TY - JOUR A1 - Saussele, Susanne A1 - Hehlmann, Ruediger A1 - Fabarius, Alice A1 - Jeromin, Sabine A1 - Proetel, Ulrike A1 - Rinaldetti, Sebastien A1 - Kohlbrenner, Katharina A1 - Einsele, Hermann A1 - Falge, Christine A1 - Kanz, Lothar A1 - Neubauer, Andreas A1 - Kneba, Michael A1 - Stegelmann, Frank A1 - Pfreundschuh, Michael A1 - Waller, Cornelius F. A1 - Oppliger Leibundgut, Elisabeth A1 - Heim, Dominik A1 - Krause, Stefan W. A1 - Hofmann, Wolf-Karsten A1 - Hasford, Joerg A1 - Pfirrmann, Markus A1 - Müller, Martin C. A1 - Hochhaus, Andreas A1 - Lauseker, Michael T1 - Defining therapy goals for major molecular remission in chronic myeloid leukemia: results of the randomized CML Study IV JF - Leukemia N2 - Major molecular remission (MMR) is an important therapy goal in chronic myeloid leukemia (CML). So far, MMR is not a failure criterion according to ELN management recommendation leading to uncertainties when to change therapy in CML patients not reaching MMR after 12 months. At monthly landmarks, for different molecular remission status Hazard ratios (HR) were estimated for patients registered to CML study IV who were divided in a learning and a validation sample. The minimum HR for MMR was found at 2.5 years with 0.28 (compared to patients without remission). In the validation sample, a significant advantage for progression-free survival (PFS) for patients in MMR could be detected (p-value 0.007). The optimal time to predict PFS in patients with MMR could be validated in an independent sample at 2.5 years. With our model we provide a suggestion when to define lack of MMR as therapy failure and thus treatment change should be considered. The optimal response time for 1% BCR-ABL at about 12-15 months was confirmed and for deep molecular remission no specific time point was detected. Nevertheless, it was demonstrated that the earlier the MMR is achieved the higher is the chance to attain deep molecular response later. KW - Chronic myeloid leukaemia KW - Molecularly targeted therapy KW - Risk factors KW - Risk factors KW - Translational research Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227528 VL - 32 IS - 5 ER - TY - JOUR A1 - Rinaldetti, Sébastien A1 - Pfirrmann, Markus A1 - Manz, Kirsi A1 - Guilhot, Joelle A1 - Dietz, Christian A1 - Panagiotidis, Panayiotidis A1 - Spiess, Birgit A1 - Seifarth, Wolfgang A1 - Fabarius, Alice A1 - Müller, Martin A1 - Pagoni, Maria A1 - Dimou, Maria A1 - Dengler, Jolanta A1 - Waller, Cornelius F. A1 - Brümmendorf, Tim H. A1 - Herbst, Regina A1 - Burchert, Andreas A1 - Janßen, Carsten A1 - Goebeler, Maria Elisabeth A1 - Jost, Philipp J. A1 - Hanzel, Stefan A1 - Schafhausen, Philippe A1 - Prange-Krex, Gabriele A1 - Illmer, Thomas A1 - Janzen, Viktor A1 - Klausmann, Martine A1 - Eckert, Robert A1 - Büschel, Gerd A1 - Kiani, Alexander A1 - Hofmann, Wolf-Karsten A1 - Mahon, François-Xavier A1 - Saussele, Susanne T1 - Effect of ABCG2, OCT1, and ABCB1 (MDR1) Gene Expression on Treatment-Free Remission in a EURO-SKI Subtrial JF - Clinical Lymphoma, Myeloma & Leukemia N2 - Within the EURO-SKI trial, 132 chronic phase CML patients discontinued imatinib treatment. RNA was isolated from peripheral blood in order to analyze the expression of MDR1, ABCG2 and OCT1. ABCG2 was predictive for treatment-free remission in Cox regression analysis. High transcript levels of the ABCG2 efflux transporter (>4.5 parts per thousand) were associated with a twofold higher risk of relapse. Introduction: Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated. Materials and Methods: RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial. Plasmid standards were designed including subgenic inserts of OCT1, ABCG2, and ABCB1 together with GUSB as reference gene. For expression analyses, quantitative real-time polymerase chain reaction was used. Multiple Cox regression analysis was performed. In addition, gene expression cutoffs for patient risk stratification were investigated. Results: The TFR rate of 132 patients, 12 months after TKI discontinuation, was 54% (95% confidence interval [CI], 46%-62%). ABCG2 expression (parts per thousand) was retained as the only significant variable (P=.02; hazard ratio, 1.04; 95% CI, 1.01-1.07) in multiple Cox regression analysis. Only for the ABCG2 efflux transporter, a significant cutoff was found (P=.04). Patients with an ABCG2/GUSB transcript level >4.5 parts per thousand (n=93) showed a 12-month TFR rate of 47% (95% CI, 37%-57%), whereas patients with low ABCG2 expression (<= 4.5 parts per thousand; n=39) had a 12-month TFR rate of 72% (95% CI, 55%-82%). Conclusion: In this study, we investigated the effect of pharmacogenetics in the context of a CML treatment discontinuation trial. The transcript levels of the efflux transporter ABCG2 predicted TFR after TKI discontinuation. (C) 2018 The Authors. Published by Elsevier Inc. KW - ABCG2 KW - Biomarker KW - CML KW - Imatinib KW - Prediction Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226281 VL - 18 IS - 4 ER - TY - JOUR A1 - Schulz, Herbert A1 - Ruppert, Ann-Kathrin A1 - Herms, Stefan A1 - Wolf, Christiane A1 - Mirza-Schreiber, Nazanin A1 - Stegle, Oliver A1 - Czamara, Darina A1 - Forstner, Andreas J. A1 - Sivalingam, Sugirthan A1 - Schoch, Susanne A1 - Moebus, Susanne A1 - Pütz, Benno A1 - Hillmer, Axel A1 - Fricker, Nadine A1 - Vatter, Hartmut A1 - Müller-Myhsok, Bertram A1 - Nöthen, Markus M. A1 - Becker, Albert J. A1 - Hoffmann, Per A1 - Sander, Thomas A1 - Cichon, Sven T1 - Genome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus JF - Nature Communications N2 - Emerging evidence emphasizes the strong impact of regulatory genomic elements in neurodevelopmental processes and the complex pathways of brain disorders. The present genome-wide quantitative trait loci analyses explore the \(cis\)-regulatory effects of single-nucleotide polymorphisms (SNPs) on DNA methylation (meQTL) and gene expression (eQTL) in 110 human hippocampal biopsies. We identify \(cis\)-meQTLs at 14,118 CpG methylation sites and \(cis\)-eQTLs for 302 3′-mRNA transcripts of 288 genes. Hippocampal \(cis\)-meQTL-CpGs are enriched in flanking regions of active promoters, CpG island shores, binding sites of the transcription factor CTCF and brain eQTLs. \(Cis\)-acting SNPs of hippocampal meQTLs and eQTLs significantly overlap schizophrenia-associated SNPs. Correlations of CpG methylation and RNA expression are found for 34 genes. Our comprehensive maps of \(cis\)-acting hippocampal meQTLs and eQTLs provide a link between disease-associated SNPs and the regulatory genome that will improve the functional interpretation of non-coding genetic variants in the molecular genetic dissection of brain disorders. KW - psychiatry KW - epigenetics in the nervous system KW - epigenomics KW - gene expression KW - neurological disorders Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173168 VL - 8 ER - TY - JOUR A1 - Wallaschek, Nina A1 - Reuter, Saskia A1 - Silkenat, Sabrina A1 - Wolf, Katharina A1 - Niklas, Carolin A1 - Özge, Kayisoglu A1 - Aguilar, Carmen A1 - Wiegering, Armin A1 - Germer, Christoph-Thomas A1 - Kircher, Stefan A1 - Rosenwald, Andreas A1 - Shannon-Lowe, Claire A1 - Bartfeld, Sina T1 - Ephrin receptor A2, the epithelial receptor for Epstein-Barr virus entry, is not available for efficient infection in human gastric organoids JF - PLoS Pathogens N2 - Epstein-Barr virus (EBV) is best known for infection of B cells, in which it usually establishes an asymptomatic lifelong infection, but is also associated with the development of multiple B cell lymphomas. EBV also infects epithelial cells and is associated with all cases of undifferentiated nasopharyngeal carcinoma (NPC). EBV is etiologically linked with at least 8% of gastric cancer (EBVaGC) that comprises a genetically and epigenetically distinct subset of GC. Although we have a very good understanding of B cell entry and lymphomagenesis, the sequence of events leading to EBVaGC remains poorly understood. Recently, ephrin receptor A2 (EPHA2) was proposed as the epithelial cell receptor on human cancer cell lines. Although we confirm some of these results, we demonstrate that EBV does not infect healthy adult stem cell-derived gastric organoids. In matched pairs of normal and cancer-derived organoids from the same patient, EBV only reproducibly infected the cancer organoids. While there was no clear pattern of differential expression between normal and cancer organoids for EPHA2 at the RNA and protein level, the subcellular location of the protein differed markedly. Confocal microscopy showed EPHA2 localization at the cell-cell junctions in primary cells, but not in cancer cell lines. Furthermore, histologic analysis of patient tissue revealed the absence of EBV in healthy epithelium and presence of EBV in epithelial cells from inflamed tissue. These data suggest that the EPHA2 receptor is not accessible to EBV on healthy gastric epithelial cells with intact cell-cell contacts, but either this or another, yet to be identified receptor may become accessible following cellular changes induced by inflammation or transformation, rendering changes in the cellular architecture an essential prerequisite to EBV infection. KW - Organoids KW - ephitelial cells KW - gastrointestinal infections KW - cancers and neoplasms KW - Epstein-Barr virus KW - flow cytometry KW - epithelium Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259206 VL - 17 IS - 2 ER - TY - JOUR A1 - Pattschull, Grit A1 - Walz, Susanne A1 - Gründl, Marco A1 - Schwab, Melissa A1 - Rühl, Eva A1 - Baluapuri, Apoorva A1 - Cindric-Vranesic, Anita A1 - Kneitz, Susanne A1 - Wolf, Elmar A1 - Ade, Carsten P. A1 - Rosenwald, Andreas A1 - von Eyss, Björn A1 - Gaubatz, Stefan T1 - The Myb-MuvB complex is required for YAP-dependent transcription of mitotic genes JF - Cell Reports N2 - YAP and TAZ, downstream effectors of the Hippo pathway, are important regulators of proliferation. Here, we show that the ability of YAP to activate mitotic gene expression is dependent on the Myb-MuvB (MMB) complex, a master regulator of genes expressed in the G2/M phase of the cell cycle. By carrying out genome-wide expression and binding analyses, we found that YAP promotes binding of the MMB subunit B-MYB to the promoters of mitotic target genes. YAP binds to B-MYB and stimulates B-MYB chromatin association through distal enhancer elements that interact with MMB-regulated promoters through chromatin looping. The cooperation between YAP and B-MYB is critical for YAP-mediated entry into mitosis. Furthermore, the expression of genes coactivated by YAP and B-MYB is associated with poor survival of cancer patients. Our findings provide a molecular mechanism by which YAP and MMB regulate mitotic gene expression and suggest a link between two cancer-relevant signaling pathways. KW - YAP KW - B-MYB KW - Myb-MuvB KW - mitotic genes KW - enhancer KW - transcription Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202039 VL - 27 IS - 12 ER - TY - JOUR A1 - Topsakal, Vedat A1 - Agrawal, Sumit A1 - Atlas, Marcus A1 - Baumgartner, Wolf-Dieter A1 - Brown, Kevin A1 - Bruce, Iain A. A1 - Dazert, Stefan A1 - Hagen, Rudolf A1 - Lassaletta, Luis A1 - Mlynski, Robert A1 - Raine, Christopher H. A1 - Rajan, Gunesh P. A1 - Schmutzhard, Joachim A1 - Sprinzl, Georg Mathias A1 - Staecker, Hinrich A1 - Usami, Shin-ichi A1 - Van Rompaey, Vincent A1 - Zernotti, Mario A1 - Heyning, Paul van de T1 - Minimally traumatic cochlear implant surgery: expert opinion in 2010 and 2020 JF - Journal of Personalized Medicine N2 - This study aimed to discover expert opinion on the surgical techniques and materials most likely to achieve maximum postoperative residual hearing preservation in cochlear implant (CI) surgery and to determine how these opinions have changed since 2010. A previously published questionnaire used in a study published in 2010 was adapted and expanded. The questionnaire was distributed to an international group of experienced CI surgeons. Present results were compared, via descriptive statistics, to those from the 2010 survey. Eighteen surgeons completed the questionnaire. Respondents clearly favored the following: round window insertion, slow array insertion, and the peri- and postoperative use of systematic antibiotics. Insertion depth was regarded as important, and electrode arrays less likely to induce trauma were preferred. The usefulness of dedicated soft-surgery training was also recognized. A lack of agreement was found on whether the middle ear cavity should be flushed with a non-aminoglycoside antibiotic solution or whether a sheath or insertion tube should be used to avoid contaminating the array with blood or bone dust. In conclusion, this paper demonstrates how beliefs about CI soft surgery have changed since 2010 and shows areas of current consensus and disagreement. KW - electric acoustic stimulation (EAS) KW - cochlear implants KW - atraumatic surgery KW - hearing preservation KW - partial deafness treatment Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288196 SN - 2075-4426 VL - 12 IS - 10 ER - TY - JOUR A1 - Pinkawa, Michael A1 - Aebersold, Daniel M. A1 - Böhmer, Dirk A1 - Flentje, Michael A1 - Ghadjar, Pirus A1 - Schmidt-Hegemann, Nina-Sophie A1 - Höcht, Stefan A1 - Hölscher, Tobias A1 - Müller, Arndt-Christian A1 - Niehoff, Peter A1 - Sedlmayer, Felix A1 - Wolf, Frank A1 - Zamboglou, Constantinos A1 - Zips, Daniel A1 - Wiegel, Thomas T1 - Radiotherapy in nodal oligorecurrent prostate cancer JF - Strahlentherapie und Onkologie N2 - Objective The current article encompasses a literature review and recommendations for radiotherapy in nodal oligorecurrent prostate cancer. Materials and methods A literature review focused on studies comparing metastasis-directed stereotactic ablative radiotherapy (SABR) vs. external elective nodal radiotherapy (ENRT) and studies analyzing recurrence patterns after local nodal treatment was performed. The DEGRO Prostate Cancer Expert Panel discussed the results and developed treatment recommendations. Results Metastasis-directed radiotherapy results in high local control (often > 90% within a follow-up of 1–2 years) and can be used to improve progression-free survival or defer androgen deprivation therapy (ADT) according to prospective randomized phase II data. Distant progression after involved-node SABR only occurs within a few months in the majority of patients. ENRT improves metastases-free survival rates with increased toxicity in comparison to SABR according to retrospective comparative studies. The majority of nodal recurrences after initial local treatment of pelvic nodal metastasis are detected within the true pelvis and common iliac vessels. Conclusion ENRT with or without a boost should be preferred to SABR in pelvic nodal recurrences. In oligometastatic prostate cancer with distant (extrapelvic) nodal recurrences, SABR alone can be performed in selected cases. Application of additional systemic treatments should be based on current guidelines, with ADT as first-line treatment for hormone-sensitive prostate cancer. Only in carefully selected patients can radiotherapy be initially used without additional ADT outside of the current standard recommendations. Results of (randomized) prospective studies are needed for definitive recommendations. KW - prostate cancer KW - oligorecurrence KW - metastasis-directed therapy KW - radiation therapy KW - androgen deprivation therapy KW - stereotactic body radiotherapy KW - oligmometastases KW - lymph node metastases Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307763 SN - 0179-7158 SN - 1439-099X VL - 197 IS - 7 ER -