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  - Altmann, Stephan
A1  - Mut, Jürgen
A1  - Wolf, Natalia
A1  - Meißner-Weigl, Jutta
A1  - Rudert, Maximilian
A1  - Jakob, Franz
A1  - Gutmann, Marcus
A1  - Lühmann, Tessa
A1  - Seibel, Jürgen
A1  - Ebert, Regina
T1  - Metabolic glycoengineering in hMSC-TERT as a model for skeletal precursors by using modified azide/alkyne monosaccharides
JF  - International Journal of Molecular Sciences
N2  - Metabolic glycoengineering enables a directed modification of cell surfaces by introducing target molecules to surface proteins displaying new features. Biochemical pathways involving glycans differ in dependence on the cell type; therefore, this technique should be tailored for the best results. We characterized metabolic glycoengineering in telomerase-immortalized human mesenchymal stromal cells (hMSC-TERT) as a model for primary hMSC, to investigate its applicability in TERT-modified cell lines. The metabolic incorporation of N-azidoacetylmannosamine (Ac\(_4\)ManNAz) and N-alkyneacetylmannosamine (Ac\(_4\)ManNAl) into the glycocalyx as a first step in the glycoengineering process revealed no adverse effects on cell viability or gene expression, and the in vitro multipotency (osteogenic and adipogenic differentiation potential) was maintained under these adapted culture conditions. In the second step, glycoengineered cells were modified with fluorescent dyes using Cu-mediated click chemistry. In these analyses, the two mannose derivatives showed superior incorporation efficiencies compared to glucose and galactose isomers. In time-dependent experiments, the incorporation of Ac\(_4\)ManNAz was detectable for up to six days while Ac\(_4\)ManNAl-derived metabolites were absent after two days. Taken together, these findings demonstrate the successful metabolic glycoengineering of immortalized hMSC resulting in transient cell surface modifications, and thus present a useful model to address different scientific questions regarding glycosylation processes in skeletal precursors.
KW  - hMSC-TERT
KW  - metabolic glycoengineering
KW  - glycocalyx
KW  - modified monosaccharides
KW  - click chemistry
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259247
SN  - 1422-0067
VL  - 22
IS  - 6
ER  - 
TY  - THES
A1  - Wolf, Jürgen
T1  - Hämodynamische Auswirkungen synthetischer, pflanzlicher und endogener Cannabinoide im Modell der isolierten Kaninchenlunge
T1  - Hemodynamic effects of synthetic, plant-derived and endogenous cannabinoids in the model of an isolated rabbit lung
N2  - Cannabinoide zeigen komplexe kardiovaskuläre Effekte. Das endogene Cannabinoid Anandamid (Arachidonylethanolamid) induziert in verschiedenen Organsystemen eine hauptsächlich über periphere CB1-Rezeptoren vermittelte Vasodilatation. Der Einfluss von Cannabinoiden auf die pulmonale Strombahn ist jedoch unklar. Am Modell einer isolierten, perfundierten und ventilierten Kaninchenlunge konnte gezeigt werden, dass die endogenen Cannabinoide Anandamid und 2-Arachidonylglycerol (2-AG) dosisabhängig den pulmonalarteriellen Druck erhöhen. Cannabinoide, die abweichend zu Anandamid und 2-AG keine Arachidonsäurestruktur haben, z.B. das synthetische HU-210 oder das pflanzliche Δ9-THC, erhöhen den pulmonalarteriellen Druck nicht. Im Gegensatz zu Anandamid und 2-AG führen die stoffwechselstabilen, gegen enzymatischen Abbau geschützten Analoga von Anandamid und 2-AG, R-Methanandamid und Noladinäther, zu keinem Anstieg des pulmonalarteriellen Druckes. Blockade des CB1-Rezeptors durch den spezifischen Antagonisten AM-251 verhindert die pulmonalarterielle Druckerhöhung nach Anandamidgabe nicht. Wir folgern daraus, dass Abbauprodukte von Anandamid und 2-AG für die Druckerhöhung verantwortlich sind. Erstmalig konnten wir quantitativ Anandamid und 2-AG mittels Flüssigkeitschromatographie / Massenspektrometrie in der Kaninchenlunge nachweisen. Dies legt eine physiologische Relevanz der beiden Endocannabinoide bei der Tonus-Regulation des Lungenkreislaufes nahe.
N2  - Cannabionoids show complex cardiovascular actions. The endogenous cannabinoid anandamide (arachidonyl ethanolamide) induces vasodilation mainly via CB1 receptors in several organ systems. However the effect of cannabinoids on the pulmonary circulation is unclear. In an isolated, buffer-perfused and ventilated rabbit lung it could be shown that the endogenous cannabinoids anandamide and 2-arachidonylglycerol (2-AG) increase dose-dependently pulmonary arterial pressure. Cannabinoids with a chemical structure different from anandamide and 2-AG, e.g. the synthetic HU-210 and the plant-derived Δ9-THC, do not increase pulmonary arterial pressure. In sharp contrast to anandamide and 2-AG, the metabolically stable analogues R-methanandamide and noladin ether were without effect. The specific CB1-receptor antagonist AM-251 failed to prevent the increase of pulmonary arterial pressure following anandamide. We conclude that breakdown products of anandamide and 2-AG are responsible for the pulmonary vasoconstriction. Finally, we found anandamide and 2-AG, as detected by liquid chromatography / mass spectrometry, in native rabbit lung tissue. This finding suggests a physiological relevance of both endogenous cannabinoids in the regulation of pulmonary-arterial vascular tone.
KW  - Cannabinoide
KW  - Anandamid
KW  - pulmonalarterieller Druck
KW  - isolierte Kaninchenlunge
KW  - CB1 Rezeptor
KW  - cannabinoids
KW  - anandamide
KW  - pulmonary arterial pressure
KW  - isolated rabbit lung
KW  - CB1 receptor
Y1  - 2005
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-15858
ER  - 
TY  - JOUR
A1  - Simon, Christian M.
A1  - Rauskolb, Stefanie
A1  - Gunnersen, Jennifer M.
A1  - Holtmann, Bettina
A1  - Drepper, Carsten
A1  - Dombert, Benjamin
A1  - Braga, Massimiliano
A1  - Wiese, Stefan
A1  - Jablonka, Sibylle
A1  - Pühringer, Dirk
A1  - Zielasek, Jürgen
A1  - Hoeflich, Andreas
A1  - Silani, Vincenzo
A1  - Wolf, Eckhard
A1  - Kneitz, Susanne
A1  - Sommer, Claudia
A1  - Toyka, Klaus V.
A1  - Sendtner, Michael
T1  - Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy
JF  - Acta Neuropathologica
N2  - Diabetic neuropathy (DNP), afflicting sensory and motor nerve fibers, is a major complication in diabetes.The underlying cellular mechanisms of axon degeneration are poorly understood. IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP. We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which the IGF1 receptor(IGF1R) was conditionally depleted in motoneurons, indicating that reduced activity of IGF1 on IGF1R in motoneurons is responsible for the observed effect. These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration. Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP.
KW  - Motor nerve biopsy
KW  - Diabetic polyneuropathy
KW  - Neuropathy
KW  - Neurotrophic factors
KW  - Axonal degeneration
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154569
VL  - 130
SP  - 373
EP  - 387
ER  - 
TY  - JOUR
A1  - Häder, Antje
A1  - Schäuble, Sascha
A1  - Gehlen, Jan
A1  - Thielemann, Nadja
A1  - Buerfent, Benedikt C.
A1  - Schüller, Vitalia
A1  - Hess, Timo
A1  - Wolf, Thomas
A1  - Schröder, Julia
A1  - Weber, Michael
A1  - Hünniger, Kerstin
A1  - Löffler, Jürgen
A1  - Vylkova, Slavena
A1  - Panagiotou, Gianni
A1  - Schumacher, Johannes
A1  - Kurzai, Oliver
T1  - Pathogen-specific innate immune response patterns are distinctly affected by genetic diversity
JF  - Nature Communications
N2  - Innate immune responses vary by pathogen and host genetics. We analyze quantitative trait loci (eQTLs) and transcriptomes of monocytes from 215 individuals stimulated by fungal, Gram-negative or Gram-positive bacterial pathogens. We identify conserved monocyte responses to bacterial pathogens and a distinct antifungal response. These include 745 response eQTLs (reQTLs) and corresponding genes with pathogen-specific effects, which we find first in samples of male donors and subsequently confirm for selected reQTLs in females. reQTLs affect predominantly upregulated genes that regulate immune response via e.g., NOD-like, C-type lectin, Toll-like and complement receptor-signaling pathways. Hence, reQTLs provide a functional explanation for individual differences in innate response patterns. Our identified reQTLs are also associated with cancer, autoimmunity, inflammatory and infectious diseases as shown by external genome-wide association studies. Thus, reQTLs help to explain interindividual variation in immune response to infection and provide candidate genes for variants associated with a range of diseases.
KW  - antimicrobial responses
KW  - immunogenetics
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357441
VL  - 14
ER  - 
TY  - JOUR
A1  - Triphan, Simon M. F.
A1  - Jobst, Bertram J.
A1  - Anjorin, Angela
A1  - Sedlaczek, Oliver
A1  - Wolf, Ursula
A1  - Terekhov, Maxim
A1  - Hoffmann, Christian
A1  - Ley, Sebastian
A1  - Düber, Christoph
A1  - Biederer, Jürgen
A1  - Kauczor, Hans-Ulrich
A1  - Jakob, Peter M.
A1  - Wielpütz, Mark O.
T1  - Reproducibility and comparison of oxygen-enhanced T\(_1\) quantification in COPD and asthma patients
JF  - PLoS ONE
N2  - T\(_1\) maps have been shown to yield useful diagnostic information on lung function in patients with chronic obstructive pulmonary disease (COPD) and asthma, both for native T\(_1\) and ΔT\(_1\), the relative reduction while breathing pure oxygen. As parameter quantification is particularly interesting for longitudinal studies, the purpose of this work was both to examine the reproducibility of lung T\(_1\) mapping and to compare T\(_1\) found in COPD and asthma patients using IRSnapShotFLASH embedded in a full MRI protocol. 12 asthma and 12 COPD patients (site 1) and further 15 COPD patients (site 2) were examined on two consecutive days. In each patient, T\(_1\) maps were acquired in 8 single breath-hold slices, breathing first room air, then pure oxygen. Maps were partitioned into 12 regions each to calculate average values. In asthma patients, the average T\(_{1,RA}\) = 1206ms (room air) was reduced to T\(_{1,O2}\) = 1141ms under oxygen conditions (ΔT\(_1\) = 5.3%, p < 5⋅10\(^{−4})\), while in COPD patients both native T\(_{1,RA}\) = 1125ms was significantly shorter (p < 10\(^{−3})\) and the relative reduction to T\(_{1,O2}\) = 1081ms on average ΔT\(_1\) = 4.2%(p < 10\(^{−5}\)). On the second day, with T\(_{1,RA}\) = 1186ms in asthma and T\(_{1,RA}\) = 1097ms in COPD, observed values were slightly shorter on average in all patient groups. ΔT\(_1\) reduction was the least repeatable parameter and varied from day to day by up to 23% in individual asthma and 30% in COPD patients. While for both patient groups T\(_1\) was below the values reported for healthy subjects, the T\(_1\) and ΔT\(_1\) found in asthmatics lies between that of the COPD group and reported values for healthy subjects, suggesting a higher blood volume fraction and better ventilation. However, it could be demonstrated that lung T\(_1\) quantification is subject to notable inter-examination variability, which here can be attributed both to remaining contrast agent from the previous day and the increased dependency of lung T\(_1\) on perfusion and thus current lung state.
KW  - Medicine
KW  - Chronic obstrusive pulmonary disease
KW  - Asthma
KW  - Oxygen
KW  - Magnetic resonance imaging
KW  - Breathing
KW  - Pulmonary imaging
KW  - Protons
KW  - Diagnostic medicine
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171833
VL  - 12
IS  - 2
ER  - 
TY  - JOUR
A1  - Meder, Lydia
A1  - König, Katharina
A1  - Ozretić, Luka
A1  - Schultheis, Anne M.
A1  - Ueckeroth, Frank
A1  - Ade, Carsten P.
A1  - Albus, Kerstin
A1  - Boehm, Diana
A1  - Rommerscheidt-Fuss, Ursula
A1  - Florin, Alexandra
A1  - Buhl, Theresa
A1  - Hartmann, Wolfgang
A1  - Wolf, Jürgen
A1  - Merkelbach-Bruse, Sabine
A1  - Eilers, Martin
A1  - Perner, Sven
A1  - Heukamp, Lukas C.
A1  - Buettner, Reinhard
T1  - NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas
JF  - International Journal of Cancer
N2  - Small cell lung cancers (SCLCs) and extrapulmonary small cell cancers (SCCs) are very aggressive tumors arising de novo as primary small cell cancer with characteristic genetic lesions in RB1 and TP53. Based on murine models, neuroendocrine stem cells of the terminal bronchioli have been postulated as the cellular origin of primary SCLC. However, both in lung and many other organs, combined small cell/non-small cell tumors and secondary transitions from non-small cell carcinomas upon cancer therapy to neuroendocrine and small cell tumors occur. We define features of "small cell-ness" based on neuroendocrine markers, characteristic RB1 and TP53 mutations and small cell morphology. Furthermore, here we identify a pathway driving the pathogenesis of secondary SCLC involving inactivating NOTCH mutations, activation of the NOTCH target ASCL1 and canonical WNT-signaling in the context of mutual bi-allelic RB1 and TP53 lesions. Additionaly, we explored ASCL1 dependent RB inactivation by phosphorylation, which is reversible by CDK5 inhibition. We experimentally verify the NOTCH-ASCL1-RB-p53 signaling axis in vitro and validate its activation by genetic alterations in vivo. We analyzed clinical tumor samples including SCLC, SCC and pulmonary large cell neuroendocrine carcinomas and adenocarcinomas using amplicon-based Next Generation Sequencing, immunohistochemistry and fluorescence in situ hybridization. In conclusion, we identified a novel pathway underlying rare secondary SCLC which may drive small cell carcinomas in organs other than lung, as well.
KW  - lung cancer
KW  - small cell lung cancer
KW  - achaete-scute homolog 1
KW  - neurogenic locus notch homolog
KW  - retinoblastoma protein
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-190853
VL  - 138
IS  - 4
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  -