@article{ElHelouBiegnerBodeetal.2019, author = {El-Helou, Sabine M. and Biegner, Anika-Kerstin and Bode, Sebastian and Ehl, Stephan R. and Heeg, Maximilian and Maccari, Maria E. and Ritterbusch, Henrike and Speckmann, Carsten and Rusch, Stephan and Scheible, Raphael and Warnatz, Klaus and Atschekzei, Faranaz and Beider, Renata and Ernst, Diana and Gerschmann, Stev and Jablonka, Alexandra and Mielke, Gudrun and Schmidt, Reinhold E. and Sch{\"u}rmann, Gesine and Sogkas, Georgios and Baumann, Ulrich H. and Klemann, Christian and Viemann, Dorothee and Bernuth, Horst von and Kr{\"u}ger, Renate and Hanitsch, Leif G. and Scheibenbogen, Carmen M. and Wittke, Kirsten and Albert, Michael H. and Eichinger, Anna and Hauck, Fabian and Klein, Christoph and Rack-Hoch, Anita and Sollinger, Franz M. and Avila, Anne and Borte, Michael and Borte, Stephan and Fasshauer, Maria and Hauenherm, Anja and Kellner, Nils and M{\"u}ller, Anna H. and {\"U}lzen, Anett and Bader, Peter and Bakhtiar, Shahrzad and Lee, Jae-Yun and Heß, Ursula and Schubert, Ralf and W{\"o}lke, Sandra and Zielen, Stefan and Ghosh, Sujal and Laws, Hans-Juergen and Neubert, Jennifer and Oommen, Prasad T. and H{\"o}nig, Manfred and Schulz, Ansgar and Steinmann, Sandra and Klaus, Schwarz and D{\"u}ckers, Gregor and Lamers, Beate and Langemeyer, Vanessa and Niehues, Tim and Shai, Sonu and Graf, Dagmar and M{\"u}glich, Carmen and Schmalzing, Marc T. and Schwaneck, Eva C. and Tony, Hans-Peter and Dirks, Johannes and Haase, Gabriele and Liese, Johannes G. and Morbach, Henner and Foell, Dirk and Hellige, Antje and Wittkowski, Helmut and Masjosthusmann, Katja and Mohr, Michael and Geberzahn, Linda and Hedrich, Christian M. and M{\"u}ller, Christiane and R{\"o}sen-Wolff, Angela and Roesler, Joachim and Zimmermann, Antje and Behrends, Uta and Rieber, Nikolaus and Schauer, Uwe and Handgretinger, Rupert and Holzer, Ursula and Henes, J{\"o}rg and Kanz, Lothar and Boesecke, Christoph and Rockstroh, J{\"u}rgen K. and Schwarze-Zander, Carolynne and Wasmuth, Jan-Christian and Dilloo, Dagmar and H{\"u}lsmann, Brigitte and Sch{\"o}nberger, Stefan and Schreiber, Stefan and Zeuner, Rainald and Ankermann, Tobias and Bismarck, Philipp von and Huppertz, Hans-Iko and Kaiser-Labusch, Petra and Greil, Johann and Jakoby, Donate and Kulozik, Andreas E. and Metzler, Markus and Naumann-Bartsch, Nora and Sobik, Bettina and Graf, Norbert and Heine, Sabine and Kobbe, Robin and Lehmberg, Kai and M{\"u}ller, Ingo and Herrmann, Friedrich and Horneff, Gerd and Klein, Ariane and Peitz, Joachim and Schmidt, Nadine and Bielack, Stefan and Groß-Wieltsch, Ute and Classen, Carl F. and Klasen, Jessica and Deutz, Peter and Kamitz, Dirk and Lassy, Lisa and Tenbrock, Klaus and Wagner, Norbert and Bernbeck, Benedikt and Brummel, Bastian and Lara-Villacanas, Eusebia and M{\"u}nstermann, Esther and Schneider, Dominik T. and Tietsch, Nadine and Westkemper, Marco and Weiß, Michael and Kramm, Christof and K{\"u}hnle, Ingrid and Kullmann, Silke and Girschick, Hermann and Specker, Christof and Vinnemeier-Laubenthal, Elisabeth and Haenicke, Henriette and Schulz, Claudia and Schweigerer, Lothar and M{\"u}ller, Thomas G. and Stiefel, Martina and Belohradsky, Bernd H. and Soetedjo, Veronika and Kindle, Gerhard and Grimbacher, Bodo}, title = {The German national registry of primary immunodeficiencies (2012-2017)}, series = {Frontiers in Immunology}, volume = {10}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2019.01272}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226629}, year = {2019}, abstract = {Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57\% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36\% of patients. Familial cases were observed in 21\% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74\%) and immune dysregulation (22\%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE-syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49\% of all patients received immunoglobulin G (IgG) substitution (70\%-subcutaneous; 29\%-intravenous; 1\%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.}, language = {en} } @article{HaukeHorvathGrossetal.2018, author = {Hauke, Jan and Horvath, Judit and Groß, Eva and Gehrig, Andrea and Honisch, Ellen and Hackmann, Karl and Schmidt, Gunnar and Arnold, Norbert and Faust, Ulrike and Sutter, Christian and Hentschel, Julia and Wang-Gohrke, Shan and Smogavec, Mateja and Weber, Bernhard H. F. and Weber-Lassalle, Nana and Weber-Lassalle, Konstantin and Borde, Julika and Ernst, Corinna and Altm{\"u}ller, Janine and Volk, Alexander E. and Thiele, Holger and H{\"u}bbel, Verena and N{\"u}rnberg, Peter and Keupp, Katharina and Versmold, Beatrix and Pohl, Esther and Kubisch, Christian and Grill, Sabine and Paul, Victoria and Herold, Natalie and Lichey, Nadine and Rhiem, Kerstin and Ditsch, Nina and Ruckert, Christian and Wappenschmidt, Barbara and Auber, Bernd and Rump, Andreas and Niederacher, Dieter and Haaf, Thomas and Ramser, Juliane and Dworniczak, Bernd and Engel, Christoph and Meindl, Alfons and Schmutzler, Rita K. and Hahnen, Eric}, title = {Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer}, series = {Cancer Medicine}, journal = {Cancer Medicine}, doi = {10.1002/cam4.1376}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227902}, pages = {1349-1358}, year = {2018}, abstract = {The prevalence of germ line mutations in non-BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK2 gene (2.5\%), followed by ATM (1.5\%) and PALB2 (1.2\%). The mutation prevalence in each of the remaining genes was 0.3\% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM (OR: 3.63, 95\%CI: 2.67-4.94), CDH1 (OR: 17.04, 95\%CI: 3.54-82), CHEK2 (OR: 2.93, 95\%CI: 2.29-3.75), PALB2 (OR: 9.53, 95\%CI: 6.25-14.51), and TP53 (OR: 7.30, 95\%CI: 1.22-43.68). NBN germ line mutations were not significantly associated with BC risk (OR:1.39, 95\%CI: 0.73-2.64). Due to their low mutation prevalence, the RAD51C and RAD51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK2 and TP53 in BC index patients. Compared with the overall sample, only TP53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK2, PALB2, and TP53 genes with bilateral BC. Both, ATM and CHEK2, were negatively associated with triple-negative breast cancer (TNBC) and estrogen receptor (ER)-negative tumor phenotypes. A particularly high CHEK2 mutation prevalence (5.2\%) was observed in patients with human epidermal growth factor receptor 2 (HER2)-positive tumors.}, language = {en} } @article{MarenholzEsparzaGordilloRueschendorfetal.2015, author = {Marenholz, Ingo and Esparza-Gordillo, Jorge and R{\"u}schendorf, Franz and Bauerfeind, Anja and Strachan, David P. and Spycher, Ben D. and Baurecht, Hansj{\"o}rg and Magaritte-Jeannin, Patricia and S{\"a}{\"a}f, Annika and Kerkhof, Marjan and Ege, Markus and Baltic, Svetlana and Matheson, Melanie C. and Li, Jin and Michel, Sven and Ang, Wei Q. and McArdle, Wendy and Arnold, Andreas and Homuth, Georg and Demenais, Florence and Bouzigon, Emmanuelle and S{\"o}derh{\"a}ll, Cilla and Pershagen, G{\"o}ran and de Jongste, Johan C. and Postma, Dirkje S. and Braun-Fahrl{\"a}nder, Charlotte and Horak, Elisabeth and Ogorodova, Ludmila M. and Puzyrev, Valery P. and Bragina, Elena Yu and Hudson, Thomas J. and Morin, Charles and Duffy, David L. and Marks, Guy B. and Robertson, Colin F. and Montgomery, Grant W. and Musk, Bill and Thompson, Philip J. and Martin, Nicholas G. and James, Alan and Sleiman, Patrick and Toskala, Elina and Rodriguez, Elke and F{\"o}lster-Holst, Regina and Franke, Andre and Lieb, Wolfgang and Gieger, Christian and Heinzmann, Andrea and Rietschel, Ernst and Keil, Thomas and Cichon, Sven and N{\"o}then, Markus M. and Pennel, Craig E. and Sly, Peter D. and Schmidt, Carsten O. and Matanovic, Anja and Schneider, Valentin and Heinig, Matthias and H{\"u}bner, Norbert and Holt, Patrick G. and Lau, Susanne and Kabesch, Michael and Weidinger, Stefan and Hakonarson, Hakon and Ferreira, Manuel A. R. and Laprise, Catherine and Freidin, Maxim B. and Genuneit, Jon and Koppelman, Gerard H. and Mel{\´e}n, Erik and Dizier, Marie-H{\´e}l{\`e}ne and Henderson, A. John and Lee, Young Ae}, title = {Meta-analysis identifies seven susceptibility loci involved in the atopic march}, series = {Nature Communications}, volume = {6}, journal = {Nature Communications}, number = {8804}, doi = {10.1038/ncomms9804}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-139835}, year = {2015}, abstract = {Eczema often precedes the development of asthma in a disease course called the 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P = 2.1 x 10(-8)) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P = 5.3 x 10(-9)). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.}, language = {en} } @article{DornelasAntaoMoyesetal.2018, author = {Dornelas, Maria and Ant{\~a}o, Laura H. and Moyes, Faye and Bates, Amanda E. and Magurran, Anne E. and Adam, Dušan and Akhmetzhanova, Asem A. and Appeltans, Ward and Arcos, Jos{\´e} Manuel and Arnold, Haley and Ayyappan, Narayanan and Badihi, Gal and Baird, Andrew H. and Barbosa, Miguel and Barreto, Tiago Egydio and B{\"a}ssler, Claus and Bellgrove, Alecia and Belmaker, Jonathan and Benedetti-Cecchi, Lisandro and Bett, Brian J. and Bjorkman, Anne D. and Błażewicz, Magdalena and Blowes, Shane A. and Bloch, Christopher P. Bloch and Bonebrake, Timothy C. and Boyd, Susan and Bradford, Matt and Brooks, Andrew J. and Brown, James H. and Bruelheide, Helge and Budy, Phaedra and Carvalho, Fernando and Casta{\~n}eda-Moya, Edward and Chen, Chaolun Allen and Chamblee, John F. and Chase, Tory J. and Siegwart Collier, Laura and Collinge, Sharon K. and Condit, Richard and Cooper, Elisabeth J. and Cornelissen, J. Hans C. and Cotano, Unai and Crow, Shannan Kyle and Damasceno, Gabriella and Davies, Claire H. and Davis, Robert A. and Day, Frank P. and Degraer, Steven and Doherty, Tim S. and Dunn, Timothy E. and Durigan, Giselda and Duffy, J. Emmett and Edelist, Dor and Edgar, Graham J. and Elahi, Robin and Elmendorf, Sarah C. and Enemar, Anders and Ernest, S. K. Morgan and Escribano, Rub{\´e}n and Estiarte, Marc and Evans, Brian S. and Fan, Tung-Yung and Turini Farah, Fabiano and Loureiro Fernandes, Luiz and Farneda, F{\´a}bio Z. and Fidelis, Alessandra and Fitt, Robert and Fosaa, Anna Maria and Franco, Geraldo Antonio Daher Correa and Frank, Grace E. and Fraser, William R. and Garc{\´i}a, Hernando and Cazzolla Gatti, Roberto and Givan, Or and Gorgone-Barbosa, Elizabeth and Gould, William A. and Gries, Corinna and Grossman, Gary D. and Gutierr{\´e}z, Julio R. and Hale, Stephen and Harmon, Mark E. and Harte, John and Haskins, Gary and Henshaw, Donald L. and Hermanutz, Luise and Hidalgo, Pamela and Higuchi, Pedro and Hoey, Andrew and Van Hoey, Gert and Hofgaard, Annika and Holeck, Kristen and Hollister, Robert D. and Holmes, Richard and Hoogenboom, Mia and Hsieh, Chih-hao and Hubbell, Stephen P. and Huettmann, Falk and Huffard, Christine L. and Hurlbert, Allen H. and Ivanauskas, Nat{\´a}lia Macedo and Jan{\´i}k, David and Jandt, Ute and Jażdżewska, Anna and Johannessen, Tore and Johnstone, Jill and Jones, Julia and Jones, Faith A. M. and Kang, Jungwon and Kartawijaya, Tasrif and Keeley, Erin C. and Kelt, Douglas A. and Kinnear, Rebecca and Klanderud, Kari and Knutsen, Halvor and Koenig, Christopher C. and Kortz, Alessandra R. and Kr{\´a}l, Kamil and Kuhnz, Linda A. and Kuo, Chao-Yang and Kushner, David J. and Laguionie-Marchais, Claire and Lancaster, Lesley T. and Lee, Cheol Min and Lefcheck, Jonathan S. and L{\´e}vesque, Esther and Lightfoot, David and Lloret, Francisco and Lloyd, John D. and L{\´o}pez-Baucells, Adri{\`a} and Louzao, Maite and Madin, Joshua S. and Magn{\´u}sson, Borgþ{\´o}r and Malamud, Shahar and Matthews, Iain and McFarland, Kent P. and McGill, Brian and McKnight, Diane and McLarney, William O. and Meador, Jason and Meserve, Peter L. and Metcalfe, Daniel J. and Meyer, Christoph F. J. and Michelsen, Anders and Milchakova, Nataliya and Moens, Tom and Moland, Even and Moore, Jon and Moreira, Carolina Mathias and M{\"u}ller, J{\"o}rg and Murphy, Grace and Myers-Smith, Isla H. and Myster, Randall W. and Naumov, Andrew and Neat, Francis and Nelson, James A. and Nelson, Michael Paul and Newton, Stephen F. and Norden, Natalia and Oliver, Jeffrey C. and Olsen, Esben M. and Onipchenko, Vladimir G. and Pabis, Krzysztof and Pabst, Robert J. and Paquette, Alain and Pardede, Sinta and Paterson, David M. and P{\´e}lissier, Rapha{\"e}l and Pe{\~n}uelas, Josep and P{\´e}rez-Matus, Alejandro and Pizarro, Oscar and Pomati, Francesco and Post, Eric and Prins, Herbert H. T. and Priscu, John C. and Provoost, Pieter and Prudic, Kathleen L. and Pulliainen, Erkki and Ramesh, B. R. and Ramos, Olivia Mendivil and Rassweiler, Andrew and Rebelo, Jose Eduardo and Reed, Daniel C. and Reich, Peter B. and Remillard, Suzanne M. and Richardson, Anthony J. and Richardson, J. Paul and van Rijn, Itai and Rocha, Ricardo and Rivera-Monroy, Victor H. and Rixen, Christian and Robinson, Kevin P. and Rodrigues, Ricardo Ribeiro and de Cerqueira Rossa-Feres, Denise and Rudstam, Lars and Ruhl, Henry and Ruz, Catalina S. and Sampaio, Erica M. and Rybicki, Nancy and Rypel, Andrew and Sal, Sofia and Salgado, Beatriz and Santos, Flavio A. M. and Savassi-Coutinho, Ana Paula and Scanga, Sara and Schmidt, Jochen and Schooley, Robert and Setiawan, Fakhrizal and Shao, Kwang-Tsao and Shaver, Gaius R. and Sherman, Sally and Sherry, Thomas W. and Siciński, Jacek and Sievers, Caya and da Silva, Ana Carolina and da Silva, Fernando Rodrigues and Silveira, Fabio L. and Slingsby, Jasper and Smart, Tracey and Snell, Sara J. and Soudzilovskaia, Nadejda A. and Souza, Gabriel B. G. and Souza, Flaviana Maluf and Souza, Vin{\´i}cius Castro and Stallings, Christopher D. and Stanforth, Rowan and Stanley, Emily H. and Sterza, Jos{\´e} Mauro and Stevens, Maarten and Stuart-Smith, Rick and Suarez, Yzel Rondon and Supp, Sarah and Tamashiro, Jorge Yoshio and Tarigan, Sukmaraharja and Thiede, Gary P. and Thorn, Simon and Tolvanen, Anne and Toniato, Maria Teresa Zugliani and Totland, {\O}rjan and Twilley, Robert R. and Vaitkus, Gediminas and Valdivia, Nelson and Vallejo, Martha Isabel and Valone, Thomas J. and Van Colen, Carl and Vanaverbeke, Jan and Venturoli, Fabio and Verheye, Hans M. and Vianna, Marcelo and Vieira, Rui P. and Vrška, Tom{\´a}š and Vu, Con Quang and Vu, Lien Van and Waide, Robert B. and Waldock, Conor and Watts, Dave and Webb, Sara and Wesołowski, Tomasz and White, Ethan P. and Widdicombe, Claire E. and Wilgers, Dustin and Williams, Richard and Williams, Stefan B. and Williamson, Mark and Willig, Michael R. and Willis, Trevor J. and Wipf, Sonja and Woods, Kerry D. and Woehler, Eric J. and Zawada, Kyle and Zettler, Michael L.}, title = {BioTIME: A database of biodiversity time series for the Anthropocene}, series = {Global Ecology and Biogeography}, volume = {27}, journal = {Global Ecology and Biogeography}, doi = {10.1111/geb.12729}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222846}, pages = {760-786}, year = {2018}, abstract = {Motivation The BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community-led open-source database of biodiversity time series. Our goal is to accelerate and facilitate quantitative analysis of temporal patterns of biodiversity in the Anthropocene. Main types of variables included The database contains 8,777,413 species abundance records, from assemblages consistently sampled for a minimum of 2 years, which need not necessarily be consecutive. In addition, the database contains metadata relating to sampling methodology and contextual information about each record. Spatial location and grain BioTIME is a global database of 547,161 unique sampling locations spanning the marine, freshwater and terrestrial realms. Grain size varies across datasets from 0.0000000158 km2 (158 cm2) to 100 km2 (1,000,000,000,000 cm2). Time period and grain BioTIME records span from 1874 to 2016. The minimal temporal grain across all datasets in BioTIME is a year. Major taxa and level of measurement BioTIME includes data from 44,440 species across the plant and animal kingdoms, ranging from plants, plankton and terrestrial invertebrates to small and large vertebrates. Software format .csv and .SQL.}, language = {en} } @article{KleinschnitzGrundWingleretal.2010, author = {Kleinschnitz, Christoph and Grund, Henrike and Wingler, Kirstin and Armitage, Melanie E. and Jones, Emma and Mittal, Manish and Barit, David and Schwarz, Tobias and Geis, Christian and Kraft, Peter and Barthel, Konstanze and Schuhmann, Michael K. and Herrmann, Alexander M. and Meuth, Sven G. and Stoll, Guido and Meurer, Sabine and Schrewe, Anja and Becker, Lore and Gailus-Durner, Valerie and Fuchs, Helmut and Klopstock, Thomas and de Angelis, Martin Hrabe and Jandeleit-Dahm, Karin and Shah, Ajay M. and Weissmann, Norbert and Schmidt, Harald H. H. W.}, title = {Post-Stroke Inhibition of Induced NADPH Oxidase Type 4 Prevents Oxidative Stress and Neurodegeneration}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68416}, year = {2010}, abstract = {Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90\% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox42/2) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox42/2 mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy.}, subject = {Schlaganfall}, language = {en} } @phdthesis{Schmidt2015, author = {Schmidt, Thomas Christian}, title = {Theoretical Investigations on the Interactions of Small Compounds with their Molecular Environments}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127860}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Im ersten Teil dieser Arbeit wird eine Kombination theoretischer Methoden f{\"u}r die strukturbasierte Entwicklung neuer Wirkstoffe pr{\"a}sentiert. Ausgehend von der Kristallstruktur eines kovalenten Komplexes einer Modellverbindung mit dem Zielprotein wurde mit Hilfe von quantenmechanischen und QM/MM Rechnungen die genaue Geometrie des vorausgehenden nicht-kovalenten Komplexes betimmt. Letztere ist der bestimmende Faktor f{\"u}r die Reaktivit{\"a}t des Inhibitors gegen{\"u}ber der katalytisch aktiven Aminos{\"a}ure und damit f{\"u}r die Ausbildung einer kovalenten Bindung. Aus diesem Grund wurde diese Geometrie auch f{\"u}r die Optimierung der Substitutionsmusters des Ihnibitors verwendet, um dessen Affinit{\"a}t zum Zielenzyme zu verbessern ohne dass dieser seine F{\"a}higkeit kovalent an das aktive Zentrum zu binden verliert. Die Optimierung des Substitutionsmuster wurde doch Methode des Molekularen Dockings unterst{\"u}tzt, das diese optimal dazu geeignet sind, Bindungsaffinit{\"a}ten vorherzusagen, die durch eine Modifikation der chemischen Struktur entstehen. Eine Auswahl der besten Strukturen wurde anschließend verwendet, um zu {\"u}berpr{\"u}fen, ob die ver{\"a}nderten Molek{\"u}le noch gen{\"u}gen Reaktivit{\"a}t gegen{\"u}ber dem Zielprotein aufweisen. Molek{\"u}ldynamik Simulationen der neuen Verbindungen haben jedoch gezeigt, dass die ver{\"a}nderten Verbindungen nur so and das Protein binden, dass die Bilung eine kovalenten Bindung zum Enzym nicht mehr m{\"o}glich ist. Daher wurden in einem weiteren Schritt die Modellverbindungen weiter modifiziert. Neben {\"A}nderungen im Substitutionsmuster wurde auch die chemische Struktur im Kern ver{\"a}ndert. Die Bindungsaffinit{\"a}ten wurde wieder mittels Docking {\"u}berpr{\"u}ft. F{\"u}r die besten Bindungsposen wurden wieder Simulationen zur Molek{\"u}ldynamik durchgef{\"u}hrt, wobei diesmal die Ausbildung einer kovalenten Bindung zum Enzyme m{\"o}glich erscheint. In einer abschließenden Serie von QM/MM Rechnungen unter Ber{\"u}cksichtigung verschiedener Protonierungszust{\"a}nde des Inhibitors und des Proteins konnten Reaktionspfade und zugeh{\"o}rige Reaktionsenergien bestimmt werden. Die Ergebnisse lassen darauf schließen, dass eines der neu entwickelten Molek{\"u}le sowohl eine stark verbesserte Bindungsaffinit{\"a}t wie auch die M{\"o}glichkeit der kovalenten Bindung an Enzyme aufweist. Der zweite Teil der Arbeit konzentriert sich auf die Umgebungseinfl{\"u}sse auf die Elektronenverteilung eines Inhibitormodells. Als Grundlage dient ein vinylsulfon-basiertes Moek{\"u}l, f{\"u}r das eine experimentell bestimmte Kristallstruktur sowie ein theoretisch berechneter Protein Komplex verf{\"u}gbar sind. Ein Referendatensatz f{\"u}r diese Systeme wurde erstellt, indem der Konformationsraum des Inhibitors nach m{\"o}glichen Minimumsstrukturen abgesucht wurde, welche sp{\"a}ter mit den Geometrien des Molek{\"u}ls im Kristall und im Protein verglichen werden konnten. The Geometrie in der Kristallumgebung konnte direkt aus den experimentellen Daten {\"u}bernommen werden. Rechnungen zum nicht-kovalenten Protein Komplex hingegen haben gezeigt, dass f{\"u}r das Modellsystem mehrere Geometrien des Inhibiors sowie zwei Protonierungszust{\"a}nde f{\"u}r die katalytisch aktiven Aminos{\"a}uren m{\"o}glich sind. F{\"u}r die Analyse wurden daher alle m{\"o}glichen Proteinkomplexe mit der Kristallstruktur verglichen. Ebenso wurden Vergleiche mit der Geometrie des isolierten Molek{\"u}ls im Vakuum sowie der Geometrie in w{\"a}ssriger L{\"o}sung angestellt. F{\"u}r die Geometrie des Molek{\"u}ls an sich ergab sich eine gute {\"U}bereinstimmung f{\"u}r alle Modellsysteme, f{\"u}r die Wechselwirkungen mit der Umgebung jedoch nicht. Die Ausbildung von Dimeren in der Kristallumgebung hat einen stark stablisierenden Effekt und ist einer der Gr{\"u}nde, warum dieser Kristall so gut wie keine Fehlordungen aufweist. In den Proteinkomplexen hingegen ergibt sich eine Abstoßung zwischen dem Inhibitor und einer der katalytisch aktiven Aminos{\"a}uren. Als Ursache f{\"u}r diese Abstoßung konnte die Einf{\"u}hrung der Methylaminfunktion ausgemacht werden. Vermutlicherweise f{\"u}hrt diese strukturelle {\"A}nderung auch dazu, dass der Modellinhibitor nicht in der Lage ist, so wie die Leitstruktur K11777 an das aktive Zentrum des Enzyms zu binden.}, subject = {Theoretische Chemie}, language = {en} } @article{MuellerThomasRudeliusRondaketal.2014, author = {M{\"u}ller-Thomas, Catharina and Rudelius, Martina and Rondak, Ina-Christine and Haferlach, Torsten and Schanz, Julie and Huberle, Christina and Schmidt, Burkard and Blaser, Rainer and Kremer, Marcus and Peschel, Christian and Germing, Ulrich and Platzbecker, Uwe and Goetze, Katharina}, title = {Response to azacitidine is independent of p53 expression in higher-risk myelodysplastic syndromes and secondary acute myeloid leukemia}, series = {HAEMATOLOGICA}, volume = {99}, journal = {HAEMATOLOGICA}, number = {10}, issn = {1592-8721}, doi = {10.3324/haematol.2014.104760}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115313}, pages = {E179-E181}, year = {2014}, abstract = {No abstract available.}, language = {en} } @article{PinkawaAebersoldBoehmeretal.2021, author = {Pinkawa, Michael and Aebersold, Daniel M. and B{\"o}hmer, Dirk and Flentje, Michael and Ghadjar, Pirus and Schmidt-Hegemann, Nina-Sophie and H{\"o}cht, Stefan and H{\"o}lscher, Tobias and M{\"u}ller, Arndt-Christian and Niehoff, Peter and Sedlmayer, Felix and Wolf, Frank and Zamboglou, Constantinos and Zips, Daniel and Wiegel, Thomas}, title = {Radiotherapy in nodal oligorecurrent prostate cancer}, series = {Strahlentherapie und Onkologie}, volume = {197}, journal = {Strahlentherapie und Onkologie}, number = {7}, issn = {0179-7158}, doi = {10.1007/s00066-021-01778-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307763}, pages = {575-580}, year = {2021}, abstract = {Objective The current article encompasses a literature review and recommendations for radiotherapy in nodal oligorecurrent prostate cancer. Materials and methods A literature review focused on studies comparing metastasis-directed stereotactic ablative radiotherapy (SABR) vs. external elective nodal radiotherapy (ENRT) and studies analyzing recurrence patterns after local nodal treatment was performed. The DEGRO Prostate Cancer Expert Panel discussed the results and developed treatment recommendations. Results Metastasis-directed radiotherapy results in high local control (often > 90\% within a follow-up of 1-2 years) and can be used to improve progression-free survival or defer androgen deprivation therapy (ADT) according to prospective randomized phase II data. Distant progression after involved-node SABR only occurs within a few months in the majority of patients. ENRT improves metastases-free survival rates with increased toxicity in comparison to SABR according to retrospective comparative studies. The majority of nodal recurrences after initial local treatment of pelvic nodal metastasis are detected within the true pelvis and common iliac vessels. Conclusion ENRT with or without a boost should be preferred to SABR in pelvic nodal recurrences. In oligometastatic prostate cancer with distant (extrapelvic) nodal recurrences, SABR alone can be performed in selected cases. Application of additional systemic treatments should be based on current guidelines, with ADT as first-line treatment for hormone-sensitive prostate cancer. Only in carefully selected patients can radiotherapy be initially used without additional ADT outside of the current standard recommendations. Results of (randomized) prospective studies are needed for definitive recommendations.}, language = {en} } @article{PrelogHilligardtSchmidtetal.2016, author = {Prelog, Martina and Hilligardt, Deborah and Schmidt, Christian A. and Przybylski, Grzegorz K. and Leierer, Johannes and Almanzar, Giovanni and El Hajj, Nady and Lesch, Klaus-Peter and Arolt, Volker and Zwanzger, Peter and Haaf, Thomas and Domschke, Katharina}, title = {Hypermethylation of FOXP3 Promoter and Premature Aging of the Immune System in Female Patients with Panic Disorder?}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0157930}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-179684}, year = {2016}, abstract = {Immunological abnormalities associated with pathological conditions, such as higher infection rates, inflammatory diseases, cancer or cardiovascular events are common in patients with panic disorder. In the present study, T cell receptor excision circles (TRECs), Forkhead-Box-Protein P3 gene (FOXP3) methylation of regulatory T cells (Tregs) and relative telomere lengths (RTLs) were investigated in a total and subsamples of 131 patients with panic disorder as compared to 131 age- and sex-matched healthy controls in order to test for a potential dysfunction and premature aging of the immune system in anxiety disorders. Significantly lower TRECs (p = 0.004) as well as significant hypermethylation of the FOXP3 promoter region (p = 0.005) were observed in female (but not in male) patients with panic disorder as compared to healthy controls. No difference in relative telomere length was discerned between patients and controls, but significantly shorter telomeres in females, smokers and older persons within the patient group. The presently observed reduced TRECs in panic disorder patients and FOXP3 hypermethylation in female patients with panic disorder potentially reflect impaired thymus and immunosuppressive Treg function, which might partly account for the known increased morbidity and mortality of anxiety disorders conferred by e.g. cancer and cardiovascular disorders.}, language = {en} }