TY - JOUR A1 - Degenkolbe, Elisa A1 - König, Jana A1 - Zimmer, Julia A1 - Walther, Maria A1 - Reißner, Carsten A1 - Nickel, Joachim A1 - Plöger, Frank A1 - Raspopovic, Jelena A1 - Sharpe, James A1 - Dathe, Katharina A1 - Hecht, Jacqueline T. A1 - Mundlos, Stefan A1 - Doelken, Sandra C. A1 - Seemann, Petra T1 - A GDF5 Point Mutation Strikes Twice - Causing BDA1 and SYNS2 JF - PLOS Genetics N2 - Growth and Differentiation Factor 5 (GDF5) is a secreted growth factor that belongs to the Bone Morphogenetic Protein (BMP) family and plays a pivotal role during limb development. GDF5 is a susceptibility gene for osteoarthritis (OA) and mutations in GDF5 are associated with a wide variety of skeletal malformations ranging from complex syndromes such as acromesomelic chondrodysplasias to isolated forms of brachydactylies or multiple synostoses syndrome 2 (SYNS2). Here, we report on a family with an autosomal dominant inherited combination of SYNS2 and additional brachydactyly type A1 (BDA1) caused by a single point mutation in GDF5 (p.W414R). Functional studies, including chondrogenesis assays with primary mesenchymal cells, luciferase reporter gene assays and Surface Plasmon Resonance analysis, of the GDF5 W-414R variant in comparison to other GDF5 mutations associated with isolated BDA1 (p.R399C) or SYNS2 (p.E491K) revealed a dual pathomechanism characterized by a gain-and loss-of-function at the same time. On the one hand insensitivity to the main GDF5 antagonist NOGGIN (NOG) leads to a GDF5 gain of function and subsequent SYNS2 phenotype. Whereas on the other hand, a reduced signaling activity, specifically via the BMP receptor type IA (BMPR1A), is likely responsible for the BDA1 phenotype. These results demonstrate that one mutation in the overlapping interface of antagonist and receptor binding site in GDF5 can lead to a GDF5 variant with pathophysiological relevance for both, BDA1 and SYNS2 development. Consequently, our study assembles another part of the molecular puzzle of how loss and gain of function mutations in GDF5 affect bone development in hands and feet resulting in specific types of brachydactyly and SYNS2. These novel insights into the biology of GDF5 might also provide further clues on the pathophysiology of OA. KW - dominant-negative mutatio KW - morphogenetic protein receptors KW - brachtydacyly type A2 KW - BMP KW - gene encoding noggin KW - growth factor beta KW - signal tranduction KW - molecular mechanism KW - crystal-structure KW - differentiation Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127556 SN - 1553-7404 VL - 9 IS - 10 ER - TY - JOUR A1 - Schmitt, Jana A1 - Keller, Andreas A1 - Nourkami-Tutdibi, Nasenien A1 - Heisel, Sabrina A1 - Habel, Nunja A1 - Leidinger, Petra A1 - Ludwig, Nicole A1 - Gessler, Manfred A1 - Graf, Norbert A1 - Berthold, Frank A1 - Lenhof, Hans-Peter A1 - Meese, Eckart T1 - Autoantibody Signature Differentiates Wilms Tumor Patients from Neuroblastoma Patients JF - PLoS ONE N2 - Several studies report autoantibody signatures in cancer. The majority of these studies analyzed adult tumors and compared the seroreactivity pattern of tumor patients with the pattern in healthy controls. Here, we compared the autoimmune response in patients with neuroblastoma and patients with Wilms tumor representing two different childhood tumors. We were able to differentiate untreated neuroblastoma patients from untreated Wilms tumor patients with an accuracy of 86.8%, a sensitivity of 87.0% and a specificity of 86.7%. The separation of treated neuroblastoma patients from treated Wilms tumor patients' yielded comparable results with an accuracy of 83.8%. We furthermore identified the antigens that contribute most to the differentiation between both tumor types. The analysis of these antigens revealed that neuroblastoma was considerably more immunogenic than Wilms tumor. The reported antigens have not been found to be relevant for comparative analyses between other tumors and controls. In summary, neuroblastoma appears as a highly immunogenic tumor as demonstrated by the extended number of antigens that separate this tumor from Wilms tumor. KW - Heparan-sulfate KW - N-Myc KW - Serum autoantibodies KW - Suppressors EXT1 KW - Neuro-blastoma KW - Allelic loss KW - Lung-cancer KW - Children KW - Amplification KW - Therapy Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133794 VL - 6 IS - 12 ER - TY - THES A1 - Frank, Petra T1 - Weiblichkeit im Kontext von potestas und violentia : Untersuchungen zum Nibelungenlied T1 - Femininity in the Context of potestas and violentia: Studies on the Nibelungenlied N2 - Thema der Arbeit ist die Bedeutung von Macht und Gewalt für die Konstruktion von Weiblichkeit im Nibelungenlied; es handelt sich hierbei um einen der prominentesten Erzähltexte der mittelalterlichen Literaturgeschichte, der um 1200 vermutlich von einem Kleriker am Passauer Bischofshof verschriftlicht wurde. Die These, welche die vorliegende Untersuchung leitet, besteht in der Annahme, daß die Unterschiede zwischen männlichem und weiblichem Geschlecht, die im Text zutage treten, bestimmt werden durch unterschiedliche Teilhabe an Macht und Ausübung von Gewalt. In der Arbeit werden Fragestellungen der Historischen Anthropologie mit solchen der Gender Theorie verknüpft. Die Grundannahme, daß Weiblichkeit im Nibelungenlied ein soziokulturelles Produkt darstellt, an dessen Erzeugung sowohl der männliche Erzähler als auch die handelnden Figuren beteiligt sind, basiert auf zentralen Ergebnissen der Gender Studies. Das Thema der Gewalt und der historisierende Ansatz sind der Historischen Anthropologie verpflichtet. Die Untersuchung geht dementsprechend vom mittelalterlichen Gewaltbegriff aus, dessen Bedeutungsspektrum neben der willkürlichen und unrechtmäßigen Anwendung von Zwang und Unterdrückung sämtliche Grade und Formen rechtmäßiger Herrschaft umfaßt. Für die Beschreibung der zu beobachtenden Verletzungen geltender sozialer Regeln wird zudem TURNERs Theorie der Konfliktverlaufsmuster herangezogen. Die Entscheidung, das im Nibelungenlied enwickelte Konzept von Weiblichkeit als eine kulturelle Sonderwelt zu beschreiben, das auf einen außerepischen, aber gleichfalls immer nur textuell vermittelten Horizont kulturellen Wissens und sozialer Praktiken zu beziehen ist, läuft methodisch auf eine Diskursanalyse hinaus. Um Einblick in diesen Horizont zu bieten, werden zu Beginn der Untersuchung eine Reihe von für die Zeit um 1200 repräsentativen rechtlichen, theologischen und didaktischen Texten vorgestellt: der Sachsenspiegel Eikes von Repgow, einschlägige Bibelstellen, Äußerungen von Augustinus und Thomas von Aquin sowie die Winsbeckin und der Wälsche Gast Thomasins von Zerklaere. Im Zentrum der Arbeit steht die detaillierte Analyse des Nibelungenliedes. Das Reden über Gewalt und deren narrative Inszenierungen werden anhand der beiden Protagonistinnen des Epos untersucht, um den Diskurs des Werkes auf den eingangs vorgestellten außerliterarischen Rahmen beziehen zu können. N2 - Contents of the Thesis: The subject of the thesis is the significance of power and violence for the construction of femininity in the Nibelungenlied. It deals with one of the most prominent narrative texts of medieval literary history, presumably written down by a cleric at the bishop’s court of Passau (Bavaria) around the year 1200. The study is guided by the assumption that the differences between the male and the female sex becoming evident in the text are determined by the differing participation in power and exertion of violence. The dissertation links problems of Historical Anthropology to those of Gender Theory. The principal idea that femininity in the Nibelungenlied is a socio-cultural product generated both by the male narrator and the protagonists is based on central results of Gender Studies. The subject of violence and the historicising approach are committed to Historical Anthropology. Therefore, the thesis proceeds from the medieval concept of violence. The range of meanings of this concept comprises not only the arbitrary and unlawful exertion of force and suppression but also all gradations and forms of lawful rule. In addition, TURNER’s conflict theory is used for the description of the observed violation of prevailing social rules. The dissertation describes the concept of femininity developed in the Nibelungenlied as a cultural particular world. This concept is to be related to an extra-epic but also only textually communicated horizon of cultural knowledge and social practices. Methodically, this leads to a discourse analysis. In order to give an insight into this horizon, a number of legal, theological, and didactic texts representative for the time around 1200 are described at the beginning of the study: the Sachsenspiegel (Saxon Mirror) of Eike von Repgow, relevant Bible passages, statements of St. Augustine and Thomas Aquinas, Die Winsbeckin, and Wälscher Gast of Thomasin of Zerclaere. The detailed analysis of the Nibelungenlied is the focus of the dissertation. Conversations about violence and its narrative representation are examined as depicted in the two female protagonists of the epic in order to be able to relate its discourse to the extra-literary context presented at the beginning. KW - Nibelungenlied KW - Frau KW - Macht KW - Frau KW - Gewalt KW - Herrschaft KW - Mittelalter KW - Nibelungenlied KW - gender KW - power KW - violence KW - Middle Ages KW - Nibelungenlied Y1 - 2004 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-11694 ER - TY - JOUR A1 - Petzke, Frank A1 - Klose, Petra A1 - Welsch, Patrick A1 - Sommer, Claudia A1 - Häuser, Winfried T1 - Opioids for chronic low back pain: An updated systematic review and meta‐analysis of efficacy, tolerability and safety in randomized placebo‐controlled studies of at least 4 weeks of double‐blind duration JF - European Journal of Pain N2 - Background and Objective This updated systematic review evaluated the efficacy, tolerability and safety of opioids compared to placebo in non‐malignant chronic low back pain. Databases and Data Treatment Clinicaltrials.gov, CENTRAL, MEDLINE and PsycINFO were searched from October 2013 to May 2019. Randomized controlled trials comparing opioids with placebo and at least 4 weeks of double‐blinded duration were analysed. Primary outcomes were pain relief of 50% or greater, disability, tolerability and safety. Effects were summarized by a random effects model using risk differences or standardized mean differences. We added nine new studies with 2,980 participants for a total of 21 studies with 7,650 participants. Study duration ranged between 4 and 15 weeks. Studies with a parallel and cross‐over design: Based on very low to low‐quality evidence, opioids provided no clinically relevant pain relief of 50% or greater, but a clinically relevant reduction of disability compared to placebo. Enriched enrolment randomized withdrawal (EERW) design: Based on very low to low‐quality evidence, opioids provided a clinically relevant pain relief of 50% or greater, but not a clinically relevant reduction of disability compared to placebo. There was no clinically relevant harm with regard to serious adverse events by opioids compared to placebo in studies with parallel/cross‐over and EERW design. There was a relevant harm with regard to drop out rates due to adverse events in studies with parallel/cross‐over, but not in studies with EERW design. Conclusions Opioids may provide a safe and clinically relevant pain relief for 4–15 weeks in highly selected patients. Significance Within the context of randomized controlled trials of 4–15 weeks, opioids provided a clinically relevant pain relief of 30% or greater and a clinically relevant reduction of disability compared to placebo in non‐malignant chronic low back pain. Number needed to treat for an additional drop out due to side effects was 11 (95% confidence interval: 6–33). Assessment of abuse and addiction was incomplete. The frequency of serious adverse events including deaths did not differ from placebo. KW - opioids KW - back pain KW - systematic review Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218498 VL - 24 IS - 3 SP - 497 EP - 517 ER - TY - JOUR A1 - Sommer, Claudia A1 - Klose, Petra A1 - Welsch, Patrick A1 - Petzke, Frank A1 - Häuser, Winfried T1 - Opioids for chronic non‐cancer neuropathic pain. An updated systematic review and meta‐analysis of efficacy, tolerability and safety in randomized placebo‐controlled studies of at least 4 weeks duration JF - European Journal of Pain N2 - Background and Objective This updated systematic review evaluated the efficacy, tolerability and safety of opioids compared to placebo in chronic non‐cancer neuropathic pain. Databases and Data Treatment Clinicaltrials.gov, CENTRAL, PubMed and PsycINFO were searched from October 2013 to June 2019. Randomized controlled trials comparing opioids with placebo and at least 4 weeks double‐blinded duration were analysed. Primary outcomes were pain relief of 50% or greater, disability, tolerability and safety. Effects were summarized by a random effects model using risk differences (RD) or standardized mean differences (SMD). We added four new studies with 662 participants for a total of 16 included studies with 2,199 participants. Study duration ranged between 4 and 12 weeks. Studies with a parallel and cross‐over design: Based on low to moderate quality evidence, opioids (buprenorphine, hydromorphone, morphine, oxycodone, tramadol) provided a clinically relevant pain relief of 50% or greater and reduction of disability compared to placebo. There was no clinically relevant harm with regards to the drop out rate due to adverse and serious adverse events by opioids compared to placebo. Enriched enrolment randomized withdrawal design: Based on low to moderate quality evidence, tapentadol provided a clinically relevant pain relief of 50% or greater and reduction of disability compared to placebo in diabetic polyneuropathy. There was no clinically relevant harm with regards to the drop out rate due to adverse and serious adverse events by tapentadol compared to placebo. Conclusions Some opioids provided a short‐term substantial pain relief in highly selected patients in some neuropathic pain syndromes. Significance Some opioids (buprenorphine, morphine, oxycodone, tramadol, tapentadol) provide substantial pain relief compared to placebo in postherpetic neuralgia and peripheral neuropathies of different aetiologies for 4–12 weeks. There is insufficient evidence to support or refute the suggestion that these drugs are effective in other neuropathic pain conditions. The safety of opioids with regards to abuse and deaths in the studies analysed cannot be extrapolated to routine clinical care. Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218487 VL - 24 IS - 1 SP - 3 EP - 18 ER - TY - JOUR A1 - Holländer, Olivia A1 - Schwender, Kristina A1 - Böhme, Petra A1 - Fleckhaus, Jan A1 - Haas, Cordula A1 - Han, Yang A1 - Heidorn, Frank A1 - Klein-Unseld, Rachel A1 - Lichtenwald, Julia A1 - Naue, Jana A1 - Neubauer, Jacqueline A1 - Poetsch, Micaela A1 - Schneider, Peter M. A1 - Wagner, Wolfgang A1 - Vennemann, Marielle T1 - Forensische DNA-Methylierungsanalyse T1 - Forensic DNA methylation analysis : First technical collaborative exercise by the working group on molecular age estimation of the German Society of Legal Medicine BT - Erster, technischer Ringversuch der Arbeitsgruppe „Molekulare Altersschätzung“ der Deutschen Gesellschaft für Rechtsmedizin JF - Rechtsmedizin N2 - Die quantitative Analyse der relativen DNA-Methylierung gilt als eine der vielversprechendsten Methoden der molekularen Altersschätzung. Viele Studien der letzten Jahre identifizierten geeignete Positionen im Genom, deren DNA-Methylierung sich altersabhängig verändert. Für den Einsatz dieser Methode in der Routine- bzw. Fallarbeit ist es von großer Bedeutung, angewandte Analysetechniken zu validieren. Als ein Teilaspekt dieser Validierung sollte die Vergleichbarkeit der Analyseergebnisse zur DNA-Methylierung mithilfe der Mini- und Pyrosequenzierung zwischen verschiedenen Laboren evaluiert werden. Die Arbeitsgruppe „Molekulare Altersschätzung“ der Deutschen Gesellschaft für Rechtsmedizin (DGRM) führte hierzu den ersten, technischen Ringversuch durch, der 4 Positionen in den Genen PDE4C, EDARADD, SST und KLF14 umfasste. Diese Marker waren in vorangegangenen Studien als altersabhängige Biomarker charakterisiert worden. Am Ringversuch nahmen 12 Labore teil, wobei jedes die Wahl zwischen der Minisequenzierung und/oder der Pyrosequenzierung für die quantitative Methylierungsanalyse hatte. Jedem teilnehmenden Labor wurden Blut- und Speichelproben von 3 Personen unterschiedlichen Alters übersandt. Die Wahl der Reagenzien für die Probenbearbeitung wurde den Teilnehmern freigestellt. Die Ergebnisse der Minisequenzierung zeigten systematische Abweichungen zwischen den Laboren, die am ehesten auf die Verwendung unterschiedlicher Reagenzien und Analyseplattformen zurückzuführen sein können. Die Resultate der Pyrosequenzierung hingegen wiesen nicht auf systematische Abweichungen zwischen den Laboren hin, hier zeigte sich jedoch die Tendenz einer markerabhängigen Abweichung. Darüber hinaus konnten Unterschiede hinsichtlich technischer Probleme zwischen Laboren mit mehr Erfahrung in der jeweiligen Sequenzierungsmethode und Laboren mit weniger Erfahrung festgestellt werden. Sowohl die Beobachtung von systematischen als auch die von markerabhängigen Abweichungen lässt den Schluss zu, dass eine Übertragung von Analysemethoden zwischen Laboren grundsätzlich möglich ist, eine Anpassung des jeweiligen Modells zur Altersschätzung jedoch notwendig sein kann. N2 - Quantitative analysis of relative DNA methylation is currently one of the most promising methods of molecular age estimation. In recent years numerous studies identified potential DNA methylation markers showing age-dependent changes in their relative methylation state. For routine application of this method validation is an important prerequisite. One aspect of validation is the degree of comparability of analytical data between laboratories. The working group on molecular age estimation of the German Society for Legal Medicine (DGRM) conducted a first technical proficiency test comprising four age estimation markers within the genes PDE4C, EDARADD, SST and KLF14. These positions were previously characterized as age-dependent biomarkers. A total of 12 laboratories participated using pyrosequencing and/or minisequencing techniques for quantitative analysis of DNA methylation. Each laboratory received blood and buccal swab samples from three individuals of different ages. Laboratories were free in their choice of reagents and material for sequencing. Minisequencing results showed systematic deviations between laboratories, which are believed to originate from differing reagents and sequencing platforms. The results of pyrosequencing did not show clear signs of systematic deviation but did show differences in the comparability between markers. Different levels of technical problems were reported, which correlated with the amount of experience with the sequencing technology. Both systematic and specific differences between analytical data produced in different laboratory settings lead to the conclusion that while it is generally possible to transfer an age estimation method to another laboratory, a mathematical model for age estimation might need to be adjusted accordingly. KW - DNA-Methylierung KW - Pyrosequenzierung KW - Minisequenzierung KW - Ergebnisreproduzierbarkeit KW - Laborleistungstests KW - DNA methylation KW - minisequencing KW - pyrosequencing KW - reproducibility of results KW - laboratory proficiency testing Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307131 SN - 0937-9819 SN - 1434-5196 VL - 31 IS - 3 ER - TY - JOUR A1 - Naue, Jana A1 - Pfeifer, Manuel A1 - Augustin, Christa A1 - Becker, Julia A1 - Fleckhaus, Jan A1 - Grabmüller, Melanie A1 - Han, Yang A1 - Heidorn, Frank A1 - Hollaender, Olivia A1 - Klein-Unseld, Rachel A1 - Kulstein, Galina A1 - Lichtenwald, Julia A1 - Neubauer, Jacqueline A1 - Suarez, Philippe A1 - Haas, Cordula A1 - Schneider, Peter M. A1 - Vennemann, Marielle A1 - Böhme, Petra T1 - Forensische DNA-Methylierungsanalyse T1 - Forensic DNA methylation analysis : Second technical collaborative exercise by the working group on “molecular age estimation” of the German Society of Legal Medicine BT - Zweiter, technischer Ringversuch der Arbeitsgruppe „Molekulare Altersschätzung“ der Deutschen Gesellschaft für Rechtsmedizin JF - Rechtsmedizin N2 - Mit der Entdeckung altersabhängiger epigenetischer Veränderungen, der DNA-Methylierung (DNAm), hat sich eine neue Möglichkeit aufgezeigt, das Alter eines Individuums zu schätzen. Die Methode wurde intensiv erforscht und ihre Anwendung in der forensischen Fallarbeit durch die Aktualisierung des § 81e der Strafprozessordnung (StPO) in Deutschland reguliert. Zur Untersuchung des DNAm-Grades müssen neue Techniken etabliert und validiert werden. Dies macht die Prüfung der Vergleichbarkeit von Messergebnissen aus verschiedenen forensischen Laboren erforderlich. Hierzu führte die Arbeitsgruppe „Molekulare Altersschätzung“ der Deutschen Gesellschaft für Rechtsmedizin (DGRM) im Winter 2019/2020 den 2. Ringversuch (RV) zur quantitativen DNAm-Analyse mithilfe der Mini- und der Pyrosequenzierung durch. Dieser basierte auf den Erfahrungen des 1. RV 2018/2019, dessen Ergebnisse in dieser Ausgabe ebenfalls vorgestellt werden. Die aktuelle Studie umfasst Analyseergebnisse aus 12 Laboren (ingesamt 14 teilnehmende Labore), von denen einige beide Methoden angewandt haben. Zusätzlich führten 4 Labore eine Altersschätzung an den RV-Proben mit eigenen Markerkombinationen und Modellen durch. Da diese auf unterschiedlichen Referenzdaten und Markerkombinationen beruhen, erfolgte kein qualitativer Vergleich der Modelle, sondern das grundsätzliche Potenzial der Methodik wurde verdeutlicht. Ziele des RV waren die Evaluierung der Vergleichbarkeit der DNAm-Messungen und die Bewertung möglicher Einflussfaktoren, wie Extraktionsmethode und verwendetes Gerät. Die Ergebnisse zeigen, dass sich die gemessenen DNAm-Werte der untersuchten Marker sowohl zwischen Mini- und Pyrosequenzierung als auch innerhalb der jeweiligen Methode zwischen den Laboren unterscheiden können, sodass mit Schwankungen gerechnet werden muss. N2 - With the discovery of age-related epigenetic changes DNA methylation (DNAm) has shown new possibilities for the estimation of the age of an individual. The method has been intensively researched and its application in forensic casework is regulated by an amendment of § 81e of the German Code of Criminal Procedures (StPO). To investigate the degree of DNAm new techniques must be established and validated. This necessitates investigation of the comparability of measurement results from different forensic laboratories. In winter 2019/2020 the molecular age estimation working group of the German Society of Legal Medicine (DGRM) conducted a second proficiency test to investigate this comparability using minisequencing and pyrosequencing for quantitative analysis of DNAm. This was based on the experience from the first proficiency test in 2018/2019, the results of which are presented in this edition of the journal. The current study includes the results of DNAm analysis from 12 laboratories (in total 14 participating laboratories), some of which have used both methods. In addition, four laboratories performed an age estimation using their own marker combinations and models. As these are based on different reference data and marker combinations, no qualitative comparison of the models was done but the fundamental potential of the methodology was clarified. The aim of the interlaboratory comparison was to evaluate the comparability of the DNAm measurements and to assess possible influencing factors, such as the extraction method and the device used. The results showed that the measured DNAm values of the investigated markers can differ between minisequencing and pyrosequencing as well as within the respective method between laboratories, so that fluctuations are to be expected. KW - Epigenetik KW - Biomarker KW - Minisequenzierung KW - Pyrosequenzierung KW - Laborleistungstests KW - epigenetics KW - biomarker KW - minisequencing KW - pyrosequencing KW - laboratory proficiency testing Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307129 SN - 0937-9819 SN - 1434-5196 VL - 31 IS - 3 ER -