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1004 Publications visible to you, out of a total of 1004
A modular transcriptome map of mature B cell lymphomas.
GLA - German Lymphoma Alliance, MMML-MYC-SYS, oBIG - omics Bioinformatics for Health

Abstract (Expand)

BACKGROUND: Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic … phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma. METHODS: We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics. RESULTS: We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt's lymphoma and particularly on 'double-hit' MYC and BCL2 transformed lymphomas. CONCLUSIONS: The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities.

Authors: H. Loeffler-Wirth, M. Kreuz, L. Hopp, A. Arakelyan, A. Haake, S. B. Cogliatti, A. C. Feller, M. L. Hansmann, D. Lenze, P. Moller, H. K. Muller-Hermelink, E. Fortenbacher, E. Willscher, G. Ott, A. Rosenwald, C. Pott, C. Schwaenen, H. Trautmann, S. Wessendorf, H. Stein, M. Szczepanowski, L. Trumper, M. Hummel, W. Klapper, R. Siebert, M. Loeffler, H. Binder

Date Published: 30th Apr 2019

Publication Type: Not specified

Human Diseases: B-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, Burkitt lymphoma

DNA methylation, transcriptome and genetic copy number signatures of diffuse cerebral WHO grade II/III gliomas resolve cancer heterogeneity and development.
GGN - German Glioma Network

Abstract (Expand)

BACKGROUND: Diffuse lower WHO grade II and III gliomas (LGG) are slowly progressing brain tumors, many of which eventually transform into a more aggressive type. LGG is characterized by widespread … genetic and transcriptional heterogeneity, yet little is known about the heterogeneity of the DNA methylome, its function in tumor biology, coupling with the transcriptome and tumor microenvironment and its possible impact for tumor development. METHODS: We here present novel DNA methylation data of an LGG-cohort collected in the German Glioma Network containing about 85% isocitrate dehydrogenase (IDH) mutated tumors and performed a combined bioinformatics analysis using patient-matched genome and transcriptome data. RESULTS: Stratification of LGG based on gene expression and DNA-methylation provided four consensus subtypes. We characterized them in terms of genetic alterations, functional context, cellular composition, tumor microenvironment and their possible impact for treatment resistance and prognosis. Glioma with astrocytoma-resembling phenotypes constitute the largest fraction of nearly 60%. They revealed largest diversity and were divided into four expression and three methylation groups which only partly match each other thus reflecting largely decoupled expression and methylation patterns. We identified a novel G-protein coupled receptor and a cancer-related 'keratinization' methylation signature in in addition to the glioma-CpG island methylator phenotype (G-CIMP) signature. These different signatures overlap and combine in various ways giving rise to diverse methylation and expression patterns that shape the glioma phenotypes. The decrease of global methylation in astrocytoma-like LGG associates with higher WHO grade, age at diagnosis and inferior prognosis. We found analogies between astrocytoma-like LGG with grade IV IDH-wild type tumors regarding possible worsening of treatment resistance along a proneural-to-mesenchymal axis. Using gene signature-based inference we elucidated the impact of cellular composition of the tumors including immune cell bystanders such as macrophages. CONCLUSIONS: Genomic, epigenomic and transcriptomic factors act in concert but partly also in a decoupled fashion what underpins the need for integrative, multidimensional stratification of LGG by combining these data on gene and cellular levels to delineate mechanisms of gene (de-)regulation and to enable better patient stratification and individualization of treatment.

Authors: H. Binder, E. Willscher, H. Loeffler-Wirth, L. Hopp, D. T. W. Jones, S. M. Pfister, M. Kreuz, D. Gramatzki, E. Fortenbacher, B. Hentschel, M. Tatagiba, U. Herrlinger, H. Vatter, J. Matschke, M. Westphal, D. Krex, G. Schackert, J. C. Tonn, U. Schlegel, H. J. Steiger, W. Wick, R. G. Weber, M. Weller, M. Loeffler

Date Published: 25th Apr 2019

Publication Type: Not specified

Human Diseases: brain glioma

Necessity of transnasal gastroscopy in routine diagnostics: a patient-centred requirement analysis
Genetical Statistics and Systems Biology

Abstract (Expand)

Introduction Numerous indications require regular upper gastrointestinal endoscopy (oesophagogastroduodenoscopy; EGD) in outpatients. In most cases, peroral gastroscopy is performed. The aim of this …s study was to evaluate the need of transnasal gastroscopy (nEGD) in outpatients. Methods A questionnaire was used to assess patients’ preferred choice of method, previous experience with EGD, psychological aspects and sociodemographic data. Furthermore, patient satisfaction with and potentially perceived discomfort during the examination as well as preference for a method in regard to future examinations was evaluated. Results From September 2016 to March 2017, a total of 283 outpatients at endoscopy of the University Hospital of Leipzig were approached to participate in the study. 196 patients were eligible, of whom 116 (60%) chose nEGD. For 87 patients (87/283, 31%) nEGD had to be excluded for medical reasons. The average age in the total sample was 53 (\pm17) years. 147 (77%) have had previous experience with peroral EGD (oEGD). Of the nEGD examined patients 83% were fairly up to extremely satisfied with the procedure. Satisfaction significantly predicted the choice of future EGD examinations. Nasal pain experienced during nEGDs was associated with rejection of nEGD in further EGD examinations (p\textless0.01). Patients who did choose a specific procedure were more likely to select the same procedure as their future preference (\textgreekq^2= 73.6, df=1, p\textless0.001); this preference was unaffected by the procedure that had been chosen previously (reselecting nEGD: 84%, oEGD: 89%, p=0.874). Conclusion nEGD without sedation is a viable alternative. Patient satisfaction with nEGD is high, and reselection rate for nEGD is similar to that for oEGD. As a result of this study nEGD is now offered as a routine procedure at the University of Leipzig. Trial registration number NCT03663491.

Authors: Anna-Livia Schuldt, Holger Kirsten, Jan Tuennemann, Mario Heindl, Florian van Bommel, Juergen Feisthammel, Marcus Hollenbach, Albrecht Hoffmeister

Date Published: 14th Apr 2019

Publication Type: Journal article

Sequential organ failure assessment score is an excellent operationalization of disease severity of adult patients with hospitalized community acquired pneumonia - results from the prospective observational PROGRESS study.
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND: CAP (Community acquired pneumonia) is frequent, with a high mortality rate and a high burden on health care systems. Development of predictive biomarkers, new therapeutic concepts, and … epidemiologic research require a valid, reproducible, and quantitative measure describing CAP severity. METHODS: Using time series data of 1532 patients enrolled in the PROGRESS study, we compared putative measures of CAP severity for their utility as an operationalization. Comparison was based on ability to correctly identify patients with an objectively severe state of disease (death or need for intensive care with at least one of the following: substantial respiratory support, treatment with catecholamines, or dialysis). We considered IDSA/ATS minor criteria, CRB-65, CURB-65, Halm criteria, qSOFA, PSI, SCAP, SIRS-Score, SMART-COP, and SOFA. RESULTS: SOFA significantly outperformed other scores in correctly identifying a severe state of disease at the day of enrollment (AUC = 0.948), mainly caused by higher discriminative power at higher score values. Runners-up were the sum of IDSA/ATS minor criteria (AUC = 0.916) and SCAP (AUC = 0.868). SOFA performed similarly well on subsequent study days (all AUC > 0.9) and across age groups. In univariate and multivariate analysis, age, sex, and pack-years significantly contributed to higher SOFA values whereas antibiosis before hospitalization predicted lower SOFA. CONCLUSIONS: SOFA score can serve as an excellent operationalization of CAP severity and is proposed as endpoint for biomarker and therapeutic studies. TRIAL REGISTRATION: clinicaltrials.gov NCT02782013 , May 25, 2016, retrospectively registered.

Authors: P. Ahnert, P. Creutz, K. Horn, F. Schwarzenberger, M. Kiehntopf, H. Hossain, M. Bauer, F. M. Brunkhorst, K. Reinhart, U. Volker, T. Chakraborty, M. Witzenrath, M. Loffler, N. Suttorp, M. Scholz

Date Published: 4th Apr 2019

Publication Type: Journal article

Human Diseases: pneumonia

Towards a Software Tool for Planning IHE-Compliant Information Systems.
3LGM² Enterprise Architecture Modeling

Abstract (Expand)

As hospital information systems are complex and the requirements for interoperability grow with the increasing networking in healthcare, careful planning becomes more and more necessary. The use of … standards as described in IHE profiles, for example, are an important prerequisite for enabling interoperability. Enterprise Architecture Planning (EAP) methods should support this, but none of the currently available EAP methods offers the option of using IHE profiles. The 3LGM2IHE project wants to close this gap and implement the support of IHE profiles in the 3LGM(2) tool. This paper describes how requirements for this tool were determined and presents the results.

Authors: S. Staubert, A. Strubing, J. Drepper, B. Bergh, A. Winter, A. Merzweiler

Date Published: 4th Apr 2019

Publication Type: Journal article

Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Background BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 …2 mutation carriers remains unclear. Methods We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided. Results Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer. Conclusion Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.

Authors: Frank Qian, Shengfeng Wang, Jonathan Mitchell, Lesley McGuffog, Daniel Barrowdale, Goska Leslie, Jan C. Oosterwijk, Wendy K. Chung, D. Gareth Evans, Christoph Engel, Karin Kast, Cora M. Aalfs, Muriel A. Adank, Julian Adlard, Bjarni A. Agnarsson, Kristiina Aittomäki, Elisa Alducci, Irene L. Andrulis, Banu K. Arun, Margreet G. E. M. Ausems, Jacopo Azzollini, Emmanuelle Barouk-Simonet, Julian Barwell, Muriel Belotti, Javier Benitez, Andreas Berger, Ake Borg, Angela R. Bradbury, Joan Brunet, Saundra S. Buys, Trinidad Caldes, Maria A. Caligo, Ian Campbell, Sandrine M. Caputo, Jocelyne Chiquette, Kathleen B. M. Claes, J. Margriet Collée, Fergus J. Couch, Isabelle Coupier, Mary B. Daly, Rosemarie Davidson, Orland Diez, Susan M. Domchek, Alan Donaldson, Cecilia M. Dorfling, Ros Eeles, Lidia Feliubadaló, Lenka Foretova, Jeffrey Fowler, Eitan Friedman, Debra Frost, Patricia A. Ganz, Judy Garber, Vanesa Garcia-Barberan, Gord Glendon, Andrew K. Godwin, Encarna B. Gómez Garcia, Jacek Gronwald, Eric Hahnen, Ute Hamann, Alex Henderson, Carolyn B. Hendricks, John L. Hopper, Peter J. Hulick, Evgeny N. Imyanitov, Claudine Isaacs, Louise Izatt, Ángel Izquierdo, Anna Jakubowska, Katarzyna Kaczmarek, Eunyoung Kang, Beth Y. Karlan, Carolien M. Kets, Sung-Won Kim, Zisun Kim, Ava Kwong, Yael Laitman, Christine Lasset, Min Hyuk Lee, Jong Won Lee, Jihyoun Lee, Jenny Lester, Fabienne Lesueur, Jennifer T. Loud, Jan Lubinski, Noura Mebirouk, Hanne E. J. Meijers-Heijboer, Alfons Meindl, Austin Miller, Marco Montagna, Thea M. Mooij, Patrick J. Morrison, Emmanuelle Mouret-Fourme, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Dieter Niederacher, Finn C. Nielsen, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Kai-Ren Ong, Laura Ottini, Sue K. Park, Paolo Peterlongo, Georg Pfeiler, Catherine M. Phelan, Bruce Poppe, Nisha Pradhan, Paolo Radice, Susan J. Ramus, Johanna Rantala, Mark Robson, Gustavo C. Rodriguez, Rita K. Schmutzler, Christina G. Hutten Selkirk, Payal D. Shah, Jacques Simard, Christian F. Singer, Johanna Sokolowska, Dominique Stoppa-Lyonnet, Christian Sutter, Yen Yen Tan, R. Manuel Teixeira, Soo H. Teo, Mary Beth Terry, Mads Thomassen, Marc Tischkowitz, Amanda E. Toland, Katherine M. Tucker, Nadine Tung, Christi J. van Asperen, Klaartje van Engelen, Elizabeth J. van Rensburg, Shan Wang-Gohrke, Barbara Wappenschmidt, Jeffrey N. Weitzel, Drakoulis Yannoukakos, Mark H. Greene, Matti A. Rookus, Douglas F. Easton, Georgia Chenevix-Trench, Antonis C. Antoniou, David E. Goldgar, Olufunmilayo I. Olopade, Timothy R. Rebbeck, Dezheng Huo

Date Published: 1st Apr 2019

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Association of Chromosome 9p21 with Subsequent Coronary Heart Disease Events: A GENIUS-CHD Study of Individual Participant Data
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions …s about its value for stratification of residual risk. METHODS A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103,357 Europeans with established CHD at baseline from the GENIUS-CHD Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/MI), occurred in 13,040 of the 93,115 participants with available outcome data. Effect estimates were compared to case/control risk obtained from CARDIoGRAMPlusC4D including 47,222 CHD cases and 122,264 controls free of CHD. RESULTS Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/MI among those with established CHD at baseline (GENIUS-CHD OR 1.02; 95% CI 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D OR 1.20; 95% CI 1.18-1.22; p for interaction Conclusions: In contrast to studies comparing individuals with CHD to disease free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

Authors: Riyaz S. Patel, Amand F. Schmidt, Vinicius Tragante, Raymond O. McCubrey, Michael V. Holmes, Laurence J. Howe, Kenan Direk, Axel Åkerblom, Karin Leander, Salim S. Virani, Karol A. Kaminski, Jochen D. Muehlschlegel, Marie-Pierre Dubé, Hooman Allayee, Peter Almgren, Maris Alver, Ekaterina V. Baranova, Hassan Behlouli, Bram Boeckx, Peter S. Braund, Lutz P. Breitling, Graciela Delgado, Nubia E. Duarte, Line Dufresne, Niclas Eriksson, Luisa Foco, Crystel M. Gijsberts, Yan Gong, Jaana Hartiala, Mahyar Heydarpour, Jaroslav A. Hubacek, Marcus Kleber, Daniel Kofink, Pekka Kuukasjärvi, Vei-Vei Lee, Andreas Leiherer, Petra A. Lenzini, Daniel Levin, Leo-Pekka Lyytikäinen, Nicola Martinelli, Ute Mons, Christopher P. Nelson, Kjell Nikus, Anna P. Pilbrow, Rafal Ploski, Yan V. Sun, Michael W. T. Tanck, W. H. Wilson Tang, Stella Trompet, Sander W. van der Laan, Jessica van Setten, Ragnar O. Vilmundarson, Chiara Viviani Anselmi, Efthymia Vlachopoulou, Eric Boerwinkle, Carlo Briguori, John F. Carlquist, Kathryn F. Carruthers, Gavino Casu, John Deanfield, Panos Deloukas, Frank Dudbridge, Natalie Fitzpatrick, Bruna Gigante, Stefan James, Marja-Liisa Lokki, Paulo A. Lotufo, Nicola Marziliano, Ify R. Mordi, Joseph B. Muhlestein, Christopher Newton-Cheh, Jan Pitha, Christoph H. Saely, Ayman Samman-Tahhan, Pratik B. Sandesara, Andrej Teren, Adam Timmis, Frans van de Werf, Els Wauters, Arthur A. M. Wilde, Ian Ford, David J. Stott, Ale Algra, Maria G. Andreassi, Diego Ardissino, Benoit J. Arsenault, Christie M. Ballantyne, Thomas O. Bergmeijer, Connie R. Bezzina, Simon C. Body, Peter Bogaty, Gert J. de Borst, Hermann Brenner, Ralph Burkhardt, Clara Carpeggiani, Gianluigi Condorelli, Rhonda M. Cooper-DeHoff, Sharon Cresci, Ulf de Faire, Robert N. Doughty, Heinz Drexel, James C. Engert, Keith A. A. Fox, Domenico Girelli, Emil Hagström, Stanley L. Hazen, Claes Held, Harry Hemingway, Imo E. Hoefer, G. Kees Hovingh, Julie A. Johnson, Pim A. de Jong, J. Wouter Jukema, Marcin P. Kaczor, Mika Kähönen, Jiri Kettner, Marek Kiliszek, Olaf H. Klungel, Bo Lagerqvist, Diether Lambrechts, Jari O. Laurikka, Terho Lehtimäki, Daniel Lindholm, B. K. Mahmoodi, Anke H. Maitland-van der Zee, Ruth McPherson, Olle Melander, Andres Metspalu, Witold Pepinski, Oliviero Olivieri, Grzegorz Opolski, Colin N. Palmer, Gerard Pasterkamp, Carl J. Pepine, Alexandre C. Pereira, Louise Pilote, Arshed A. Quyyumi, A. Mark Richards, Marek Sanak, Markus Scholz, Agneta Siegbahn, Juha Sinisalo, J. Gustav Smith, John A. Spertus, Alexandre F. R. Stewart, Wojciech Szczeklik, Anna Szpakowicz, Jurriën M. ten Berg, George Thanassoulis, Joachim Thiery, Yolanda van der Graaf, Frank L. J. Visseren, Johannes Waltenberger, Pim van der Harst, Jean-Claude Tardif, Naveed Sattar, Chim C. Lang, Guillaume Paré, James M. Brophy, Jeffrey L. Anderson, Winfried März, Lars Wallentin, Vicky A. Cameron, Benjamin D. Horne, Nilesh J. Samani, Aroon D. Hingorani, Folkert W. Asselbergs

Date Published: 1st Apr 2019

Publication Type: Journal article

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