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 - Goebeler, M. A1 - Bata-Csörgő, Z. A1 - Simone, C. de A1 - Didona, B. A1 - Remenyik, E. A1 - Reznichenko, N. A1 - Stoevesandt, J. A1 - Ward, E. S. A1 - Parys, W. A1 - Haard, H. de A1 - Dupuy, P. A1 - Verheesen, P. A1 - Schmidt, E. A1 - Joly, P. T1 - Treatment of pemphigus vulgaris and foliaceus with efgartigimod, a neonatal Fc receptor inhibitor: a phase II multicentre, open-label feasibility trial JF - British Journal of Dermatology N2 - Background Pemphigus vulgaris and pemphigus foliaceus are potentially life-threatening autoimmune disorders triggered by IgG autoantibodies against mucosal and epidermal desmogleins. There is an unmet need for fast-acting drugs that enable patients to achieve early sustained remission with reduced corticosteroid reliance. Objectives To investigate efgartigimod, an engineered Fc fragment that inhibits the activity of the neonatal Fc receptor, thereby reducing serum IgG levels, for treating pemphigus. Methods Thirty-four patients with mild-to-moderate pemphigus vulgaris or foliaceus were enrolled in an open-label phase II adaptive trial. In sequential cohorts, efgartigimod was dosed at 10 or 25 mg kg\(^{-1}\) intravenously with various dosing frequencies, as monotherapy or as add-on therapy to low-dose oral prednisone. Safety endpoints comprised the primary outcome. The study is registered at ClinicalTrials.gov (identifier NCT03334058). Results Adverse events were mostly mild and were reported by 16 of 19 (84%) patients receiving efgartigimod 10 mg kg\(^{-1}\) and 13 of 15 (87%) patients receiving 25 mg kg−1, with similar adverse event profiles between dose groups. A major decrease in serum total IgG and anti-desmoglein autoantibodies was observed and correlated with improved Pemphigus Disease Area Index scores. Efgartigimod, as monotherapy or combined with prednisone, demonstrated early disease control in 28 of 31 (90%) patients after a median of 17 days. Optimized, prolonged treatment with efgartigimod in combination with a median dose of prednisone 0·26 mg \(^{-1}\) per day (range 0·06–0·48) led to complete clinical remission in 14 of 22 (64%) patients within 2–41 weeks. Conclusions Efgartigimod was well tolerated and exhibited an early effect on disease activity and outcome parameters, providing support for further evaluation as a therapy for pemphigus. KW - pemphigus vulgaris KW - efgartigimod KW - pemphigus foliaceus Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258328 VL - 186 IS - 3 ER - TY - JOUR A1 - Hacker, Jörg A1 - Ulmer, E. A1 - Fasske, E. A1 - Schmidt, G. T1 - Isolation and characterization of coliphage Omega18A specific for Escherichia coli O18ac strains N2 - The bactedophage Q18A, specific for Escherichia coli 018ac srrains, was isolated frorn sewage. The results of host range and conjugation experiments showed that the sensitivity of bacteria to the phage is associated with rhe presence of 018ac antigens. With sorne of rhe 018 strains rhe phage Q18A produces clear Iysis on bacterial lawns only when applied at a high multiplicity and moreover the phage does not multiply. With rhe help of the phage Ql8A, E. coli 0 18ac strains could be divided inro rwo serologically clistinct subgroups called 018A and 018A1• E. coli strains belanging to the sugroup 0 ISAare sensitive to phage Q t8A wheteas bacteria of subgroup A1 are resistanr. N2 - Der Bakteriophage Q18A, der spezifisch Escherichia coli 018ac Bakterien lysierr, wurde aus Abwasser isoliert. Die Untersuchungen des Wirtsbereichs und Konjugationsversuche zeigten, daß die Sensitivität der Bakterien gegenüber dem Phagen mit dem Vorhandensein des 0 '18ac Antigens assoziiert ist. Bei eir1igen 0 18 Stämmen wird nur bei Anwendung hoher Phagenkonzentrationen eine klare Lysis auf dem Bakterienrasen erzeugt. Darüber hinaus läßt sich der Phage auf diesen Stämmen nicht vermehren. Mit Hilfe des Phagen Q l8A konnten E, wli 0 18ac Stämme in zwei serologische Subgruppen unteneilt werden, die als 0 lHA und 0 l8A 1 bezeichnet werden. E. coli Bakterien der Subgruppe 0 ISA sind gegenüber dem Phagen Ql8A sensitiv und diejenigen der Subgruppe 0 18A 1 sind resistent. KW - Escherichia coli Y1 - 1987 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-73001 ER - TY - JOUR A1 - Groeneweg, Femke L. A1 - van Royen, Martin E. A1 - Fenz, Susanne A1 - Keizer, Veer I. P. A1 - Geverts, Bart A1 - Prins, Jurrien A1 - de Kloet, E. Ron A1 - Houtsmuller, Adriaan B. A1 - Schmidt, Thomas S. A1 - Schaaf, Marcel J. M. T1 - Quantitation of Glucocorticoid Receptor DNA-Binding Dynamics by Single-Molecule Microscopy and FRAP JF - PLOS ONE N2 - Recent advances in live cell imaging have provided a wealth of data on the dynamics of transcription factors. However, a consistent quantitative description of these dynamics, explaining how transcription factors find their target sequences in the vast amount of DNA inside the nucleus, is still lacking. In the present study, we have combined two quantitative imaging methods, single-molecule microscopy and fluorescence recovery after photobleaching, to determine the mobility pattern of the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), two ligand-activated transcription factors. For dexamethasone-activated GR, both techniques showed that approximately half of the population is freely diffusing, while the remaining population is bound to DNA. Of this DNA-bound population about half the GRs appeared to be bound for short periods of time (similar to 0.7 s) and the other half for longer time periods (similar to 2.3 s). A similar pattern of mobility was seen for the MR activated by aldosterone. Inactive receptors (mutant or antagonist-bound receptors) show a decreased DNA binding frequency and duration, but also a higher mobility for the diffusing population. Likely, very brief (<= 1 ms) interactions with DNA induced by the agonists underlie this difference in diffusion behavior. Surprisingly, different agonists also induce different mobilities of both receptors, presumably due to differences in ligand-induced conformational changes and receptor complex formation. In summary, our data provide a consistent quantitative model of the dynamics of GR and MR, indicating three types of interactions with DNA, which fit into a model in which frequent low-affinity DNA binding facilitates the search for high-affinity target sequences. KW - NF-KAPPA-B KW - image correlation spectroscopy KW - human mineralocorticoid receptor KW - nuclear-pore complexes KW - in-vivo KW - living cells KW - mobility KW - transcription KW - protein KW - reveals Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117085 VL - 9 IS - 3 ER - TY - JOUR A1 - Schmitt, T. A1 - Egu, D.T. A1 - Walter, E. A1 - Sigmund, A.M. A1 - Eichkorn, R. A1 - Yazdi, A. A1 - Schmidt, E. A1 - Sárdy, M. A1 - Eming, R. A1 - Goebeler, M. A1 - Waschke, J. T1 - Ca\(^{2+}\) signalling is critical for autoantibody‐induced blistering of human epidermis in pemphigus JF - British Journal of Dermatology N2 - Background Pemphigus is a severe bullous autoimmune skin disease. Pemphigus foliaceus (PF) is characterized by antidesmoglein (Dsg) 1 IgG causing epidermal blistering; mucosal pemphigus vulgaris (mPV) by anti‐Dsg3 IgG inducing erosions in the mucosa; and mucocutaneous pemphigus vulgaris (PV) by affecting both, with autoantibodies targeting Dsg1 and Dsg3. Objectives To characterize the Ca\(^{2+}\) flux pathway and delineate its importance in pemphigus pathogenesis and clinical phenotypes caused by different antibody profiles. Methods Immunoprecipitation, Ca\(^{2+}\) flux analysis, Western blotting, immunofluorescence staining, dissociation assays and a human skin ex vivo model were used. Results PV IgG and PF IgG, but neither Dsg3‐specific monoclonal antibody (AK23) nor mPV IgG, caused Ca\(^{2+}\) influx in primary human keratinocytes. Phosphatidylinositol 4‐kinase α interacts with Dsg1 but not with Dsg3. Its downstream target – phospholipase‐C‐γ1 (PLC) – was activated by PV IgG and PF IgG but not AK23 or mPV IgG. PLC releases inositol 1,4,5‐trisphosphate (IP3) causing IP3 receptor (IP3R) activation and Ca2+ flux from the endoplasmic reticulum into the cytosol, which stimulates Ca2+ release‐activated channels (CRAC)‐mediated Ca\(^{2+}\) influx. Inhibitors against PLC, IP3R and CRAC effectively blocked PV IgG and PF IgG‐induced Ca\(^{2+}\) influx; ameliorated alterations of Dsg1 and Dsg3 localization, and reorganization of keratin and actin filaments; and inhibited loss of cell adhesion in vitro. Finally, inhibiting PLC or IP3R was protective against PV IgG‐induced blister formation and redistribution of Dsg1 and Dsg3 in human skin ex vivo. Conclusions Ca2+‐mediated signalling is important for epidermal blistering and dependent on the autoantibody profile, which indicates different roles for signalling complexes organized by Dsg1 and Dsg3. Interfering with PLC and Ca\(^{2+}\) signalling may be a promising approach to treat epidermal manifestations of pemphigus. KW - pemphigus KW - epidermis KW - Ca\(^{2+}\) signalling Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262810 VL - 185 IS - 3 SP - 595 EP - 604 ER - TY - JOUR A1 - Eisenhardt, Anja E. A1 - Sprenger, Adrian A1 - Röring, Michael A1 - Herr, Ricarda A1 - Weinberg, Florian A1 - Köhler, Martin A1 - Braun, Sandra A1 - Orth, Joachim A1 - Diedrich, Britta A1 - Lanner, Ulrike A1 - Tscherwinski, Natalja A1 - Schuster, Simon A1 - Dumaz, Nicolas A1 - Schmidt, Enrico A1 - Baumeister, Ralf A1 - Schlosser, Andreas A1 - Dengjel, Jörn A1 - Brummer, Tilman T1 - Phospho-proteomic analyses of B-Raf protein complexes reveal new regulatory principles JF - Oncotarget N2 - B-Raf represents a critical physiological regulator of the Ras/RAF/MEK/ERK-pathway and a pharmacological target of growing clinical relevance, in particular in oncology. To understand how B-Raf itself is regulated, we combined mass spectrometry with genetic approaches to map its interactome in MCF-10A cells as well as in B-Raf deficient murine embryonic fibroblasts (MEFs) and B-Raf/Raf-1 double deficient DT40 lymphoma cells complemented with wildtype or mutant B-Raf expression vectors. Using a multi-protease digestion approach, we identified a novel ubiquitination site and provide a detailed B-Raf phospho-map. Importantly, we identify two evolutionary conserved phosphorylation clusters around T401 and S419 in the B-Raf hinge region. SILAC labelling and genetic/biochemical follow-up revealed that these clusters are phosphorylated in the contexts of oncogenic Ras, sorafenib induced Raf dimerization and in the background of the V600E mutation. We further show that the vemurafenib sensitive phosphorylation of the T401 cluster occurs in trans within a Raf dimer. Substitution of the Ser/Thr-residues of this cluster by alanine residues enhances the transforming potential of B-Raf, indicating that these phosphorylation sites suppress its signaling output. Moreover, several B-Raf phosphorylation sites, including T401 and S419, are somatically mutated in tumors, further illustrating the importance of phosphorylation for the regulation of this kinase. KW - BRAF KW - proteomics KW - phosphorylation KW - sorafenib KW - protein-protein interaction Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166529 VL - 7 IS - 18 ER - TY - JOUR A1 - Schmidt, B. A1 - Wachter, E. A1 - Sebald, Walter A1 - Neupert, W. T1 - Processing peptidase of Neurospora mitochondria. Two-step cleavage of imported ATPase subunit 9 N2 - Subunit 9 (dicyclohexylcarbodümide binding protein, 'proteolipid') of the mitochondrial F 1F0-ATPase is a nuclearly coded protein in Neurospora crassa. lt is synthesized on free cytoplasmic ribosomes as a larger precursor with an NH2-terminal peptide extension. The peptide extension is cleaved ofT after transport of the protein into the mitochondria. A processing activity referred to as processing peptidase that cleaves the precursor to subunit 9 and other mitochondrial proteins is described and characterized using a cell-free system. Precursor synthesized in vitro was incubated with extracts of mitochondria. Processing peptidase required Mn2 + for its activity. Localization studies suggested that it is a soluble component of the mitochondrial matrix. The precursor was cleaved in two sequential steps via an intermediate-sized polypeptide. The intermediate form in the processing of subunit 9 was also seen in vivo and upon import of the precursor into isolated mitochondria in vitro. The two dcavage sites in the precursor molecule were determined. The data indicate that: {a) the correct NH2-terminus of the mature protein was generated, (b) the NH2-terminal amino acid of the intermediate-sized polypeptide is isoleueine in position -31. The cleavage sites show similarity ofprimary structure. It is concluded that processing peptidase removes the peptide extension from the precursor to subunit 9 (and probably other precursors) after translocation of these polypeptides (or the NHrterminal part of these polypeptides) into the matrix space of mitochondria. KW - Biochemie Y1 - 1984 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-62674 ER - TY - JOUR A1 - Kleinschnitz, Christoph A1 - Grund, Henrike A1 - Wingler, Kirstin A1 - Armitage, Melanie E. A1 - Jones, Emma A1 - Mittal, Manish A1 - Barit, David A1 - Schwarz, Tobias A1 - Geis, Christian A1 - Kraft, Peter A1 - Barthel, Konstanze A1 - Schuhmann, Michael K. A1 - Herrmann, Alexander M. A1 - Meuth, Sven G. A1 - Stoll, Guido A1 - Meurer, Sabine A1 - Schrewe, Anja A1 - Becker, Lore A1 - Gailus-Durner, Valerie A1 - Fuchs, Helmut A1 - Klopstock, Thomas A1 - de Angelis, Martin Hrabe A1 - Jandeleit-Dahm, Karin A1 - Shah, Ajay M. A1 - Weissmann, Norbert A1 - Schmidt, Harald H. H. W. T1 - Post-Stroke Inhibition of Induced NADPH Oxidase Type 4 Prevents Oxidative Stress and Neurodegeneration N2 - 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. KW - Schlaganfall Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68416 ER - TY - JOUR A1 - Sonnenschein-van der Voort, Agnes M. M. A1 - Arends, Lidia R. A1 - de Jongste, Johan C. A1 - Annesi-Maesano, Isabella A1 - Arshad, S. Hasan A1 - Barros, Henrique A1 - Basterrechea, Mikel A1 - Bisgaard, Hans A1 - Chatzi, Leda A1 - Corpeleijn, Eva A1 - Correia, Sofia A1 - Craig, Leone C. A1 - Devereux, Graham A1 - Dogaru, Cristian A1 - Dostal, Miroslav A1 - Duchen, Karel A1 - Eggesbø, Merete A1 - van der Ent, C. Kors A1 - Fantini, Maria P. A1 - Forastiere, Francesco A1 - Frey, Urs A1 - Gehring, Ulrike A1 - Gori, Davide A1 - van der Gugten, Anne C. A1 - Hanke, Wojciech A1 - Henderson, A. John A1 - Heude, Barbara A1 - Iñiguez, Carmen A1 - Inskip, Hazel M. A1 - Keil, Thomas A1 - Kelleher, Cecily C. A1 - Kogevinas, Manolis A1 - Kreiner-Møller, Eskil A1 - Kuehni, Claudia E. A1 - Küpers, Leanne K. A1 - Lancz, Kinga A1 - Larsen, Pernille S. A1 - Lau, Susanne A1 - Ludvigsson, Johnny A1 - Mommers, Monique A1 - Andersen, Anne-Marie Nybo A1 - Palkovicova, Lubica A1 - Pike, Katherine C. A1 - Pizzi, Constanza A1 - Polanska, Kinga A1 - Porta, Daniela A1 - Richiardi, Lorenzo A1 - Roberts, Graham A1 - Schmidt, Anne A1 - Sram, Radim J. A1 - Sunyer, Jordi A1 - Thijs, Carel A1 - Torrent, Maties A1 - Viljoen, Karien A1 - Wijga, Alet H. A1 - Vrijheid, Martine A1 - Jaddoe, Vincent W. V. A1 - Duijts, Liesbeth T1 - Preterm birth, infant weight gain, and childhood asthma risk: A meta-analysis of 147,000 European children JF - The Journal of Allergy and Clinical Immunology N2 - Background Preterm birth, low birth weight, and infant catch-up growth seem associated with an increased risk of respiratory diseases in later life, but individual studies showed conflicting results. Objectives We performed an individual participant data meta-analysis for 147,252 children of 31 birth cohort studies to determine the associations of birth and infant growth characteristics with the risks of preschool wheezing (1-4 years) and school-age asthma (5-10 years). Methods First, we performed an adjusted 1-stage random-effect meta-analysis to assess the combined associations of gestational age, birth weight, and infant weight gain with childhood asthma. Second, we performed an adjusted 2-stage random-effect meta-analysis to assess the associations of preterm birth (gestational age <37 weeks) and low birth weight (<2500 g) with childhood asthma outcomes. Results Younger gestational age at birth and higher infant weight gain were independently associated with higher risks of preschool wheezing and school-age asthma (P < .05). The inverse associations of birth weight with childhood asthma were explained by gestational age at birth. Compared with term-born children with normal infant weight gain, we observed the highest risks of school-age asthma in children born preterm with high infant weight gain (odds ratio [OR], 4.47; 95% CI, 2.58-7.76). Preterm birth was positively associated with an increased risk of preschool wheezing (pooled odds ratio [pOR], 1.34; 95% CI, 1.25-1.43) and school-age asthma (pOR, 1.40; 95% CI, 1.18-1.67) independent of birth weight. Weaker effect estimates were observed for the associations of low birth weight adjusted for gestational age at birth with preschool wheezing (pOR, 1.10; 95% CI, 1.00-1.21) and school-age asthma (pOR, 1.13; 95% CI, 1.01-1.27). Conclusion Younger gestational age at birth and higher infant weight gain were associated with childhood asthma outcomes. The associations of lower birth weight with childhood asthma were largely explained by gestational age at birth." KW - gestational age KW - low birth weight KW - infant growth KW - wheezing KW - asthma KW - epidemiology KW - cohort studies KW - children Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120714 VL - 133 IS - 5 ER - TY - JOUR A1 - Marenholz, Ingo A1 - Esparza-Gordillo, Jorge A1 - Rüschendorf, Franz A1 - Bauerfeind, Anja A1 - Strachan, David P. A1 - Spycher, Ben D. A1 - Baurecht, Hansjörg A1 - Magaritte-Jeannin, Patricia A1 - Sääf, Annika A1 - Kerkhof, Marjan A1 - Ege, Markus A1 - Baltic, Svetlana A1 - Matheson, Melanie C. A1 - Li, Jin A1 - Michel, Sven A1 - Ang, Wei Q. A1 - McArdle, Wendy A1 - Arnold, Andreas A1 - Homuth, Georg A1 - Demenais, Florence A1 - Bouzigon, Emmanuelle A1 - Söderhäll, Cilla A1 - Pershagen, Göran A1 - de Jongste, Johan C. A1 - Postma, Dirkje S. A1 - Braun-Fahrländer, Charlotte A1 - Horak, Elisabeth A1 - Ogorodova, Ludmila M. A1 - Puzyrev, Valery P. A1 - Bragina, Elena Yu A1 - Hudson, Thomas J. A1 - Morin, Charles A1 - Duffy, David L. A1 - Marks, Guy B. A1 - Robertson, Colin F. A1 - Montgomery, Grant W. A1 - Musk, Bill A1 - Thompson, Philip J. A1 - Martin, Nicholas G. A1 - James, Alan A1 - Sleiman, Patrick A1 - Toskala, Elina A1 - Rodriguez, Elke A1 - Fölster-Holst, Regina A1 - Franke, Andre A1 - Lieb, Wolfgang A1 - Gieger, Christian A1 - Heinzmann, Andrea A1 - Rietschel, Ernst A1 - Keil, Thomas A1 - Cichon, Sven A1 - Nöthen, Markus M. A1 - Pennel, Craig E. A1 - Sly, Peter D. A1 - Schmidt, Carsten O. A1 - Matanovic, Anja A1 - Schneider, Valentin A1 - Heinig, Matthias A1 - Hübner, Norbert A1 - Holt, Patrick G. A1 - Lau, Susanne A1 - Kabesch, Michael A1 - Weidinger, Stefan A1 - Hakonarson, Hakon A1 - Ferreira, Manuel A. R. A1 - Laprise, Catherine A1 - Freidin, Maxim B. A1 - Genuneit, Jon A1 - Koppelman, Gerard H. A1 - Melén, Erik A1 - Dizier, Marie-Hélène A1 - Henderson, A. John A1 - Lee, Young Ae T1 - Meta-analysis identifies seven susceptibility loci involved in the atopic march JF - Nature Communications N2 - 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. KW - chromosome 11Q13 KW - risk KW - genomewide association KW - hay fever KW - birth cohort KW - filaggrin mutations KW - food allergy KW - juvenile myoclonic epilepsy KW - childhood asthma KW - dermatitis Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-139835 VL - 6 IS - 8804 ER - TY - JOUR A1 - Wieber, M. A1 - Schmidt, E. A1 - Burschka, Christian T1 - Dimethyl-tellur-bis(alkylxanthogenate) T1 - Tellurium-Dimethyl-bis(alkylxanthates) N2 - Man erhält Dimethyl-tellur-bis(alkylxanthogenate) des Typs R2Te(S2COR'lz mit R = CH3, sowie R' = CHs, C2Hs, i-CsH7 durch Umsetzung von Dimethyltellur-diiodid mit den stöchiometrischen Mengen der jeweiligen Natriumxanthogenate. Ebemalls führt eine Einschiebung von CS2 in die Te-O-Bindung von Dimethyl-tellur-bis(alkoxyden) zu den Dimethyl-tellur-bis(alkylxanthogenaten). Die Röntgenstrukturanalyse von (CH3hTe(S2COCH3)2 zeigt, daß das Molekül im Kristall als V'-pentagonale Bipyramide vorliegt. N2 - Tellurium dimethyl-bis(alkylxanthates) of the type R2Te(S2COR')2 with R = CH3 and R' = CH3, C2H5, i-CsH 7 are obtained by reaction of tellurium dimethyldiiodide with freshly prepared sodium xanthates. Another preparative method is the insertion of CS2 in tellurium dimethylbis(alkoxydes). The X-ray analysis of (CH3)2Te(S2COCHsh shows, that in the crystal the molecule has a IjJ-pentagonal bipyramidal configLlration around tellurium. KW - Chemie Y1 - 1985 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-31934 ER - TY - JOUR A1 - Kann, Simone A1 - Blessmann, Joerg A1 - Winkelmann, Yvonne A1 - Hansen, Jessica A1 - Maya Amaya, Leonardo J. A1 - Rivera Salcedo, Gadith E. A1 - Halas, Hussein El A1 - Schmidt‐Chanasit, Jonas A1 - Keoviengkhone, Latdamone A1 - Sopraseuth, Vatsana A1 - Deschermeier, Christina A1 - Mika, Angela T1 - Dengue virus detection in Lao PDR and Colombia: Comparative evaluation of PCR tests JF - Tropical Medicine & International Health N2 - Objectives Dengue virus (DENV) detection by polymerase chain reaction (PCR) facilitates diagnosis of dengue fever, which is the most frequent arboviral disease globally. Two studies were performed in countries with high dengue incidence, to assess the diagnostic performance of different PCR techniques. Methods/Results Two hundred and seventy‐nine acute phase blood samples from febrile patients were analyzed for DENV by the RealStar Dengue RT‐PCR kit (Altona Diagnostics) as gold standard in comparison with the Tropical Fever Core multiplex PCR (Fast Track Diagnostics). In total, 102 samples collected in Savannakhet Province (Lao PDR, Southeast Asia) in 2013 and 35 samples from Valledupar (Colombia, South America) tested positive for DENV by RealStar RT‐PCR. In comparison, the Tropical Fever Core multiplex PCR detected 65.0% (65/102) and 68.6% (24/35) of these samples as positive for DENV in Savannakhet and Valledupar, respectively. Diagnostic sensitivity of the multiplex PCR strongly correlated with viral load. A subset of DENV PCR‐confirmed samples was additionally tested by BNITM in house Dengue Type RT‐PCR in comparison with two commercial test kits (RealStar Dengue Type RT‐PCR [Altona Diagnostics], Dengue differentiation PCR [Fast Track Diagnostics]). The leading dengue serotype in Savannakhet was DENV‐3 (58% [29/50]), while DENV‐1 (53.8% [14/26]) was the predominant serotype found in samples collected in Valledupar by BNITM‐type PCR. However, three DENV serotypes were circulating in Valledupar and in Savannakhet. In 2015, additional studies found predominantly DENV‐4 (71% [12/17]) in Savannakhet. Conclusions Both studies emphasized that routine diagnostics in both regions will benefit from an expanded use of highly sensitive pan‐dengue PCRs. KW - Colombia KW - dengue infections KW - dengue serotypes KW - Lao PDR KW - PCR diagnostics Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262703 VL - 26 IS - 10 SP - 1296 EP - 1302 ER - TY - JOUR A1 - Gratwohl, A A1 - Pfirrmann, M A1 - Zander, A A1 - Kröger, N A1 - Beelen, D A1 - Novotny, J A1 - Nerl, C A1 - Scheid, C A1 - Spiekermann, K A1 - Mayer, J A1 - Sayer, HG A1 - Falge, C A1 - Bunjes, D A1 - Döhner, H A1 - Ganser, A A1 - Schmidt-Wolf, I A1 - Schwerdtfeger, R A1 - Baurmann, H A1 - Kuse, R A1 - Schmitz, N A1 - Wehmeier, A A1 - Fischer, J Th A1 - Ho, AD A1 - Wilhelm, M A1 - Goebeler, M-E A1 - Lindemann, HW A1 - Bormann, M A1 - Hertenstein, B A1 - Schlimok, G A1 - Baerlocher, GM A1 - Aul, C A1 - Pfreundschuh, M A1 - Fabian, M A1 - Staib, P A1 - Edinger, M A1 - Schatz, M A1 - Fauser, A A1 - Arnold, R A1 - Kindler, T A1 - Wulf, G A1 - Rosselet, A A1 - Hellmann, A A1 - Schäfer, E A1 - Prümmer, O A1 - Schenk, M A1 - Hasford, J A1 - Heimpel, H A1 - Hossfeld, DK A1 - Kolb, H-J A1 - Büsche, G A1 - Haferlach, C A1 - Schnittger, S A1 - Müller, MC A1 - Reiter, A A1 - Berger, U A1 - Saußele, S A1 - Hochhaus, A A1 - Hehlmann, R T1 - Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment JF - Leukemia N2 - Tyrosine kinase inhibitors represent today's treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69–0.82) vs 0.69 (95% CI: 0.61–0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (P<0.001) and non-high-risk disease (P=0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56% vs 39%; P = 0.005) and free of drug treatment (56% vs 6%; P<0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered. KW - chronic myeloid leukemia KW - stem cell transplantation KW - drug treatment KW - CML KW - tyrosine kinase inhibitors KW - allogeneic hematopoietic stem cell transplantation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150368 VL - 30 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 - Schmid, Rafael A1 - Schmidt, Sonja K. A1 - Hazur, Jonas A1 - Detsch, Rainer A1 - Maurer, Evelyn A1 - Boccaccini, Aldo R. A1 - Hauptstein, Julia A1 - Teßmar, Jörg A1 - Blunk, Torsten A1 - Schrüfer, Stefan A1 - Schubert, Dirk W. A1 - Horch, Raymund E. A1 - Bosserhoff, Anja K. A1 - Arkudas, Andreas A1 - Kengelbach-Weigand, Annika T1 - Comparison of hydrogels for the development of well-defined 3D cancer models of breast cancer and melanoma JF - Cancers N2 - Bioprinting offers the opportunity to fabricate precise 3D tumor models to study tumor pathophysiology and progression. However, the choice of the bioink used is important. In this study, cell behavior was studied in three mechanically and biologically different hydrogels (alginate, alginate dialdehyde crosslinked with gelatin (ADA–GEL), and thiol-modified hyaluronan (HA-SH crosslinked with PEGDA)) with cells from breast cancer (MDA-MB-231 and MCF-7) and melanoma (Mel Im and MV3), by analyzing survival, growth, and the amount of metabolically active, living cells via WST-8 labeling. Material characteristics were analyzed by dynamic mechanical analysis. Cell lines revealed significantly increased cell numbers in low-percentage alginate and HA-SH from day 1 to 14, while only Mel Im also revealed an increase in ADA–GEL. MCF-7 showed a preference for 1% alginate. Melanoma cells tended to proliferate better in ADA–GEL and HA-SH than mammary carcinoma cells. In 1% alginate, breast cancer cells showed equally good proliferation compared to melanoma cell lines. A smaller area was colonized in high-percentage alginate-based hydrogels. Moreover, 3% alginate was the stiffest material, and 2.5% ADA–GEL was the softest material. The other hydrogels were in the same range in between. Therefore, cellular responses were not only stiffness-dependent. With 1% alginate and HA-SH, we identified matrices that enable proliferation of all tested tumor cell lines while maintaining expected tumor heterogeneity. By adapting hydrogels, differences could be accentuated. This opens up the possibility of understanding and analyzing tumor heterogeneity by biofabrication. KW - breast cancer KW - melanoma KW - biofabrication KW - hydrogel KW - tumor heterogeneity Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-211195 SN - 2072-6694 VL - 12 IS - 8 ER - TY - JOUR A1 - Otto, C. A1 - Schmidt, S. A1 - Kastner, C. A1 - Denk, S. A1 - Kettler, J. A1 - Müller, N. A1 - Germer, C.T. A1 - Wolf, E. A1 - Gallant, P. A1 - Wiegering, A. T1 - Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells JF - Neoplasia N2 - The transcriptional regulator BRD4 has been shown to be important for the expression of several oncogenes including MYC. Inhibiting of BRD4 has broad antiproliferative activity in different cancer cell types. The small molecule JQ1 blocks the interaction of BRD4 with acetylated histones leading to transcriptional modulation. Depleting BRD4 via engineered bifunctional small molecules named PROTACs (proteolysis targeting chimeras) represents the next-generation approach to JQ1-mediated BRD4 inhibition. PROTACs trigger BRD4 for proteasomale degradation by recruiting E3 ligases. The aim of this study was therefore to validate the importance of BRD4 as a relevant target in colorectal cancer (CRC) cells and to compare the efficacy of BRD4 inhibition with BRD4 degradation on downregulating MYC expression. JQ1 induced a downregulation of both MYC mRNA and MYC protein associated with an antiproliferative phenotype in CRC cells. dBET1 and MZ1 induced degradation of BRD4 followed by a reduction in MYC expression and CRC cell proliferation. In SW480 cells, where dBET1 failed, we found significantly lower levels of the E3 ligase cereblon, which is essential for dBET1-induced BRD4 degradation. To gain mechanistic insight into the unresponsiveness to dBET1, we generated dBET1-resistant LS174t cells and found a strong downregulation of cereblon protein. These findings suggest that inhibition of BRD4 by JQ1 and degradation of BRD4 by dBET1 and MZ1 are powerful tools for reducing MYC expression and CRC cell proliferation. In addition, downregulation of cereblon may be an important mechanism for developing dBET1 resistance, which can be evaded by incubating dBET1-resistant cells with JQ1 or MZ1. KW - Cancer Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202451 VL - 21 IS - 11 ER - TY - JOUR A1 - Otto, Christoph A1 - Kastner, Carolin A1 - Schmidt, Stefanie A1 - Uttinger, Konstantin A1 - Baluapuri, Apoorva A1 - Denk, Sarah A1 - Rosenfeldt, Mathias T. A1 - Rosenwald, Andreas A1 - Roehrig, Florian A1 - Ade, Carsten P. A1 - Schuelein-Voelk, Christina A1 - Diefenbacher, Markus E. A1 - Germer, Christoph-Thomas A1 - Wolf, Elmar A1 - Eilers, Martin A1 - Wiegering, Armin T1 - RNA polymerase I inhibition induces terminal differentiation, growth arrest, and vulnerability to senolytics in colorectal cancer cells JF - Molecular Oncology N2 - Ribosomal biogenesis and protein synthesis are deregulated in most cancers, suggesting that interfering with translation machinery may hold significant therapeutic potential. Here, we show that loss of the tumor suppressor adenomatous polyposis coli (APC), which constitutes the initiating event in the adenoma carcinoma sequence for colorectal cancer (CRC), induces the expression of RNA polymerase I (RNAPOL1) transcription machinery, and subsequently upregulates ribosomal DNA (rDNA) transcription. Targeting RNAPOL1 with a specific inhibitor, CX5461, disrupts nucleolar integrity, and induces a disbalance of ribosomal proteins. Surprisingly, CX5461-induced growth arrest is irreversible and exhibits features of senescence and terminal differentiation. Mechanistically, CX5461 promotes differentiation in an MYC-interacting zinc-finger protein 1 (MIZ1)- and retinoblastoma protein (Rb)-dependent manner. In addition, the inhibition of RNAPOL1 renders CRC cells vulnerable towards senolytic agents. We validated this therapeutic effect of CX5461 in murine- and patient-derived organoids, and in a xenograft mouse model. These results show that targeting ribosomal biogenesis together with targeting the consecutive, senescent phenotype using approved drugs is a new therapeutic approach, which can rapidly be transferred from bench to bedside. KW - CRC KW - CX5461 KW - MIZ1 KW - MYC KW - ribosome KW - RNAPOL1 Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312806 VL - 16 IS - 15 ER - TY - JOUR A1 - Audehm, P. A1 - Schmidt, M. A1 - Brück, S. A1 - Tietze, T. A1 - Gräfe, J. A1 - Macke, S. A1 - Schütz, G. A1 - Goering, E. T1 - Pinned orbital moments - A new contribution to magnetic anisotropy JF - Scientific Reports N2 - Reduced dimensionality and symmetry breaking at interfaces lead to unusual local magnetic configurations, such as glassy behavior, frustration or increased anisotropy. The interface between a ferromagnet and an antiferromagnet is such an example for enhanced symmetry breaking. Here we present detailed X-ray magnetic circular dichroism and X-ray resonant magnetic reflectometry investigations on the spectroscopic nature of uncompensated pinned magnetic moments in the antiferromagnetic layer of a typical exchange bias system. Unexpectedly, the pinned moments exhibit nearly pure orbital moment character. This strong orbital pinning mechanism has not been observed so far and is not discussed in literature regarding any theory for local magnetocrystalline anisotropy energies in magnetic systems. To verify this new phenomenon we investigated the effect at different temperatures. We provide a simple model discussing the observed pure orbital moments, based on rotatable spin magnetic moments and pinned orbital moments on the same atom. This unexpected observation leads to a concept for a new type of anisotropy energy. KW - pinned orbital moments KW - ferromagnet KW - antiferromagnet KW - anisotropy energy Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167727 VL - 6 IS - 25517 ER - TY - JOUR A1 - Schmidt-Hieber, M. A1 - Silling, G. A1 - Schalk, E. A1 - Heinz, W. A1 - Panse, J. A1 - Penack, O. A1 - Christopeit, M. A1 - Buchheidt, D. A1 - Meyding-Lamadé, U. A1 - Hähnel, S. A1 - Wolf, H. H. A1 - Ruhnke, M. A1 - Schwartz, S. A1 - Maschmeyer, G. T1 - CNS infections in patients with hematological disorders (including allogeneic stem-cell transplantation)-Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) JF - Annals of Oncology N2 - Infections of the central nervous system (CNS) are infrequently diagnosed in immunocompetent patients, but they do occur in a significant proportion of patients with hematological disorders. In particular, patients undergoing allogeneic hematopoietic stem-cell transplantation carry a high risk for CNS infections of up to 15%. Fungi and Toxoplasma gondii are the predominant causative agents. The diagnosis of CNS infections is based on neuroimaging, cerebrospinal fluid examination and biopsy of suspicious lesions in selected patients. However, identification of CNS infections in immunocompromised patients could represent a major challenge since metabolic disturbances, side-effects of antineoplastic or immunosuppressive drugs and CNS involvement of the underlying hematological disorder may mimic symptoms of a CNS infection. The prognosis of CNS infections is generally poor in these patients, albeit the introduction of novel substances (e.g. voriconazole) has improved the outcome in distinct patient subgroups. This guideline has been developed by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) with the contribution of a panel of 14 experts certified in internal medicine, hematology/oncology, infectious diseases, intensive care, neurology and neuroradiology. Grades of recommendation and levels of evidence were categorized by using novel criteria, as recently published by the European Society of Clinical Microbiology and Infectious Diseases. KW - Central nervous system KW - Polymerase chain raction KW - Herpes simplex encephalitis KW - Invasive fungal-infections KW - Clinical practice guidelines KW - Liposomal amphotericin-B KW - Immunocompromised patient KW - Progressive multifocal leukoencephalopathy KW - Varicella-zoster-virus KW - Diagnosis KW - Treatment KW - Bone-marrow-transplantation KW - Real-time PCR KW - Guideline KW - Central nervous system infection Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188210 VL - 27 IS - 7 ER - TY - JOUR A1 - Trujillo‐Viera, Jonathan A1 - El‐Merahbi, Rabih A1 - Schmidt, Vanessa A1 - Karwen, Till A1 - Loza‐Valdes, Angel A1 - Strohmeyer, Akim A1 - Reuter, Saskia A1 - Noh, Minhee A1 - Wit, Magdalena A1 - Hawro, Izabela A1 - Mocek, Sabine A1 - Fey, Christina A1 - Mayer, Alexander E. A1 - Löffler, Mona C. A1 - Wilhelmi, Ilka A1 - Metzger, Marco A1 - Ishikawa, Eri A1 - Yamasaki, Sho A1 - Rau, Monika A1 - Geier, Andreas A1 - Hankir, Mohammed A1 - Seyfried, Florian A1 - Klingenspor, Martin A1 - Sumara, Grzegorz T1 - Protein Kinase D2 drives chylomicron‐mediated lipid transport in the intestine and promotes obesity JF - EMBO Molecular Medicine N2 - Lipids are the most energy‐dense components of the diet, and their overconsumption promotes obesity and diabetes. Dietary fat content has been linked to the lipid processing activity by the intestine and its overall capacity to absorb triglycerides (TG). However, the signaling cascades driving intestinal lipid absorption in response to elevated dietary fat are largely unknown. Here, we describe an unexpected role of the protein kinase D2 (PKD2) in lipid homeostasis. We demonstrate that PKD2 activity promotes chylomicron‐mediated TG transfer in enterocytes. PKD2 increases chylomicron size to enhance the TG secretion on the basolateral side of the mouse and human enterocytes, which is associated with decreased abundance of APOA4. PKD2 activation in intestine also correlates positively with circulating TG in obese human patients. Importantly, deletion, inactivation, or inhibition of PKD2 ameliorates high‐fat diet‐induced obesity and diabetes and improves gut microbiota profile in mice. Taken together, our findings suggest that PKD2 represents a key signaling node promoting dietary fat absorption and may serve as an attractive target for the treatment of obesity. KW - chylomicron KW - fat absorption KW - intestine KW - obesity KW - protein kinase D2/PKD2/PRKD2 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239018 VL - 13 IS - 5 ER - TY - JOUR A1 - Haussmann, Alexander A1 - Schmidt, Martina E. A1 - Illmann, Mona L. A1 - Schröter, Marleen A1 - Hielscher, Thomas A1 - Cramer, Holger A1 - Maatouk, Imad A1 - Horneber, Markus A1 - Steindorf, Karen T1 - Meta-analysis of randomized controlled trials on yoga, psychosocial, and mindfulness-based interventions for cancer-related fatigue: What intervention characteristics are related to higher efficacy? JF - Cancers N2 - Cancer-related fatigue (CRF) is a burdensome sequela of cancer treatments. Besides exercise, recommended therapies for CRF include yoga, psychosocial, and mindfulness-based interventions. However, interventions conducted vary widely, and not all show a significant effect. This meta-analysis aimed to explore intervention characteristics related to greater reductions in CRF. We included randomized controlled trials published before October 2021. Standardized mean differences were used to assess intervention efficacy for CRF and multimodel inference to explore intervention characteristics associated with higher efficacy. For the meta-analysis, we included 70 interventions (24 yoga interventions, 31 psychosocial interventions, and 15 mindfulness-based interventions) with 6387 participants. The results showed a significant effect of yoga, psychosocial, and mindfulness-based interventions on CRF but with high heterogeneity between studies. For yoga and mindfulness-based interventions, no particular intervention characteristic was identified to be advantageous for reducing CRF. Regarding psychosocial interventions, a group setting and work on cognition were related to higher intervention effects on CRF. The results of this meta-analysis suggest options to maximize the intervention effects of psychosocial interventions for CRF. The effects of yoga and mindfulness-based interventions for CRF appear to be independent of their design, although the limited number of studies points to the need for further research. KW - fatigue KW - cancer KW - psychosocial KW - mindfulness KW - yoga KW - quality of life KW - patient-reported outcomes Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270753 SN - 2072-6694 VL - 14 IS - 8 ER -