuals of the same family. The cause of this variability is largely unknown, but it is hypothesized that additional genetic factors contribute to differences in age at onset (AAO). Here we investigated whether truncating and rare missense variants in genes of different DNA-repair pathways contribute to this phenomenon. Methods We used extreme phenotype sampling to recruit 133 BRCA1-positive patients with either early breast cancer onset, below 35 (early AAO cohort) or cancer-free by age 60 (controls). Next Generation Sequencing (NGS) was used to screen for variants in 311 genes involved in different DNA-repair pathways. Results Patients with an early AAO (73 women) had developed breast cancer at a median age of 27 years (interquartile range (IQR); 25.00–27.00 years). A total of 3703 variants were detected in all patients and 43 of those (1.2%) were truncating variants. The truncating variants were found in 26 women of the early AAO group (35.6%; 95%-CI 24.7 - 47.7%) compared to 16 women of controls (26.7%; 95%-CI 16.1 to 39.7%). When adjusted for environmental factors and family history, the odds ratio indicated an increased breast cancer risk for those carrying an additional truncating DNA-repair variant to BRCA1 mutation (OR: 3.1; 95%-CI 0.92 to 11.5; p-value = 0.07), although it did not reach the conventionally acceptable significance level of 0.05. Conclusions To our knowledge this is the first time that the combined effect of truncating variants in DNA-repair genes on AAO in patients with hereditary breast cancer is investigated. Our results indicate that co-occurring truncating variants might be associated with an earlier onset of breast cancer in BRCA1-positive patients. Larger cohorts are needed to confirm these results. KW - breast cancer KW - age at onset KW - DNA-repair genes KW - next-generation-sequencing KW - panel sequencing KW - extreme phenotypes KW - hereditary breast and ovarian cancer KW - BRCA1 KW - DNA-repair Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237676 VL - 19 ER - TY - JOUR A1 - Simsekyilmaz, Sakine A1 - Liehn, Elisa A. A1 - Weinandy, Stefan A1 - Schreiber, Fabian A1 - Megens, Remco T. A. A1 - Theelen, Wendy A1 - Smeets, Ralf A1 - Jockenhövel, Stefan A1 - Gries, Thomas A1 - Möller, Martin A1 - Klee, Doris A1 - Weber, Christian A1 - Zernecke, Alma T1 - Targeting In-Stent-Stenosis with RGD- and CXCL1-Coated Mini-Stents in Mice JF - PLoS ONE N2 - Atherosclerotic lesions that critically narrow the artery can necessitate an angioplasty and stent implantation. Long-term therapeutic effects, however, are limited by excessive arterial remodeling. We here employed a miniaturized nitinol-stent coated with star-shaped polyethylenglycole (star-PEG), and evaluated its bio-functionalization with RGD and CXCL1 for improving in-stent stenosis after implantation into carotid arteries of mice. Nitinol foils or stents (bare metal) were coated with star-PEG, and bio-functionalized with RGD, or RGD/CXCL1. Cell adhesion to star-PEG-coated nitinol foils was unaltered or reduced, whereas bio-functionalization with RGD but foremost RGD/CXCL1 increased adhesion of early angiogenic outgrowth cells (EOCs) and endothelial cells but not smooth muscle cells when compared with bare metal foils. Stimulation of cells with RGD/CXCL1 furthermore increased the proliferation of EOCs. In vivo, bio-functionalization with RGD/CXCL1 significantly reduced neointima formation and thrombus formation, and increased re-endothelialization in apoE\(^{-/-}\) carotid arteries compared with bare-metal nitinol stents, star-PEG-coated stents, and stents bio-functionalized with RGD only. Bio-functionalization of star-PEG-coated nitinol-stents with RGD/CXCL1 reduced in-stent neointima formation. By supporting the adhesion and proliferation of endothelial progenitor cells, RGD/CXCL1 coating of stents may help to accelerate endothelial repair after stent implantation, and thus may harbor the potential to limit the complication of in-stent restenosis in clinical approaches. KW - carotid arteries KW - polymers KW - stent implantation KW - coatings KW - endothelial cells KW - mice KW - fluorescence microscopy KW - stem cells Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-179745 VL - 11 IS - 5 ER - TY - JOUR A1 - Schümann, Franziska Lea A1 - Groß, Elisabeth A1 - Bauer, Marcus A1 - Rohde, Christian A1 - Sandmann, Sarah A1 - Terziev, Denis A1 - Müller, Lutz P. A1 - Posern, Guido A1 - Wienke, Andreas A1 - Fend, Falko A1 - Hansmann, Martin-Leo A1 - Klapper, Wolfram A1 - Rosenwald, Andreas A1 - Stein, Harald A1 - Dugas, Martin A1 - Müller-Tidow, Carsten A1 - Wickenhauser, Claudia A1 - Binder, Mascha A1 - Weber, Thomas T1 - Divergent effects of EZH1 and EZH2 protein expression on the prognosis of patients with T-cell lymphomas JF - Biomedicines N2 - T-cell lymphomas are highly heterogeneous and their prognosis is poor under the currently available therapies. Enhancers of zeste homologue 1 and 2 (EZH1/2) are histone H3 lysine-27 trimethyltransferases (H3K27me3). Despite the rapid development of new drugs inhibiting EZH2 and/or EZH1, the molecular interplay of these proteins and the impact on disease progression and prognosis of patients with T-cell lymphomas remains insufficiently understood. In this study, EZH1/2 mutation status was evaluated in 33 monomorphic epitheliotropic intestinal T-cell lymphomas by next generation sequencing and EZH1/2 and H3K27me3 protein expression levels were detected by immunohistochemistry in 46 T-cell lymphomas. Correlations with clinicopathologic features were analyzed and survival curves generated. No EZH1 mutations and one (3%) EZH2 missense mutation were identified. In univariable analysis, high EZH1 expression was associated with an improved overall survival (OS) and progression-free survival (PFS) whereas high EZH2 and H3K27me3 expression were associated with poorer OS and PFS. Multivariable analysis revealed EZH1 (hazard ratio (HR) = 0.183; 95% confidence interval (CI): 0.044–0.767; p = 0.020;) and EZH2 (HR = 8.245; 95% CI: 1.898–35.826; p = 0.005) to be independent, divergent prognostic markers for OS. In conclusion, EZH1/2 protein expression had opposing effects on the prognosis of T-cell lymphoma patients. KW - T-cell non-Hodgkin's lymphomas KW - PTCL KW - epigenetics KW - EZH1 KW - EZH2 KW - H3K27me3 KW - immunohistochemistry KW - next generation sequencing Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252155 SN - 2227-9059 VL - 9 IS - 12 ER - TY - JOUR A1 - Butt, Elke A1 - Stempfle, Katrin A1 - Lister, Lorenz A1 - Wolf, Felix A1 - Kraft, Marcella A1 - Herrmann, Andreas B. A1 - Viciano, Cristina Perpina A1 - Weber, Christian A1 - Hochhaus, Andreas A1 - Ernst, Thomas A1 - Hoffmann, Carsten A1 - Zernecke, Alma A1 - Frietsch, Jochen J. T1 - Phosphorylation-dependent differences in CXCR4-LASP1-AKT1 interaction between breast cancer and chronic myeloid leukemia JF - Cells N2 - The serine/threonine protein kinase AKT1 is a downstream target of the chemokine receptor 4 (CXCR4), and both proteins play a central role in the modulation of diverse cellular processes, including proliferation and cell survival. While in chronic myeloid leukemia (CML) the CXCR4 is downregulated, thereby promoting the mobilization of progenitor cells into blood, the receptor is highly expressed in breast cancer cells, favoring the migratory capacity of these cells. Recently, the LIM and SH3 domain protein 1 (LASP1) has been described as a novel CXCR4 binding partner and as a promoter of the PI3K/AKT pathway. In this study, we uncovered a direct binding of LASP1, phosphorylated at S146, to both CXCR4 and AKT1, as shown by immunoprecipitation assays, pull-down experiments, and immunohistochemistry data. In contrast, phosphorylation of LASP1 at Y171 abrogated these interactions, suggesting that both LASP1 phospho-forms interact. Finally, findings demonstrating different phosphorylation patterns of LASP1 in breast cancer and chronic myeloid leukemia may have implications for CXCR4 function and tyrosine kinase inhibitor treatment. KW - LASP1 KW - CXCR4 KW - AKT1 KW - CML KW - breast cancer Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200638 SN - 2073-4409 VL - 9 IS - 2 ER - TY - JOUR A1 - Vollmuth, Christoph A1 - Muljukov, Olga A1 - Abu-Mugheisib, Mazen A1 - Angermeier, Anselm A1 - Barlinn, Jessica A1 - Busetto, Loraine A1 - Grau, Armin J. A1 - Günther, Albrecht A1 - Gumbinger, Christoph A1 - Hubert, Nikolai A1 - Hüttemann, Katrin A1 - Klingner, Carsten A1 - Naumann, Markus A1 - Palm, Frederick A1 - Remi, Jan A1 - Rücker, Viktoria A1 - Schessl, Joachim A1 - Schlachetzki, Felix A1 - Schuppner, Ramona A1 - Schwab, Stefan A1 - Schwartz, Andreas A1 - Trommer, Adrian A1 - Urbanek, Christian A1 - Volbers, Bastian A1 - Weber, Joachim A1 - Wojciechowski, Claudia A1 - Worthmann, Hans A1 - Zickler, Philipp A1 - Heuschmann, Peter U. A1 - Haeusler, Karl Georg A1 - Hubert, Gordian Jan T1 - Impact of the coronavirus disease 2019 pandemic on stroke teleconsultations in Germany in the first half of 2020 JF - European Journal of Neurology N2 - Background and purpose The effects of the coronavirus disease 2019 (COVID-19) pandemic on telemedical care have not been described on a national level. Thus, we investigated the medical stroke treatment situation before, during, and after the first lockdown in Germany. Methods In this nationwide, multicenter study, data from 14 telemedical networks including 31 network centers and 155 spoke hospitals covering large parts of Germany were analyzed regarding patients' characteristics, stroke type/severity, and acute stroke treatment. A survey focusing on potential shortcomings of in-hospital and (telemedical) stroke care during the pandemic was conducted. Results Between January 2018 and June 2020, 67,033 telemedical consultations and 38,895 telemedical stroke consultations were conducted. A significant decline of telemedical (p < 0.001) and telemedical stroke consultations (p < 0.001) during the lockdown in March/April 2020 and a reciprocal increase after relaxation of COVID-19 measures in May/June 2020 were observed. Compared to 2018–2019, neither stroke patients' age (p = 0.38), gender (p = 0.44), nor severity of ischemic stroke (p = 0.32) differed in March/April 2020. Whereas the proportion of ischemic stroke patients for whom endovascular treatment (14.3% vs. 14.6%; p = 0.85) was recommended remained stable, there was a nonsignificant trend toward a lower proportion of recommendation of intravenous thrombolysis during the lockdown (19.0% vs. 22.1%; p = 0.052). Despite the majority of participating network centers treating patients with COVID-19, there were no relevant shortcomings reported regarding in-hospital stroke treatment or telemedical stroke care. Conclusions Telemedical stroke care in Germany was able to provide full service despite the COVID-19 pandemic, but telemedical consultations declined abruptly during the lockdown period and normalized after relaxation of COVID-19 measures in Germany. KW - COVID-19 KW - SARS-CoV- 2 KW - stroke KW - telemedicine KW - survey Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259396 VL - 28 IS - 10 ER - TY - JOUR A1 - Brevik, Erlend J A1 - van Donkelaar, Marjolein M. J. A1 - Weber, Heike A1 - Sánchez-Mora, Cristina A1 - Jacob, Christian A1 - Rivero, Olga A1 - Kittel-Schneider, Sarah A1 - Garcia-martinez, Iris A1 - Aebi, Marcel A1 - van Hulzen, Kimm A1 - Cormand, Bru A1 - Ramos-Quiroga, Josep A A1 - Lesch, Klaus-Peter A1 - Reif, Andreas A1 - Ribases, Marta A1 - Franke, Barbara A1 - Posserud, Maj-Britt A1 - Johansson, Stefan A1 - Lundervold, Astri J. A1 - Haavik, Jan A1 - Zayats, Tetyana T1 - Genome-wide analyses of aggressiveness in attention-deficit hyperactivity disorder JF - American Journal of Medical Genetics Part B-Neuropsychiatric Genetics N2 - Aggressiveness is a behavioral trait that has the potential to be harmful to individuals and society. With an estimated heritability of about 40%, genetics is important in its development. We performed an exploratory genome-wide association (GWA) analysis of childhood aggressiveness in attention deficit hyperactivity disorder (ADHD) to gain insight into the underlying biological processes associated with this trait. Our primary sample consisted of 1,060 adult ADHD patients (aADHD). To further explore the genetic architecture of childhood aggressiveness, we performed enrichment analyses of suggestive genome-wide associations observed in aADHD among GWA signals of dimensions of oppositionality (defiant/vindictive and irritable dimensions) in childhood ADHD (cADHD). No single polymorphism reached genome-wide significance (P<5.00E-08). The strongest signal in aADHD was observed at rs10826548, within a long noncoding RNA gene (beta = -1.66, standard error (SE) = 0.34, P = 1.07E-06), closely followed by rs35974940 in the neurotrimin gene (beta = 3.23, SE = 0.67, P = 1.26E-06). The top GWA SNPs observed in aADHD showed significant enrichment of signals from both the defiant/vindictive dimension (Fisher's P-value = 2.28E-06) and the irritable dimension in cADHD (Fisher's P-value = 0.0061). In sum, our results identify a number of biologically interesting markers possibly underlying childhood aggressiveness and provide targets for further genetic exploration of aggressiveness across psychiatric disorders. KW - Large multicenter ADHD KW - Antisocial behavior KW - Diagnostic approach KW - Rating scale KW - Gene KW - Deficit/hyperactivity disorder KW - Susceptibility loci KW - Conduct disorder KW - Association KW - Adult KW - ADHD KW - Aggression KW - GWAS Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188116 VL - 171B IS - 5 ER - TY - JOUR A1 - Gottschalk, Michael G. A1 - Richter, Jan A1 - Ziegler, Christiane A1 - Schiele, Miriam A. A1 - Mann, Julia A1 - Geiger, Maximilian J. A1 - Schartner, Christoph A1 - Homola, György A. A1 - Alpers, Georg W. A1 - Büchel, Christian A1 - Fehm, Lydia A1 - Fydrich, Thomas A1 - Gerlach, Alexander L. A1 - Gloster, Andrew T. A1 - Helbig-Lang, Sylvia A1 - Kalisch, Raffael A1 - Kircher, Tilo A1 - Lang, Thomas A1 - Lonsdorf, Tina B. A1 - Pané-Farré, Christiane A. A1 - Ströhle, Andreas A1 - Weber, Heike A1 - Zwanzger, Peter A1 - Arolt, Volker A1 - Romanos, Marcel A1 - Wittchen, Hans-Ulrich A1 - Hamm, Alfons A1 - Pauli, Paul A1 - Reif, Andreas A1 - Deckert, Jürgen A1 - Neufang, Susanne A1 - Höfler, Michael A1 - Domschke, Katharina T1 - Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes JF - Translational Psychiatry N2 - Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system. KW - human behaviour KW - molecular neuroscience KW - personalized medicine KW - predictive markers KW - psychiatric disorders Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227479 VL - 9 ER -